We are IntechOpen, the world's leading publisher of Open Access books Built by scientists, for scientists

3,550+

Open access books available

112,000+

International authors and editors

115M+

Downloads

151 Countries delivered to Our authors are among the

Top 1% most cited scientists

12.2%

Contributors from top 500 universities

Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI)

## Interested in publishing with us? Contact book.department@intechopen.com

Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com

## **Meet the editors**

Tomasz Jarzembowski was born in 1968 in Gdansk, Poland. He obtained his PhD degree in 2000 from the Medical University of Gdańsk (UG). After specialization in clinical microbiology in 2003, he started studying biofilm formation and antibiotic resistance at the single-cell level. In 2015, he obtained his DSc degree. His later study in cooperation with experts in nephrology and im-

munology results in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID, a member of editorial board of international journals, and a reviewer.

Agnieszka Daca was born in 1982 in Świecie, Poland. She prepared and defended her PhD degree thesis in 2011 from the Medical University of Gdańsk and discussed the immunological changes observed in the blood of patients with SLE. After her PhD degree defense, the cooperation of Tomasz Jarzembowski and the experiments characterizing bacteria virulence traits and

their interaction with immune system cells have started, resulting in the designation of diagnostic method assessing virulence potential of bacteria isolated from the urine of immunocompromised patients. These experiments have also turned her attention to innate immune system changes in patients with lupus nephritis. Currently, she is working as an assistant professor at the Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk. She is also a member of ESCMID.

Professor Maria Alicja Dębska-Ślizień works in the field of nephrology and transplantology since 1985. She is the head and the chair of the Department of Nephrology, Transplantology, and Internal Medicine, GUMed, since 2015. She is a specialist in the field of internal diseases, nephrology, and clinical transplantation. Her fundamental topics of clinical and scientific interest are optimi-

zation of the treatment of patients with renal failure by means of kidney transplantation (preemptive transplantation, transplantation from living donors). She has an active participation in the European Rare Kidney Disease Reference Network (i.e., congenital glomerulopathy, TSC, ADP-KD). Her other activities include optimization of hemodialysis treatment, nephro-oncology, and coordination with the Polish Renal Replacement Therapy Registry. She is a member of the Polish Society of Nephrology,

the Polish Transplantation Society (secretary-general), and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA). Currently, she is also a member of the main board of the Polish Society of Nephrology and the Polish Transplantation Society. She is an author and coauthor of about 500 publications in domestic and foreign magazines. She is an editor and coeditor of the monograph and several guides for the sick and dozens of chapters in textbooks. She is a lecturer in Polish and international congresses. She has been awarded numerous prizes for both her native university and the Polish Transplantation Society for her scientific activity. Her closest family is her husband and two children (daughter and son). Her nonprofessional interests are mountain climbing, skiing, and reading books.

Contents

**Preface VII**

**Possible Solutions 13**

Giovanni Antonini

**Virulome 65** Payam Behzadi

Chapter 1 **Management of Complicated Urinary Tract Infection 1** Ran Pang, Jianhua Deng and Xinyao Zhou

Chapter 2 **Management of Urinary Tract Infections: Problems and**

Chapter 3 **Urinary Tract Infections in Renal Transplant Recipients 33** Justyna Gołębiewska and Alicja Dębska-Ślizień

Chapter 4 **Urinary Tract Infection in Renal Allograft Recipents 47**

Chapter 5 **Uropathogenic Escherichia coli and Fimbrial Adhesins**

Nashaat S. Hamza and Abdalla Khalil

Chapter 6 **Resistant Gram-Negative Urinary Tract Bacterial Infections 85**

Kanodia and Kamlesh S. Suthar

Lorenza Murgia, Ottavia Stalio, Alyexandra Arienzo, Valeria Ferrante, Valentina Cellitti, Salvatore Di Somma, Paolo Visca and

Lovelesh Kumar Nigam, Aruna V. Vanikar, Rashmi D. Patel, Kamal V.

## Contents

## **Preface XIII**


Preface

Urinary tract infection (UTI) is a problem so common and so significant in routine clinical practice that accurate diagnostics are especially important. The first milestone in the diag‐ nostics of UTI was set almost 60 years ago, when the definition of significant bacteriuria was intended by Kass to provide a means of differentiation between contamination of urine and true urinary infection. Until now, the gold standard for the diagnosis of UTI is the estima‐ tion of inoculum of bacteria in the urine sample. According to this assumption, the number of bacteria (cfu/mL) smaller than 105 cfu/ml is likely to result from contamination from the urethral meatus. However, this threshold may miss many relevant infections. Nowadays, therefore, there are other recommendations for the diagnosis of UTI from a count of 103 cfu/mL, depending on the types of bacteria detected and clinical conditions. Additional‐ ly, the quantitative character of the diagnostic procedure requires proper conditions, sam‐ pling, and transport, which may be difficult to complete in routine practice. As a result, diagnostics may suffer from prelaboratory errors. Furthermore, apart from detection of the

UTI incidence depends on many factors, e.g., age, gender, and accompanying diseases. From a clinical point of view, the most demanding groups of UTI patients are the people with compromised immune systems. The incidence of UTI is high in this group, both due to the impaired functioning of the immune system and the frequent presence of additional medical devices, such as catheters. The presence of catheters in itself increases in turn the risk of the development of a complicated UTI. Complicated UTI is associated with an increased rate of therapy failures, as a result of possible biofilm formation on foreign elements and antibiotic resistance, as well as the increased possibility of an infection recurrence. The higher risk of complicated UTI calls for unequivocal diagnostic test results to start efficient therapy as quickly as possible, preferably at the bedside. These are the arguments for the constant search for novel diagnostic tools and techniques, which will be quicker to perform, easier to

What makes UTI so inspiring, and engages so many outstanding scientific teams in relent‐ less work on the topic, is the development of new techniques, which allow us to explore ever newer aspects of bacterial and human life mechanisms. It allows us to discover much more bacterial survival strategies dictated by the evolution-driven will of survival on the one hand and the human body's ways to defend itself against these novel invasions on the other hand. The balance between these two elements—bacterial desire to colonize the hu‐ man's body and man's wish to survive—seems to be what allows us to exist in continuous

cohabitation, but it can also lead to the failure of even the best-planned treatment.

pathogen in urine, the presence of clinical symptoms is also essential.

interpret, and less susceptible to preanalytical errors.

#### Preface Foreword

Urinary tract infections (UTIs) belong to high frequently occurring diseases causing big discomfort for patients and often disabling their daily job duties. UTIs are one of the most frequent reasons for medical interventions, they generate 40% of all hospital infections, and additionally, they induce 10% to 20% of posthospital infections. The disease occurs 50 times more frequently in females than in males. UTI appears in various manifestations; there is a need to define uniform terminology connected with this disease for easier recognition of the disease and to undertake proper decision to choose a suitable course of the therapy process. Urinary tract infection (UTI) is a problem so common and so significant in routine clinical practice that accurate diagnostics are especially important. The first milestone in the diag‐ nostics of UTI was set almost 60 years ago, when the definition of significant bacteriuria was intended by Kass to provide a means of differentiation between contamination of urine and true urinary infection. Until now, the gold standard for the diagnosis of UTI is the estima‐ tion of inoculum of bacteria in the urine sample. According to this assumption, the number of bacteria (cfu/mL) smaller than 105 cfu/ml is likely to result from contamination from the

UTIs are caused by various infectious agents in terms of etiological factors, such as bacteria and fungi, such that *Candida albicans* responsible for candidiasis, *Schistosoma* spp. responsible for schistosomiasis (bilharziasis), *Actinomyces israelii* (*A. bovis*) responsible for actinomycosis, nematodes from genera *Wuchereria bancrofti* and *Brugia malayi* responsible for filariasis, or *Echinococcus granulosus* responsible for echinococcosis. Gram-negative rods from family *Enterobacteriaceae* with dominated uropathogenic strains of *Escherichia coli* (UPEC) are the most frequently reported etiological factors of UTI. These strains are responsible for 85% cases of uncomplicated infections and 45% cases of complicated infections. There are also the other Gram-negative bacteria responsible for UTI such as *Proteus* spp., *Klebsiella* spp., *Enterobacter* spp., *Providencia* spp., *Pseudomonas aeruginosa*, and *Acinetobacter* spp., and from the Gram-positive group, they are *Staphylococcus aureus*, *S. saprophyticus*, *Streptococcus agalactiae*, *Enterococcus* spp., and *Corynebacterium urealyticum*. The dominating bacteria causing in-hospital infections are *E. coli* (50%) and then in order *Enterobacter* spp., *Acinetobacter* spp., *Pseudomonas* spp., *Serratia marcescens*, *Providencia* spp., *Staphylococcus* spp., *Enterococcus* spp., and fungi. Interestingly, most of these bacteria are constituents of the physiological biocenosis in the intestinal tract or urinary-sexual systems in human; therefore, UTIs are mostly endogenous infections. What is interesting too is that although the etiology of UTI did not change in the last decade, the recent bacterial pathogens acquired a set of new characters, which implicate difficulties in effective therapy. The most important new property of the strains is acquisition of antibiotic resistance mechanisms and of new virulence genes through horizontal gene transfer (HGT). The emergency of new bacteria phenotypes is reported too. The other properties such as biofilm formation and mobile genetic elements (MGEs) additionally obstruct both diagnosis and therapy. urethral meatus. However, this threshold may miss many relevant infections. Nowadays, therefore, there are other recommendations for the diagnosis of UTI from a count of 103 cfu/mL, depending on the types of bacteria detected and clinical conditions. Additional‐ ly, the quantitative character of the diagnostic procedure requires proper conditions, sam‐ pling, and transport, which may be difficult to complete in routine practice. As a result, diagnostics may suffer from prelaboratory errors. Furthermore, apart from detection of the pathogen in urine, the presence of clinical symptoms is also essential. UTI incidence depends on many factors, e.g., age, gender, and accompanying diseases. From a clinical point of view, the most demanding groups of UTI patients are the people with compromised immune systems. The incidence of UTI is high in this group, both due to the impaired functioning of the immune system and the frequent presence of additional medical devices, such as catheters. The presence of catheters in itself increases in turn the risk of the development of a complicated UTI. Complicated UTI is associated with an increased rate of therapy failures, as a result of possible biofilm formation on foreign elements and antibiotic resistance, as well as the increased possibility of an infection recurrence. The higher risk of complicated UTI calls for unequivocal diagnostic test results to start efficient therapy as quickly as possible, preferably at the bedside. These are the arguments for the constant search for novel diagnostic tools and techniques, which will be quicker to perform, easier to interpret, and less susceptible to preanalytical errors. What makes UTI so inspiring, and engages so many outstanding scientific teams in relent‐

Furthermore, an increased risk of UTI is caused by physiological factors like advanced age of patients or pregnancy and also by pathological factors such as systemic diseases, interference with instrumentation of urinary tracts, immunosuppressive agents, or diabetes. less work on the topic, is the development of new techniques, which allow us to explore ever newer aspects of bacterial and human life mechanisms. It allows us to discover much more bacterial survival strategies dictated by the evolution-driven will of survival on the one hand and the human body's ways to defend itself against these novel invasions on the

UTIs are complex and dynamic pathologic phenomena, and the number of UTI patients remains high. A group of UTI is involved into two big global phenomena, namely, a quick increase of antibiotic resistance of pathogens and the emerging of new biochemical phenotypes of bacteria that enhance virulence and cause diagnostic problems. other hand. The balance between these two elements—bacterial desire to colonize the hu‐ man's body and man's wish to survive—seems to be what allows us to exist in continuous cohabitation, but it can also lead to the failure of even the best-planned treatment.

New diagnostic methods are introduced particularly to recognize microbiological etiological factors, but both diagnosis and therapy require strict cooperation among leading doctor, microbiologist diagnostician, and clinical pharmacologist.

UTIs are still a big challenge for medicine demanding systematic epidemiologic reports and research study to improve their diagnostics and therapy process. That is the reason why various forms of studies published as original papers, monographs, and recommendations are needed and expected by practitioners. The presented book is an attempt to answer these demands.

> **Jacek Miedzobrodzki, PharmD** Laboratory Diagnostician, Public Health Specialist Professor of Microbiology

Preface

Urinary tract infection (UTI) is a problem so common and so significant in routine clinical practice that accurate diagnostics are especially important. The first milestone in the diag‐ nostics of UTI was set almost 60 years ago, when the definition of significant bacteriuria was intended by Kass to provide a means of differentiation between contamination of urine and true urinary infection. Until now, the gold standard for the diagnosis of UTI is the estima‐ tion of inoculum of bacteria in the urine sample. According to this assumption, the number of bacteria (cfu/mL) smaller than 105 cfu/ml is likely to result from contamination from the urethral meatus. However, this threshold may miss many relevant infections. Nowadays, therefore, there are other recommendations for the diagnosis of UTI from a count of 103 cfu/mL, depending on the types of bacteria detected and clinical conditions. Additional‐ ly, the quantitative character of the diagnostic procedure requires proper conditions, sam‐ pling, and transport, which may be difficult to complete in routine practice. As a result, diagnostics may suffer from prelaboratory errors. Furthermore, apart from detection of the

UTI incidence depends on many factors, e.g., age, gender, and accompanying diseases. From a clinical point of view, the most demanding groups of UTI patients are the people with compromised immune systems. The incidence of UTI is high in this group, both due to the impaired functioning of the immune system and the frequent presence of additional medical devices, such as catheters. The presence of catheters in itself increases in turn the risk of the development of a complicated UTI. Complicated UTI is associated with an increased rate of therapy failures, as a result of possible biofilm formation on foreign elements and antibiotic resistance, as well as the increased possibility of an infection recurrence. The higher risk of complicated UTI calls for unequivocal diagnostic test results to start efficient therapy as quickly as possible, preferably at the bedside. These are the arguments for the constant search for novel diagnostic tools and techniques, which will be quicker to perform, easier to

What makes UTI so inspiring, and engages so many outstanding scientific teams in relent‐ less work on the topic, is the development of new techniques, which allow us to explore ever newer aspects of bacterial and human life mechanisms. It allows us to discover much more bacterial survival strategies dictated by the evolution-driven will of survival on the one hand and the human body's ways to defend itself against these novel invasions on the other hand. The balance between these two elements—bacterial desire to colonize the hu‐ man's body and man's wish to survive—seems to be what allows us to exist in continuous

cohabitation, but it can also lead to the failure of even the best-planned treatment.

pathogen in urine, the presence of clinical symptoms is also essential.

interpret, and less susceptible to preanalytical errors.

## Preface

Urinary tract infection (UTI) is a problem so common and so significant in routine clinical practice that accurate diagnostics are especially important. The first milestone in the diag‐ nostics of UTI was set almost 60 years ago, when the definition of significant bacteriuria was intended by Kass to provide a means of differentiation between contamination of urine and true urinary infection. Until now, the gold standard for the diagnosis of UTI is the estima‐ tion of inoculum of bacteria in the urine sample. According to this assumption, the number of bacteria (cfu/mL) smaller than 105 cfu/ml is likely to result from contamination from the urethral meatus. However, this threshold may miss many relevant infections. Nowadays, therefore, there are other recommendations for the diagnosis of UTI from a count of 103 cfu/mL, depending on the types of bacteria detected and clinical conditions. Additional‐ ly, the quantitative character of the diagnostic procedure requires proper conditions, sam‐ pling, and transport, which may be difficult to complete in routine practice. As a result, diagnostics may suffer from prelaboratory errors. Furthermore, apart from detection of the pathogen in urine, the presence of clinical symptoms is also essential.

UTI incidence depends on many factors, e.g., age, gender, and accompanying diseases. From a clinical point of view, the most demanding groups of UTI patients are the people with compromised immune systems. The incidence of UTI is high in this group, both due to the impaired functioning of the immune system and the frequent presence of additional medical devices, such as catheters. The presence of catheters in itself increases in turn the risk of the development of a complicated UTI. Complicated UTI is associated with an increased rate of therapy failures, as a result of possible biofilm formation on foreign elements and antibiotic resistance, as well as the increased possibility of an infection recurrence. The higher risk of complicated UTI calls for unequivocal diagnostic test results to start efficient therapy as quickly as possible, preferably at the bedside. These are the arguments for the constant search for novel diagnostic tools and techniques, which will be quicker to perform, easier to interpret, and less susceptible to preanalytical errors.

What makes UTI so inspiring, and engages so many outstanding scientific teams in relent‐ less work on the topic, is the development of new techniques, which allow us to explore ever newer aspects of bacterial and human life mechanisms. It allows us to discover much more bacterial survival strategies dictated by the evolution-driven will of survival on the one hand and the human body's ways to defend itself against these novel invasions on the other hand. The balance between these two elements—bacterial desire to colonize the hu‐ man's body and man's wish to survive—seems to be what allows us to exist in continuous cohabitation, but it can also lead to the failure of even the best-planned treatment.

These as well as many other vital topics regarding UTI complications, management, and treatment, in addition to antibiotic resistance and bacterial virulence traits allowing us to mitigate or avoid antibiotic action, are presented in this book.

Each and every one of the authors contributing in this publication performed an excellent work for which we are grateful and hope that every reader of this book will find something inspiring in it.

**Tomasz Jarzembowski**

**Chapter 1**

**Provisional chapter**

**Management of Complicated Urinary Tract Infection**

The management of complicated urinary tract infection (UTI) remains a challenge since the coexisted conditions may significantly decrease the successful rate of treatment. In this chapter, the specific conditions including indwelling catheter, urolithiasis, neurogenic bladder, vesicoureteral reflux and pregnancy are listed. In terms of each condition, the potential influence on UTI and management strategy is discussed. Not only is the current evidence reviewed but also we present our experience on management of

Urinary tract infection (UTI), defined as an inflammatory response of the urothelium induced by a pathogenic organism, is one of the most common infectious diseases. It is estimated that one-third of the women may experience UTI by the age of 24, and half of the women suffer from at least one symptomatic UTI during their lifetime [1]. Basically, UTI can be classified as uncomplicated and complicated infection. The former is normally confined to bladder, which can be treated by short-course antibiotics. The latter refers to an infection associated with a condition which can increase the rate of therapy failures significantly. It is reported that 25–30% of adult women with UTI have at least one risk factor causing complicated UTI [2]. The common conditions which may result in complicated UTI are presented in **Table 1**. Not only do these factors decrease treatments' successful rate but also increase the recurrence risk of UTI. Therefore, when a complicated UTI is treated, management of the conditions needs to

**Keywords:** urinary tract infection, catheter, urolithiasis, neurogenic bladder,

**Management of Complicated Urinary Tract Infection**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.74556

Ran Pang, Jianhua Deng and Xinyao Zhou

Ran Pang, Jianhua Deng and Xinyao Zhou

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74556

**Abstract**

complicated UTI.

**1. Introduction**

be taken into consideration.

vesicoureteral reflux, pregnancy

Department of Microbiology Medical University of Gdańsk Poland

**Agnieszka Daca** Department of Pathology and Experimental Rheumatology Medical University of Gdańsk Poland

#### **Maria Alicja Dębska-Ślizień**

Department of Nephrology, Transplantology, and Internal Diseases Medical University of Gdańsk Poland

#### **Management of Complicated Urinary Tract Infection Management of Complicated Urinary Tract Infection**

DOI: 10.5772/intechopen.74556

Ran Pang, Jianhua Deng and Xinyao Zhou Ran Pang, Jianhua Deng and Xinyao Zhou

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.74556

**Abstract**

These as well as many other vital topics regarding UTI complications, management, and treatment, in addition to antibiotic resistance and bacterial virulence traits allowing us to

Each and every one of the authors contributing in this publication performed an excellent work for which we are grateful and hope that every reader of this book will find something

> **Tomasz Jarzembowski** Department of Microbiology Medical University of Gdańsk

> Medical University of Gdańsk

**Maria Alicja Dębska-Ślizień**

Medical University of Gdańsk

Department of Pathology and Experimental Rheumatology

Department of Nephrology, Transplantology, and Internal Diseases

Poland

Poland

Poland

**Agnieszka Daca**

mitigate or avoid antibiotic action, are presented in this book.

inspiring in it.

VIII Preface

The management of complicated urinary tract infection (UTI) remains a challenge since the coexisted conditions may significantly decrease the successful rate of treatment. In this chapter, the specific conditions including indwelling catheter, urolithiasis, neurogenic bladder, vesicoureteral reflux and pregnancy are listed. In terms of each condition, the potential influence on UTI and management strategy is discussed. Not only is the current evidence reviewed but also we present our experience on management of complicated UTI.

**Keywords:** urinary tract infection, catheter, urolithiasis, neurogenic bladder, vesicoureteral reflux, pregnancy

## **1. Introduction**

Urinary tract infection (UTI), defined as an inflammatory response of the urothelium induced by a pathogenic organism, is one of the most common infectious diseases. It is estimated that one-third of the women may experience UTI by the age of 24, and half of the women suffer from at least one symptomatic UTI during their lifetime [1]. Basically, UTI can be classified as uncomplicated and complicated infection. The former is normally confined to bladder, which can be treated by short-course antibiotics. The latter refers to an infection associated with a condition which can increase the rate of therapy failures significantly. It is reported that 25–30% of adult women with UTI have at least one risk factor causing complicated UTI [2]. The common conditions which may result in complicated UTI are presented in **Table 1**. Not only do these factors decrease treatments' successful rate but also increase the recurrence risk of UTI. Therefore, when a complicated UTI is treated, management of the conditions needs to be taken into consideration.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host


catheter, intermittent catheterization and suprapubic catheterization. Condom catheter is the most common external equipment, which is suitable for patients with severe storage lower urinary tract dysfunction such as urinary incontinence. It has been reported that condom catheter has a significant advantage in comparison with indwelling catheter. A randomized controlled trail (RCT) demonstrated that condom catheter might reduce 80% risks of catheter-associated UTI or death compared to indwelling catheter. Additionally, patients with condom catheter presented a significant higher satisfaction rate than ones with the

Management of Complicated Urinary Tract Infection http://dx.doi.org/10.5772/intechopen.74556 3

For patients with severe voiding lower urinary tract dysfunction, intermittent or suprapubic catheterization is an option to replace indwelling catheter. An early study investigated the incidence of bacteriuria in patients with intermittent or indwelling catheterization. Based on the results of urine culture, 32% of patients treated with intermittent catheterization had bacteriuria, which is significantly lower than 61% in ones with an indwelling catheter [12]. Another study revealed that patients with intermittent catheterization had less chance to suffer from pyelonephritis than the counterparts with indwelling catheterization (5 vs. 25%, P < 0.01) [13]. In a multicentered RCT, 87 patients with a postvoid residual (PVR) bladder volume of more than 150 ml were allocated to receive intermittent or indwelling catheterization. After 3 days, a significant lower risk of developing bacteriuria was found in the intermittent catheterization group compared with the indwelling catheterization group (14 vs. 38%, P = 0.02), so was the risk of UTI (12 vs. 33%, P = 0.03). In terms of patients' satisfaction, no marked difference was

In general, intermittent catheterization can be practiced by a clean or sterile technique. Originally, sterile intermittent catheterization was applied as a standard method. In 1947, Guttman published the first report about sterile intermittent catheterization. In the report, he showed that this technique could decrease the risk of UTI and might be helpful for patients' recovery of micturition. About 19 years later, Guttman further reported his experience in the use of sterile intermittent catheterization. During 11 years, he applied this technique to manage a total of 476 patients. Based on the data from 409 males, the technique was related to an extremely low incidence in UTI, vesicoureteral reflux, hydronephrosis and urolithiasis. Although sterile intermittent catheterization has some advantages, it is costly and time-consuming. In 1970, Hence Lapides and Betty S. Lowe introduced another technique, that is, clean and intermittent self-catheterization. Subsequently, they published a series of articles in which they showed that this technique could not increase the incidence of UTI. Later, a number of emerged evidence suggested that sterile intermittent catheterization could not provide an extra benefit compared to clean techniques. Two RCTs demonstrated that different technique was associated neither with overgrowth of microorganisms in urinary tract nor with the

Suprapubic catheterization provides a treatment option for patients who are not suitable for intermittent catheterization such as those with low compliance bladder. Evidence has illustrated that suprapubic catheter may bring more benefits for patients compared to transurethral catheter. A retrospective cohort study showed that patients with suprapubic catheter had less clinical visits due to pain than ones with indwelling urethral catheter [17]. The result from a metaanalysis revealed that suprapubic catheterization was associated with a significant lower risk of

indwelling catheter [11].

found between these two groups [14].

symptomatic UTI [15, 16].

**Table 1.** Specific conditions causing complicated UTI.

## **2. Catheter-associated UTI**

Catheter-associated UTI is one of the most common complicated UTIs. It has been reported that catheter-associated UTI may lengthen the patients' hospital stay and increase the mortality and the direct medical cost [3, 4]. Typically, the microorganisms can enter urinary tract through the extraluminal or intraluminal route. The former means microbial pathogens can invade the bladder through the gap between the catheter and urethra, whereas the latter indicates that causative agents migrate to bladder along the internal lumen of the catheter. According to the data from National Healthcare Safety Network (NHSN), the top three pathogens causing catheter-associated UTI are *Escherichia coli* (21.4%), *Candida spp.* (21.0%) and *Enterococcus spp.* (14.9%), followed by *Pseudomonas aeruginosa* (10.0%), *Klebsiella pneumoniae* (7.7%) and *Enterobacter spp.* (4.1%) [5]. With the duration of catheterization prolonging, the pathogens may induce the formation of biofilm on the surface of the catheter, which causes the occurrence of antibiotic resistance [6]. Traditionally, antimicrobial therapy was considered as a prevention strategy for catheter-associated UTI. However, a survey in two Dutch district hospitals showed that the use of antibiotics was associated with the development of bacteriuria in patients catheterized for 3–14 days [7]. A recent cohort study further revealed that empirical antibiotic treatment had no effect on patients' prognosis [8]. Both European Association of Urology (EAU) and Infectious Diseases Society of America (IDSA) guidelines recommend against the use of systemic antimicrobial prophylaxis for catheter-associated UTI [9, 10]. By contrast, the consistent recommendation identified across guidelines is removal of the catheter as soon as possible. However, some patients have to be catheterized for a long time due to various disorders. For those patients, some practical strategies are developed to prevent and manage the catheter-associated UTI.

## **2.1. Alternatives to indwelling urethral catheter**

Instead of indwelling urethral catheterization, some alternative approaches have been developed to minimize the catheter-associated UTI. Those approaches include use of external catheter, intermittent catheterization and suprapubic catheterization. Condom catheter is the most common external equipment, which is suitable for patients with severe storage lower urinary tract dysfunction such as urinary incontinence. It has been reported that condom catheter has a significant advantage in comparison with indwelling catheter. A randomized controlled trail (RCT) demonstrated that condom catheter might reduce 80% risks of catheter-associated UTI or death compared to indwelling catheter. Additionally, patients with condom catheter presented a significant higher satisfaction rate than ones with the indwelling catheter [11].

For patients with severe voiding lower urinary tract dysfunction, intermittent or suprapubic catheterization is an option to replace indwelling catheter. An early study investigated the incidence of bacteriuria in patients with intermittent or indwelling catheterization. Based on the results of urine culture, 32% of patients treated with intermittent catheterization had bacteriuria, which is significantly lower than 61% in ones with an indwelling catheter [12]. Another study revealed that patients with intermittent catheterization had less chance to suffer from pyelonephritis than the counterparts with indwelling catheterization (5 vs. 25%, P < 0.01) [13]. In a multicentered RCT, 87 patients with a postvoid residual (PVR) bladder volume of more than 150 ml were allocated to receive intermittent or indwelling catheterization. After 3 days, a significant lower risk of developing bacteriuria was found in the intermittent catheterization group compared with the indwelling catheterization group (14 vs. 38%, P = 0.02), so was the risk of UTI (12 vs. 33%, P = 0.03). In terms of patients' satisfaction, no marked difference was found between these two groups [14].

**2. Catheter-associated UTI**

**Table 1.** Specific conditions causing complicated UTI.

**Category Specific conditions** Foreign bodies Indwelling catheter

2 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Structural or functional abnormality of urinary tract Neurogenic bladder

Others Pregnancy

**2.1. Alternatives to indwelling urethral catheter**

Catheter-associated UTI is one of the most common complicated UTIs. It has been reported that catheter-associated UTI may lengthen the patients' hospital stay and increase the mortality and the direct medical cost [3, 4]. Typically, the microorganisms can enter urinary tract through the extraluminal or intraluminal route. The former means microbial pathogens can invade the bladder through the gap between the catheter and urethra, whereas the latter indicates that causative agents migrate to bladder along the internal lumen of the catheter. According to the data from National Healthcare Safety Network (NHSN), the top three pathogens causing catheter-associated UTI are *Escherichia coli* (21.4%), *Candida spp.* (21.0%) and *Enterococcus spp.* (14.9%), followed by *Pseudomonas aeruginosa* (10.0%), *Klebsiella pneumoniae* (7.7%) and *Enterobacter spp.* (4.1%) [5]. With the duration of catheterization prolonging, the pathogens may induce the formation of biofilm on the surface of the catheter, which causes the occurrence of antibiotic resistance [6]. Traditionally, antimicrobial therapy was considered as a prevention strategy for catheter-associated UTI. However, a survey in two Dutch district hospitals showed that the use of antibiotics was associated with the development of bacteriuria in patients catheterized for 3–14 days [7]. A recent cohort study further revealed that empirical antibiotic treatment had no effect on patients' prognosis [8]. Both European Association of Urology (EAU) and Infectious Diseases Society of America (IDSA) guidelines recommend against the use of systemic antimicrobial prophylaxis for catheter-associated UTI [9, 10]. By contrast, the consistent recommendation identified across guidelines is removal of the catheter as soon as possible. However, some patients have to be catheterized for a long time due to various disorders. For those patients, some practical strategies are developed to prevent and manage the catheter-associated UTI.

Urolithiasis

Vesicoureteral reflux Obstructive uropathy

Diabetes mellitus Renal failure

Immunosuppression after kidney transplantation

Instead of indwelling urethral catheterization, some alternative approaches have been developed to minimize the catheter-associated UTI. Those approaches include use of external In general, intermittent catheterization can be practiced by a clean or sterile technique. Originally, sterile intermittent catheterization was applied as a standard method. In 1947, Guttman published the first report about sterile intermittent catheterization. In the report, he showed that this technique could decrease the risk of UTI and might be helpful for patients' recovery of micturition. About 19 years later, Guttman further reported his experience in the use of sterile intermittent catheterization. During 11 years, he applied this technique to manage a total of 476 patients. Based on the data from 409 males, the technique was related to an extremely low incidence in UTI, vesicoureteral reflux, hydronephrosis and urolithiasis. Although sterile intermittent catheterization has some advantages, it is costly and time-consuming. In 1970, Hence Lapides and Betty S. Lowe introduced another technique, that is, clean and intermittent self-catheterization. Subsequently, they published a series of articles in which they showed that this technique could not increase the incidence of UTI. Later, a number of emerged evidence suggested that sterile intermittent catheterization could not provide an extra benefit compared to clean techniques. Two RCTs demonstrated that different technique was associated neither with overgrowth of microorganisms in urinary tract nor with the symptomatic UTI [15, 16].

Suprapubic catheterization provides a treatment option for patients who are not suitable for intermittent catheterization such as those with low compliance bladder. Evidence has illustrated that suprapubic catheter may bring more benefits for patients compared to transurethral catheter. A retrospective cohort study showed that patients with suprapubic catheter had less clinical visits due to pain than ones with indwelling urethral catheter [17]. The result from a metaanalysis revealed that suprapubic catheterization was associated with a significant lower risk of bacteriuria and less discomfort compared with transurethral catheter [18]. A prospective openlabeled study presented that women with postoperative urinary retention favored suprapubic catheter due to a better catheter-specific quality of life [19]. According to the result from a network meta-analysis, indwelling urethral catheter did not increase the risk of UTI compared with either suprapubic tube or intermittent catheterization when duration of catheter was less than 5 days. In contrast, suprapubic tube or intermittent catheterization was associated with a lower rate of UTI when long-term catheterization is needed [20]. Based on our experience, suprapubic catheter has a significant advantage for male patients. We used suprapubic catheter to manage more than 20 male patients who suffered from recurrent acute bacterial prostatitis or epididymitis secondary to indwelling urethral catheter. We found that no one experienced these genitourinary infections again after the technique of catheterization was changed. Additionally, suprapubic catheter allows patients to observe their recovery of voiding function. We encourage patients to try to urinate with a closed suprapubic catheter if they have a low detrusor leak-point pressure (<40 cmH2 0) assessed by urodynamics, which means patients' attempt of voiding cannot bring about upper urinary tract deterioration. After spontaneous voiding, patients need to open the suprapubic catheter and measure the PVR. Once the PVR is low enough, the removal of suprapubic catheter can be taken into consideration.

It has been shown that antibiotic-coated catheter has a significant antimicrobial activity. Desai et al. found that nitrofurazone-impregnated catheter could decrease the adherence of pathogenic microorganisms to catheter markedly, but the effect could only persist for 5 days after the catheterization [26]. Regev-Shoshani et al. further reported that both nitrofurazoneand nitric oxide-coated catheters had a great effect on the prevention of microbial growth and biofilm formation, which was more effective than silver-coated catheter [27]. Despite lack of available clinical data so far, the antibiotic-coated catheter may bring potential benefits for

Management of Complicated Urinary Tract Infection http://dx.doi.org/10.5772/intechopen.74556 5

Hydrophilic catheter may decrease the friction between catheter and urethra during catheterization. Consequently, it reduces the potential mucosal trauma which can result in the bacterial colonization. A multicentered RCT showed that the use of hydrophilic catheter might decrease approximately one-third the risk of developing symptomatic UTI compared with standard catheter [28]. Similarly, the evidence from a meta-analysis supported marked ben-

A novel trefoil catheter has been developed. Although it has not been reported for use in clinical practice, the preclinical study has shown its advantages. Sun et al. performed an experiment in which 66 rabbits were catheterized using either conventional or novel trefoil catheter randomly and reported that the novel catheter could decrease the incidence of bacteriuria. In addition, it was also found that the trefoil catheter caused a significant slighter mucosal

Catheter care is important for patients with an indwelling catheter since appropriate care can decrease the incidence of UTI. Both EAU and IDSA guidelines recommend maintaining a closed drainage system all the time [9, 10]. Once any breaks are detected, both the catheter and collecting system must be replaced as soon as possible. Besides, it is crucial to keep the drainage tubing being below the level of the patient's bladder and above the level of the collection bag, which can avoid the reflux of urine in drainage system. To minimize the risk of UTI, different types of collecting systems were developed. However, current evidence fails to show their different effects on prevention of UTI. Sullivan et al. conducted a RCT, in which 51 hospitalized dogs were catheterized with either an open or closed urine collection system. After analyzing the incidence of bacteriuria, they concluded that the type of urine collection system (open vs. closed) was not associated with the risk of developing

In terms of the time point to change catheter, most guidelines recommend against changing catheter routinely. Instead, it is recommended to change the catheter before blockage occurs. Furthermore, some strategies including bladder irrigation with citric acid solution and oral acetohydroxamic acid have been proven to be effective for prevention of catheter blockage [32, 33]. By contrast, bladder washing with saline is not recommended due to lack of

inflammation than conventional catheter based on endoscopic assessment [30].

efits of hydrophilic catheter in terms of the incidence of UTI [29].

patients with indwelling catheter.

**2.3. Catheter care**

bacteriuria [31].

effectiveness [34].

#### **2.2. Catheter selection**

To prevent the catheter-associated UTI, some special catheters have been designed and developed. They mainly include silver-coated, antibiotic-coated, hydrophilic and novel trefoil catheters.

As is known, silver is a kind of antiseptic. So it was hypothesized that catheter coated with silver could reduce the risk of UTI in patients treated by the indwelling catheter. Based on this hypothesis, a variety of silver-coated catheters have been developed. However, the efficacy of these catheters on UTI prevention varies from one to another. Evidence showed that silver alloy-coated catheter might reduce the incidence of UTI, but the silver oxide-coated one would not. A prospective single-center study conducted in Hong Kong investigated the incidence of UTI in patients with a silver alloy and hydrogel-coated catheter, which was compared with the counterparts with a standard catheter. The results showed that the incidence of UTI per 1000 catheter days was 6.4 and 9.4 in the silver-coated catheter group and standard catheter group, respectively. The silver-coated catheter group presented a 31% reduction in risk of UTI [21]. Lederer et al. reported the similar results in a retrospective cohort study in which 7 medical centers with 2778 active acute care beds in the United States were involved. They found that the silver alloy and hydrogel-coated catheter could cause a 47 and 58% relative reduction in UTI rate, respectively, compared to the conventional catheter when a different definition was applied [22]. In contrast, two clinical trials revealed that the use of silver oxide-coated catheter could not reduce the incidence of UTI and bacteriuria in comparison with standard catheter [23, 24]. Besides the two silver-coated catheters mentioned earlier, another silver nanoparticle-fabricated catheter has been developed. According to an experimental study, this silver nanoparticle catheter had significant antimicrobial and antibiofilm properties, as well as a remarkable ability to cause disorganization of bacterial cell membrane, which may prevent UTI effectively [25].

It has been shown that antibiotic-coated catheter has a significant antimicrobial activity. Desai et al. found that nitrofurazone-impregnated catheter could decrease the adherence of pathogenic microorganisms to catheter markedly, but the effect could only persist for 5 days after the catheterization [26]. Regev-Shoshani et al. further reported that both nitrofurazoneand nitric oxide-coated catheters had a great effect on the prevention of microbial growth and biofilm formation, which was more effective than silver-coated catheter [27]. Despite lack of available clinical data so far, the antibiotic-coated catheter may bring potential benefits for patients with indwelling catheter.

Hydrophilic catheter may decrease the friction between catheter and urethra during catheterization. Consequently, it reduces the potential mucosal trauma which can result in the bacterial colonization. A multicentered RCT showed that the use of hydrophilic catheter might decrease approximately one-third the risk of developing symptomatic UTI compared with standard catheter [28]. Similarly, the evidence from a meta-analysis supported marked benefits of hydrophilic catheter in terms of the incidence of UTI [29].

A novel trefoil catheter has been developed. Although it has not been reported for use in clinical practice, the preclinical study has shown its advantages. Sun et al. performed an experiment in which 66 rabbits were catheterized using either conventional or novel trefoil catheter randomly and reported that the novel catheter could decrease the incidence of bacteriuria. In addition, it was also found that the trefoil catheter caused a significant slighter mucosal inflammation than conventional catheter based on endoscopic assessment [30].

## **2.3. Catheter care**

bacteriuria and less discomfort compared with transurethral catheter [18]. A prospective openlabeled study presented that women with postoperative urinary retention favored suprapubic catheter due to a better catheter-specific quality of life [19]. According to the result from a network meta-analysis, indwelling urethral catheter did not increase the risk of UTI compared with either suprapubic tube or intermittent catheterization when duration of catheter was less than 5 days. In contrast, suprapubic tube or intermittent catheterization was associated with a lower rate of UTI when long-term catheterization is needed [20]. Based on our experience, suprapubic catheter has a significant advantage for male patients. We used suprapubic catheter to manage more than 20 male patients who suffered from recurrent acute bacterial prostatitis or epididymitis secondary to indwelling urethral catheter. We found that no one experienced these genitourinary infections again after the technique of catheterization was changed. Additionally, suprapubic catheter allows patients to observe their recovery of voiding function. We encourage patients to try to urinate with a closed suprapubic catheter if they

4 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

patients' attempt of voiding cannot bring about upper urinary tract deterioration. After spontaneous voiding, patients need to open the suprapubic catheter and measure the PVR. Once the PVR is low enough, the removal of suprapubic catheter can be taken into consideration.

To prevent the catheter-associated UTI, some special catheters have been designed and developed. They mainly include silver-coated, antibiotic-coated, hydrophilic and novel trefoil catheters.

As is known, silver is a kind of antiseptic. So it was hypothesized that catheter coated with silver could reduce the risk of UTI in patients treated by the indwelling catheter. Based on this hypothesis, a variety of silver-coated catheters have been developed. However, the efficacy of these catheters on UTI prevention varies from one to another. Evidence showed that silver alloy-coated catheter might reduce the incidence of UTI, but the silver oxide-coated one would not. A prospective single-center study conducted in Hong Kong investigated the incidence of UTI in patients with a silver alloy and hydrogel-coated catheter, which was compared with the counterparts with a standard catheter. The results showed that the incidence of UTI per 1000 catheter days was 6.4 and 9.4 in the silver-coated catheter group and standard catheter group, respectively. The silver-coated catheter group presented a 31% reduction in risk of UTI [21]. Lederer et al. reported the similar results in a retrospective cohort study in which 7 medical centers with 2778 active acute care beds in the United States were involved. They found that the silver alloy and hydrogel-coated catheter could cause a 47 and 58% relative reduction in UTI rate, respectively, compared to the conventional catheter when a different definition was applied [22]. In contrast, two clinical trials revealed that the use of silver oxide-coated catheter could not reduce the incidence of UTI and bacteriuria in comparison with standard catheter [23, 24]. Besides the two silver-coated catheters mentioned earlier, another silver nanoparticle-fabricated catheter has been developed. According to an experimental study, this silver nanoparticle catheter had significant antimicrobial and antibiofilm properties, as well as a remarkable ability to cause disorganization of bacterial cell membrane,

0) assessed by urodynamics, which means

have a low detrusor leak-point pressure (<40 cmH2

which may prevent UTI effectively [25].

**2.2. Catheter selection**

Catheter care is important for patients with an indwelling catheter since appropriate care can decrease the incidence of UTI. Both EAU and IDSA guidelines recommend maintaining a closed drainage system all the time [9, 10]. Once any breaks are detected, both the catheter and collecting system must be replaced as soon as possible. Besides, it is crucial to keep the drainage tubing being below the level of the patient's bladder and above the level of the collection bag, which can avoid the reflux of urine in drainage system. To minimize the risk of UTI, different types of collecting systems were developed. However, current evidence fails to show their different effects on prevention of UTI. Sullivan et al. conducted a RCT, in which 51 hospitalized dogs were catheterized with either an open or closed urine collection system. After analyzing the incidence of bacteriuria, they concluded that the type of urine collection system (open vs. closed) was not associated with the risk of developing bacteriuria [31].

In terms of the time point to change catheter, most guidelines recommend against changing catheter routinely. Instead, it is recommended to change the catheter before blockage occurs. Furthermore, some strategies including bladder irrigation with citric acid solution and oral acetohydroxamic acid have been proven to be effective for prevention of catheter blockage [32, 33]. By contrast, bladder washing with saline is not recommended due to lack of effectiveness [34].

## **3. Urolithiasis**

Urolithiasis is one of the most common urological diseases with a rising incidence around the world. In general, UTI is usually considered as a complication of urolithiasis. Actually, it is also a potential pathogenic factor for a special urinary stone, struvite. Basically, the formation of struvite originates with the bacterial decomposition for urea. Some bacteria, including Proteus and Klebsiella, can decompose urea into ammonia and carbon dioxide, which can be further converted into ammonium and bicarbonate, respectively, and consequently, elevate the pH value of urine. With an alkaline urinary environment, the ammonium has a strong ability to combine with magnesium and phosphate. Once these chemical substances become supersaturated in urine, they will crystallize and deposit the struvite. The existence of urinary stone, especially struvite, may cause UTI difficult to treat because the stone may act as a nidus for microorganisms and result in obstruction in urinary tract.

antibiotics can prevent bacteriuria and UTI in patients performing clean intermittent selfcatheterization due to neurogenic bladder. Two double-blind, placebo-controlled, crossover trials showed that nitrofurantoin prophylaxis could reduce the risk of bacteriuria and UTI significantly [41, 42]. On the contrary, a Cochrane systematic review demonstrated that the evidence failed to prove the certain benefits of antibiotic prophylaxis in patients with clean intermittent self-catheterization [43]. In a recently published case series study, Cox L et al. described a successful treatment in reduction of UTI in patients with clean intermittent selfcatheterization using intravesical instillations of gentamicin [44]. However, the treatment

Management of Complicated Urinary Tract Infection http://dx.doi.org/10.5772/intechopen.74556 7

Vesicoureteral reflux is the most common risk factor for UTI in children. It is reported that 30–40% of children with their first UTI episode are affected by this disorder [45, 46]. In general, vesicoureteral reflux is graded from I to V (mild to severe) according to the height of reflux up the ureter and degree of dilatation of the ureter. A high grade of vesicoureteral reflux, defined as grade IV and V, may lead to the renal scars due to UTI, which may further cause renal failure. Conventionally, antibiotic prophylaxis has been considered as the standard management for patients with vesicoureteral reflux. However, a large cohort study revealed that continuous antibiotic prophylaxis could not decrease the risk of recurrent UTI but might increase the risk of bacteria resistant to the antibiotic in children with vesicoureteral reflux [47]. As an approach to eliminate reflux, some invasive interventions including anti-reflux surgery and injection of bulking agent are used to reduce the breakthrough UTI. Basically, the surgical options include open or laparoscopic ureteral reimplantation. Based on clinical assessment, the reported successful rate for open and laparoscopic approach is 80–95% and 90–93%, respectively [48–50]. In contrast, the endoscopic injection presents a lower treatment successful rate in the range of 50–93% [48]. From our experience, surgical intervention may be an effective therapy for the

patients who still suffer from UTI even on continuous antibiotic prophylaxis.

It is reported that pregnant women have an increasing risk of UTI, especially upper UTI, because the physiological changes induced by pregnancy make them more likely to suffer from pyelonephritis. On the one hand, elevated level of progesterone during pregnancy can induce the relaxation of ureteric smooth muscles, which may lead to the urine retention in the renal collecting system and ureter. On the other hand, the noticeable increase in renal blood volume and glomerular filtration rate may contribute to the renal pelvic and ureteral dilation. The dilated upper urinary tract provides pathogens with a permissive environment to grow and reproduce. As a result, bacteriuria will develop pyelonephritis in 25–40% of pregnant women. The independent risk factors include history of UTI, low socioeconomic status, indigence, intercurrent diabetes and sickle cell trait. Therefore, short-course antibiotic therapy should be applied to prevent developing ascending UTI, once the bacteriuria is identified in pregnant

strategy needs to be further verified by well-designed RCTs.

**5. Vesicoureteral reflux**

**6. Pregnancy**

According to our experience, when UTI and urolithiasis coexist, the individualized management strategy should be taken into consideration. If the stone causes a urinary tract obstruction, the initial treatment should focus on the decompression of the collecting system, which can avoid the infection being exacerbated. Normally, the best way of decompression is to remove the stone as soon as possible, which can be achieved either by ureteroscopic lithotripsy or by percutaneous nephrolithotripsy. However, if the patient cannot tolerate these minimally invasive surgeries, indwelling ureteral stent and percutaneous nephrostomy tube could be the optional treatment. Only with an unobstructed collecting system can the subsequent antibiotic therapy for UTI be efficient. For patients with coexistence of UTI and nonobstructive stone, empiric antibiotic therapy can be the initial treatment. Only when the UTI fails to manage, the invasive intervention is considered to remove the stone.

## **4. Neurogenic bladder**

Neurogenic bladder refers to the bladder dysfunction secondary to a certain disease of the central nervous system or peripheral nerves. The specific conditions causing neurogenic bladder are various and the most common one is spinal cord injury, followed by multiple sclerosis, cerebral vascular events and Parkinson's disease [35]. Moreover, long-standing diabetes plays an important role in the development of neurogenic bladder. It is reported that patients with neurogenic bladder have a significant increased incidence of UTI.An observational study in which 46,000 patients with neurogenic bladder were investigated and followed up showed that 29.2–36.4% of patients were diagnosed with lower UTI annually [35]. Another study revealed that 81% of patients with spinal cord injury experienced at least one UTI during a period of 5 years [36]. The etiology of UTI caused by neurogenic bladder is diverse. It is reported that the bladder ischemia and defect of glycosaminoglycan layer induced by bladder overdistension reduce the barrier function of urothelium [37, 38]. Moreover, immunological impairment of bladder mucosa involving NK cell, B and T cell further decreases the bladder's ability to defend the pathogens [39, 40].

For patients with neurogenic bladder, the clean intermittent self-catheterization is the most common technique to avoid bladder overdistension. It remains a big issue whether prophylactic antibiotics can prevent bacteriuria and UTI in patients performing clean intermittent selfcatheterization due to neurogenic bladder. Two double-blind, placebo-controlled, crossover trials showed that nitrofurantoin prophylaxis could reduce the risk of bacteriuria and UTI significantly [41, 42]. On the contrary, a Cochrane systematic review demonstrated that the evidence failed to prove the certain benefits of antibiotic prophylaxis in patients with clean intermittent self-catheterization [43]. In a recently published case series study, Cox L et al. described a successful treatment in reduction of UTI in patients with clean intermittent selfcatheterization using intravesical instillations of gentamicin [44]. However, the treatment strategy needs to be further verified by well-designed RCTs.

## **5. Vesicoureteral reflux**

**3. Urolithiasis**

**4. Neurogenic bladder**

Urolithiasis is one of the most common urological diseases with a rising incidence around the world. In general, UTI is usually considered as a complication of urolithiasis. Actually, it is also a potential pathogenic factor for a special urinary stone, struvite. Basically, the formation of struvite originates with the bacterial decomposition for urea. Some bacteria, including Proteus and Klebsiella, can decompose urea into ammonia and carbon dioxide, which can be further converted into ammonium and bicarbonate, respectively, and consequently, elevate the pH value of urine. With an alkaline urinary environment, the ammonium has a strong ability to combine with magnesium and phosphate. Once these chemical substances become supersaturated in urine, they will crystallize and deposit the struvite. The existence of urinary stone, especially struvite, may cause UTI difficult to treat because the stone may act as a nidus

6 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

According to our experience, when UTI and urolithiasis coexist, the individualized management strategy should be taken into consideration. If the stone causes a urinary tract obstruction, the initial treatment should focus on the decompression of the collecting system, which can avoid the infection being exacerbated. Normally, the best way of decompression is to remove the stone as soon as possible, which can be achieved either by ureteroscopic lithotripsy or by percutaneous nephrolithotripsy. However, if the patient cannot tolerate these minimally invasive surgeries, indwelling ureteral stent and percutaneous nephrostomy tube could be the optional treatment. Only with an unobstructed collecting system can the subsequent antibiotic therapy for UTI be efficient. For patients with coexistence of UTI and nonobstructive stone, empiric antibiotic therapy can be the initial treatment. Only when the UTI fails

Neurogenic bladder refers to the bladder dysfunction secondary to a certain disease of the central nervous system or peripheral nerves. The specific conditions causing neurogenic bladder are various and the most common one is spinal cord injury, followed by multiple sclerosis, cerebral vascular events and Parkinson's disease [35]. Moreover, long-standing diabetes plays an important role in the development of neurogenic bladder. It is reported that patients with neurogenic bladder have a significant increased incidence of UTI.An observational study in which 46,000 patients with neurogenic bladder were investigated and followed up showed that 29.2–36.4% of patients were diagnosed with lower UTI annually [35]. Another study revealed that 81% of patients with spinal cord injury experienced at least one UTI during a period of 5 years [36]. The etiology of UTI caused by neurogenic bladder is diverse. It is reported that the bladder ischemia and defect of glycosaminoglycan layer induced by bladder overdistension reduce the barrier function of urothelium [37, 38]. Moreover, immunological impairment of bladder mucosa involving NK cell,

B and T cell further decreases the bladder's ability to defend the pathogens [39, 40].

For patients with neurogenic bladder, the clean intermittent self-catheterization is the most common technique to avoid bladder overdistension. It remains a big issue whether prophylactic

for microorganisms and result in obstruction in urinary tract.

to manage, the invasive intervention is considered to remove the stone.

Vesicoureteral reflux is the most common risk factor for UTI in children. It is reported that 30–40% of children with their first UTI episode are affected by this disorder [45, 46]. In general, vesicoureteral reflux is graded from I to V (mild to severe) according to the height of reflux up the ureter and degree of dilatation of the ureter. A high grade of vesicoureteral reflux, defined as grade IV and V, may lead to the renal scars due to UTI, which may further cause renal failure. Conventionally, antibiotic prophylaxis has been considered as the standard management for patients with vesicoureteral reflux. However, a large cohort study revealed that continuous antibiotic prophylaxis could not decrease the risk of recurrent UTI but might increase the risk of bacteria resistant to the antibiotic in children with vesicoureteral reflux [47]. As an approach to eliminate reflux, some invasive interventions including anti-reflux surgery and injection of bulking agent are used to reduce the breakthrough UTI. Basically, the surgical options include open or laparoscopic ureteral reimplantation. Based on clinical assessment, the reported successful rate for open and laparoscopic approach is 80–95% and 90–93%, respectively [48–50]. In contrast, the endoscopic injection presents a lower treatment successful rate in the range of 50–93% [48]. From our experience, surgical intervention may be an effective therapy for the patients who still suffer from UTI even on continuous antibiotic prophylaxis.

## **6. Pregnancy**

It is reported that pregnant women have an increasing risk of UTI, especially upper UTI, because the physiological changes induced by pregnancy make them more likely to suffer from pyelonephritis. On the one hand, elevated level of progesterone during pregnancy can induce the relaxation of ureteric smooth muscles, which may lead to the urine retention in the renal collecting system and ureter. On the other hand, the noticeable increase in renal blood volume and glomerular filtration rate may contribute to the renal pelvic and ureteral dilation. The dilated upper urinary tract provides pathogens with a permissive environment to grow and reproduce. As a result, bacteriuria will develop pyelonephritis in 25–40% of pregnant women. The independent risk factors include history of UTI, low socioeconomic status, indigence, intercurrent diabetes and sickle cell trait. Therefore, short-course antibiotic therapy should be applied to prevent developing ascending UTI, once the bacteriuria is identified in pregnant women. It is investigated that the antibiotic therapy can reduce the incidence of pyelonephritis by 75% [51]. Generally, a three-day course of antibiotic therapy directed by urine culture is recommended for both symptomatic lower UTI and asymptomatic bacteriuria. When the result of culture is not available, an empiric therapy with a ß-lactam or nitrofurantoin can be used as the initial treatment. For patients with upper UTI, a 14- to 21-day course of intravenous antibiotic therapy should be adopted. The reported effective antibiotic includes a third-generation cephalosporin, gentamicin or aztreonam, which can be used as the initial treatment before the result of culture is available. In addition, it is crucial to identify whether an obstruction exists in every pregnant woman. Once the obstruction is diagnosed, it can be relieved by ureteral stent or percutaneous nephrostomy tube. For patients with ureteral stent or percutaneous nephrostomy tube, it is necessary to use the antibiotic continuously until after delivery.

**References**

costs. Disease-a-Month. 2003;**49**(2):53-70

tional studies. Critical Care Medicine. 2011;**39**(5):1167-1173

Infection Control and Hospital Epidemiology. 2008;**29**(11):996-1011

associated urinary tract infections. Urology Journal. 2017;**14**(2):3028-3034

urinary tract infection. The Journal of Hospital Infection. 1991;**18**(1):45-56

microbial Agents. 2001;**17**(4):259-268

Epidemiology. 2002;**23**(1):27-31

2017;**65**(11):1799-1805

2008;**31**(Suppl 1):S68-S78

Association. 2006;**56**(9):401-404

[1] Foxman B. Epidemiology of urinary tract infections: Incidence, morbidity, and economic

Management of Complicated Urinary Tract Infection http://dx.doi.org/10.5772/intechopen.74556 9

[2] Hooton TM. Recurrent urinary tract infection in women. International Journal of Anti-

[3] Chant C et al. Relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill patients: A systematic review and meta-analysis of observa-

[4] Tambyah PA, Knasinski V, Maki DG. The direct costs of nosocomial catheter-associated urinary tract infection in the era of managed care. Infection Control and Hospital

[5] Hidron AI et al. NHSN annual update: Antimicrobial-resistant pathogens associated with healthcare-associated infections: Annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007.

[6] Kirmusaoglu S et al. The effect of urinary catheters on microbial biofilms and catheter

[7] Hustinx WN et al. Impact of concurrent antimicrobial therapy on catheter-associated

[8] Babich T et al. Empirical antibiotic treatment does not improve outcomes in catheterassociated urinary tract infection: Prospective cohort study. Clinical Infectious Diseases.

[9] Hooton TM et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 International clinical practice guidelines from the Infectious

[10] Tenke P et al. European and Asian guidelines on management and prevention of catheter-associated urinary tract infections. International Journal of Antimicrobial Agents.

[11] Saint S et al. Condom versus indwelling urinary catheters: A randomized trial. Journal

[12] Johansson I et al. Intermittent versus indwelling catheters for older patients with hip

[13] Turi MH et al. Proportion of complications in patients practicing clean intermittent self-catheterization (CISC) vs indwelling catheter. The Journal of the Pakistan Medical

[14] Hakvoort RA et al. Comparing clean intermittent catheterisation and transurethral indwelling catheterisation for incomplete voiding after vaginal prolapse surgery: A multicentre randomised trial. British Journal of Obstetrics and Gynaecology. 2011;**118**(9):1055-1060

Diseases Society of America. Clinical Infectious Diseases. 2010;**50**(5):625-663

of the American Geriatrics Society. 2006;**54**(7):1055-1061

fractures. Journal of Clinical Nursing. 2002;**11**(5):651-656

## **7. Conclusion**

The treatment of complicated UTI remains a challenge because the coexisted conditions are diverse. Appropriate management for these conditions is the prerequisite achieving a successful treatment for complicated UTI.

## **Acknowledgements**

This work was supported by Beijing Municipal Science & Technology Commission No. Z161100000516156 and grant 2014S292 from Guang An Men Hospital, China Academy of Chinese Medical Sciences.

## **Conflict of interest**

None.

## **Author details**

Ran Pang1 \*, Jianhua Deng2 and Xinyao Zhou<sup>3</sup>

\*Address all correspondence to: pangran2002@gmail.com

1 Department of Urology, Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing, P.R. China

2 Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China

3 Department of Rumatology, Guang An Men Hospital, China Academy of Chinese Medical Sciences, Beijing, P.R. China

## **References**

women. It is investigated that the antibiotic therapy can reduce the incidence of pyelonephritis by 75% [51]. Generally, a three-day course of antibiotic therapy directed by urine culture is recommended for both symptomatic lower UTI and asymptomatic bacteriuria. When the result of culture is not available, an empiric therapy with a ß-lactam or nitrofurantoin can be used as the initial treatment. For patients with upper UTI, a 14- to 21-day course of intravenous antibiotic therapy should be adopted. The reported effective antibiotic includes a third-generation cephalosporin, gentamicin or aztreonam, which can be used as the initial treatment before the result of culture is available. In addition, it is crucial to identify whether an obstruction exists in every pregnant woman. Once the obstruction is diagnosed, it can be relieved by ureteral stent or percutaneous nephrostomy tube. For patients with ureteral stent or percutaneous nephros-

The treatment of complicated UTI remains a challenge because the coexisted conditions are diverse. Appropriate management for these conditions is the prerequisite achieving a success-

This work was supported by Beijing Municipal Science & Technology Commission No. Z161100000516156 and grant 2014S292 from Guang An Men Hospital, China Academy of

tomy tube, it is necessary to use the antibiotic continuously until after delivery.

8 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

**7. Conclusion**

ful treatment for complicated UTI.

**Acknowledgements**

Chinese Medical Sciences.

**Conflict of interest**

**Author details**

\*, Jianhua Deng2

Sciences, Beijing, P.R. China

Sciences, Beijing, P.R. China

and Xinyao Zhou<sup>3</sup>

Medical Sciences and Peking Union Medical College, Beijing, P.R. China

1 Department of Urology, Guang An Men Hospital, China Academy of Chinese Medical

2 Department of Urology, Peking Union Medical College Hospital, Chinese Academy of

3 Department of Rumatology, Guang An Men Hospital, China Academy of Chinese Medical

\*Address all correspondence to: pangran2002@gmail.com

None.

Ran Pang1


[15] King RB et al. Clean and sterile intermittent catheterization methods in hospitalized patients with spinal cord injury. Archives of Physical Medicine and Rehabilitation. 1992; **73**(9):798-802

[28] Cardenas DD et al. Intermittent catheterization with a hydrophilic-coated catheter delays urinary tract infections in acute spinal cord injury: A prospective, randomized,

Management of Complicated Urinary Tract Infection http://dx.doi.org/10.5772/intechopen.74556 11

[29] Chartier-Kastler E, Denys P. Intermittent catheterization with hydrophilic catheters as a treatment of chronic neurogenic urinary retention. Neurourology and Urodynamics.

[30] Sun Y et al. Decreased urethral mucosal damage and delayed bacterial colonization during short-term urethral catheterization using a novel trefoil urethral catheter profile in

[31] Sullivan LA, Campbell VL, Onuma SC. Evaluation of open versus closed urine collection systems and development of nosocomial bacteriuria in dogs. Journal of the American

[32] Burns JR, Gauthier JF. Prevention of urinary catheter incrustations by acetohydroxamic

[33] Mayes J, Bliss J, Griffiths P. Preventing blockage of long-term indwelling catheters in adults: Are citric acid solutions effective? British Journal of Community Nursing. 2003;

[34] Muncie Jr HL et al. Once-daily irrigation of long-term urethral catheters with normal

[35] Manack A et al. Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database. Neurourology and Urodynamics. 2011;**30**(3):395-401

[36] Biering-Sorensen F et al. Urological situation five years after spinal cord injury. Scan-

[37] Perlow DL, Gikas PW, Horowitz EM. Effect of vesical overdistention on bladder mucin.

[38] Vasudeva P, Madersbacher H. Factors implicated in pathogenesis of urinary tract infections in neurogenic bladders: Some revered, few forgotten, others ignored. Neurourology

[39] Iversen PO et al. Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury. Blood. 2000;**96**(6):2081-2083

[40] Schlager TA et al. Bladder epithelium is abnormal in patients with neurogenic bladder

[41] Johnson HW et al. A short-term study of nitrofurantoin prophylaxis in children man-

[42] Schlager TA et al. Nitrofurantoin prophylaxis for bacteriuria and urinary tract infection in children with neurogenic bladder on intermittent catheterization. The Journal of

aged with clean intermittent catheterization. Pediatrics. 1994;**93**(5):752-755

saline. Lack of benefit. Archives of Internal Medicine. 1989;**149**(2):441-443

dinavian Journal of Urology and Nephrology. 1999;**33**(3):157-161

due to myelomeningocele. Spinal Cord. 2004;**42**(3):163-168

multicenter trial. Physical Medicine and Rehabilitation. 2011;**3**(5):408-417

rabbits. The Journal of Urology. 2011;**186**(4):1497-1501

Veterinary Medical Association. 2010;**237**(2):187-190

acid. The Journal of Urology. 1984;**132**(3):455-456

2011;**30**(1):21-31

**8**(4):172-175

Urology. 1981;**18**(4):380-383

and Urodynamics. 2014;**33**(1):95-100

Pediatrics. 1998;**132**(4):704-708


[28] Cardenas DD et al. Intermittent catheterization with a hydrophilic-coated catheter delays urinary tract infections in acute spinal cord injury: A prospective, randomized, multicenter trial. Physical Medicine and Rehabilitation. 2011;**3**(5):408-417

[15] King RB et al. Clean and sterile intermittent catheterization methods in hospitalized patients with spinal cord injury. Archives of Physical Medicine and Rehabilitation. 1992;

[16] Moore KN, Burt J, Voaklander DC. Intermittent catheterization in the rehabilitation setting: A comparison of clean and sterile technique. Clinical Rehabilitation. 2006;

[17] Dunn TS, Figge J, Wolf D. A comparison of outcomes of transurethral versus suprapubic catheterization after Burch cystourethropexy. International Urogynecology Journal and

[18] McPhail MJ, Abu-Hilal M, Johnson CD. A meta-analysis comparing suprapubic and transurethral catheterization for bladder drainage after abdominal surgery. The British

[19] Takase-Sanchez MM et al. Suprapubic versus transurethral bladder drainage following reconstructive pelvic surgery: A comparison of patient satisfaction and quality of life.

[20] Han CS et al. Comparison of urinary tract infection rates associated with transurethral catheterization, Suprapubic tube and clean intermittent catheterization in the postoperative setting: A network meta-analysis. The Journal of Urology. 2017;**198**(6):1353-1358

[21] Chung PH et al. A prospective interventional study to examine the effect of a silver alloy and hydrogel-coated catheter on the incidence of catheter-associated urinary tract infec-

[22] Lederer JW et al. Multicenter cohort study to assess the impact of a silver-alloy and hydrogel-coated urinary catheter on symptomatic catheter-associated urinary tract infections. Journal of Wound, Ostomy, and Continence Nursing. 2014;**41**(5):473-480 [23] Johnson JR et al. Prevention of catheter-associated urinary tract infection with a silver oxide-coated urinary catheter: Clinical and microbiologic correlates. The Journal of

[24] Riley DK et al. A large randomized clinical trial of a silver-impregnated urinary catheter: Lack of efficacy and staphylococcal superinfection. The American Journal of Medicine.

[25] Thomas R et al. Inhibitory effect of silver nanoparticle fabricated urinary catheter on colonization efficiency of coagulase negative Staphylococci. Journal of Photochemistry

[26] Desai DG et al. Silver or nitrofurazone impregnation of urinary catheters has a minimal effect on uropathogen adherence. The Journal of Urology. 2010;**184**(6):2565-2571

[27] Regev-Shoshani G et al. Comparative efficacy of commercially available and emerging antimicrobial urinary catheters against bacteriuria caused by *E. coli* in vitro. Urology.

Pelvic Floor Dysfunction. 2005;**16**(1):60-62. Discussion 62

10 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

International Urogynecology Journal. 2017;**28**(5):721-728

tion. Hong Kong Medical Journal. 2017;**23**(3):239-245

Infectious Diseases. 1990;**162**(5):1145-1150

and Photobiology. B. 2015;**149**:68-77

1995;**98**(4):349-356

2011;**78**(2):334-339

Journal of Surgery. 2006;**93**(9):1038-1044

**73**(9):798-802

**20**(6):461-468


[43] Niel-Weise BS et al. Urinary catheter policies for long-term bladder drainage. Cochrane Database of Systematic Reviews. 2012;**8**:CD004201

**Chapter 2**

**Provisional chapter**

**Management of Urinary Tract Infections: Problems and**

In clinically suspected urinary tract infections (UTIs), empirical antibiotic treatment is usually started long before the laboratory results of urine culture and antibiogram are available. Although molecular diagnostic approaches are being applied to the diagnosis of many infections, UTIs are generally diagnosed by traditional culture methods. Patient care could greatly benefit from the development of a rapid, accurate, inexpensive test that could be done at patient's bedside, allowing the practitioner to plan targeted, more effective therapy. Such a test would potentially reduce incorrect or unnecessary use of antibacterial drugs and reduce the emergence of bacterial resistance. In response to this pressing and unmet clinical need, several methods have been developed in the last few years. Among these, the new point-of-care test (POCT) for detecting UTIs named Micro Biological Survey (MBS) UTI CHECK holds promise, as it allows semi-quantitative determination of bacterial load in urine leading to a fast detection of UTIs and to evaluation of bacterial antibiotic susceptibility. This new technology operates through a colorimetric survey performed in low-cost, ready-to-use, disposable vials, in which 1 ml of urine is inoculated without any preliminary treatment and requiring neither specialized personnel nor a specialized equipment.

**Keywords:** urinary tract infections, point-of-care test, clinical microbiology analysis,

**1. Introduction: definition and background over urinary tract** 

**Management of Urinary Tract Infections: Problems and** 

DOI: 10.5772/intechopen.71588

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Urinary tract infections (UTIs) are caused by the presence and multiplication of microorganisms in the urinary tract, sometimes spreading to the bloodstream and possibly resulting in several clinical syndromes (e.g., pyelonephritis, cystitis, urethritis, epididymitis and prostatitis) [1].

Lorenza Murgia, Ottavia Stalio, Alyexandra Arienzo,

Lorenza Murgia, Ottavia Stalio, Alyexandra Arienzo, Valeria Ferrante, Valentina Cellitti, Salvatore Di Somma,

Additional information is available at the end of the chapter

UTIs diagnosis, antimicrobial resistance

Additional information is available at the end of the chapter

**Possible Solutions**

**Possible Solutions**

Giovanni Antonini

**Abstract**

**infections (UTIs)**

Valeria Ferrante, Valentina Cellitti, Salvatore Di Somma, Paolo Visca and

Paolo Visca and Giovanni Antonini

http://dx.doi.org/10.5772/intechopen.71588


**Provisional chapter**

## **Management of Urinary Tract Infections: Problems and Possible Solutions Management of Urinary Tract Infections: Problems and Possible Solutions**

DOI: 10.5772/intechopen.71588

[43] Niel-Weise BS et al. Urinary catheter policies for long-term bladder drainage. Cochrane

[44] Cox L et al. Gentamicin bladder instillations decrease symptomatic urinary tract infections in neurogenic bladder patients on intermittent catheterization. Canadian Urological

[45] Marild S, Jodal U. Incidence rate of first-time symptomatic urinary tract infection in

[46] Jacobson SH, Hansson S, Jakobsson B. Vesico-ureteric reflux: Occurrence and long-term

[47] Conway PH et al. Recurrent urinary tract infections in children: Risk factors and association with prophylactic antimicrobials. Journal of the American Medical Association.

[48] Elmore JM et al. Incidence of urinary tract infections in children after successful ureteral reimplantation versus endoscopic dextranomer/hyaluronic acid implantation. Journal of

[49] Akhavan A, Avery D, Lendvay TS. Robot-assisted extravesical ureteral reimplantation: Outcomes and conclusions from 78 ureters. Journal of Pediatric Urology. 2014;

[50] Arlen AM et al. Outcomes of complex robot-assisted extravesical ureteral reimplantation in the pediatric population. Journal of Pediatric Urology. 2016;**12**(3):169e1-169e6 [51] Sweet RL. Bacteriuria and pyelonephritis during pregnancy. Seminars in Perinatology.

children under 6 years of age. Acta Paediatrica. 1998;**87**(5):549-552

risks. Acta Paediatrica. Supplement. 1999;**88**(431):22-30

Urology. 2008;**179**(6):2364-2367. Discussion 2367-8

Database of Systematic Reviews. 2012;**8**:CD004201

12 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Association Journal. 2017;**11**(9):350

2007;**298**(2):179-186

**10**(5):864-868

1977;**1**(1):25-40

Lorenza Murgia, Ottavia Stalio, Alyexandra Arienzo, Valeria Ferrante, Valentina Cellitti, Salvatore Di Somma, Paolo Visca and Giovanni Antonini Lorenza Murgia, Ottavia Stalio, Alyexandra Arienzo, Valeria Ferrante, Valentina Cellitti, Salvatore Di Somma, Paolo Visca and Giovanni Antonini

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71588

#### **Abstract**

In clinically suspected urinary tract infections (UTIs), empirical antibiotic treatment is usually started long before the laboratory results of urine culture and antibiogram are available. Although molecular diagnostic approaches are being applied to the diagnosis of many infections, UTIs are generally diagnosed by traditional culture methods. Patient care could greatly benefit from the development of a rapid, accurate, inexpensive test that could be done at patient's bedside, allowing the practitioner to plan targeted, more effective therapy. Such a test would potentially reduce incorrect or unnecessary use of antibacterial drugs and reduce the emergence of bacterial resistance. In response to this pressing and unmet clinical need, several methods have been developed in the last few years. Among these, the new point-of-care test (POCT) for detecting UTIs named Micro Biological Survey (MBS) UTI CHECK holds promise, as it allows semi-quantitative determination of bacterial load in urine leading to a fast detection of UTIs and to evaluation of bacterial antibiotic susceptibility. This new technology operates through a colorimetric survey performed in low-cost, ready-to-use, disposable vials, in which 1 ml of urine is inoculated without any preliminary treatment and requiring neither specialized personnel nor a specialized equipment.

**Keywords:** urinary tract infections, point-of-care test, clinical microbiology analysis, UTIs diagnosis, antimicrobial resistance

## **1. Introduction: definition and background over urinary tract infections (UTIs)**

Urinary tract infections (UTIs) are caused by the presence and multiplication of microorganisms in the urinary tract, sometimes spreading to the bloodstream and possibly resulting in several clinical syndromes (e.g., pyelonephritis, cystitis, urethritis, epididymitis and prostatitis) [1].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Most UTIs are caused by bacteria, and when they occur in the urine without causing symptoms, this condition is called asymptomatic bacteriuria; when growth of bacteria leads to a panel of symptoms, this condition is referred to as symptomatic bacteriuria [1]. Urinary tract infections can manifest as bacteriuria with limited clinical symptoms and sepsis, depending on localized or systemic extension [2].

but rarely have important implications for diagnosis, also considering the long time often

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

15

The gold standard for diagnosis of bacteriuria is culture of appropriate urine sample [6, 7]. Sampling by needle aspiration minimizes the risk of contamination, while catheter and midstream sampling show a higher risk of contamination and therefore yield more false positive results [5]. However, needle aspiration is invasive and midstream sampling is preferred in clinical practice [8]. Routine culture is generally carried out streaking 10 μl of urine sample on agar plates containing selective or differential media and reading results after at least 24–48hours of incubation, considering characteristic colony morphologies and average quantitation. If there is the need for more accurate quantitative results, 100 μl plating following serial dilutions of urine sample must be performed [9]. The main value of urine culture is to identify microorganisms, most often bacteria; indirect indicators of the presence of bacteria

The number of bacteria in urine has been considered relevant for the diagnosis of UTIs since the Sixties, when Kass developed the concept of significant bacteriuria (10<sup>5</sup> CFU/ml) opening up to quantitative microbiology for the diagnosis of infectious diseases; his notion is still generally used to help diagnosis. Nevertheless, it has recently become clear that no fixed bacterial count can be applied to all kinds of UTIs and all circumstances, and even low bacterial concentrations are considered clinically relevant considering specific clinical pictures, sampling protocols and patient's sex. The problem of counting low numbers must then be

Along with pathogen identification, outlining its antimicrobial susceptibility profile is considered to be crucial to ensure an appropriate treatment [10]. Antimicrobial susceptibility testing is routinely performed using the Kirby-Bauer disk diffusion technique according to Clinical and Laboratory Standards Institute (CLSI) guidelines, meaning culturing bacteria from urine samples on agar plates in presence of disks containing selected antibiotics; interpretation of results requires the measurement of halos of inhibition around disks according to reference tables [11].

As with most bacterial infections, diagnosis of UTI depends on culturing the clinical sample in the clinical laboratory, and results are typically delayed of two to three days from sample acquisition [10]. This is due to the need for sample transport to the laboratory and the time required for bacteria to grow on culture media [10]. Thus, the standard method for UTI diag-

Since the patient cannot remain untreated during this rather prolonged period before definitive diagnosis is obtained, physicians usually prescribe broad spectrum antibiotics prior to antibiogram results. This practice has many undesirable consequences in the short and long terms, such as treatment failure leading to spread or chronicization of infection, increased health care costs, and increased antibiotic resistance by a growing number of bacterial strains. Given these drawbacks, it is obvious that a rapid and accurate method of UTI diagnosis and bacterial antibiotic susceptibility assessment would offer significant health

nosis is time consuming and logistically difficult [6].

(for example, urinary nitrites) are much less valuable than urine culture [5].

required for obtaining results with traditional methods [5].

considered [2].

benefits [12].

The onset of UTIs is mostly due to the ascent of microorganisms from the urethra, especially organisms of enteric origin, e.g., *Escherichia coli*, which is the causative pathogen in 70–95% of acute, uncomplicated UTIs in adults, followed by other Enterobacteriaceae, such as *Proteus mirabilis* and *Klebsiella* spp., and by *Staphylococcus saprophyticus* in 5–10% of cases [2]; hence, the higher frequency of UTIs in women than men, depending on anatomic structure, and the increased risk of infection following bladder catheterization, which compromises natural defense mechanisms. A small fraction of UTIs can have hematogenous origin, and usually involve a few relatively uncommon microorganisms (e.g., *Staphylococcus aureus*, *Candida* spp., *Salmonella* spp. and *Mycobacterium tuberculosis*), which cause primary infections elsewhere in the body and thus reach the urinary tract [2].

UTIs are among the most prevailing infectious diseases with a substantial financial burden on society [3]. The incidence of community-acquired UTIs is highest in young women [1]: almost half of all women will experience at least one episode of UTI during their lifetime, and nearly 1 in 3 women will have had at least one episode of UTI by the age of 24 years [2]. Urinary tract infection incidence increases with age for both sexes. It is estimated that 10% of men and 20% of women over the age of 65 years have asymptomatic bacteriuria [1].

Reports from European countries and the USA show that ca. 15% of all community-prescribed antibiotics are dispensed for UTIs [3]. UTIs account for many annual hospital admissions, especially among the elderly: in the UK, the number of emergency admissions of older people with a primary diagnosis of UTI showed a 200% increase from 2001/2002 to 2012/2013, parallel to a related increase in bed days, which both are the second highest increase (in absolute terms) among groups of conditions [4]. Nevertheless, UTIs are believed to have been greatly overcoded in recent years: part of the increase may be due to changes in coding practice, part to increased emergence of antibiotic resistance [4]. Moreover, UTIs represent at least 40% of all hospital acquired infections and most of them occur following catheterization, which is considered one of the main risk factors associated to onset of UTIs [3].

## **2. Current laboratory standards in UTI diagnosis**

The clinical evidence of UTI is based on a number of basic criteria, including clinical symptoms, and laboratory data which should provide evidence of the presence of microorganisms by culturing of urine samples, or other specific tests [2]. However, the diagnosis of UTIs is primarily based on symptoms and signs. Tests that suggest or prove the presence of bacteria or white cells in the urine may contribute additional information to inform management but rarely have important implications for diagnosis, also considering the long time often required for obtaining results with traditional methods [5].

Most UTIs are caused by bacteria, and when they occur in the urine without causing symptoms, this condition is called asymptomatic bacteriuria; when growth of bacteria leads to a panel of symptoms, this condition is referred to as symptomatic bacteriuria [1]. Urinary tract infections can manifest as bacteriuria with limited clinical symptoms and sepsis, depending

14 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The onset of UTIs is mostly due to the ascent of microorganisms from the urethra, especially organisms of enteric origin, e.g., *Escherichia coli*, which is the causative pathogen in 70–95% of acute, uncomplicated UTIs in adults, followed by other Enterobacteriaceae, such as *Proteus mirabilis* and *Klebsiella* spp., and by *Staphylococcus saprophyticus* in 5–10% of cases [2]; hence, the higher frequency of UTIs in women than men, depending on anatomic structure, and the increased risk of infection following bladder catheterization, which compromises natural defense mechanisms. A small fraction of UTIs can have hematogenous origin, and usually involve a few relatively uncommon microorganisms (e.g., *Staphylococcus aureus*, *Candida* spp., *Salmonella* spp. and *Mycobacterium tuberculosis*), which cause primary infections elsewhere in

UTIs are among the most prevailing infectious diseases with a substantial financial burden on society [3]. The incidence of community-acquired UTIs is highest in young women [1]: almost half of all women will experience at least one episode of UTI during their lifetime, and nearly 1 in 3 women will have had at least one episode of UTI by the age of 24 years [2]. Urinary tract infection incidence increases with age for both sexes. It is estimated that 10% of men and 20%

Reports from European countries and the USA show that ca. 15% of all community-prescribed antibiotics are dispensed for UTIs [3]. UTIs account for many annual hospital admissions, especially among the elderly: in the UK, the number of emergency admissions of older people with a primary diagnosis of UTI showed a 200% increase from 2001/2002 to 2012/2013, parallel to a related increase in bed days, which both are the second highest increase (in absolute terms) among groups of conditions [4]. Nevertheless, UTIs are believed to have been greatly overcoded in recent years: part of the increase may be due to changes in coding practice, part to increased emergence of antibiotic resistance [4]. Moreover, UTIs represent at least 40% of all hospital acquired infections and most of them occur following catheterization, which is considered one of the main risk factors associated

The clinical evidence of UTI is based on a number of basic criteria, including clinical symptoms, and laboratory data which should provide evidence of the presence of microorganisms by culturing of urine samples, or other specific tests [2]. However, the diagnosis of UTIs is primarily based on symptoms and signs. Tests that suggest or prove the presence of bacteria or white cells in the urine may contribute additional information to inform management

of women over the age of 65 years have asymptomatic bacteriuria [1].

**2. Current laboratory standards in UTI diagnosis**

on localized or systemic extension [2].

the body and thus reach the urinary tract [2].

to onset of UTIs [3].

The gold standard for diagnosis of bacteriuria is culture of appropriate urine sample [6, 7]. Sampling by needle aspiration minimizes the risk of contamination, while catheter and midstream sampling show a higher risk of contamination and therefore yield more false positive results [5]. However, needle aspiration is invasive and midstream sampling is preferred in clinical practice [8]. Routine culture is generally carried out streaking 10 μl of urine sample on agar plates containing selective or differential media and reading results after at least 24–48hours of incubation, considering characteristic colony morphologies and average quantitation. If there is the need for more accurate quantitative results, 100 μl plating following serial dilutions of urine sample must be performed [9]. The main value of urine culture is to identify microorganisms, most often bacteria; indirect indicators of the presence of bacteria (for example, urinary nitrites) are much less valuable than urine culture [5].

The number of bacteria in urine has been considered relevant for the diagnosis of UTIs since the Sixties, when Kass developed the concept of significant bacteriuria (10<sup>5</sup> CFU/ml) opening up to quantitative microbiology for the diagnosis of infectious diseases; his notion is still generally used to help diagnosis. Nevertheless, it has recently become clear that no fixed bacterial count can be applied to all kinds of UTIs and all circumstances, and even low bacterial concentrations are considered clinically relevant considering specific clinical pictures, sampling protocols and patient's sex. The problem of counting low numbers must then be considered [2].

Along with pathogen identification, outlining its antimicrobial susceptibility profile is considered to be crucial to ensure an appropriate treatment [10]. Antimicrobial susceptibility testing is routinely performed using the Kirby-Bauer disk diffusion technique according to Clinical and Laboratory Standards Institute (CLSI) guidelines, meaning culturing bacteria from urine samples on agar plates in presence of disks containing selected antibiotics; interpretation of results requires the measurement of halos of inhibition around disks according to reference tables [11].

As with most bacterial infections, diagnosis of UTI depends on culturing the clinical sample in the clinical laboratory, and results are typically delayed of two to three days from sample acquisition [10]. This is due to the need for sample transport to the laboratory and the time required for bacteria to grow on culture media [10]. Thus, the standard method for UTI diagnosis is time consuming and logistically difficult [6].

Since the patient cannot remain untreated during this rather prolonged period before definitive diagnosis is obtained, physicians usually prescribe broad spectrum antibiotics prior to antibiogram results. This practice has many undesirable consequences in the short and long terms, such as treatment failure leading to spread or chronicization of infection, increased health care costs, and increased antibiotic resistance by a growing number of bacterial strains. Given these drawbacks, it is obvious that a rapid and accurate method of UTI diagnosis and bacterial antibiotic susceptibility assessment would offer significant health benefits [12].

The introduction of partial and complete automation in clinical diagnostic in the 2000s has allowed the management of large-scale sample volumes and workflows optimization still providing reliable results for both pathogen identification and antibiotic susceptibility testing [10, 13].

bladder, the most common pathogens isolated being *Chlamydia trachomatis*, Enterobacteriaceae (typically *E. coli*) and *Neisseria gonorrhoeae*. For this last species, to reach correct diagnosis and plan following treatment, culture of mid-stream urine should be performed, together with nucleic acid amplification test (NAAT) on first voided urine or Gram staining in order to spe-

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

17

Urine culture is recommended to determine the presence or absence of clinically significant bacteriuria in patients prior to urological interventions (e.g., surgery) and the presence of bacteriuria is controlled by directed pre-operative treatment of the detected pathogen [2, 6]. Urine culture is considered a valuable tool during patients' follow-up: in women whose symptoms do not resolve or recur within 2–4 weeks after the completion of treatment, urine culture and antimicrobial susceptibility test should be performed and a new antibiotic regimen should be considered. Afterward, in patients who underwent antibiotic treatment, a follow-up with subsequent urine culture should verify the treatment efficacy [2]. Urine culture is also recommended in women who present with atypical symptoms, pregnant women and

In case of complicated UTIs, a broader range of bacteria is expected to be involved (often within the Enterobacteriaceae family), and these are more likely to show antibiotic resistance. Moreover, patients with a complicated UTI are more prone to have recurrent infections (more than 3 episodes/year) [2, 8, 27, 28]. Therefore, the choice of a therapy for these conditions must be supported by urine culture and antimicrobial susceptibility testing to avoid ineffective

Urine culture is also required in pediatric settings, where UTIs are the most common infections in children and infants, together with upper respiratory and gastrointestinal ones, with 30% recurrence rate reported within a year after initial UTI [2, 29]. Diagnosing pediatric UTIs may be difficult, because of communication difficulties in describing symptoms and vagueness of signs in small children; therefore, the definitive diagnosis of infection in children

In febrile patients with negative results on dipstick, microscopic, or automated urinalysis, urine culture is unnecessary if there is an alternative cause of the fever or inflammatory signs. However, if the dipstick and/or urinalysis are positive, confirmation of UTI by urine culture is mandatory [29]. In febrile children with signs of UTI (clinical signs, positive dipstick and/or positive microscopy, better if urine culture is available), antibiotic treatment should be initiated as soon as possible to eradicate the infection, prevent bacteremia, improve clinical outcome, diminish the likelihood of renal involvement during the acute phase of infection, and reduce the risk of immediate and long-term complications, including renal scarring and renal failure [29, 30].

The gold standard for diagnosis and successful management of UTIs is to obtain identification and quantification of the infecting agents, along with antibiotic susceptibility assessment to

cifically detect *Neisseria gonorrhoeae* or *Chlamydia trachomatis* [6, 26].

males with suspected UTI [2].

antibiotics administration.

requires a positive urine culture [2].

**4. Empirical treatment of UTIs**

Large-scale systems, anyway, are expensive and require more dedicate space, equipment and more personnel competence, which makes them applicable to a large hospital setting, but are difficult to establish in a small hospital, or in a limited-resource setting (e.g., developing countries). These high-throughput culture-based instruments, moreover, remain relatively slow and are not amenable for point-of-care use [10].

The introduction of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) technology in microbiology has allowed rapid and reliable bacterial identification, featuring both high sensitivity and specificity, improving efficiency and saving consumables and labor [14, 15]. MALDI-TOF technique is usually coupled with culture of urine samples, to allow isolation of bacteria and therefore obtain pure cultures, which will undergo MALDI-TOF analysis after some sample treatment. Recently, extensive databases have been developed that include protein profiles of main microorganisms involved in infections; some studies have therefore investigated the possibility to apply MALDI-TOF analysis directly to urine samples, yielding promising results also when coupling such analysis with screening methods, such as automated microscopic urine sediment analysis [16, 17]. It must be considered, however, that such high-throughput technology has high installation and maintenance costs, and requires dedicated spaces, limiting its use in routine analyses to centralized laboratories. Moreover, the technique cannot currently identify two species of bacteria when present simultaneously, and cannot determine antibiotic susceptibility; thus, traditional culture of urine samples is still necessary [18].

Nevertheless, the occurrence of more than one bacterial strain in urine samples participating in the infection should not be overlooked. Polymicrobic infections are more often associated with catheterization and aging, reaching 10% incidence rates in the community and 30% in hospital setting among elderly people [19]. Bacterial strains recovered from polymicrobic infection show metabolic alterations and altered virulence traits, such as antibiotic resistance [19]. However, relationships between coinfecting strains are not yet fully understood [20], although some studies are exploiting such infections' mechanisms [21, 22]. As clinical laboratories tend to report cultures showing single or clearly predominant bacteria and will not routinely report occurrence of polymicrobic associations, unless significant numbers of each species are detected, quite a large portion of UTIs are not correctly diagnosed nor treated, threatening patient's safety [19, 23–25]. Therefore, an improvement of diagnosis and clinical pathways is needed in order to enhance not only detection of pathogens in urine, but also profiling the whole microflora and determining the antimicrobial susceptibility of individual components.

## **3. When a urine culture followed by antibiogram is needed**

Even though the incidence of UTIs is higher in women [6], also related pathologies in men, such as epididymitis and prostatitis, may be caused by migration of pathogens from the urethra or bladder, the most common pathogens isolated being *Chlamydia trachomatis*, Enterobacteriaceae (typically *E. coli*) and *Neisseria gonorrhoeae*. For this last species, to reach correct diagnosis and plan following treatment, culture of mid-stream urine should be performed, together with nucleic acid amplification test (NAAT) on first voided urine or Gram staining in order to specifically detect *Neisseria gonorrhoeae* or *Chlamydia trachomatis* [6, 26].

Urine culture is recommended to determine the presence or absence of clinically significant bacteriuria in patients prior to urological interventions (e.g., surgery) and the presence of bacteriuria is controlled by directed pre-operative treatment of the detected pathogen [2, 6].

Urine culture is considered a valuable tool during patients' follow-up: in women whose symptoms do not resolve or recur within 2–4 weeks after the completion of treatment, urine culture and antimicrobial susceptibility test should be performed and a new antibiotic regimen should be considered. Afterward, in patients who underwent antibiotic treatment, a follow-up with subsequent urine culture should verify the treatment efficacy [2]. Urine culture is also recommended in women who present with atypical symptoms, pregnant women and males with suspected UTI [2].

In case of complicated UTIs, a broader range of bacteria is expected to be involved (often within the Enterobacteriaceae family), and these are more likely to show antibiotic resistance. Moreover, patients with a complicated UTI are more prone to have recurrent infections (more than 3 episodes/year) [2, 8, 27, 28]. Therefore, the choice of a therapy for these conditions must be supported by urine culture and antimicrobial susceptibility testing to avoid ineffective antibiotics administration.

Urine culture is also required in pediatric settings, where UTIs are the most common infections in children and infants, together with upper respiratory and gastrointestinal ones, with 30% recurrence rate reported within a year after initial UTI [2, 29]. Diagnosing pediatric UTIs may be difficult, because of communication difficulties in describing symptoms and vagueness of signs in small children; therefore, the definitive diagnosis of infection in children requires a positive urine culture [2].

In febrile patients with negative results on dipstick, microscopic, or automated urinalysis, urine culture is unnecessary if there is an alternative cause of the fever or inflammatory signs. However, if the dipstick and/or urinalysis are positive, confirmation of UTI by urine culture is mandatory [29]. In febrile children with signs of UTI (clinical signs, positive dipstick and/or positive microscopy, better if urine culture is available), antibiotic treatment should be initiated as soon as possible to eradicate the infection, prevent bacteremia, improve clinical outcome, diminish the likelihood of renal involvement during the acute phase of infection, and reduce the risk of immediate and long-term complications, including renal scarring and renal failure [29, 30].

## **4. Empirical treatment of UTIs**

The introduction of partial and complete automation in clinical diagnostic in the 2000s has allowed the management of large-scale sample volumes and workflows optimization still providing reli-

Large-scale systems, anyway, are expensive and require more dedicate space, equipment and more personnel competence, which makes them applicable to a large hospital setting, but are difficult to establish in a small hospital, or in a limited-resource setting (e.g., developing countries). These high-throughput culture-based instruments, moreover, remain relatively slow

The introduction of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) technology in microbiology has allowed rapid and reliable bacterial identification, featuring both high sensitivity and specificity, improving efficiency and saving consumables and labor [14, 15]. MALDI-TOF technique is usually coupled with culture of urine samples, to allow isolation of bacteria and therefore obtain pure cultures, which will undergo MALDI-TOF analysis after some sample treatment. Recently, extensive databases have been developed that include protein profiles of main microorganisms involved in infections; some studies have therefore investigated the possibility to apply MALDI-TOF analysis directly to urine samples, yielding promising results also when coupling such analysis with screening methods, such as automated microscopic urine sediment analysis [16, 17]. It must be considered, however, that such high-throughput technology has high installation and maintenance costs, and requires dedicated spaces, limiting its use in routine analyses to centralized laboratories. Moreover, the technique cannot currently identify two species of bacteria when present simultaneously, and cannot determine antibiotic susceptibility; thus,

Nevertheless, the occurrence of more than one bacterial strain in urine samples participating in the infection should not be overlooked. Polymicrobic infections are more often associated with catheterization and aging, reaching 10% incidence rates in the community and 30% in hospital setting among elderly people [19]. Bacterial strains recovered from polymicrobic infection show metabolic alterations and altered virulence traits, such as antibiotic resistance [19]. However, relationships between coinfecting strains are not yet fully understood [20], although some studies are exploiting such infections' mechanisms [21, 22]. As clinical laboratories tend to report cultures showing single or clearly predominant bacteria and will not routinely report occurrence of polymicrobic associations, unless significant numbers of each species are detected, quite a large portion of UTIs are not correctly diagnosed nor treated, threatening patient's safety [19, 23–25]. Therefore, an improvement of diagnosis and clinical pathways is needed in order to enhance not only detection of pathogens in urine, but also profiling the whole microflora and determining the antimicrobial susceptibility of individual components.

Even though the incidence of UTIs is higher in women [6], also related pathologies in men, such as epididymitis and prostatitis, may be caused by migration of pathogens from the urethra or

**3. When a urine culture followed by antibiogram is needed**

able results for both pathogen identification and antibiotic susceptibility testing [10, 13].

16 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

and are not amenable for point-of-care use [10].

traditional culture of urine samples is still necessary [18].

The gold standard for diagnosis and successful management of UTIs is to obtain identification and quantification of the infecting agents, along with antibiotic susceptibility assessment to direct a specific therapy [31]. The use of microbiological culture method is well established in the diagnosis of infectious diseases [32]; however, such reference method is time-consuming, requiring on average 24–48hours, thus laboratory results are not immediately available, especially at patient's presentation in the Emergency Department [32, 33]. For this reason, in order to avoid even serious complications (e.g., sepsis) and mitigate patients' discomfort, the initial treatment specified by international guidelines as first step in UTIs management is most often empirical [32]. Nevertheless, this empirical approach contributes to mis- and overuse of antibiotics [10], resulting from unnecessary or inappropriate antimicrobial therapy, participating in recent arise in bacterial resistance. In fact, for people with symptoms of UTI and bacteriuria the main aim of treatment is relief of symptoms, but in case of unsuccessful treatment it could cause some alteration of urinary tract microflora, leading to an increased risk of clinical adverse events, including infections with multi-drug-resistant organisms and the development of antibiotic-resistant UTIs [1]. Infections caused by multi-drug-resistant pathogens, such as extended-spectrum beta-lactamase (ESBL) and carbapenemase producing Gram-negative bacteria, methicillin-resistant *Staphylococcus aureus* (MRSA), and bacteria resistant to broad-spectrum antibiotics, such as fluoroquinolones and cephalosporins, are indeed increasingly recorded among UTIs and are the cause of a serious challenge to the public health system today [2, 10, 34].

Therefore, the development and implementation of new clinical tools in routine medical practice could help optimizing antibiotic administration, leading to a more prudent and rational use of antibiotics. A rapid screen may be a more practical approach to yield benefits for the

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

19

The advent of new innovative diagnostic devices for UTI management, complementary to the reference culture-based methods, may lead to a new deal improving routine practice. Immunocompromised patients (e.g., diabetes mellitus, chronic kidney disease, and kidney transplant) with UTIs could particularly benefit from such diagnostic improvements. Clinical diagnosis of UTIs in this category of patients is challenging, because causative pathogens may be slightly different to those in the general population, and because of patients' clinical picture complexity. Early diagnosis is imperative in this group, and treatment of UTIs should

**5. Alternative and non-culture-based methods for the detection of UTIs**

Because of the clinical importance of early UTI diagnosis, alternative rapid near-patient urine tests have been developed, such as urine dipsticks, which are widely used [31] in spite of their uncertain diagnostic accuracy [6]. The urine dipsticks test is commonly used for presumptive diagnosis of UTIs: it detects the presence of biochemical markers in urine samples which may be useful to establish the diagnosis of UTI [2]. Although many urine biomarkers for UTIs have recently been considered [45], markers that showed best results in diagnostic accuracy are nitrite and leukocyte esterase [6]. Although being cost-effective [46], such test shows low sensitivity that limits its clinical usefulness, [6] and analysis may be biased since a number of bacterial species are unreactive in these tests (e.g., no reduction of nitrates) [47, 48]. Furthermore, urine dipstick test does not detect bacteria, nor their concentration, which is essential to diagnose UTIs according to guidelines, and provides no information about antimicrobial susceptibility. Urine dipsticks are, anyway, cheap, easy to use, can be performed at doctor's office, in pharmacies or at home (even though urine dipstick test is not intended for self-diagnosis purposes [49], are available without prescription and provide results of easy interpretation within minutes. Among hospital tests routinely used for urine analysis, microscopy examination of urine sediment has since long time been used, also undergoing automation to improve results. Although sensitivity is high, specificity is too low for exclusive use in clinical settings. Moreover, such technique requires sample centrifugation, and experienced personnel is needed to avoid

Flow cytometry found applications in many fields, also including medical disciplines [50]. Automated platforms of urinary flow cytometry have been widely adopted by centralized laboratories [10]. Flow cytometry allows of rapid detection of bacteria, white blood cells, red blood cells, epithelial cells, casts, crystals, yeasts and spermatozoa. They offer the benefit of standardize urine sediment analysis and reduce the error associated with subjective interpretation of results [51]. Nevertheless, the poor quality of available studies was confirmed in a

patient, the physician, and the laboratory [43].

errors in microscopic examination [6].

be tailored according to individual patient characteristics [44].

The spread of antibiotic resistance is a threat to patients undergoing urological surgery in general [2], and multi-drug-resistant bacterial infections can limit the availability of effective treatment options, especially in low-income countries, rendering some UTIs difficult to treat and increasing healthcare costs [30].

This situation is generally promoted by several factors, including the overuse and misuse of antimicrobials in human and veterinary medicine and, indirectly, in agriculture. Measures to prevent and control the increase of antimicrobial resistance as well as the dissemination of resistance genes are crucial [35]. Prudent prescribing and rational use of antibiotics is a key component of action plans for reducing antimicrobial resistance [1, 2, 35, 36]. Antimicrobial stewardship programs have become a priority to optimize the outcome of prevention and treatment of infection while limiting overuse and misuse of antimicrobial agents [6], also following a systematic audit approach [37, 38]. In addition, non-antibiotic strategies are being explored [6]. There are many non-antimicrobial measures recommended, especially for recurrent UTIs [2, 28, 39, 40], but only a few results from well-designed studies are available for evidence-based recommendations [2, 41].

In general, the choice of antibiotics should be based, among other factors, upon identification and susceptibility pattern of the organism causing the UTI and the ecological collateral effects including selection of resistant bacteria by the chosen antimicrobial [2].

It must be considered, though, that the in vitro susceptibility of community-acquired uropathogens varies according to age and geographic region, and, as magnitude and variability of antimicrobial resistance patterns in the community grow, so does the need for continuous large-scale surveillance systems, in order to create databases linking epidemiological, clinical and laboratory data [42].

Therefore, the development and implementation of new clinical tools in routine medical practice could help optimizing antibiotic administration, leading to a more prudent and rational use of antibiotics. A rapid screen may be a more practical approach to yield benefits for the patient, the physician, and the laboratory [43].

direct a specific therapy [31]. The use of microbiological culture method is well established in the diagnosis of infectious diseases [32]; however, such reference method is time-consuming, requiring on average 24–48hours, thus laboratory results are not immediately available, especially at patient's presentation in the Emergency Department [32, 33]. For this reason, in order to avoid even serious complications (e.g., sepsis) and mitigate patients' discomfort, the initial treatment specified by international guidelines as first step in UTIs management is most often empirical [32]. Nevertheless, this empirical approach contributes to mis- and overuse of antibiotics [10], resulting from unnecessary or inappropriate antimicrobial therapy, participating in recent arise in bacterial resistance. In fact, for people with symptoms of UTI and bacteriuria the main aim of treatment is relief of symptoms, but in case of unsuccessful treatment it could cause some alteration of urinary tract microflora, leading to an increased risk of clinical adverse events, including infections with multi-drug-resistant organisms and the development of antibiotic-resistant UTIs [1]. Infections caused by multi-drug-resistant pathogens, such as extended-spectrum beta-lactamase (ESBL) and carbapenemase producing Gram-negative bacteria, methicillin-resistant *Staphylococcus aureus* (MRSA), and bacteria resistant to broad-spectrum antibiotics, such as fluoroquinolones and cephalosporins, are indeed increasingly recorded among UTIs and are the cause of a serious challenge to the public health

18 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The spread of antibiotic resistance is a threat to patients undergoing urological surgery in general [2], and multi-drug-resistant bacterial infections can limit the availability of effective treatment options, especially in low-income countries, rendering some UTIs difficult to treat

This situation is generally promoted by several factors, including the overuse and misuse of antimicrobials in human and veterinary medicine and, indirectly, in agriculture. Measures to prevent and control the increase of antimicrobial resistance as well as the dissemination of resistance genes are crucial [35]. Prudent prescribing and rational use of antibiotics is a key component of action plans for reducing antimicrobial resistance [1, 2, 35, 36]. Antimicrobial stewardship programs have become a priority to optimize the outcome of prevention and treatment of infection while limiting overuse and misuse of antimicrobial agents [6], also following a systematic audit approach [37, 38]. In addition, non-antibiotic strategies are being explored [6]. There are many non-antimicrobial measures recommended, especially for recurrent UTIs [2, 28, 39, 40], but only a few results from well-designed studies are available for

In general, the choice of antibiotics should be based, among other factors, upon identification and susceptibility pattern of the organism causing the UTI and the ecological collateral effects

It must be considered, though, that the in vitro susceptibility of community-acquired uropathogens varies according to age and geographic region, and, as magnitude and variability of antimicrobial resistance patterns in the community grow, so does the need for continuous large-scale surveillance systems, in order to create databases linking epidemiological, clinical

including selection of resistant bacteria by the chosen antimicrobial [2].

system today [2, 10, 34].

and increasing healthcare costs [30].

evidence-based recommendations [2, 41].

and laboratory data [42].

The advent of new innovative diagnostic devices for UTI management, complementary to the reference culture-based methods, may lead to a new deal improving routine practice. Immunocompromised patients (e.g., diabetes mellitus, chronic kidney disease, and kidney transplant) with UTIs could particularly benefit from such diagnostic improvements. Clinical diagnosis of UTIs in this category of patients is challenging, because causative pathogens may be slightly different to those in the general population, and because of patients' clinical picture complexity. Early diagnosis is imperative in this group, and treatment of UTIs should be tailored according to individual patient characteristics [44].

## **5. Alternative and non-culture-based methods for the detection of UTIs**

Because of the clinical importance of early UTI diagnosis, alternative rapid near-patient urine tests have been developed, such as urine dipsticks, which are widely used [31] in spite of their uncertain diagnostic accuracy [6]. The urine dipsticks test is commonly used for presumptive diagnosis of UTIs: it detects the presence of biochemical markers in urine samples which may be useful to establish the diagnosis of UTI [2]. Although many urine biomarkers for UTIs have recently been considered [45], markers that showed best results in diagnostic accuracy are nitrite and leukocyte esterase [6]. Although being cost-effective [46], such test shows low sensitivity that limits its clinical usefulness, [6] and analysis may be biased since a number of bacterial species are unreactive in these tests (e.g., no reduction of nitrates) [47, 48]. Furthermore, urine dipstick test does not detect bacteria, nor their concentration, which is essential to diagnose UTIs according to guidelines, and provides no information about antimicrobial susceptibility. Urine dipsticks are, anyway, cheap, easy to use, can be performed at doctor's office, in pharmacies or at home (even though urine dipstick test is not intended for self-diagnosis purposes [49], are available without prescription and provide results of easy interpretation within minutes.

Among hospital tests routinely used for urine analysis, microscopy examination of urine sediment has since long time been used, also undergoing automation to improve results. Although sensitivity is high, specificity is too low for exclusive use in clinical settings. Moreover, such technique requires sample centrifugation, and experienced personnel is needed to avoid errors in microscopic examination [6].

Flow cytometry found applications in many fields, also including medical disciplines [50]. Automated platforms of urinary flow cytometry have been widely adopted by centralized laboratories [10]. Flow cytometry allows of rapid detection of bacteria, white blood cells, red blood cells, epithelial cells, casts, crystals, yeasts and spermatozoa. They offer the benefit of standardize urine sediment analysis and reduce the error associated with subjective interpretation of results [51]. Nevertheless, the poor quality of available studies was confirmed in a recent meta-analysis, which also showed current low accuracy and specificity of such method that should not be used as the sole screening tool for UTIs ([51], and references therein).

Rapid and definitive near-the-patient diagnosis of UTI would have a favorable impact on its management [10]: a rapid turnaround of results could influence clinical decisions such as triage, referral, and decision to discharge the patient. Prompt clinical interventions could be provided by caregivers, meaning timely antibiotic treatment could be initiated and imprecise empirical treatment avoided [10, 55]. This would improve health outcome also providing diagnostics tools for limited-resource settings [55]. Point-of-care tests (POCTs) can provide considerable savings in health care costs by reducing the number of patients visiting health centers simultaneously improving the quality of life for patients by reducing their number of visits to health care facilities [55]. An early diagnosis based on POCTs can also enable clinicians to start antibiotic administration earlier and thereby increase chances of successfully treating the disease. In future, innovation through rapid and reliable POCTs is advisable, updating technologies to ensure efficient data management and simplify use by healthcare professionals, eventually lowering medical costs [55]. POCTs could allow a better screening and follow-up of patients not only by hospitals, but also by pharmacies and general practitioners, helping decentralize diagnosis and therefore reduce the workload of laboratories, with consequent reduction of costs related to urine analysis and management of UTIs and reduction of human errors leading to mix-ups of patient samples sent to off-site

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

21

Several POCT for UTIs have been developed and are currently commercially available. They can be distinguished in: (*i*) culture-based devices, (*ii*) (semi-)automated urine analyzers and (*iii*) enzymatic assays [56]. All culture-based devices allow semi-quantification of bacterial growth and evaluation of the infecting bacterial species. Most often, samples need to be cultured and appreciable bacterial growth can be achieved in not less than 16–24 hours. The (semi-)automated urine analyzers have the same read-out as the urine dipstick test and UTI diagnosis is based on the presence of markers such as nitrites and leukocytes. Although the human error involved in visual interpretation can be eliminated and results can be obtained in 1–2 minutes, these tests do not significantly improve current practice exhibiting very low sensitivity and limited positive

Biosensors offer a promising approach for improving molecular diagnostic in POC settings [10]. Biosensors are binary systems composed of a recognition and a transducer element that can generate a measurable proportional signal following binding of the target analyte to the recognition element (e.g., antibody, enzyme), which allows quantitative detection of a biological entity [10]. Even though biosensors technology has been applied successfully to the field of clinical diagnostic (e.g., blood glucose and pregnancy tests), no such tests have been implemented to date to improve routine diagnosis of UTIs [55]. Indeed, key features of biosensors, such as portability, rapidity, and cost-effectiveness in comparison with their macro-scale counterparts, could be crucial for the development of a POCT for UTI pathogens identification and antimicrobial susceptibility assessment. Nevertheless, considering the urine matrix, such biosensors would require multistep sample preparation with amplification/enrichment steps to improve target detection, and such biological matrix could impair sensor performance with its variations in biochemical parameters (e.g., inhibitors, non-specific binding). Moreover, such tests should have a multiplex approach to ensure identification of a broad

predictive value. The same problem has been reported for enzymatic assays [57–61].

laboratories [55].

Dipslide technology has been proposed to simplify traditional culture-based methods: the test allows the detection of bacteria in liquid matrices by observing growth on different agar media (e.g., CLED agar and MacConkey agar) after immersion into sample and following 24-hour incubation. Overall, despite being simple to use and cost-effective, dipslide technology can only be considered as a guide to support further analyses: such test shows low accuracy when compared to the reference culture method [6], and no reliable detection of <104 CFU/ml can be obtained [7]. For this reason, dipslides are currently unsuited to routine use in clinical setting with further studies required to determine the best combination of culture media [6].

For the short term, molecular biology techniques such as real-time PCR could be used to complement conventional culture-based methods for pathogens identification, especially with regard to shortening the time to obtain results, shortening the time to decision of antibiotic therapy [32]. However, this method is limited by the broadness of the panel of pathogens included in the test, and both sensibility and specificity are low when compared to urine culture. Moreover, such technology requires many steps for sample preparation and does not allow a viable count, also considering that up to now the clearance of bacterial DNA from urine is unclear. The need for quantification in UTI diagnosis should drive future developments of commercial real-time PCR pathogen detection tools to include a quantification option [32].

In addition, possible new routes have been explored aiming to develop new clinical tools to help rapidly identify uropathogens, such as: the detection of volatile organic compounds in urine by gas chromatography and mass spectrometry and following comparison between profiles using compounds databases [52]; the use of Raman and Surface Enhanced Raman Spectroscopy, which can provide quantification and identification of bacteria populations and possibly assessment of antibiotic susceptibility, although results are still preliminary and must be significantly expanded [12]; the use of impedance spectroscopy to detect ultra-low concentrations of *E. coli* in human urine and provide quantification for UTI diagnosis [53].

Although rapid, these technologies do not provide microbiological diagnosis nor susceptibility information, which remain the cornerstone of diagnosis, particularly in settings of complicated UTI [10].

In summary, laboratory urine culture remains the gold standard investigation for UTI diagnosis [6].

## **6. The importance of point-of-care tests in UTI diagnosis**

Some tests have been developed aiming to provide rapid and accurate diagnostic information to direct treatment decisions at the patient's bedside, which seem to have yielded good consent among practitioners [54].

Rapid and definitive near-the-patient diagnosis of UTI would have a favorable impact on its management [10]: a rapid turnaround of results could influence clinical decisions such as triage, referral, and decision to discharge the patient. Prompt clinical interventions could be provided by caregivers, meaning timely antibiotic treatment could be initiated and imprecise empirical treatment avoided [10, 55]. This would improve health outcome also providing diagnostics tools for limited-resource settings [55]. Point-of-care tests (POCTs) can provide considerable savings in health care costs by reducing the number of patients visiting health centers simultaneously improving the quality of life for patients by reducing their number of visits to health care facilities [55]. An early diagnosis based on POCTs can also enable clinicians to start antibiotic administration earlier and thereby increase chances of successfully treating the disease. In future, innovation through rapid and reliable POCTs is advisable, updating technologies to ensure efficient data management and simplify use by healthcare professionals, eventually lowering medical costs [55]. POCTs could allow a better screening and follow-up of patients not only by hospitals, but also by pharmacies and general practitioners, helping decentralize diagnosis and therefore reduce the workload of laboratories, with consequent reduction of costs related to urine analysis and management of UTIs and reduction of human errors leading to mix-ups of patient samples sent to off-site laboratories [55].

recent meta-analysis, which also showed current low accuracy and specificity of such method that should not be used as the sole screening tool for UTIs ([51], and references therein).

20 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Dipslide technology has been proposed to simplify traditional culture-based methods: the test allows the detection of bacteria in liquid matrices by observing growth on different agar media (e.g., CLED agar and MacConkey agar) after immersion into sample and following 24-hour incubation. Overall, despite being simple to use and cost-effective, dipslide technology can only be considered as a guide to support further analyses: such test shows low accuracy when compared to the reference culture method [6], and no reliable detection of <104 CFU/ml can be obtained [7]. For this reason, dipslides are currently unsuited to routine use in clinical setting

For the short term, molecular biology techniques such as real-time PCR could be used to complement conventional culture-based methods for pathogens identification, especially with regard to shortening the time to obtain results, shortening the time to decision of antibiotic therapy [32]. However, this method is limited by the broadness of the panel of pathogens included in the test, and both sensibility and specificity are low when compared to urine culture. Moreover, such technology requires many steps for sample preparation and does not allow a viable count, also considering that up to now the clearance of bacterial DNA from urine is unclear. The need for quantification in UTI diagnosis should drive future developments of commercial real-time PCR pathogen detection tools to include a quantification

In addition, possible new routes have been explored aiming to develop new clinical tools to help rapidly identify uropathogens, such as: the detection of volatile organic compounds in urine by gas chromatography and mass spectrometry and following comparison between profiles using compounds databases [52]; the use of Raman and Surface Enhanced Raman Spectroscopy, which can provide quantification and identification of bacteria populations and possibly assessment of antibiotic susceptibility, although results are still preliminary and must be significantly expanded [12]; the use of impedance spectroscopy to detect ultra-low concentrations of *E. coli* in human urine and provide quantification for UTI diagnosis [53].

Although rapid, these technologies do not provide microbiological diagnosis nor susceptibility information, which remain the cornerstone of diagnosis, particularly in settings of com-

In summary, laboratory urine culture remains the gold standard investigation for UTI diag-

Some tests have been developed aiming to provide rapid and accurate diagnostic information to direct treatment decisions at the patient's bedside, which seem to have yielded good

**6. The importance of point-of-care tests in UTI diagnosis**

with further studies required to determine the best combination of culture media [6].

option [32].

plicated UTI [10].

consent among practitioners [54].

nosis [6].

Several POCT for UTIs have been developed and are currently commercially available. They can be distinguished in: (*i*) culture-based devices, (*ii*) (semi-)automated urine analyzers and (*iii*) enzymatic assays [56]. All culture-based devices allow semi-quantification of bacterial growth and evaluation of the infecting bacterial species. Most often, samples need to be cultured and appreciable bacterial growth can be achieved in not less than 16–24 hours. The (semi-)automated urine analyzers have the same read-out as the urine dipstick test and UTI diagnosis is based on the presence of markers such as nitrites and leukocytes. Although the human error involved in visual interpretation can be eliminated and results can be obtained in 1–2 minutes, these tests do not significantly improve current practice exhibiting very low sensitivity and limited positive predictive value. The same problem has been reported for enzymatic assays [57–61].

Biosensors offer a promising approach for improving molecular diagnostic in POC settings [10]. Biosensors are binary systems composed of a recognition and a transducer element that can generate a measurable proportional signal following binding of the target analyte to the recognition element (e.g., antibody, enzyme), which allows quantitative detection of a biological entity [10]. Even though biosensors technology has been applied successfully to the field of clinical diagnostic (e.g., blood glucose and pregnancy tests), no such tests have been implemented to date to improve routine diagnosis of UTIs [55]. Indeed, key features of biosensors, such as portability, rapidity, and cost-effectiveness in comparison with their macro-scale counterparts, could be crucial for the development of a POCT for UTI pathogens identification and antimicrobial susceptibility assessment. Nevertheless, considering the urine matrix, such biosensors would require multistep sample preparation with amplification/enrichment steps to improve target detection, and such biological matrix could impair sensor performance with its variations in biochemical parameters (e.g., inhibitors, non-specific binding). Moreover, such tests should have a multiplex approach to ensure identification of a broad panel of pathogens in different clinical scenarios, and should provide antimicrobial susceptibility testing to drive treatment, but genetic non-culture based approaches are limited by the fast evolution rate of defense mechanisms among bacteria. Biosensors POCTs could anyway complement reference methods helping saving resources in terms of materials, money and time, because rapid, simple and cost-effective tests could optimize further analyses therefore reducing the burden on laboratories [10].

The Micro Biological Survey (MBS) POCT "UTI CHECK" appears to hold good promise for early detection and antimicrobial susceptibility profiling of uropathogens. The MBS method allows rapid and accurate bacterial quantification through an automated colorimetric culture-based test; urine samples are inoculated into disposable ready-to-use reaction vials, which color will change thanks to redox indicators following bacterial growth after incubation (see **Figure 1**). Results of preliminary *in vitro* validation studies [62, 63] showed that the results obtained with this method are comparable to the reference culture-based methods.

Such findings encouraged further research in hospital settings, and clinical trials have been carried out [31] in which the efficacy of the MBS POCT was compared to the reference method, used in hospital routine, and other methods, such as urine dipsticks: the MBS POCT

**Figure 1. MBS "UTI CHECK."** MBS "UTI CHECK" is an automated colorimetric culture-based test. It is composed by mono-use, disposable and ready-to-use reaction vials (right) in which 1 ml of urine can be inoculated without any preliminary treatment. Up to eight urine-inoculated reaction vials can be independently allocated in an automatic thermostated optical reader (left) that it is able to detect color change induced by the growth of bacteria and automatically correlates the time required for color change with the number of bacteria present in the urine samples. Different vials contain selected antibiotics and the occurrence of the color change in the presence of antibiotics indicates antibiotic resistance of bacteria present into the urine sample.

**Product**

**Manufacturer/**

**Description of** 

**Analysis** 

**Additional** 

**Positive result** 

**Method** 

**Number** 

**Threshold for** 

**Accuracy**

**Sensitivity** 

**Specificity** 

**Ref**

**(%) (95%** 

**(%) (95%** 

**CI)**

**CI)**

**principle**

**of samples** 

**significant** 

**tested;**

**growth**

**Test** 

**population**

**equipment** 

**outcomes**

**required**

**location**

FLEXICULT™

Statens Serum

Chromogenic

24 hours

Incubator

Semiquantification

Microbial

N = 200/124

≥105 CFU/ml

—

87.0%

83.2%

[23]

(67.9–95.5)

(74.7–89.2)

culture and

(outpatient

susceptibility

setting)/76

(secondary

care setting)

of bacterial

growth,

testing

evaluation of

the species

present, and

assessment of

sensitivity to

the antibiotics

in each of the

plate segments

Uricult Trio

Orion

Plastic slide

16–24 hours

Incubator

Semiquantification

Microbial

198 (pediatric

≥104 CFU/ml

—

68%

82%

[26]

patients aged

0–7)

culture

Diagnostics/

with two

when

opposing agar

incubated

of bacterial

growth,

evaluation of

the species

present

434 (primary

≥103 to

88%

88%

90%

[27]

Management of Urinary Tract Infections: Problems and Possible Solutions

health care

≥105 CFU/ml

setting)

for doubtful

uropathogens

media

at 36.8 °C

or 1–3 days

at room

temperature

DipStreak

Novamed/

Plastic paddle

18–24 hours

Incubator

Semiquantification

Microbial

N = 1070 (251

>105 CFU/

98%

95.7%

99.2%

[28]

http://dx.doi.org/10.5772/intechopen.71588

23

culture

hospitalized

ml (single

patients

organism +

mixed culture)

and 819

outpatients)

of bacterial

growth,

evaluation of

the species

present

with two

opposing agar

media, housed

in a closed

transparent

plastic tube

(Chromostreak)

Israel

Finland

agar plate with

6 segments – 5

evaluating

anti-biotic

sensitivities

and 1 control

segment

Institut

Diagnostica/

Denmark

**device**

**time**


panel of pathogens in different clinical scenarios, and should provide antimicrobial susceptibility testing to drive treatment, but genetic non-culture based approaches are limited by the fast evolution rate of defense mechanisms among bacteria. Biosensors POCTs could anyway complement reference methods helping saving resources in terms of materials, money and time, because rapid, simple and cost-effective tests could optimize further analyses therefore

22 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The Micro Biological Survey (MBS) POCT "UTI CHECK" appears to hold good promise for early detection and antimicrobial susceptibility profiling of uropathogens. The MBS method allows rapid and accurate bacterial quantification through an automated colorimetric culture-based test; urine samples are inoculated into disposable ready-to-use reaction vials, which color will change thanks to redox indicators following bacterial growth after incubation (see **Figure 1**). Results of preliminary *in vitro* validation studies [62, 63] showed that the results obtained with this method are comparable to the reference culture-based

Such findings encouraged further research in hospital settings, and clinical trials have been carried out [31] in which the efficacy of the MBS POCT was compared to the reference method, used in hospital routine, and other methods, such as urine dipsticks: the MBS POCT

**Figure 1. MBS "UTI CHECK."** MBS "UTI CHECK" is an automated colorimetric culture-based test. It is composed by mono-use, disposable and ready-to-use reaction vials (right) in which 1 ml of urine can be inoculated without any preliminary treatment. Up to eight urine-inoculated reaction vials can be independently allocated in an automatic thermostated optical reader (left) that it is able to detect color change induced by the growth of bacteria and automatically correlates the time required for color change with the number of bacteria present in the urine samples. Different vials contain selected antibiotics and the occurrence of the color change in the presence of antibiotics indicates antibiotic

reducing the burden on laboratories [10].

resistance of bacteria present into the urine sample.

methods.

Management of Urinary Tract Infections: Problems and Possible Solutions http://dx.doi.org/10.5772/intechopen.71588 23


**Table 1.** Features of main POCTs for UTI diagnosis. showed high accuracy, sensitivity and specificity, comparable to the reference method's and higher than urine dipsticks' [31]. Although not providing bacterial identification, MBS "UTI CHECK" allows bacteria detection and quantification in urine samples. Preliminary results showed that this POCT can provide uropathogens' susceptibility pattern to a panel of antibiotics. The analytical time required for UTI diagnosis is usually less than 3 hours (up to

Management of Urinary Tract Infections: Problems and Possible Solutions

susceptibility assessment is obtained in less than 10 hours, which could guide downstream medical decisions with crucial information within few hours. Notably, this method features cost-effectiveness, user-friendliness, portability, easy interpretation of results, which all can lead to successful use at the patient's bedside [31]. The MBS point-of-care testing device could be developed into a valuable aid for the management of UTIs, possibly addressing more precise diagnosis and appropriate therapy also proving useful in treatment outcome evaluation. Features of main POCTs available on market, including MBS "UTI CHECK," are summarized

To date, hospital settings rely mainly on laboratory analysis following urine culture reference method; this approach requires a considerable effort in terms of workload and up to 3 days to achieve results. Furthermore, it can lead to unnecessary antimicrobial overuse which ulti-

The unnecessary use of antibiotic treatment may be minimized following two roads: on one hand by the establishment of antibiotic stewardship programs which require healthcare staff involvement in regular training in best use of antimicrobial agents for an improved adherence to local, national or international guidelines and regular consultation with infectious diseases physicians, with audit [6]; on the other hand by improving diagnostic pathways [1], possibly relying on use of POCTs that feature incorporation of pathogen identification with antimicrobial susceptibility testing, sufficiently versatile to be adaptable for different pathogen profiles in different clinical scenarios [10]. The advent of accurate and robust POCTs could allow a more rational screening before treatment or admission and to improve follow-up of patients for treatment outcome evaluation and for monitoring of antimicrobial prescribing

Such approach could ultimately lead to treatment customization according to individual patients' characteristics through fast antibiotic susceptibility testing results [44], with the ulti-

Prof. Vincenzo Ziparo (Istituto Dermopatico dell'Immacolata – IRCCS, Rome, Italy) is grate-

CFU/ml) and antimicrobial

http://dx.doi.org/10.5772/intechopen.71588

25

5–6 hours when the bacterial load is equal or less than 1 × 105

mately promotes the emergence of resistance [31].

performance and local pathogen resistance profiles [6].

mate aim of improving patients' welfare and reduce healthcare costs.

in **Table 1**.

**7. Conclusions**

**Acknowledgements**

fully acknowledged for helpful discussions.

showed high accuracy, sensitivity and specificity, comparable to the reference method's and higher than urine dipsticks' [31]. Although not providing bacterial identification, MBS "UTI CHECK" allows bacteria detection and quantification in urine samples. Preliminary results showed that this POCT can provide uropathogens' susceptibility pattern to a panel of antibiotics. The analytical time required for UTI diagnosis is usually less than 3 hours (up to 5–6 hours when the bacterial load is equal or less than 1 × 105 CFU/ml) and antimicrobial susceptibility assessment is obtained in less than 10 hours, which could guide downstream medical decisions with crucial information within few hours. Notably, this method features cost-effectiveness, user-friendliness, portability, easy interpretation of results, which all can lead to successful use at the patient's bedside [31]. The MBS point-of-care testing device could be developed into a valuable aid for the management of UTIs, possibly addressing more precise diagnosis and appropriate therapy also proving useful in treatment outcome evaluation. Features of main POCTs available on market, including MBS "UTI CHECK," are summarized in **Table 1**.

## **7. Conclusions**

To date, hospital settings rely mainly on laboratory analysis following urine culture reference method; this approach requires a considerable effort in terms of workload and up to 3 days to achieve results. Furthermore, it can lead to unnecessary antimicrobial overuse which ultimately promotes the emergence of resistance [31].

The unnecessary use of antibiotic treatment may be minimized following two roads: on one hand by the establishment of antibiotic stewardship programs which require healthcare staff involvement in regular training in best use of antimicrobial agents for an improved adherence to local, national or international guidelines and regular consultation with infectious diseases physicians, with audit [6]; on the other hand by improving diagnostic pathways [1], possibly relying on use of POCTs that feature incorporation of pathogen identification with antimicrobial susceptibility testing, sufficiently versatile to be adaptable for different pathogen profiles in different clinical scenarios [10]. The advent of accurate and robust POCTs could allow a more rational screening before treatment or admission and to improve follow-up of patients for treatment outcome evaluation and for monitoring of antimicrobial prescribing performance and local pathogen resistance profiles [6].

Such approach could ultimately lead to treatment customization according to individual patients' characteristics through fast antibiotic susceptibility testing results [44], with the ultimate aim of improving patients' welfare and reduce healthcare costs.

## **Acknowledgements**

**Product** DiaSlide

Novamed/

Hinged plastic

24 hours

Incubator

Semiquantification

Microbial

473

≥104 CFU/ml

—

98.3%

97.5%

[29]

culture

(prescreened

hospital urine

specimens

using

UriScreen)

of bacterial

growth

case containing

two opposing

agar media

onSite

Trek

Hinged plastic

Not specified

Incubator

Semiquantification

Microbial

culture

of bacterial

growth,

evaluation of

the species

present

MBS

MBS srl/Italy

Mono-use

3–5 hours

MBS

Semiquantification

Measure of

N = 223

≥105 CFU/

99%

92.6%

100%

[17]

24 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

(75.7–99.1)

(94.9–100)

the catalytic

(emergency

ml (single

department)

organism +

mixed culture)

activity of

redox enzymes

Multireader

of bacterial

load,

assessment

of bacteria

of sensitivity

to selected

antibiotics

**Table 1.**

Features of main POCTs for UTI diagnosis.

disposable

vials for

chromogenic

analysis

UTI CHECK

case containing

two opposing

agar media

Diagnostics

System/USA

Israel

**Manufacturer/**

**Description of** 

**Analysis** 

**Additional** 

**Positive result** 

**Method** 

**Number** 

**Threshold for** 

**Accuracy**

**Sensitivity** 

**Specificity** 

**Ref**

**(%) (95%** 

**(%) (95%** 

**CI)**

**CI)**

**principle**

**of samples** 

**significant** 

**tested;**

**growth**

**Test** 

**population**

**equipment** 

**outcomes**

**required**

**location**

**device**

**time**

Prof. Vincenzo Ziparo (Istituto Dermopatico dell'Immacolata – IRCCS, Rome, Italy) is gratefully acknowledged for helpful discussions.

## **Author details**

Lorenza Murgia1 , Ottavia Stalio<sup>1</sup> , Alyexandra Arienzo<sup>1</sup> , Valeria Ferrante2 , Valentina Cellitti<sup>2</sup> , Salvatore Di Somma3 , Paolo Visca1 and Giovanni Antonini1,2\*

[9] European Confederation of Laboratory Medicine. European urinalysis guidelines. Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum. 2000;**231**:1-86

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

27

[10] Mach KE, Wong PK, Liao JC. Biosensor diagnosis of urinary tract infections: A path to

[11] Clinical and Laboratory Standards Institute. Supplemental Tables. Performance Standards for Antimicrobial Susceptibility Testing; Fifteenth Informational Supplement. CLSI

[12] Kastanos E, Kyriakides A, Hadjigeorgiou K, Pitris C. A novel method for bacterial UTI diagnosis using Raman Spectroscopy. International Journal of Spectroscopy. 2012;

[13] Croxatto A, Prod'hom G, Faverjon F, Rochais Y, Greub G. Laboratory automation in clinical bacteriology: what system to choose? Clinical Microbiology and Infection 2016;

[14] Gaillot O, Blondiaux N, Loïez C, Wallet F, Lemaître N, Herwegh S, Courcol RJ. Costeffectiveness of switch to matrix-assisted laser desorption ionization–time of flight mass spectrometry for routine bacterial identification. Journal of Clinical Microbiology.

[15] Neville SA, LeCordier A, Ziochos H, Chater MJ, Gosbell IB, Maley MW, van Hal SJ. Utility of matrix-assisted laser desorption ionization–time of flight mass spectrometry following introduction for routine laboratory bacterial identification. Journal of Clinical

[16] Ferreira L, Sánchez-Juanes F, González-Ávila M, Cembrero-Fuciños D, Herrero-Hernández A, Manuel González-Buitrago J, Muñoz-Bellido JL. Direct identification of urinary tract pathogens from urine samples by matrix-assisted laser desorption ionization–time of flight mass spectrometry. Journal of Clinical Microbiology. 2010;**48**(6):2110-

[17] Íñigo M, Coello A, Fernández-Rivas G, Rivaya B, Hidalgo J, Quesada MD, Ausina V. Direct identification of urinary tract pathogens from urine samples, combining urine screening methods and matrix-assisted laser desorption ionization–time of flight mass spectrometry. Journal of Clinical Microbiology. 2016;**54**(4):988-993. DOI: 10.1128/JCM.02832-15 [18] Wang X-H, Zhang G, Fan Y-Y, Yang X, Sui W-J, Lu X-X. Direct identification of bacteria causing urinary tract infections by combining matrix-assisted laser desorption ionization–time of flight mass spectrometry with UF-1000i urine flow cytometry. Journal of Microbiological Methods. 2013;**92**(3):231-235. DOI: https://doi.org/10.1016/j.

[19] Croxall G, Weston V, Joseph S, Manning G, Cheetham P, McNally A. Increased human pathogenic potential of *Escherichia coli* from polymicrobial urinary tract infections in comparison to isolates from monomicrobial culture samples. Journal of Medical Micro-

biology. 2011;**60**:102-109. DOI: 10.1099/jmm.0.020602-0

better treatment? Trends in Pharmacological Sciences. 2011;**32**(6):330-336

Publication M100-S15, M2-A8 and M7-A6. Pennsylvania: CLSI; 2005

Article ID: 195317, 13 pages. DOI: 10.1155/2012/195317

2011;**39**(12):4412. DOI: 10.1128/JCM.05429-11

2115. DOI: 10.1128/JCM.02215-09

mimet.2012.12.016

**22**:217-235. DOI: http://dx.doi.org/10.1016/j.cmi.2015.09.030

Microbiology 2011;**49**(8):2980-2984. DOI:10.1128/JCM.00431-11

\*Address all correspondence to: giovanni.antonini@uniroma3.it

1 Department of Sciences, Roma Tre University, Rome, Italy

2 Interuniversity Consortium "Biostructures and Biosystems National Institute", Rome, Italy

3 Emergency Medicine, Department of Medical-Surgery Sciences and Translational Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy

## **References**


[9] European Confederation of Laboratory Medicine. European urinalysis guidelines. Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum. 2000;**231**:1-86

**Author details**

Lorenza Murgia1

**References**

[Accessed 31st October 2017]

& Organisation (CHSEO); 2014

DOI: 10.3238/arztebl.2010.0361

Available from: http://www.sign.ac.uk

uroweb.org/ [Accessed 31st October 2017]

Salvatore Di Somma3

, Ottavia Stalio<sup>1</sup>

, Paolo Visca1

\*Address all correspondence to: giovanni.antonini@uniroma3.it

26 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

1 Department of Sciences, Roma Tre University, Rome, Italy

, Alyexandra Arienzo<sup>1</sup>

and Giovanni Antonini1,2\*

2 Interuniversity Consortium "Biostructures and Biosystems National Institute", Rome, Italy

[1] National Institute for Health and Care Excellence. Urinary Tract Infections in Adults –

[2] Grabe M, Bartoletti R, Bjerklund Johansen TE, Cai T, Çek M, Köves B, Naber KG, Pickard RS, Tenke P, Wagenlehner F, Wullt B. Guidelines on urological infections.

[3] Grabe M, Bartoletti R, Bjerklund Johansen TE, Çek HM, Pickard RS, Tenke P, Wagenlehner F, Wullt B. Guidelines on urological infections. 2014. Available from: http://uroweb.org/

[4] Wittenberg R, Sharpin L, McCormick B, Hurst J. Understanding emergency hospital admissions of older people. Report No. 6. Oxford: Centre for Health Service Economics

[5] Scottish Intercollegiate Guidelines Network (SIGN). Management of Suspected Bacterial Urinary Tract Infection in Adults. Edinburgh: SIGN (SIGN Publication No. 88); 2012

[6] Pickard R, Bartoletti R, Bjerklund-Johansen TE, Bonkat G, Bruyère F, Çek M, Grabe M, Tenke P, Wagenlehner F, Wullt B, Guidelines Associates: Cai T, Köves B, Pilatz A, Pradere B, Veeratterapillay R. Guidelines on urological infections. 2016. Available from: http://

[7] Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers-Pradier E. The diagnosis of urinary tract infection. Deutsches Ärzteblatt International. 2010;**107**(21):361-367.

[8] Takhar SS, Moran GJ. Diagnosis and management of urinary tract infection in the emergency department and outpatient settings. Infectious Disease Clinics of North America

2014;**28**:33-48. DOI: http://dx.doi.Org/10.1016/j.idc.2013.10.003

3 Emergency Medicine, Department of Medical-Surgery Sciences and Translational

Quality Standard. 2015. Available from: http://nice.org.uk/guidance/qs90

2015. Available from: http://uroweb.org/ [Accessed 31st October 2017]

Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy

, Valeria Ferrante2

, Valentina Cellitti<sup>2</sup>

,


[20] Mach KE, CB D, Phull H, Haake DA, Shih M-C, Baron EJ, Liao JC. Multiplex pathogen identification for polymicrobial urinary tract infections using biosensor technology: A prospective clinical study. The Journal of Urology. 2009;**182**:2735-2741. DOI: 10.1016/j. juro.2009.08.028

[32] Lehmann LE, Hauser S, Malinka T, et al. Rapid qualitative urinary tract infection pathogen identification by SeptiFast® real-time PCR. Bereswill S, ed. PLoS One 2011;**6**(2):e17146.

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

29

[33] Stalenhoefa JE, van Dissel JT, van Nieuwkoop C. Febrile urinary tract infection in the emergency room. Current Opinion in Infectious Diseases 2015;**28**:106-111. DOI: 10.1097/

[34] Routh JC, et al. Increasing prevalence and associated risk factors for methicillin resistant Staphylococcus aureus bacteriuria. The Journal of Urology. 2009;**181**:1694-1698

[35] Linhares I, Raposo T, Rodrigues A, Almeida A. Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria. BioMed Research International.

[36] Mandal J, Acharya NS, Buddhapriya D, Parija SC. Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant *Esche-*

[37] Malmartel A, Dutron M, Ghasarossian C. Tracking unnecessary negative urinalyses to reduce healthcare costs: a transversal study. European Journal of Clinical Microbiology

[38] Sobolewski K, Costello J, Miller L. Development of antibiotic stewardship practices targeting urinary tract infections in a hospital with consultant-based infectious disease ser-

[39] Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: a review. Clinical Therapeutics. 2008;**30**(3):453-468. DOI: 10.1016/j.clinthera.

[40] Tsai CC, Lai TM, Lin PP, Hsieh YM. Evaluation of lactic acid bacteria isolated from fermented plant products for antagonistic activity against urinary tract pathogen Staphylococcus sapro-

[41] Beerepoot MA, et al. Nonantibiotic prophylaxis for recurrent urinary tract infections: A systematic review and meta-analysis of randomized controlled trials. The Journal of

[42] Gupta K, Sahm DF, Mayfield D, Stamm WE. Antimicrobial resistance among uropathogens that cause community-acquired urinary tract infections in women: A nationwide analysis. Clinical Infectious Diseases. 2001;**33**(1):89-94. DOI: https://doi.org/10.1086/320880

[43] Pezzlo M. Detection of urinary tract infections by rapid methods. Clinical Microbiology

[44] Tandogdu Z, Cai T, Koves B, Wagenlehner F, Bjerklund-Johansen TE. Urinary tract infections in immunocompromised patients with diabetes, chronic kidney disease, and kidney transplant. European Urology Focus. 2016;**2**(4):394-399. DOI: 10.1016/j.euf.2016.08.006

Reviews. 1988;**1**(3):268-280. DOI: 10.1128/CMR.1.3.268

phyticus. Probiotics Antimicrob Proteins. 2017. DOI: 10.1007/s12602-017-9302-x

& Infectious Diseases. 2017;**36**(9):1559-1563. DOI: 10.1007/s10096-017-2968-x

2015; Article ID: 354084, 11 pages. DOI: 10.1155/2015/354084

vices. Physical Therapy. 2017;**42**(8):527-532

Urology. 2013;**190**(6):1981-1989

2008.03.013

*richia coli*. The Indian Journal of Medical Research. 2012;**136**(5):842-849

DOI:10.1371/journal.pone.0017146

QCO.0000000000000121


[32] Lehmann LE, Hauser S, Malinka T, et al. Rapid qualitative urinary tract infection pathogen identification by SeptiFast® real-time PCR. Bereswill S, ed. PLoS One 2011;**6**(2):e17146. DOI:10.1371/journal.pone.0017146

[20] Mach KE, CB D, Phull H, Haake DA, Shih M-C, Baron EJ, Liao JC. Multiplex pathogen identification for polymicrobial urinary tract infections using biosensor technology: A prospective clinical study. The Journal of Urology. 2009;**182**:2735-2741. DOI: 10.1016/j.

[21] Alteri CJ, Mobley HLT. Metabolism and fitness of urinary tract pathogens. Microbiology

[22] Armbruster CE, Smith SN, Johnson AO, DeOrnellas V, Eaton KA, Yep A, Mody L, Wu W, Mobley HLT. The pathogenic potential of Proteus mirabilis is enhanced by other uropathogens during polymicrobial urinary tract infection. Infection and Immunity. 2017;

[23] Alteri CJ, Himpsl SD, Mobley HLT. Preferential use of central metabolism in vivo reveals a nutritional basis for polymicrobial infection. PLoS Pathogens. 2015;**11**(1):e1004601.

[24] Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiology Spectrum. 2016;**4**(2).

[25] Mann R, Mediati DG, Duggin IG, Harry EJ, Bottomley AL. Metabolic adaptations of uropathogenic *E. coli* in the urinary tract. Frontiers in Cellular and Infection Microbiology.

[26] Zanella MC, Schoofs F, Huttner B, Huttner A. Infections urinaires basses non associées aux sondes urinaires chez l'homme. Urétrite, cystite et prostatite. Revue Médicale Suisse.

[27] Wang A, Nizran P, Malone MA, Riley T. Urinary tract infections. Primary Care: Clinics in Office Practice, DOI. 2013;**40**:687-706 http://dx.doi.Org/10.1016/j.pop.2013.06.005 [28] Osamwonyi B, Foley C. Management of recurrent urinary tract infections in adults. Surgery (Oxford). 2017;**35**(6):299-305 ISSN 0263-9319. DOI: http://dx.doi.org/10.1016/j.

[29] Stein R, et al. Urinary tract infections in children: EAU/ESPU guidelines. European

[30] Bryce A, Hay AD, Lane IF, Thornton HV, Wootton M, Costelloe C. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by *Escherichia coli* and association with routine use of antibiotics in primary care: systematic review and metaanalysis. British Medical Journal 2016;352:i939. DOI: http://dx.doi.org/10.1136/bmj.i939

[31] Arienzo A, Cellitti V, Ferrante V, Losito F, Stalio O, Cristofano F, Marino R, Magrini L, Santino I, Mari A, Visca P, Di Somma S and Antonini G on behalf of GREAT Network A pilot clinical trial on a new point-of-care test for the diagnosis and fast management of urinary tract infections in the emergency department. International Journal of Clinical & Medical Microbiology. 2016;**1**:107. DOI: http://dx.doi.org/10.15344/ijcmm/2016/107

Spectrum. 2015;**3**(3). DOI: 10.1128/microbiolspec.MBP-0016-2015

28 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

juro.2009.08.028

**85**:e00808

2017;**13**:808-814

mpsur.2017.03.004

Urology. 2015;**67**(3):546-558

DOI: 10.1371/journal.ppat.1004601

DOI: 10.1128/microbiolspec.UTI-0012-2012

2017;**7**:241. DOI: 10.3389/fcimb.2017.00241


[45] Masajtis-Zagajewska A, Nowicki M. New markers of urinary tract infection. Clinica Chimica Acta. 2017;**471**:286-291. DOI: 10.1016/j.cca.2017.06.003

[59] Holm A, Cordoba G, Sørensen TM, Jessen LR, Siersma V, Bjerrum L. Point of care susceptibility testing in primary care – does it lead to a more appropriate prescription of antibiotics in patients with uncomplicated urinary tract infections? Protocol for a randomized controlled trial. BMC Family Practice. 2015;**16**:106. DOI: 10.1186/s12875-015-0322-x [60] Schot MJC, Van Delft S, Kooijman-Buiting AMJ, de Wit NJ, Hopstaken RM. Analytical performance, agreement and user-friendliness of six point-of-care testing urine analysers for urinary tract infection in general practice. BMJ Open 2015;5(5):e006857. DOI:

Management of Urinary Tract Infections: Problems and Possible Solutions

http://dx.doi.org/10.5772/intechopen.71588

31

[61] National Institute for Health Research (NIHR), Diagnostic Evidence Cooperative Oxford. Point-of-Care Testing for Urinary Tract Infections. Horizon. Scan Report num-

[62] Bottini G, Losito F, Arienzo A, Priolisi FR, Mari A, Visca P, Antonini G. A new method for microbiological analysis that could be used for point-of-care testing (POCT). The Open Emergency Medicine Journal. 2013;**5**:13-15. DOI: 10.2174/1876542401305010013 [63] Arienzo A, Losito F, Bottini G, Priolisi FR, Mari A, Visca P, Antonini G. A new device for the prompt diagnosis of urinary tract infections. Clinical Chemistry and Laboratory

Medicine. 2014;**52**(10):1507-1511. DOI: 10.1515/cclm-2014-0294

10.1136/bmjopen-2014-006857

ber: 0045, 2016


[59] Holm A, Cordoba G, Sørensen TM, Jessen LR, Siersma V, Bjerrum L. Point of care susceptibility testing in primary care – does it lead to a more appropriate prescription of antibiotics in patients with uncomplicated urinary tract infections? Protocol for a randomized controlled trial. BMC Family Practice. 2015;**16**:106. DOI: 10.1186/s12875-015-0322-x

[45] Masajtis-Zagajewska A, Nowicki M. New markers of urinary tract infection. Clinica

[46] Turner D, Little P, Raftery J, Turner S, Smith H, Rumsby K, Mullee M. Cost effectiveness of management strategies for urinary tract infections: results from randomised con-

[47] Demilie T, Beyene G, Melaku S, Tsegaye W. Diagnostic accuracy of rapid urine dipstick test to predict urinary tract infection among pregnant women in Felege Hiwot Referral Hospital, Bahir Dar, North West Ethiopia. BMC Research Notes. 2014;**7**:481.

[48] Mambatta AK, Jayarajan J, Rashme VL, Harini S, Menon S, Kuppusamy J. Reliability of dipstick assay in predicting urinary tract infection. Journal of Family Medicine and

[49] Understanding Urine Tests, PubMed Health [Internet]. Dec 30, 2016. Available from: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072534/ [Accessed Aug 20, 2017]

[50] Jarzembowski T, Daca A, Witkowski J, Rutkowski B, Gołębiewska J, Dębska-Ślizień A. Changes of PBP5 gene expression in enterococcal isolates from renal transplantation recipients. BioMed Research International. 2013;**2013**:687156. DOI: 10.1155/2013/687156

[51] Shang Y, et al. Systematic review and meta-analysis of flow cytometry in urinary tract infection screening. Clinica Chimica Acta. 2013;**424**:90-95. DOI: 10.1016/j.cca.2013.05.014

[52] Johnson EU, Probert CSJ, Persad R, Khalid T, Ratcliffe N. Urinary volatile organic compounds: Novel approach to rapid UTI diagnosis. European Urology Supplements. 2014;

[53] Settu K, Chen C-J, Liu J-T, Chen C-L, Tsai J-Z. Impedimetric method for measuring ultralow concentrations in human urine. Biosensors and Bioelectronics. 2015;**66**:244-250 ISSN

[54] Howick J, Cals JWL, Jones C, et al. Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and

[55] Srinivasan B, Tung S. Development and applications of portable biosensors. Journal of Laboratory Automation. 2015;**20**(4):365-389. DOI: 10.1177/2211068215581349

[56] Baerheim A. Empirical treatment of uncomplicated cystitis. Scandinavian Journal of

[57] Waisman Y, Zerem E, Amir L, Mimouni M. The validity of the uriscreen test for early

[58] Bongard E, Frimodt-Møller N, Gal M, Wootton M, Howe R, Francis N, Goossens H, Butler CC. Analytic laboratory performance of a point of care urine culture kit for diagnosis and antibiotic susceptibility testing. European Journal of Clinical Microbiology &

the USA. BMJ Open. 2014;**4**(8):e005611. DOI: 10.1136/ bmjopen-2014-005611

Primary Health Care. 2012;**30**(1):1-2. DOI: 10.3109/02813432.2012.649629

detection of urinary tract infection in children. Pediatrics. 1999;**104**(4):e41

Infectious Diseases. 2015;**34**:2111-2119. DOI: 10.1007/s10096-015-2460-4

trolled trial. British Medical Journal. 2010;**340**:c346. DOI: 10.1136/bmj.c346

Chimica Acta. 2017;**471**:286-291. DOI: 10.1016/j.cca.2017.06.003

30 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Primary Care. 2015;**4**(2):265-268. DOI: 10.4103/2249-4863.154672

0956-5663. DOI: http://dx.doi.org/10.1016/j.bios.2014.11.027

DOI: 10.1186/1756-0500-7-481

**13**:e676


**Chapter 3**

**Provisional chapter**

**Urinary Tract Infections in Renal Transplant Recipients**

Renal transplantation (RTx) is the treatment-of-choice for a significant number of patients with end-stage renal disease. Despite recent accomplishments, both surgical and medical complications still exist. Urinary tract infection (UTI) is the most common infectious complication after RTx, while asymptomatic bacteriuria is the most common manifestation of bacteriuria. UTI can impair graft function, potentially reducing graft and patient survival. The aetiology changes with time after RTx. The epidemiology of most of these infections is also changing with resistant organisms being isolated more often than in the past. Several factors increase the risk of infection in RTx patients, and the presence of multiple risk factors in the same patient is not uncommon. These include immunosuppression, urinary flow impairment (most often caused by stenosis or strictures at the vesicoureteral junction, benign prostate hypertrophy or vesicoureteral reflux), and treatment-related factors such as the use of catheters and double-J stents. Early diagnosis and effective treatment are key elements in salvaging both the allograft and the patient. This chapter reviews the definitions, epidemiology, microbiology, screening, clinical manifestations, diagnosis, impact on renal allograft function, evaluation after diagnosis, treatment, prevention including long-term prophylaxis, and the unique challenges of diagnosing and managing

**Keywords:** urinary tract infections, renal transplantation, treatment, prevention, renal

Kidney transplantation is the renal replacement therapy of choice for the constantly increasing number of patients with end-stage renal disease (ESRD). The huge headway in immunosuppressive treatment has resulted in improved renal graft survival rates, at the same time making infectious complications an even more common problem in the

**Urinary Tract Infections in Renal Transplant Recipients**

DOI: 10.5772/intechopen.72430

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Justyna Gołębiewska and Alicja Dębska-Ślizień

Justyna Gołębiewska and Alicja Dębska-Ślizień

Additional information is available at the end of the chapter

recurrent bacterial UTIs in a RTx care setting.

allograft function

**1. Introduction**

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72430

**Abstract**

**Provisional chapter**

## **Urinary Tract Infections in Renal Transplant Recipients**

**Urinary Tract Infections in Renal Transplant Recipients**

DOI: 10.5772/intechopen.72430

Justyna Gołębiewska and Alicja Dębska-Ślizień Justyna Gołębiewska and Alicja Dębska-Ślizień Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72430

#### **Abstract**

Renal transplantation (RTx) is the treatment-of-choice for a significant number of patients with end-stage renal disease. Despite recent accomplishments, both surgical and medical complications still exist. Urinary tract infection (UTI) is the most common infectious complication after RTx, while asymptomatic bacteriuria is the most common manifestation of bacteriuria. UTI can impair graft function, potentially reducing graft and patient survival. The aetiology changes with time after RTx. The epidemiology of most of these infections is also changing with resistant organisms being isolated more often than in the past. Several factors increase the risk of infection in RTx patients, and the presence of multiple risk factors in the same patient is not uncommon. These include immunosuppression, urinary flow impairment (most often caused by stenosis or strictures at the vesicoureteral junction, benign prostate hypertrophy or vesicoureteral reflux), and treatment-related factors such as the use of catheters and double-J stents. Early diagnosis and effective treatment are key elements in salvaging both the allograft and the patient. This chapter reviews the definitions, epidemiology, microbiology, screening, clinical manifestations, diagnosis, impact on renal allograft function, evaluation after diagnosis, treatment, prevention including long-term prophylaxis, and the unique challenges of diagnosing and managing recurrent bacterial UTIs in a RTx care setting.

**Keywords:** urinary tract infections, renal transplantation, treatment, prevention, renal allograft function

## **1. Introduction**

Kidney transplantation is the renal replacement therapy of choice for the constantly increasing number of patients with end-stage renal disease (ESRD). The huge headway in immunosuppressive treatment has resulted in improved renal graft survival rates, at the same time making infectious complications an even more common problem in the

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

renal transplant (RTx) population, with the urinary tract being the most prevalent infection site. Apart from immunodeficiency resulting from the use of immunosuppressive drugs, RTx patients often suffer from numerous urological malformations, vesicoureteral reflux (VUR) that is a permanent symptom after RTx, and are exposed to invasive diagnostic and therapeutic procedures involving the urinary tract. That is why urinary tract infections (UTIs) are the most common infectious complication among RTx recipients with up to 60% prevalence during the first year post-transplant [1, 2]. UTIs are important not only because of the scale of the problem but due to their potential negative influence on graft and RTx recipients' outcomes.

(4) Urosepsis—life-threatening organ dysfunction caused by a dysregulated host response

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 35

Recurrent infections are defined as 3 or more episodes of symptomatic UTIs over a 12-month

(1) Relapses: defined as the isolation of the same microorganism that caused the preceding infection in a urine culture obtained ≥2 weeks after finishing the previous treatment. The isolation of the same microorganism that caused the preceding infection in a urine culture obtained <2 weeks after finishing the previous treatment should be considered a treatment

(2) Reinfections: defined by a new episode of UTI with the isolation of an agent other than the

(1) Criteria for multidrug-resistant (MDR) bacteria: non-susceptible to ≥1 agent in ≥3 antimi-

(2) Criteria for extensively drug-resistant (XDR) bacteria: non-susceptible to ≥1 agent in all but ≤2 categories (i.e. bacterial isolates remain susceptible to only one or two

(3) Criteria for pan drug-resistant (PDR) bacteria: non-susceptible to all the antimicrobials. (4) Heteroresistance is defined as the presence of mixed populations of drug-resistant and

Many factors are believed to contribute to the high incidence of UTI in RTx recipients. Some exist prior to transplant, including female gender, diabetes mellitus and underlying urinary tract abnormalities. Peri-transplant factors are often related to instrumentation of the urinary tract, including ureteral stenting and prolonged urinary catheterization. Additional risk factors contributing to UTI post-transplant include immunosuppression and graft dysfunction or rejection. It is noteworthy that so far no direct association has been found between the risk of UTI and dose or type of maintenance immunosuppression. It is the net state of immunosuppression that impairs host defense capability against infections in general. Various authors have suggested different potential UTI risk factors, and their findings are not always consistent. The potential pre-, peri- and post-transplant risk factors for UTI in RTx recipients

Of note, significant urine flow impairment, both existing pre-transplant or appearing posttransplant, seems to be of major importance. The bladder outlet obstruction, particularly in

period or 2 episodes in the previous 6 months and can be divided into:

one that caused the previous infection.

Definitions of multidrug-resistant (MDR) bacterial infections:

drug-sensitive cells in a single clinical specimen.

**4. Predisposing factors for UTIs after RTx**

crobial categories or methicillin resistance in the case of *S. aureus*.

to the upper UTI.

failure.

categories).

are shown in **Table 1**.

## **2. Epidemiology**

Urinary tract infections (UTIs) are major causes of morbidity and hospitalization in renal transplant recipients. Infections, with the urinary tract as a major site, are the most common cause of acute kidney allograft injury, and prevalence of UTI-associated acute kidney injury far outnumbers episodes of acute rejection and calcineurin inhibitor toxicity [3].

There is a wide variation in the reported incidence of UTIs, most likely associated with differences in the definition of UTI, length of follow-up and variation in the use of posttransplant antibiotic prophylaxis. In a recently published meta-analysis on the prevalence and predictive factors of UTI in patients undergoing renal transplantation that included 13 studies with a total of 3364 patients evaluated, 1033 (30.71%) had UTIs [4]. The included studies provided different estimates of prevalence, which ranged from 16.0 to 75.0%, and the pooled prevalence of UTIs was 38% (95% CI, 29–47%; p < 0.01). Of note, RTx recipients followed for 1–2 years had significantly higher prevalence than those followed for 2–5 years (34 vs. 43%).

## **3. Definitions**

All UTIs can be classified into one of the four following categories:


(4) Urosepsis—life-threatening organ dysfunction caused by a dysregulated host response to the upper UTI.

Recurrent infections are defined as 3 or more episodes of symptomatic UTIs over a 12-month period or 2 episodes in the previous 6 months and can be divided into:


Definitions of multidrug-resistant (MDR) bacterial infections:

renal transplant (RTx) population, with the urinary tract being the most prevalent infection site. Apart from immunodeficiency resulting from the use of immunosuppressive drugs, RTx patients often suffer from numerous urological malformations, vesicoureteral reflux (VUR) that is a permanent symptom after RTx, and are exposed to invasive diagnostic and therapeutic procedures involving the urinary tract. That is why urinary tract infections (UTIs) are the most common infectious complication among RTx recipients with up to 60% prevalence during the first year post-transplant [1, 2]. UTIs are important not only because of the scale of the problem but due to their potential negative influence on graft and RTx

34 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Urinary tract infections (UTIs) are major causes of morbidity and hospitalization in renal transplant recipients. Infections, with the urinary tract as a major site, are the most common cause of acute kidney allograft injury, and prevalence of UTI-associated acute kidney injury

There is a wide variation in the reported incidence of UTIs, most likely associated with differences in the definition of UTI, length of follow-up and variation in the use of posttransplant antibiotic prophylaxis. In a recently published meta-analysis on the prevalence and predictive factors of UTI in patients undergoing renal transplantation that included 13 studies with a total of 3364 patients evaluated, 1033 (30.71%) had UTIs [4]. The included studies provided different estimates of prevalence, which ranged from 16.0 to 75.0%, and the pooled prevalence of UTIs was 38% (95% CI, 29–47%; p < 0.01). Of note, RTx recipients followed for 1–2 years had significantly higher prevalence than those followed for

(1) Asymptomatic bacteriuria (AB), defined as isolation of bacterial strain in quantitative counts ≥105 CFU in a clean-catch voided urine specimen in the absence of any symptoms of lower or upper UTI or <105 CFU in patients treated with antibiotics or ≥10<sup>3</sup> CFU in a

(2) Lower UTI, which is the presence of bacteriuria and clinical manifestations of dysuria, frequency or urinary urgency and fever <38°C in the absence of acute graft pyelonephritis

(3) Upper UTI (AGPN), defined by the presence of significant bacteriuria, fever >38°C and/

single catheterized urine specimen, irrespective of the presence of leukocyturia.

far outnumbers episodes of acute rejection and calcineurin inhibitor toxicity [3].

All UTIs can be classified into one of the four following categories:

or graft pain and/or acute graft function impairment.

recipients' outcomes.

**2. Epidemiology**

2–5 years (34 vs. 43%).

(AGPN) criteria.

**3. Definitions**


## **4. Predisposing factors for UTIs after RTx**

Many factors are believed to contribute to the high incidence of UTI in RTx recipients. Some exist prior to transplant, including female gender, diabetes mellitus and underlying urinary tract abnormalities. Peri-transplant factors are often related to instrumentation of the urinary tract, including ureteral stenting and prolonged urinary catheterization. Additional risk factors contributing to UTI post-transplant include immunosuppression and graft dysfunction or rejection. It is noteworthy that so far no direct association has been found between the risk of UTI and dose or type of maintenance immunosuppression. It is the net state of immunosuppression that impairs host defense capability against infections in general. Various authors have suggested different potential UTI risk factors, and their findings are not always consistent. The potential pre-, peri- and post-transplant risk factors for UTI in RTx recipients are shown in **Table 1**.

Of note, significant urine flow impairment, both existing pre-transplant or appearing posttransplant, seems to be of major importance. The bladder outlet obstruction, particularly in


an independent risk factor for the decline in renal function in a group of 172 RTx recipients [10]. Also a more recent study analyzing the effects of recurrent UTIs on graft and patient outcomes, in a population of 2469 RTx recipients, showed both poorer graft and patient survival in patients with a history of ≥3 UTIs in any 12-month period or ≥2 UTIs in any 6-month period, irrespective of the causative organism [11]. However other reports did not confirm this relationship. Not only asymptomatic bacteriuria but also AGPN did not affect long-term renal graft function prognosis [12–15]. However, even if UTIs do not influence graft survival directly, they can pose a significant risk indirectly by leading to bacteraemia, acute rejection

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 37

UTI after kidney transplantation is most often caused by Gram-negative organisms (around 50–90%), with *Escherichia coli* as the most frequently isolated microorganism in urine cultures, similarly to general population. However, aetiology differs between the early and late periods after RTx [16]. *Enterococcus* species has emerged as an important pathogen and now

> Other Pseudomonas spp Proteus spp Klebsiella spp Escherichia coli Enterococcus faecalis Enterococcus faecium

Other Pseudomonas spp Proteus spp Klebsiella spp Escherichia coli Enterococcus faecalis Enterococcus faecium

or cytomegalovirus (CMV) infection.

**6. Aetiology and timing of infections**

a

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

and (b) during 2–12 months post-transplant [16].

b

AB lower UTI AGPN urosepsis

AB lower UTI AGPN urosepsis

**Figure 1.** Proportion of different causative agents according to the type of UTI (a) during the first month post-transplant

**Table 1.** Risk factors for UTI in renal transplant recipients.

males, may not be appreciated until after the transplant, leading to prolonged instrumentation and an increased risk of UTI. The likelihood of AGPN development is 20-fold higher in patients with vesicoureteral reflux (VUR) or strictures at the uretero-vesical junction or benign prostate hyperplasia (BPH). Active reflux has long been reported as being significantly associated with poor graft outcome [5]. In a study by Dupont et al., VUR was found in almost half of RTx patients with recurrent UTIs, and patients with VUR were more prone to develop renal scarring than those without VUR [6]. On the other hand, in a recent study by Margreiter et al., 40% of 646 consecutive RTx recipients were diagnosed with VUR by voiding cystourethrography, and VUR did not affect the occurrence of UTIs. Simple UTI was diagnosed in 24.7% of patients with VUR and 27.2% of patients without VUR (p = 0.78). Recurrent UTIs were noted in 4.2% (with VUR) versus 3.9% (without VUR) of the enrolled patients (p = 0.67). However, the authors did not analyze the incidence of UTI according to VUR grade [7]. In a retrospective cohort of 23,622 adult male primary RTx recipients, also benign prostate hyperplasia was independently associated with recurrent UTI [8]. Considering the significant influence of urinary flow abnormalities on the likelihood of AGPN development, we would strongly recommend examination for VUR or urine flow obstruction even at the first AGPN episode.

## **5. Impact on renal allograft function**

The reports on the influence of UTIs on long-term kidney allograft function are inconsistent. The true impact of the whole spectrum of clinical manifestations of UTIs, on patient and graft outcome, so far has not been established. The general assumption is that asymptomatic bacteriuria (AB) is benign, as opposed to acute graft pyelonephritis or urosepsis. Still, the paucity of symptoms might be attributable to immunosuppression with actual ongoing inflammation of unrecognized significance. In one small study, kidney transplant patients with asymptomatic bacteriuria had elevated urine IL-8 level; and the authors hypothesized that this phenomenon may reflect an impaired immune response to bacterial infection and occult inflammatory process in the urinary tract [9]. Pellé et al. showed that acute graft pyelonephritis (AGPN) was an independent risk factor for the decline in renal function in a group of 172 RTx recipients [10]. Also a more recent study analyzing the effects of recurrent UTIs on graft and patient outcomes, in a population of 2469 RTx recipients, showed both poorer graft and patient survival in patients with a history of ≥3 UTIs in any 12-month period or ≥2 UTIs in any 6-month period, irrespective of the causative organism [11]. However other reports did not confirm this relationship. Not only asymptomatic bacteriuria but also AGPN did not affect long-term renal graft function prognosis [12–15]. However, even if UTIs do not influence graft survival directly, they can pose a significant risk indirectly by leading to bacteraemia, acute rejection or cytomegalovirus (CMV) infection.

## **6. Aetiology and timing of infections**

males, may not be appreciated until after the transplant, leading to prolonged instrumentation and an increased risk of UTI. The likelihood of AGPN development is 20-fold higher in patients with vesicoureteral reflux (VUR) or strictures at the uretero-vesical junction or benign prostate hyperplasia (BPH). Active reflux has long been reported as being significantly associated with poor graft outcome [5]. In a study by Dupont et al., VUR was found in almost half of RTx patients with recurrent UTIs, and patients with VUR were more prone to develop renal scarring than those without VUR [6]. On the other hand, in a recent study by Margreiter et al., 40% of 646 consecutive RTx recipients were diagnosed with VUR by voiding cystourethrography, and VUR did not affect the occurrence of UTIs. Simple UTI was diagnosed in 24.7% of patients with VUR and 27.2% of patients without VUR (p = 0.78). Recurrent UTIs were noted in 4.2% (with VUR) versus 3.9% (without VUR) of the enrolled patients (p = 0.67). However, the authors did not analyze the incidence of UTI according to VUR grade [7]. In a retrospective cohort of 23,622 adult male primary RTx recipients, also benign prostate hyperplasia was independently associated with recurrent UTI [8]. Considering the significant influence of urinary flow abnormalities on the likelihood of AGPN development, we would strongly recommend examination for VUR or urine flow obstruction even at the

Urine flow impairment

Immunosuppression Acute rejection Reduced graft function

• Vesicoureteral reflux (VUR)

• Benign prostate hyperplasia

• Strictures at the uretero-vesical junction

**Pre-transplant Peri-transplant Post-transplant**

Ureteral stents

Bladder instrumentation Deceased-donor grafts Double kidney transplants

36 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The reports on the influence of UTIs on long-term kidney allograft function are inconsistent. The true impact of the whole spectrum of clinical manifestations of UTIs, on patient and graft outcome, so far has not been established. The general assumption is that asymptomatic bacteriuria (AB) is benign, as opposed to acute graft pyelonephritis or urosepsis. Still, the paucity of symptoms might be attributable to immunosuppression with actual ongoing inflammation of unrecognized significance. In one small study, kidney transplant patients with asymptomatic bacteriuria had elevated urine IL-8 level; and the authors hypothesized that this phenomenon may reflect an impaired immune response to bacterial infection and occult inflammatory process in the urinary tract [9]. Pellé et al. showed that acute graft pyelonephritis (AGPN) was

first AGPN episode.

Urine flow impairment Female gender Diabetes

Urinary tract anomalies Glomerulonephritis

**5. Impact on renal allograft function**

**Table 1.** Risk factors for UTI in renal transplant recipients.

UTI after kidney transplantation is most often caused by Gram-negative organisms (around 50–90%), with *Escherichia coli* as the most frequently isolated microorganism in urine cultures, similarly to general population. However, aetiology differs between the early and late periods after RTx [16]. *Enterococcus* species has emerged as an important pathogen and now

**Figure 1.** Proportion of different causative agents according to the type of UTI (a) during the first month post-transplant and (b) during 2–12 months post-transplant [16].

accounts for up to 30% of UTIs, especially in the first post-transplant month. In a study by Alangaden et al. *Enterococcus* spp. accounted for 33% of UTIs, but authors failed to identify any specific risk factor associated with the predominance of this uropathogen [17]. Also in a study by Bonkat et al., *Enterococcus* spp. were bacteria most commonly responsible for microbial ureteral stent colonization in RTx recipients. The authors found two possible explanations for this phenomenon. *Enterococcus* spp. possess biofilm formation properties on various kinds of indwelling medical devices; and routine urine cultures often fail to identify biofilm forming Gram-positive pathogens, unlike the sonication technique used in that study to dislodge adherent microorganisms [18]. Another possible explanation of a high number of *Enterococcus* spp. infections is the routine use of cephalosporins in perioperative prophylaxis. This antibiotic acts against Gram-negative *Bacilli*, therefore it promotes selection of *Enterococcus* spp.

commensal strains. As cyclosporine seemed to promote higher expression of PBP5 than tacrolimus, -lactam antibiotics may be more effective when tacrolimus-based immunosuppression

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 39

In a recently published study analyzing recurrent UTIs in a cohort of 2469 RTx recipients, the authors found pronounced differences in antimicrobial resistance patterns between nonrecurrent and recurrent UTIs [11]. Isolates from the cases of recurrent UTIs were more likely to be resistant to first- and third-generation cephalosporins, trimethoprim-sulfamethoxazole, nitrofurantoin and fluoroquinolones, to extended-spectrum b-lactams and aminoglycosides. In a retrospective case series by Winters et al., 85% of solid-organ transplant recipients diagnosed with infection due to ESBL-producing bacteria received inadequate empiric therapy [23]. This means that all RTx recipients with a history of UTI due to ESBL-producing Gramnegative pathogens, presenting with symptoms of a new UTI, should receive an empiric therapy with a carbapenem until a urine culture result with susceptibility profile is available.

UTIs in RTx recipients may either be asymptomatic or have an atypical clinical presentation. Therefore the diagnosis based solely on clinical grounds may be of questionable accuracy. What is more, every symptomatic, either lower or upper UTI in any transplant recipient, is considered complicated: as it is associated with structural and functional abnormalities of the genitourinary tract and immunocompromised status that increases the risk for acquiring an infection or of failing therapy. For this reason urine cultures should be obtained in every

Asymptomatic bacteriuria is a frequent finding in kidney allograft recipients, with almost 40% incidence [16]. So far there are no evidence-based recommendations for screening and treatment of AB in renal transplant recipients, because sufficient data is lacking [24]. The American Society of Transplantation Infectious Diseases Guidelines recommend limiting screening to the first post-transplant month, but these recommendations are mostly expert opinion [25]. Fiorante et al. showed that the incidence of AGPN was significantly higher in patients with a history of multiple episodes of AB than in patients without, despite or due to the provided antibiotic treatment [26]. Patients with no episodes of AB seem to develop significantly fewer symptomatic infections than patients with a history of recurrent AB. As reinfections seem to outnumber relapses and only a very few episodes of symptomatic UTIs are preceded by AB with the same causative agent in patients with a history of recurrent AB, it seems that AB is more of a marker of increased susceptibility to infections, not a direct risk factor [16]. This is in agreement with the findings from a non-transplant population of young women, where the treatment of AB in patients affected by recurrent UTI was associated with a higher rate of symptomatic UTI [27].

single case, in order to base therapy upon susceptibility pattern determinations.

protocols are implemented [22].

**8. Diagnosis**

**9. Asymptomatic bacteriuria**

Beginning from the second month, *Escherichia coli* is the most frequently isolated causative agent, followed by *Proteus* spp., *Klebsiella* spp., *Enterobacter* spp. and *Pseudomonas* spp. (**Figure 1**).

## **7. Multidrug-resistant bacteria**

With the widespread use of antibiotics, including the routine use of antimicrobial prophylaxis in RTx recipients, the prevalence of multidrug resistance (MDR) among uropathogenic bacteria is increasing, irrespectively of region and country. The most widely accepted definition of MDR includes lack of susceptibility to one or more agents in three or more antimicrobial categories active against the isolated bacteria. Of note, also extensively drug-resistant (XDR) and pan drug-resistant (PDR) strains have been identified.

In patients receiving trimethoprim-sulfamethoxazole prophylaxis, over 60% of UTIs have been reported as caused by trimethoprim-sulfamethoxazole-resistant organisms [19]. The treatment of AB has also been associated with antimicrobial resistance. In a study of patients with asymptomatic *E. coli* or *E*. *faecalis* bacteriuria, treatment led to selection of resistant organisms in almost 80% of treated cases [20]. The emergence of ESBL-producing, or carbapenemaseproducing, organism pathogens has been the most important threat in nosocomial infections in recent years [21]. Although antibiotic resistance has been a concern since the introduction of penicillin, the past two decades have seen a marked increase in resistance, especially related to beta-lactams. Resistance in Gram-negative pathogens continues to increase, with multidrug resistance in the *Enterobacteriaceae* becoming one of the most important crises faced by the medical community. A major contributing factor is the acquisition of large plasmids that can encode resistance factors for multiple drug classes. As seen from the recent literature, organisms such as *E. coli* and the *Klebsiella* are acquiring more diverse integrons and transposons that are included in a multiplicity of transferable plasmids capable of encoding every class of beta-lactamase.

It seems that immunosuppression may influence the resistance of enterococcal spp. to -lactambased antibiotics by affecting the expression of the penicillin-binding proteins (PBPs). In enterococcal strains isolated from RTx patients, the expression of the PBP5 gene was higher than in commensal strains. As cyclosporine seemed to promote higher expression of PBP5 than tacrolimus, -lactam antibiotics may be more effective when tacrolimus-based immunosuppression protocols are implemented [22].

In a recently published study analyzing recurrent UTIs in a cohort of 2469 RTx recipients, the authors found pronounced differences in antimicrobial resistance patterns between nonrecurrent and recurrent UTIs [11]. Isolates from the cases of recurrent UTIs were more likely to be resistant to first- and third-generation cephalosporins, trimethoprim-sulfamethoxazole, nitrofurantoin and fluoroquinolones, to extended-spectrum b-lactams and aminoglycosides.

In a retrospective case series by Winters et al., 85% of solid-organ transplant recipients diagnosed with infection due to ESBL-producing bacteria received inadequate empiric therapy [23]. This means that all RTx recipients with a history of UTI due to ESBL-producing Gramnegative pathogens, presenting with symptoms of a new UTI, should receive an empiric therapy with a carbapenem until a urine culture result with susceptibility profile is available.

## **8. Diagnosis**

accounts for up to 30% of UTIs, especially in the first post-transplant month. In a study by Alangaden et al. *Enterococcus* spp. accounted for 33% of UTIs, but authors failed to identify any specific risk factor associated with the predominance of this uropathogen [17]. Also in a study by Bonkat et al., *Enterococcus* spp. were bacteria most commonly responsible for microbial ureteral stent colonization in RTx recipients. The authors found two possible explanations for this phenomenon. *Enterococcus* spp. possess biofilm formation properties on various kinds of indwelling medical devices; and routine urine cultures often fail to identify biofilm forming Gram-positive pathogens, unlike the sonication technique used in that study to dislodge adherent microorganisms [18]. Another possible explanation of a high number of *Enterococcus* spp. infections is the routine use of cephalosporins in perioperative prophylaxis. This antibiotic acts against Gram-negative *Bacilli*, therefore it promotes selection of

38 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Beginning from the second month, *Escherichia coli* is the most frequently isolated causative agent, followed by *Proteus* spp., *Klebsiella* spp., *Enterobacter* spp. and *Pseudomonas* spp. (**Figure 1**).

With the widespread use of antibiotics, including the routine use of antimicrobial prophylaxis in RTx recipients, the prevalence of multidrug resistance (MDR) among uropathogenic bacteria is increasing, irrespectively of region and country. The most widely accepted definition of MDR includes lack of susceptibility to one or more agents in three or more antimicrobial categories active against the isolated bacteria. Of note, also extensively drug-resistant (XDR)

In patients receiving trimethoprim-sulfamethoxazole prophylaxis, over 60% of UTIs have been reported as caused by trimethoprim-sulfamethoxazole-resistant organisms [19]. The treatment of AB has also been associated with antimicrobial resistance. In a study of patients with asymptomatic *E. coli* or *E*. *faecalis* bacteriuria, treatment led to selection of resistant organisms in almost 80% of treated cases [20]. The emergence of ESBL-producing, or carbapenemaseproducing, organism pathogens has been the most important threat in nosocomial infections in recent years [21]. Although antibiotic resistance has been a concern since the introduction of penicillin, the past two decades have seen a marked increase in resistance, especially related to beta-lactams. Resistance in Gram-negative pathogens continues to increase, with multidrug resistance in the *Enterobacteriaceae* becoming one of the most important crises faced by the medical community. A major contributing factor is the acquisition of large plasmids that can encode resistance factors for multiple drug classes. As seen from the recent literature, organisms such as *E. coli* and the *Klebsiella* are acquiring more diverse integrons and transposons that are included in a multiplicity of transferable plasmids capable of encoding every

It seems that immunosuppression may influence the resistance of enterococcal spp. to -lactambased antibiotics by affecting the expression of the penicillin-binding proteins (PBPs). In enterococcal strains isolated from RTx patients, the expression of the PBP5 gene was higher than in

*Enterococcus* spp.

class of beta-lactamase.

**7. Multidrug-resistant bacteria**

and pan drug-resistant (PDR) strains have been identified.

UTIs in RTx recipients may either be asymptomatic or have an atypical clinical presentation. Therefore the diagnosis based solely on clinical grounds may be of questionable accuracy. What is more, every symptomatic, either lower or upper UTI in any transplant recipient, is considered complicated: as it is associated with structural and functional abnormalities of the genitourinary tract and immunocompromised status that increases the risk for acquiring an infection or of failing therapy. For this reason urine cultures should be obtained in every single case, in order to base therapy upon susceptibility pattern determinations.

## **9. Asymptomatic bacteriuria**

Asymptomatic bacteriuria is a frequent finding in kidney allograft recipients, with almost 40% incidence [16]. So far there are no evidence-based recommendations for screening and treatment of AB in renal transplant recipients, because sufficient data is lacking [24]. The American Society of Transplantation Infectious Diseases Guidelines recommend limiting screening to the first post-transplant month, but these recommendations are mostly expert opinion [25]. Fiorante et al. showed that the incidence of AGPN was significantly higher in patients with a history of multiple episodes of AB than in patients without, despite or due to the provided antibiotic treatment [26].

Patients with no episodes of AB seem to develop significantly fewer symptomatic infections than patients with a history of recurrent AB. As reinfections seem to outnumber relapses and only a very few episodes of symptomatic UTIs are preceded by AB with the same causative agent in patients with a history of recurrent AB, it seems that AB is more of a marker of increased susceptibility to infections, not a direct risk factor [16]. This is in agreement with the findings from a non-transplant population of young women, where the treatment of AB in patients affected by recurrent UTI was associated with a higher rate of symptomatic UTI [27]. The authors hypothesized that this phenomenon resulted from ecological effects of antibacterial agents on the human microflora. However, Rice et al. found an association between AB progression to systemic infection with acute kidney allograft injury and a unique pattern of adherence factors that is P fimbriae but not Dr. fimbriae expression [28]. So, AB might be an actual risk factor for symptomatic UTIs depending on the virulence of uropathogens.

There is no evidence to support the use of combination antibiotic therapy for the treatment of ESBL, but in haemodynamically unstable or critically ill patients, adding an aminoglycoside to carbapenem seems a reasonable strategy. Amoxicillin-clavulanate and fosfomycin showed a clinical efficacy of 84 and 93%, respectively, in the treatment of cystitis caused by ESBL-producing *E. coli* but only when the isolate showed susceptibility to those drugs [30]. Other options in the case of proven susceptibility include tigecycline, cotrimoxazole, quinolones and nitrofurantoin.

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 41

The combination antibiotic therapy is a standard of care in carbapenemase-producing *Enterobacteriaceae* infections [31, 32]. Colistin is the most active agent against these strains and should be considered the basis of treatment in most patients [33]. The options for the use of combination antibiotic therapy include aminoglycosides, fosfomycin or even high-dose carbapenems [31, 32, 34]. Tigecycline could represent an optimal choice for patients with co-infection with additional MDR pathogens [e.g. vancomycin-resistant *Enterococci* (VRE) or

In the case of severe infection with sepsis, the option of reduction/discontinuation of immunosuppression together with surgical/urological intervention should also be considered.

In severe upper UTIs and/or recurrent infections, imaging should always be obtained to rule out structural causes or persistent foci of infection. Ultrasound may confirm the presence of hydronephrosis. When there are no visible structural abnormalities on ultrasound, it may be necessary to perform fluoroscopic voiding cystourethrogram to diagnose severe vesicoureteral reflux (VUR), computed tomography urography to visualize the cause of urine flow obstruction or uroflowmetry to recognize the problem with delayed bladder emptying. In elderly RTx recipients, the aforementioned functional abnormalities may be secondary to benign prostate hyperplasia (BPH). Since most patients undergoing dialysis are oliguric or anuric, urinary obstruction due to BPH and related lower urinary tract symptoms become evident after RTx and restoration of diuresis. As opposed to native kidneys, the transplanted kidney's ureter is shorter, and there is no valve at the vesicoureteral junction preventing backflow, so low-grade BPH may cause symptoms that would not be present in a non-RTx patient. Medical therapy of BPH, both pharmacologic and surgical, such as transurethral resection of the prostate is safe and improves urinary flow and bladder emptying, to allow a significant

Appropriate attention should be given to the prevention of UTI with correction of structural abnormalities of the urinary tract in the potential RTx recipients prior to transplantation. Any

In the immediate post-transplant period, vigilance for donor-transmitted infection is important, together with routine perioperative antibiotic prophylaxis recommended by the hospital's epidemiologist, taking into account current antibiotic resistance of Gram-negative strains. In the

methicillin-resistant *Staphylococcus aureus* (MRSA)].

and durable improvement of the kidney allograft function.

type of voiding dysfunction should be considered and addressed.

**11. Prevention and prophylaxis**

A number of studies attempted to elucidate if the treatment of AB in RTx patients is in fact helpful or harmful in preventing symptomatic infections [19, 20]. One retrospective observational study included a total of 112 patients with AB. The decision as to whether, or not, to treat AB was made by the attending physician. The primary outcome, defined as hospitalization for symptomatic UTI or a 25% decline in the eGFR, occurred more frequently among patients treated with antibiotics. However, the authors called attention to the fact that those treated patients may have initially been at higher risk for adverse outcomes, thus masking the benefit of the treatment [19]. Another retrospective study included 77 RTx recipients who developed 334 AB episodes later than 1-month post transplantation. AB episodes were classified into four groups depending on the presence of pyuria and grade of bacteriuria. Spontaneous bacterial clearance occurred in 59% of untreated episodes. The resolution of bacteriuria was not more frequent in treated, as compared to untreated, episodes. However, antibiotic treatment in patients with high-grade bacteriuria and concurrent pyuria resulted more frequently in negative control cultures than untreated episodes. The authors concluded that a watch-and-wait strategy for bacteriuria in the absence of pyuria might be safe in the RTx population [20]. In 2016, the results of a randomized controlled study were published. Systematic screening and treatment of AB beyond the second month after transplantation provided no apparent benefit among KT recipients when the occurrence of acute pyelonephritis at 24-month follow-up was considered. The treatment also did not affect the secondary outcomes, which included lower UTI, acute rejection, *Clostridium* difficile infection, colonization or infection by multidrug-resistant bacteria, graft function and all-cause mortality [29].

## **10. Treatment**

Selection of initial empiric treatment should be based on local epidemiological data and the patient's history of resistant organisms. Once susceptibility data are available, the initial therapy should be deescalated, so that the most narrow-spectrum antibiotic is used to complete the course of therapy. Care should be taken to avoid treating asymptomatic patients, in order to reduce the possibility of infection with MDR pathogens.

Lower UTIs require minimum 7-day therapy with an effective agent while upper UTIs at least 2–3 weeks. The resolution of infection should be demonstrated before the cessation of treatment. Stents or catheters may be covered with bacterial biofilm, so their removal is generally required for resolution of UTI. For empirical treatment of suspected bacterial infections in RTx patients, the selection of antimicrobial agents should be based on local epidemiological data and on the patient's history of colonization or infection with antibiotic-resistant organisms.

There is no evidence to support the use of combination antibiotic therapy for the treatment of ESBL, but in haemodynamically unstable or critically ill patients, adding an aminoglycoside to carbapenem seems a reasonable strategy. Amoxicillin-clavulanate and fosfomycin showed a clinical efficacy of 84 and 93%, respectively, in the treatment of cystitis caused by ESBL-producing *E. coli* but only when the isolate showed susceptibility to those drugs [30]. Other options in the case of proven susceptibility include tigecycline, cotrimoxazole, quinolones and nitrofurantoin.

The combination antibiotic therapy is a standard of care in carbapenemase-producing *Enterobacteriaceae* infections [31, 32]. Colistin is the most active agent against these strains and should be considered the basis of treatment in most patients [33]. The options for the use of combination antibiotic therapy include aminoglycosides, fosfomycin or even high-dose carbapenems [31, 32, 34]. Tigecycline could represent an optimal choice for patients with co-infection with additional MDR pathogens [e.g. vancomycin-resistant *Enterococci* (VRE) or methicillin-resistant *Staphylococcus aureus* (MRSA)].

In the case of severe infection with sepsis, the option of reduction/discontinuation of immunosuppression together with surgical/urological intervention should also be considered.

In severe upper UTIs and/or recurrent infections, imaging should always be obtained to rule out structural causes or persistent foci of infection. Ultrasound may confirm the presence of hydronephrosis. When there are no visible structural abnormalities on ultrasound, it may be necessary to perform fluoroscopic voiding cystourethrogram to diagnose severe vesicoureteral reflux (VUR), computed tomography urography to visualize the cause of urine flow obstruction or uroflowmetry to recognize the problem with delayed bladder emptying. In elderly RTx recipients, the aforementioned functional abnormalities may be secondary to benign prostate hyperplasia (BPH). Since most patients undergoing dialysis are oliguric or anuric, urinary obstruction due to BPH and related lower urinary tract symptoms become evident after RTx and restoration of diuresis. As opposed to native kidneys, the transplanted kidney's ureter is shorter, and there is no valve at the vesicoureteral junction preventing backflow, so low-grade BPH may cause symptoms that would not be present in a non-RTx patient. Medical therapy of BPH, both pharmacologic and surgical, such as transurethral resection of the prostate is safe and improves urinary flow and bladder emptying, to allow a significant and durable improvement of the kidney allograft function.

## **11. Prevention and prophylaxis**

The authors hypothesized that this phenomenon resulted from ecological effects of antibacterial agents on the human microflora. However, Rice et al. found an association between AB progression to systemic infection with acute kidney allograft injury and a unique pattern of adherence factors that is P fimbriae but not Dr. fimbriae expression [28]. So, AB might be an

A number of studies attempted to elucidate if the treatment of AB in RTx patients is in fact helpful or harmful in preventing symptomatic infections [19, 20]. One retrospective observational study included a total of 112 patients with AB. The decision as to whether, or not, to treat AB was made by the attending physician. The primary outcome, defined as hospitalization for symptomatic UTI or a 25% decline in the eGFR, occurred more frequently among patients treated with antibiotics. However, the authors called attention to the fact that those treated patients may have initially been at higher risk for adverse outcomes, thus masking the benefit of the treatment [19]. Another retrospective study included 77 RTx recipients who developed 334 AB episodes later than 1-month post transplantation. AB episodes were classified into four groups depending on the presence of pyuria and grade of bacteriuria. Spontaneous bacterial clearance occurred in 59% of untreated episodes. The resolution of bacteriuria was not more frequent in treated, as compared to untreated, episodes. However, antibiotic treatment in patients with high-grade bacteriuria and concurrent pyuria resulted more frequently in negative control cultures than untreated episodes. The authors concluded that a watch-and-wait strategy for bacteriuria in the absence of pyuria might be safe in the RTx population [20]. In 2016, the results of a randomized controlled study were published. Systematic screening and treatment of AB beyond the second month after transplantation provided no apparent benefit among KT recipients when the occurrence of acute pyelonephritis at 24-month follow-up was considered. The treatment also did not affect the secondary outcomes, which included lower UTI, acute rejection, *Clostridium* difficile infection, colonization or infection by multidrug-resistant bacteria, graft function and all-cause

Selection of initial empiric treatment should be based on local epidemiological data and the patient's history of resistant organisms. Once susceptibility data are available, the initial therapy should be deescalated, so that the most narrow-spectrum antibiotic is used to complete the course of therapy. Care should be taken to avoid treating asymptomatic patients, in order

Lower UTIs require minimum 7-day therapy with an effective agent while upper UTIs at least 2–3 weeks. The resolution of infection should be demonstrated before the cessation of treatment. Stents or catheters may be covered with bacterial biofilm, so their removal is generally required for resolution of UTI. For empirical treatment of suspected bacterial infections in RTx patients, the selection of antimicrobial agents should be based on local epidemiological data and on the patient's history of colonization or infection with antibiotic-resistant organisms.

to reduce the possibility of infection with MDR pathogens.

actual risk factor for symptomatic UTIs depending on the virulence of uropathogens.

40 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

mortality [29].

**10. Treatment**

Appropriate attention should be given to the prevention of UTI with correction of structural abnormalities of the urinary tract in the potential RTx recipients prior to transplantation. Any type of voiding dysfunction should be considered and addressed.

In the immediate post-transplant period, vigilance for donor-transmitted infection is important, together with routine perioperative antibiotic prophylaxis recommended by the hospital's epidemiologist, taking into account current antibiotic resistance of Gram-negative strains. In the case of a positive donor's or organ preservation fluid cultures, the antibiotic should be chosen according to susceptibility profiles. The use of indwelling urethral catheters and ureteral stents should be minimized.

[4] Wu X, Dong Y, Liu Y, Li Y, Sun Y, Wang J, Wang S. The prevalence and predictive factors of urinary tract infection in patients undergoing renal transplantation: A meta-analysis.

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 43

[5] Mathew T, Kincaid-Smith P, Vikraman P. Risks of vesicoureteric reflux in the trans-

[6] Dupont PJ, Psimenou E, Lord R, Buscombe JR, Hilson AJ, Sweny P. Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symp-

[7] Margreiter M, Györi GP, Böhmig GA, Trubel S, Mühlbacher F, Steininger R. Value of routine voiding cystourethrography after renal transplantation. American Journal of

[8] Hurst FP, Neff RT, Falta EM, Jindal RM, Lentine KL, Swanson JS, Agodoa LY, Abbott KC. Incidence, predictors, and associated outcomes of prostatism after kidney transplantation. Clinical Journal of the American Society of Nephrology. 2009;**4**:329-336 [9] Ciszek M, Pączek L, Bartłomiejczyk I, Mucha K. Urine cytokines profile in renal transplant patients with asymptomatic bacteriuria. Transplantation. 2006;**81**:1653-1657 [10] Pellé G, Vimont S, Levy PP, Hertig A, Ouali N, Chassin C, Arlet G, Rondeau E, Vandewalle A. Acute pyelonephritis represents a risk factor impairing long-term kidney graft func-

[11] Britt NS, Hagopian JC, Brennan DC, Pottebaum AA, Santos CAQ, Gharabagi A, Horwedel TA. Effects of recurrent urinary tract infections on graft and patient outcomes after kidney transplantation. Nephrology, Dialysis, Transplantation. 2017;**32**:1758-1766

[12] Fiorante S, Fernandez-Ruiz M, Lopez-Medrano F, Lizasoain M, Lalueza A, Morales JM, San-Juan R, Andrés A, Otero JR, Aguado JM. Acute graft pyelonephritis in renal transplant recipients: Incidence, risk factors and long-term outcome. Nephrology, Dialysis,

[13] Giral M, Pascuariello G, Karam G, Hourmant M, Cantarovich D, Dantal J, Blancho G, Coupel S, Josien R, Daguin P, Méchineau S, Soulillou JP. Acute graft pyelonephritis and

[14] Kamath NS, John GT, Neelakantan N, Kirubakaran MG, Jacob CK. Acute graft pyelonephritis following renal transplantation. Transplant Infectious Disease. 2006;**8**:140-147

[15] Singh R, Geerlings SE, Peters-Sengers H, Idu MM, Hodiamont CJ, Ten Berge IJ, Bemelman FJ. Incidence, risk factors, and the impact of allograft pyelonephritis on renal allograft

[16] Gołębiewska JE, Dębska-Ślizień A, Rutkowski B. Treated asymptomatic bacteriuria during first year after renal transplantation. Transplant Infectious Disease. 2014;**16**:605-615

[17] Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Garnick J, El-Amm JM, West MS, Sillix DH, Chandrasekar PH, Haririan A. Infectious complications after kidney transplantation: Current epidemiology and associated risk factors. Clinical Transplantation. 2006;**20**:401

long-term kidney allograft outcome. Kidney International. 2002;**61**:1880-1886

planted kidney. The New England Journal of Medicine. 1977;**297**:414-418

American Journal of Infection Control. 2016;**44**(11):1261-1268

toms or vesicoureteric reflux. Transplantation. 2007;**84**:351-355

tion. American Journal of Transplantation. 2007;**7**:899-907

function. Transplant Infectious Disease. 2016;**18**:647-660

Transplantation. 2013;**13**:130-135

Transplantation. 2011;**26**:1065-1073

Patients should be instructed to drink a lot of fluids and urinate frequently, without waiting for the urge to urinate.

There is no consensus regarding the optimal strategy and duration of recurrent UTI prophylaxis, so the decision to give it, or not, depends on the experience of the treating physician. Traditionally trimethoprim/sulfamethoxazole prophylaxis has been used as the prevention of both asymptomatic bacteriuria/UTI and Pneumocystis pneumonia after RTx. However, over the past few years, it has become less effective as uropathogens have become more resistant to this regimen. Of note, ESBL-producing *E. coli* are usually susceptible to nitrofurantoin, while most *Klebsiella* spp. strains are resistant to this antibiotic.

Several possibilities exist in an attempt to mitigate the damage caused by resistant pathogens. In the general population, there are ongoing attempts to use nonantibiotic strategies, such as cranberry products, D-mannose, probiotics, immunoactive prophylaxis with several types of vaccines, intravesical glycosaminoglycan replenishment therapy with the use of chondroitin sulfate and low molecular weight hyaluronic acid in the treatment and/or prevention of recurrent UTIs [35]. So far the use of all these products has not been extensively studied in RTx population, except for single-case reports on the use of cranberry products. Little information is also available about the usefulness of intestinal decolonization in RTx patients.

## **Author details**

Justyna Gołębiewska\* and Alicja Dębska-Ślizień

\*Address all correspondence to: jgolebiewska@gumed.edu.pl

Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland

## **References**


[4] Wu X, Dong Y, Liu Y, Li Y, Sun Y, Wang J, Wang S. The prevalence and predictive factors of urinary tract infection in patients undergoing renal transplantation: A meta-analysis. American Journal of Infection Control. 2016;**44**(11):1261-1268

case of a positive donor's or organ preservation fluid cultures, the antibiotic should be chosen according to susceptibility profiles. The use of indwelling urethral catheters and ureteral stents

42 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Patients should be instructed to drink a lot of fluids and urinate frequently, without waiting

There is no consensus regarding the optimal strategy and duration of recurrent UTI prophylaxis, so the decision to give it, or not, depends on the experience of the treating physician. Traditionally trimethoprim/sulfamethoxazole prophylaxis has been used as the prevention of both asymptomatic bacteriuria/UTI and Pneumocystis pneumonia after RTx. However, over the past few years, it has become less effective as uropathogens have become more resistant to this regimen. Of note, ESBL-producing *E. coli* are usually susceptible to nitrofurantoin, while

Several possibilities exist in an attempt to mitigate the damage caused by resistant pathogens. In the general population, there are ongoing attempts to use nonantibiotic strategies, such as cranberry products, D-mannose, probiotics, immunoactive prophylaxis with several types of vaccines, intravesical glycosaminoglycan replenishment therapy with the use of chondroitin sulfate and low molecular weight hyaluronic acid in the treatment and/or prevention of recurrent UTIs [35]. So far the use of all these products has not been extensively studied in RTx population, except for single-case reports on the use of cranberry products. Little information

is also available about the usefulness of intestinal decolonization in RTx patients.

Department of Nephrology, Transplantology and Internal Medicine, Medical University of

[1] Veroux M, Giuffrida G, Corona D, Gagliano M, Scriffignano V, Vizcarra D, Tallarita T, Zerbo D, Virgilio C, Sciacca A, Cappello D, Stefani S, Veroux P. Infective complications in renal allograft recipients: Epidemiology and outcome. Transplantation Proceedings. 2008;

[2] Gołębiewska J, Dębska-Ślizień A, Komarnicka J, Samet A, Rutkowski B. Urinary tract infections in renal transplant recipients. Transplantation Proceedings. 2011;**43**:2985-2990

[3] Nampoory MR, Johny KV, Costandy JN, Nair MP, Said T, Homoud H, Al-Muzairai I, Samhan M, Al-Moussawi M. Infection related renal impairment: A major cause of acute

allograft dysfunction. Experimental and Clinical Transplantation. 2003;**1**:60-64

should be minimized.

for the urge to urinate.

**Author details**

Gdańsk, Poland

**References**

**40**:1873-1876

most *Klebsiella* spp. strains are resistant to this antibiotic.

Justyna Gołębiewska\* and Alicja Dębska-Ślizień

\*Address all correspondence to: jgolebiewska@gumed.edu.pl


[18] Bonkat G, Rieken M, Siegel FP, Frei R, Steiger J, Gröschl I, Gasser TC, Dell-Kuster S, Rosenthal R, Gürke L, Wyler S, Bachmann A, Widmer AF. Microbial ureteral stent colonization in renal transplant recipients: Frequency and influence on the short-time functional outcome. Transplant Infectious Disease. 2012;**14**:57

[30] Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Community infections caused by extendedspectrum beta-lactamase-producing *Escherichia coli*. Archives of Internal Medicine.

Urinary Tract Infections in Renal Transplant Recipients http://dx.doi.org/10.5772/intechopen.72430 45

[31] Clancy CJ, Chen L, Shields RK, et al. Epidemiology and molecular characterization of bacteremia due to carbapenem-resistant *Klebsiella pneumoniae* in transplant recipients.

[32] Bergamasco MD, Barroso Barbosa M, de Oliveira Garcia D, et al. Infection with *Klebsiella pneumoniae* carbapenemase (KPC)-producing *K. pneumoniae* in solid organ transplanta-

[33] Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: Results from the SENTRY antimicrobial surveillance program (2006-09). The Journal of Antimicrobial Chemotherapy.

[34] Taglietti F, Di Bella S, Galati V, Topino S, Iappelli M, Petrosillo N. Carbapenemase-producing *Klebsiella pneumoniae*-related mortality among solid organ-transplanted patients: Do we

[35] Costantini E, Giannitsas K, Illiano E. The role of nonantibiotic treatment of communityacquired urinary tract infections. Current Opinion in Urology. 2017;**27**:120-126

American Journal of Transplantation. 2013;**13**:2619-2633

know enough? Transplant Infectious Disease. 2013;**15**:E164-E165

tion. Transplant Infectious Disease. 2012;**14**:198-205

2008;**168**:1897-1902

2011;**66**:2070-2074


[30] Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Community infections caused by extendedspectrum beta-lactamase-producing *Escherichia coli*. Archives of Internal Medicine. 2008;**168**:1897-1902

[18] Bonkat G, Rieken M, Siegel FP, Frei R, Steiger J, Gröschl I, Gasser TC, Dell-Kuster S, Rosenthal R, Gürke L, Wyler S, Bachmann A, Widmer AF. Microbial ureteral stent colonization in renal transplant recipients: Frequency and influence on the short-time func-

[19] Green H, Rahamimov R, Gafter U, Leibovitci L, Paul M. Antibiotic prophylaxis for urinary tract infections in renal transplant recipients: A systematic review and meta-analysis.

[20] El Amari EB, Hadaya K, Buhler L, et al. Outcome of treated and untreated asymptomatic bacteriuria in renal transplant recipients. Nephrology, Dialysis, Transplantation.

[21] Philippon A, Arlet G, Lagrange PH. Origin and impact of plasmid-mediated extendedspectrum beta-lactamases. European Journal of Clinical Microbiology & Infectious

[22] Jarzembowski T, Daca A, Witkowski J, Rutkowski B, Gołębiewska J, Dębska-Ślizień A. Changes of PBP5 gene expression in enterococcal isolates from renal transplantation

[23] Winters HA, Parbhoo RK, Schafer JJ, et al. Extended-spectrum beta-lactamase producing bacterial infections in adult solid organ transplant recipients. The Annals of

[24] Nicolle LE, Bradley S, Colgan R, Rice CJ, Schaeffer A, Hooton TM. Infectious Diseases Society of America Guidelines for the diagnosis and treatment of asymptomatic bacteri-

[25] Parasuraman R, Julian K, The AST Infectious Diseases Community of Practice. The American Society of Transplantation Infectious Diseases Guidelines 3rd edition. Urinary tract infections in solid organ transplantation. American Journal of Transplantation.

[26] Fiorante S, Lopez-Medrano F, Lizasoain M, et al. Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients. Kidney International. 2010;

[27] Cai T, Mazzoli S, Mondaini N, et al. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: To treat or not to treat? Clinical Infectious Diseases.

[28] Rice JC, Peng T, Kuo Y-F, et al. Renal allograft injury is associated with urinary tract infection caused by *Escherichia coli* bearing adherence factors. American Journal of Transplantation.

[29] Origüen J, López-Medrano F, Fernández-Ruiz M, et al. Should asymptomatic bacteriuria be systematically treated in kidney transplant recipients? Results from a randomized

controlled trial. American Journal of Transplantation. 2016;**16**:2943-2953

tional outcome. Transplant Infectious Disease. 2012;**14**:57

44 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

recipients. BioMed Research International. 2013;**2013**:687156

uria in adults. Clinical Infectious Diseases. 2005;**40**(5):643-654

Transplant Infectious Disease. 2011;**13**:441-447

2011;**26**:4109-4114

Diseases. 1994;**13**(Suppl 1):S17

Pharmacotherapy. 2011;**45**:309

2013;**13**(Suppl 4):327-336

**78**(8):774-781

2012;**55**:771-777

2006;**6**:2375-2383


**Chapter 4**

**Provisional chapter**

**Urinary Tract Infection in Renal Allograft Recipents**

Renal replacement therapy in the form of renal transplantation (RT) is the treatment of choice in these patients. Various factors influence the graft survival, infections being most common. Infections account for 16% of patient deaths and 7.7% of death censored graft failure in renal transplant patients. Urinary tract infection (UTI) is the most common infectious complication accounting for 45–72% of all infections. According to few studies UTI may have a negative impact over the long term survival of renal allograft. There are multiple factors that predispose these patients to UTI. Elderly age group, female gender, increased duration of catheterization and anatomical abnormalities of the urinary tract are most common predisposing factors. E. coli is the most frequently isolated organisms from the urine of these patients. We would proceed further with two cases which presented as UTI in post-transplant period. The first patient transplanted (living donor related) for diabetes induced end stage renal disease had developed UTI 4 years posttransplant. The other patient underwent deceased donor renal transplant for adult polycystic disease related chronic kidney disease, presented 2 years post-transplant with UTI. **Keywords:** renal transplantation, urinary tract infection, renal allograft, graft function,

**Clinical information (Case 1):** A 53-year-old male patient, with a history of arterial hypertension, type 2 diabetes mellitus, and renal failure, caused by diabetic nephropathy diagnosed 5 years back and was on maintenance hemodialysis. The patient underwent live donor renal transplantation in June 2013. The intraoperative and post-operative period was unremarkable

**Urinary Tract Infection in Renal Allograft Recipents**

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.77171

Lovelesh Kumar Nigam, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and

Lovelesh Kumar Nigam, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77171

Kamlesh S. Suthar

Kamlesh S. Suthar

**Abstract**

immunosuppression

**1. Introduction**

#### **Urinary Tract Infection in Renal Allograft Recipents Urinary Tract Infection in Renal Allograft Recipents**

DOI: 10.5772/intechopen.77171

Lovelesh Kumar Nigam, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and Kamlesh S. Suthar Lovelesh Kumar Nigam, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and Kamlesh S. Suthar

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77171

#### **Abstract**

Renal replacement therapy in the form of renal transplantation (RT) is the treatment of choice in these patients. Various factors influence the graft survival, infections being most common. Infections account for 16% of patient deaths and 7.7% of death censored graft failure in renal transplant patients. Urinary tract infection (UTI) is the most common infectious complication accounting for 45–72% of all infections. According to few studies UTI may have a negative impact over the long term survival of renal allograft. There are multiple factors that predispose these patients to UTI. Elderly age group, female gender, increased duration of catheterization and anatomical abnormalities of the urinary tract are most common predisposing factors. E. coli is the most frequently isolated organisms from the urine of these patients. We would proceed further with two cases which presented as UTI in post-transplant period. The first patient transplanted (living donor related) for diabetes induced end stage renal disease had developed UTI 4 years posttransplant. The other patient underwent deceased donor renal transplant for adult polycystic disease related chronic kidney disease, presented 2 years post-transplant with UTI.

**Keywords:** renal transplantation, urinary tract infection, renal allograft, graft function, immunosuppression

## **1. Introduction**

**Clinical information (Case 1):** A 53-year-old male patient, with a history of arterial hypertension, type 2 diabetes mellitus, and renal failure, caused by diabetic nephropathy diagnosed 5 years back and was on maintenance hemodialysis. The patient underwent live donor renal transplantation in June 2013. The intraoperative and post-operative period was unremarkable

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

and he was put on Tacrolimus based immunosuppression thereafter consisting of Prednisone (20 mg/day), Mycophenolate sodium (360 mg/day), and Tacrolimus (1.5 mg/day level:4.6 ng/ ml). He was on regular follow-up for routine urine examination, serum creatinine and serum electrolytes and hemogram. Nearly 4 years post-transplant he was admitted with complaints of low grade intermittent febrile episodes and painful micturition. There was slight rise in the serum creatinine levels to 2.4 mg/dL (baseline: 1.8 mg/dL). The urine output was however normal. Complete blood count performed revealed neutrophilic leukocytosis with total count of 14.2 × 10 <sup>6</sup> /μl, with predominance of neutrophils on differential, the absolute neutrophil count of 14 × 10 <sup>6</sup> /μl. Urine examination revealed urine albumin of +1 by dipstick method, pH of 5.0 and specific gravity of 1.020. **Clinical information (Case 2):** A 38-year-old female patient, underwent deceased donor renal transplantation for adult polycystic kidney disease induced chronic kidney disease. The intraoperative and post-operative period was unremarkable and she was on conventional Tacrolimus based immunosuppression thereafter consisting of Prednisone (20 mg/day), Mycophenolate sodium (360 mg/day), and Tacrolimus (1.5 mg/day; level:6.8 ng/dL). She was on regular monitoring for routine urine examination, renal function tests and complete blood counts. Nearly 2 years post-transplant she was admitted with complaints of intermittent high grade febrile episodes, pain in abdomen and nausea. The serum creatinine level at the time of presentation was found to be raised to 3.6 mg/dL (baseline: 1.2 mg/dL). The patient had normal urine output. Complete blood count performed revealed neutrophilic leukocytosis with total count of 18.6 × 10<sup>6</sup> /μl, with predominance of neutrophils on differential, the absolute neutrophil count of 12 × 10<sup>6</sup> /μl. Urine examination revealed urine albumin of +2 by dipstick method, pH of 4.6 and specific gravity of 1.040. **Summary**: So here we have two patients who underwent renal transplant for end stage renal disease and presented with signs and symptoms of urinary tract infection. Both the patients presented with rise in serum creatinine as well as pyuria on urine examination(not written in the text above)clinical suspicion of urinary tract infection. We would in further sections study how we proceeded with both the cases, investigations performed and management of both. In this brief review we would discuss the incidence of urinary tract infection in post-transplant patients, risk factors and how to manage a case with UTI.

**1.2. Burden of the disease**

transplantation [22].

RT patients [23–25].

infection of the upper urinary tract.

**transplant recipients**

**1.3. Definition and diagnostic criteria for UTI**

quantitative counts of ≥102 CFU/mL in a single specimen.

**2. Risk factors associated with development of UTI in renal** 

UTI is the most common type of hospital-acquired infection, accounting for nearly 40–50% of all infectious complications among RT patients followed by viral infections, pneumonia and surgical site infections [8, 9]. As per the data from Spanish Network for the Study of Infections in Transplantation (RESITRA) the incidence of cystitis per 100 recipient-years was 13.84 for renal, 3.09 for liver, 2.41 for heart and 1.36 for lung transplant recipients [10]. The incidence of pyelonephritis per 100 recipient-years was 3.66 for renal, 0.8 for liver, 0.3 for heart and 0.6 for lung transplant recipients. UTI-associated bacteremia was seen in 39% of renal, 3% of liver, 3% of heart and none of the lung transplant recipients [11, 12]. The prevalence of UTI in RT patients ranges from 13 to 80% according to various studies [1, 2, 6, 13–16]. Few authors have also reported an incidence as low as 4% to as high as 75% [17–20]. The vast difference could however be attributed largely due to lack of uniform diagnostic criteria to define UTI, implementation of prophylactic regimen and ill-defined period of follow-up. The incidence of UTI in the early post-transplant period (first 6 months) is higher as compared to late periods. However it is this early occurrence of UTI that has a profound effect over the allograft survival. Nearly 84% of symptomatic UTI cases are recorded in the first 6 months after transplant [21].

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 49

Recurrent UTI is also one of the major cause that poses threat to renal allograft and the prevalence ranges from 2.9 to 27% in renal transplant recipients. Mohammad et al. reported an incidence of recurrent UTI in nearly 51.7% patients who underwent renal

A urinary tract infection is an infection causing signs and symptoms of cystitis or pyelonephritis (including the presence of signs of systemic inflammation), which is documented to be caused by an infectious agent. The diagnostic criteria for UTI are similar to those that are used for general population, however all symptomatic UTI are considered as complicated UTI in

Pain and tenderness over the renal allograft or costovertebral region indicates symptomatic

Asymptomatic bacteriuria in women is defined as two consecutive clean-catch voided urine specimens >24 hours apart with isolation of the same organism in quantitative counts of ≥105 CFU/mL. However in males a single clean catch urine specimen with isolation of single organism in quantitative counts of ≥105 CFU/mL is regarded as asymptomatic bacteriuria. In case of urethral catheterization bacteriuria is defined as isolation of a single organism in

Post-transplant UTI in renal allograft recipients is of multifactorial origin and is determined by interaction between host factors, abnormalities associated with the anatomy of the urinary tract and the virulence of the pathogenic organisms. A few common extensively studied

#### **1.1. Incidence of posttransplant urinary tract infections**

Transplantation has become the gold standard treatment of end-stage disease in the present era. Of all the organs that are transplanted, kidneys remain the most frequently transplanted organ [1–5]. RT is regarded as an effective treatment for patients with advanced chronic renal disease [1, 2]. Over the years various studies have been carried out globally to understand the factors that influence the graft function [1]. Multiple factors including technical expertise, donor-recipients related demographics, immunosuppressive regimens, infections, comorbid conditions have been implicated to influence the graft survival [1–3]. Infections are a common cause of morbidity and mortality after transplantation and it is widely known that RT patients have poor resistance to infection [4, 5]. Infections have been ranked second, as a cause of death in RT patients. According to the U.S. Renal Data System, the rate of first infection in the initial 3 years after kidney transplantation is reported to be 45.0 per 100 patient-years of follow-up. It has been postulated that in immunocompromised RT recipients, UTI is the most common infection that affects the graft function and is held responsible for longer hospital stay and increased health care cost [3, 6, 7]. Becerra et al. stated that the length of stay in patients who develop UTI is 74 and 76% higher in men and women renal transplant recipients respectively, when compared to those without UTI [8].

## **1.2. Burden of the disease**

and he was put on Tacrolimus based immunosuppression thereafter consisting of Prednisone (20 mg/day), Mycophenolate sodium (360 mg/day), and Tacrolimus (1.5 mg/day level:4.6 ng/ ml). He was on regular follow-up for routine urine examination, serum creatinine and serum electrolytes and hemogram. Nearly 4 years post-transplant he was admitted with complaints of low grade intermittent febrile episodes and painful micturition. There was slight rise in the serum creatinine levels to 2.4 mg/dL (baseline: 1.8 mg/dL). The urine output was however normal. Complete blood count performed revealed neutrophilic leukocytosis with total

48 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

method, pH of 5.0 and specific gravity of 1.020. **Clinical information (Case 2):** A 38-year-old female patient, underwent deceased donor renal transplantation for adult polycystic kidney disease induced chronic kidney disease. The intraoperative and post-operative period was unremarkable and she was on conventional Tacrolimus based immunosuppression thereafter consisting of Prednisone (20 mg/day), Mycophenolate sodium (360 mg/day), and Tacrolimus (1.5 mg/day; level:6.8 ng/dL). She was on regular monitoring for routine urine examination, renal function tests and complete blood counts. Nearly 2 years post-transplant she was admitted with complaints of intermittent high grade febrile episodes, pain in abdomen and nausea. The serum creatinine level at the time of presentation was found to be raised to 3.6 mg/dL (baseline: 1.2 mg/dL). The patient had normal urine output. Complete blood count performed

revealed urine albumin of +2 by dipstick method, pH of 4.6 and specific gravity of 1.040. **Summary**: So here we have two patients who underwent renal transplant for end stage renal disease and presented with signs and symptoms of urinary tract infection. Both the patients presented with rise in serum creatinine as well as pyuria on urine examination(not written in the text above)clinical suspicion of urinary tract infection. We would in further sections study how we proceeded with both the cases, investigations performed and management of both. In this brief review we would discuss the incidence of urinary tract infection in post-transplant

Transplantation has become the gold standard treatment of end-stage disease in the present era. Of all the organs that are transplanted, kidneys remain the most frequently transplanted organ [1–5]. RT is regarded as an effective treatment for patients with advanced chronic renal disease [1, 2]. Over the years various studies have been carried out globally to understand the factors that influence the graft function [1]. Multiple factors including technical expertise, donor-recipients related demographics, immunosuppressive regimens, infections, comorbid conditions have been implicated to influence the graft survival [1–3]. Infections are a common cause of morbidity and mortality after transplantation and it is widely known that RT patients have poor resistance to infection [4, 5]. Infections have been ranked second, as a cause of death in RT patients. According to the U.S. Renal Data System, the rate of first infection in the initial 3 years after kidney transplantation is reported to be 45.0 per 100 patient-years of follow-up. It has been postulated that in immunocompromised RT recipients, UTI is the most common infection that affects the graft function and is held responsible for longer hospital stay and increased health care cost [3, 6, 7]. Becerra et al. stated that the length of stay in patients who develop UTI is 74 and 76% higher in men and women renal transplant recipients respectively, when compared to those without UTI [8].

revealed neutrophilic leukocytosis with total count of 18.6 × 10<sup>6</sup>

patients, risk factors and how to manage a case with UTI.

**1.1. Incidence of posttransplant urinary tract infections**

neutrophils on differential, the absolute neutrophil count of 12 × 10<sup>6</sup>

/μl, with predominance of neutrophils on differential, the absolute neu-

/μl. Urine examination revealed urine albumin of +1 by dipstick

/μl, with predominance of

/μl. Urine examination

count of 14.2 × 10 <sup>6</sup>

trophil count of 14 × 10 <sup>6</sup>

UTI is the most common type of hospital-acquired infection, accounting for nearly 40–50% of all infectious complications among RT patients followed by viral infections, pneumonia and surgical site infections [8, 9]. As per the data from Spanish Network for the Study of Infections in Transplantation (RESITRA) the incidence of cystitis per 100 recipient-years was 13.84 for renal, 3.09 for liver, 2.41 for heart and 1.36 for lung transplant recipients [10]. The incidence of pyelonephritis per 100 recipient-years was 3.66 for renal, 0.8 for liver, 0.3 for heart and 0.6 for lung transplant recipients. UTI-associated bacteremia was seen in 39% of renal, 3% of liver, 3% of heart and none of the lung transplant recipients [11, 12]. The prevalence of UTI in RT patients ranges from 13 to 80% according to various studies [1, 2, 6, 13–16]. Few authors have also reported an incidence as low as 4% to as high as 75% [17–20]. The vast difference could however be attributed largely due to lack of uniform diagnostic criteria to define UTI, implementation of prophylactic regimen and ill-defined period of follow-up. The incidence of UTI in the early post-transplant period (first 6 months) is higher as compared to late periods. However it is this early occurrence of UTI that has a profound effect over the allograft survival. Nearly 84% of symptomatic UTI cases are recorded in the first 6 months after transplant [21].

Recurrent UTI is also one of the major cause that poses threat to renal allograft and the prevalence ranges from 2.9 to 27% in renal transplant recipients. Mohammad et al. reported an incidence of recurrent UTI in nearly 51.7% patients who underwent renal transplantation [22].

## **1.3. Definition and diagnostic criteria for UTI**

A urinary tract infection is an infection causing signs and symptoms of cystitis or pyelonephritis (including the presence of signs of systemic inflammation), which is documented to be caused by an infectious agent. The diagnostic criteria for UTI are similar to those that are used for general population, however all symptomatic UTI are considered as complicated UTI in RT patients [23–25].

Pain and tenderness over the renal allograft or costovertebral region indicates symptomatic infection of the upper urinary tract.

Asymptomatic bacteriuria in women is defined as two consecutive clean-catch voided urine specimens >24 hours apart with isolation of the same organism in quantitative counts of ≥105 CFU/mL. However in males a single clean catch urine specimen with isolation of single organism in quantitative counts of ≥105 CFU/mL is regarded as asymptomatic bacteriuria. In case of urethral catheterization bacteriuria is defined as isolation of a single organism in quantitative counts of ≥102 CFU/mL in a single specimen.

## **2. Risk factors associated with development of UTI in renal transplant recipients**

Post-transplant UTI in renal allograft recipients is of multifactorial origin and is determined by interaction between host factors, abnormalities associated with the anatomy of the urinary tract and the virulence of the pathogenic organisms. A few common extensively studied factors are listed below. Few studies have found strong correlation of increased predilection to development of UTI, whereas other researchers have not been able to prove the association.

by Ostaszewaska et al., R.Parasuraman et al., Camargo et al., Orhan Deniz Kara et al. and

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 51

HLA compatibility and association with UTI was studied by Ostaszewaska et al. They observed that individuals with more than four HLA mismatches are more likely to develop UTI [28]. Patients who develop rejection episodes show increased incidence of UTI. These individuals are subjected to increased dosages of immunosuppression which may likely predispose these individuals to increased risk of developing UTI [9]. Moradi et al. evaluated the relationship between UTI and biopsy proven chronic rejection in a cohort of 100 patients over a period of 5 years. They concluded that patients with chronic rejection had more episodes of

Apart from the important factors listed above, various other factors have been implicated in developing UTI. Older age has been related to an increased risk for UTI. The same study reported that an increase of 5 years in age at transplant increased the risk for UTI. Benign prostatic hyperplasia and menopause, was an additional risk factor for developing UTI [26, 37, 38]. Delayed graft function (DGF), usually associated with deceased donor organ transplant has been documented as a risk factor for development of UTI [9]. Study reported that occurrence of DGF strongly correlates with the incidence of UTI, with 61.8% patients with UTI developing delayed graft function [28]. Other factors that have been implicated are presence of comorbid conditions like hypertension and diabetes, prolonged cold ischemia time, serum

The most common type of UTI is bacterial followed by fungi and rarely viruses are implicated in pathogenesis of UTI. Gram negative bacteria are the most common pathogens cultured from the urine of renal transplant patients with UTI, followed by candida and viruses.

*E. coli* is the most common, accounting for more than 70% of the cases. Enterobacteriaceae, *Enterococci*, *Pseudomonas* and coagulase-negative *staphylococci* are other common agents. Mycobacterium tuberculosis, Salmonella and Mycoplasma are encountered rarely [2, 6, 38, 41, 42]. A retrospective study by Espinar MJ et al., showed that renal allograft recipients are particularly susceptible to infection by Enterobacteriaceae-producing extended-spectrum β-lactamases (ESBLs). Diabetes mellitus, previous antibiotic prophylaxis or therapy, previous UTI, relapsing infection and patients with delayed graft function after transplant represented risk factors for infection by ESBL positive Enterobacteriaceae. It was also observed that these patients present

creatinine levels of >2 mg/dL and chronic viral infections [6, 14, 26–28, 35, 37, 39].

**3. Etiology of UTI in renal transplant patients**

**2.6. Human leucocyte antigen (HLA) match and rejection episodes**

Abdulmalik MA et al. [2, 26, 28, 37, 38].

UTI as compared to those without rejection [39].

**2.7. Other proposed factors**

**3.1. Etiological agents**

**3.2. Bacteria**

#### **2.1. Gender**

Most of the studies show that incidence of UTI is more common in females as compared to male patients who undergo renal transplantation [12]. The mean distance from the urethra to anus is less in females as compared to males, which leads to increased susceptibility for vaginal colonization with uropathogens [14, 26]. Menegueti et al. reported female sex as the only risk factor for post-transplant UTI [27]. Camargo et al. also reported a higher incidence of UTI in female patients [44.4%], despite higher prevalence of male patients in the study. However few studies do report a higher incidence of UTI in males. This could be due to the larger number of male patients receiving transplant in majority of the cohorts [8]. It is well documented that women with recurrent UTI have increased susceptibility to vaginal colonization with uropathogens. Sexual intercourse, using spermicidal products, maternal history of UTI and UTI at an early age predispose these patients to recurrent infections of the urogenital tract [1].

#### **2.2. Catheterization and presence of ureteral stent**

It has been observed that increased hospital stay and late removal of the catheter is an independent risk factor for developing UTI [1]. Ostaszewaska et al. reported a strong correlation between occurrence of UTI and length of hospital stay [28]. Stamm et al. reported that the risk of UTI in renal allograft recipients is more by approximately 5% with each day of bladder catheterization [29]. Dantass et al. also had similar observations [30]. Fayek et al. report a higher rate of UTI of 14.2% in transplant recipients with stents as compared to 7.9% without stent [31].

#### **2.3. Anatomical abnormalities**

Structural abnormalities of native or transplanted kidney predisposes to increased risk of developing UTI [1, 2]. The anatomical abnormalities could be vesicoureteral reflux, neurogenic bladder or presence of benign prostatic hyperplasia, are usually associated to increased risk for developing UTI [14, 28, 29].

#### **2.4. Immunosuppressants**

A wide variety of immunosuppressants are used in transplant medicine either as induction agents or for maintenance therapy. Recipients subjected to antimetabolite (azathioprine or mycophenolate mofetil) and induction therapy with cell depleting antibodies (antithymocyte globulin) are reported to have higher incidence of UTI [1, 32–34]. Prednisone dose of >20 mg/ day and multiple rejection therapies are associated with increased risk [35].

#### **2.5. Deceased versus living donor transplants**

It has been documented by various studies that the incidence of UTI is more in patients who receive kidney from deceased donor as compared to living donor. Taminato et al., reported that there is a greater risk for the patients who receive organ from deceased donor as against recipients of living donor with an odds ratio of 2.65 [36]. Similar observations were reported by Ostaszewaska et al., R.Parasuraman et al., Camargo et al., Orhan Deniz Kara et al. and Abdulmalik MA et al. [2, 26, 28, 37, 38].

## **2.6. Human leucocyte antigen (HLA) match and rejection episodes**

HLA compatibility and association with UTI was studied by Ostaszewaska et al. They observed that individuals with more than four HLA mismatches are more likely to develop UTI [28]. Patients who develop rejection episodes show increased incidence of UTI. These individuals are subjected to increased dosages of immunosuppression which may likely predispose these individuals to increased risk of developing UTI [9]. Moradi et al. evaluated the relationship between UTI and biopsy proven chronic rejection in a cohort of 100 patients over a period of 5 years. They concluded that patients with chronic rejection had more episodes of UTI as compared to those without rejection [39].

## **2.7. Other proposed factors**

factors are listed below. Few studies have found strong correlation of increased predilection to development of UTI, whereas other researchers have not been able to prove the association.

50 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Most of the studies show that incidence of UTI is more common in females as compared to male patients who undergo renal transplantation [12]. The mean distance from the urethra to anus is less in females as compared to males, which leads to increased susceptibility for vaginal colonization with uropathogens [14, 26]. Menegueti et al. reported female sex as the only risk factor for post-transplant UTI [27]. Camargo et al. also reported a higher incidence of UTI in female patients [44.4%], despite higher prevalence of male patients in the study. However few studies do report a higher incidence of UTI in males. This could be due to the larger number of male patients receiving transplant in majority of the cohorts [8]. It is well documented that women with recurrent UTI have increased susceptibility to vaginal colonization with uropathogens. Sexual intercourse, using spermicidal products, maternal history of UTI and UTI at an early age predispose these patients to recurrent infections of the urogenital tract [1].

It has been observed that increased hospital stay and late removal of the catheter is an independent risk factor for developing UTI [1]. Ostaszewaska et al. reported a strong correlation between occurrence of UTI and length of hospital stay [28]. Stamm et al. reported that the risk of UTI in renal allograft recipients is more by approximately 5% with each day of bladder catheterization [29]. Dantass et al. also had similar observations [30]. Fayek et al. report a higher rate of UTI of 14.2% in transplant recipients with stents as compared to 7.9% without stent [31].

Structural abnormalities of native or transplanted kidney predisposes to increased risk of developing UTI [1, 2]. The anatomical abnormalities could be vesicoureteral reflux, neurogenic bladder or presence of benign prostatic hyperplasia, are usually associated to increased

A wide variety of immunosuppressants are used in transplant medicine either as induction agents or for maintenance therapy. Recipients subjected to antimetabolite (azathioprine or mycophenolate mofetil) and induction therapy with cell depleting antibodies (antithymocyte globulin) are reported to have higher incidence of UTI [1, 32–34]. Prednisone dose of >20 mg/

It has been documented by various studies that the incidence of UTI is more in patients who receive kidney from deceased donor as compared to living donor. Taminato et al., reported that there is a greater risk for the patients who receive organ from deceased donor as against recipients of living donor with an odds ratio of 2.65 [36]. Similar observations were reported

day and multiple rejection therapies are associated with increased risk [35].

**2.1. Gender**

**2.2. Catheterization and presence of ureteral stent**

**2.3. Anatomical abnormalities**

risk for developing UTI [14, 28, 29].

**2.5. Deceased versus living donor transplants**

**2.4. Immunosuppressants**

Apart from the important factors listed above, various other factors have been implicated in developing UTI. Older age has been related to an increased risk for UTI. The same study reported that an increase of 5 years in age at transplant increased the risk for UTI. Benign prostatic hyperplasia and menopause, was an additional risk factor for developing UTI [26, 37, 38]. Delayed graft function (DGF), usually associated with deceased donor organ transplant has been documented as a risk factor for development of UTI [9]. Study reported that occurrence of DGF strongly correlates with the incidence of UTI, with 61.8% patients with UTI developing delayed graft function [28]. Other factors that have been implicated are presence of comorbid conditions like hypertension and diabetes, prolonged cold ischemia time, serum creatinine levels of >2 mg/dL and chronic viral infections [6, 14, 26–28, 35, 37, 39].

## **3. Etiology of UTI in renal transplant patients**

## **3.1. Etiological agents**

The most common type of UTI is bacterial followed by fungi and rarely viruses are implicated in pathogenesis of UTI. Gram negative bacteria are the most common pathogens cultured from the urine of renal transplant patients with UTI, followed by candida and viruses.

## **3.2. Bacteria**

*E. coli* is the most common, accounting for more than 70% of the cases. Enterobacteriaceae, *Enterococci*, *Pseudomonas* and coagulase-negative *staphylococci* are other common agents. Mycobacterium tuberculosis, Salmonella and Mycoplasma are encountered rarely [2, 6, 38, 41, 42]. A retrospective study by Espinar MJ et al., showed that renal allograft recipients are particularly susceptible to infection by Enterobacteriaceae-producing extended-spectrum β-lactamases (ESBLs). Diabetes mellitus, previous antibiotic prophylaxis or therapy, previous UTI, relapsing infection and patients with delayed graft function after transplant represented risk factors for infection by ESBL positive Enterobacteriaceae. It was also observed that these patients present early with UTI and exhibit higher resistance to fluoroquinolones, trimethoprim-sulfamethoxazole and gentamicin. Pourmand MR et al. and Tawab et al. studied renal transplant recipients who developed recurrent UTI. *E. coli* was the most common cultured organism from the urine of patients with recurrent UTI. Coagulase negative staphylococci and Bacillus were rare [2, 9, 22].

## **3.3. Fungus**

Candida is the most common cause for UTI in renal transplant recipients and is usually asymptomatic. Serious complications can occur following ascending infections. Fungal balls can be formed that may cause obstruction at the ureterovesical junction [2, 3, 43].

#### **3.4. Viruses**

The most common viruses that cause viral UTI in a renal transplant patient are cytomegalovirus and type 1 human polyomavirus (BKV). Clinically they present with fever, acute graft rejection, tubulointerstitial nephropathy and renal vascular disease. BKV-associated nephropathy may be a frequent cause of recurrent post-transplant infections and these patients usually present as sterile pyuria, eosinophiluria and hematuria. Ureteral cell hyperplasia leading to ureteral obstruction has also been reported [2, 3, 40–43].

#### **3.5.** *Schistosoma haematobium*

Trematode involves the urinary tract and kidney, and the diagnosis is based on the visualization of parasite ova in urine specimens. The urine should be collected close to noon, when egg excretion is maximal. Reactivation of a prior infection due to immunosuppression has been described in solid organ transplant recipients. Any solid organ transplant recipient from an endemic at riskarea developing hematuria (with or without eosinophilia) should have urine examined to rule out the infection. *S. haematobium* should be treated with praziquantel both in the pre and posttransplant period, as chronic infection can lead to squamous cell carcinoma of the bladder [44].

#### *3.5.1. Causative organisms and identification of the organisms in our cases*

*Case 1:The microscopic examination of the urine sediment revealed plenty of pus cells with occasional red blood cells and bacilli. (***Figure 1***). Urine culture study was performed. On nutrient agar large, circular, low convex, grayish, white, moist, smooth and opaque colonies were observed. On MacConkey Agar media the colonies were circular, moist, smooth, and pink and found to be lactose fermenting. (***Figure 1a***) On Gram's stain, pink gram negative rods were identified. (***Figure 1b***) The sample was further subjected to VITEK 2 system for identification and culture sensitivity. Escherichia coli was identified as the causative organism with sensitivity to Piperacillin/ Tazobactum, Sulbactum, Imipenem, Meropenem, Amikacin, Colistin, Levofloxacin and Minocycline. However resistance to Trimetoprim/ Sulfamethoxazole, Gentamycin and Cefepime was observed.*

*The patient was treated with intravenous administration of Cefoparazone-salbactam and Levofloxacin for 7 days. Urine routine and culture sensitivity studies were performed on sixth day. There was reduction in the total leucocyte count to 8.4 × 106 /μl, with normal differential count. The serum creatinine level dropped from 2.4 to 1.8 mg/dL on seventh day. Urine routine microscopic examination revealed* 

*scattered 15–20 WBC/ hpf. The patient was shifted to oral antibiotics for next 3 days. The immunosuppression regimen constituted of Tacrolimus, Prednisone and Mycophenolate sodium. No tapering of the drugs was done. Urine examination and culture studies were negative thereafter. The patient responded well to the treatment and is on regular follow-up. His present serum creatinine is 1.8 mg/dL, 4 months* 

stain, these bacilli appeared to be as pink gram negative rods (Gram's stain, x 400).

**Figure 1.** Urine microscopy stained with hematoxylin and eosin stain shows plenty of leucocytes and few bacilli. (Hematoxylin and eosin, x 400). (a) MacConkey agar media with circular, moist, smooth, and lactose fermenting pink colonies. The left upper quadrant is the patient sample and right upper quadrant depicts the positive control. (b) Gram's

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 53

early with UTI and exhibit higher resistance to fluoroquinolones, trimethoprim-sulfamethoxazole and gentamicin. Pourmand MR et al. and Tawab et al. studied renal transplant recipients who developed recurrent UTI. *E. coli* was the most common cultured organism from the urine of patients with recurrent UTI. Coagulase negative staphylococci and Bacillus were rare [2, 9, 22].

Candida is the most common cause for UTI in renal transplant recipients and is usually asymptomatic. Serious complications can occur following ascending infections. Fungal balls

The most common viruses that cause viral UTI in a renal transplant patient are cytomegalovirus and type 1 human polyomavirus (BKV). Clinically they present with fever, acute graft rejection, tubulointerstitial nephropathy and renal vascular disease. BKV-associated nephropathy may be a frequent cause of recurrent post-transplant infections and these patients usually present as sterile pyuria, eosinophiluria and hematuria. Ureteral cell hyperplasia leading

Trematode involves the urinary tract and kidney, and the diagnosis is based on the visualization of parasite ova in urine specimens. The urine should be collected close to noon, when egg excretion is maximal. Reactivation of a prior infection due to immunosuppression has been described in solid organ transplant recipients. Any solid organ transplant recipient from an endemic at riskarea developing hematuria (with or without eosinophilia) should have urine examined to rule out the infection. *S. haematobium* should be treated with praziquantel both in the pre and posttransplant period, as chronic infection can lead to squamous cell carcinoma of the bladder [44].

*Case 1:The microscopic examination of the urine sediment revealed plenty of pus cells with occasional red blood cells and bacilli. (***Figure 1***). Urine culture study was performed. On nutrient agar large, circular, low convex, grayish, white, moist, smooth and opaque colonies were observed. On MacConkey Agar media the colonies were circular, moist, smooth, and pink and found to be lactose fermenting. (***Figure 1a***) On Gram's stain, pink gram negative rods were identified. (***Figure 1b***) The sample was further subjected to VITEK 2 system for identification and culture sensitivity. Escherichia coli was identified as the causative organism with sensitivity to Piperacillin/ Tazobactum, Sulbactum, Imipenem, Meropenem, Amikacin, Colistin, Levofloxacin and Minocycline. However resistance to Trimetoprim/* 

*The patient was treated with intravenous administration of Cefoparazone-salbactam and Levofloxacin for 7 days. Urine routine and culture sensitivity studies were performed on sixth day. There was reduc-*

*level dropped from 2.4 to 1.8 mg/dL on seventh day. Urine routine microscopic examination revealed* 

*/μl, with normal differential count. The serum creatinine* 

can be formed that may cause obstruction at the ureterovesical junction [2, 3, 43].

52 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

to ureteral obstruction has also been reported [2, 3, 40–43].

*3.5.1. Causative organisms and identification of the organisms in our cases*

*Sulfamethoxazole, Gentamycin and Cefepime was observed.*

*tion in the total leucocyte count to 8.4 × 106*

**3.5.** *Schistosoma haematobium*

**3.3. Fungus**

**3.4. Viruses**

**Figure 1.** Urine microscopy stained with hematoxylin and eosin stain shows plenty of leucocytes and few bacilli. (Hematoxylin and eosin, x 400). (a) MacConkey agar media with circular, moist, smooth, and lactose fermenting pink colonies. The left upper quadrant is the patient sample and right upper quadrant depicts the positive control. (b) Gram's stain, these bacilli appeared to be as pink gram negative rods (Gram's stain, x 400).

*scattered 15–20 WBC/ hpf. The patient was shifted to oral antibiotics for next 3 days. The immunosuppression regimen constituted of Tacrolimus, Prednisone and Mycophenolate sodium. No tapering of the drugs was done. Urine examination and culture studies were negative thereafter. The patient responded well to the treatment and is on regular follow-up. His present serum creatinine is 1.8 mg/dL, 4 months*  *after the episode of urinary tract infection.Case 2:The microscopic examination of the urine sediment revealed clusters of pus cells, scattered epithelial cells and fungal buds and pseudohyphae. (***Figure 2***) Urine culture study was performed on Sabouraud's dextrose agar. 65 g of the media was suspended in distilled water, mixed to form a uniform suspension, heated, boiled and then sterilized at 118–121°C for 15 min. The urine sample was streaked using inoculating loop and incubated in 37°C for 48 hours. The growth appeared in 48 hours as cream/white colored, smooth and pasty colonies. (***Figure 2a***). A drop of inoculated broth media was placed onto the slide and a drop of lactophenol cotton blue stain was added and examined under the microscope which revealed the presence of chlamydospores. (***Figure 2b***).*

**4. UTI and effect on renal allograft function**

development of nosocomial infection [2, 8].

**4.2. Effect on graft function**

rejection process [13].

**4.1. Negative impact of urinary tract infections in renal transplant recipients**

survival. Mortality rate in patients with UTI was reported as 12.9% [9].

cantly associated with an increased risk of subsequent death and graft loss [45].

95% CI 0.37 to 4.08) or late UTI (relative risk 2.22; 95% CI 0.90 to 5.44) [46].

It has been well documented that development of UTI in renal transplant recipients is associated with increased rates of health resource utilization, which includes length of stay as well as more economic burden. Longer hospital stay exposes these individuals to increased risk of

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 55

Mohan et al., in their prospective study of 31 patients who underwent renal transplantation, found that infections in the immediate post-transplant period adversely affected the graft

Abbott and colleagues undertook a retrospective cohort study of 28,942 Medicare primary renal transplant recipients in the U.S. Renal Data System database from 1996 through 2000, assessing Medicare claims for UTI occurring later than 6 months after transplantation based on ICD-9 codes, and found that the cumulative incidence of UTI during the first 6 months after renal transplantation was 17% (equivalent for both men and women) and at 3 years was 60% for women and 47% for men ( < 0.001 in Cox regression analysis). Late UTI was signifi-

In a study by Dhamidharka et al., who analyzed US Renal Data System database over the period of 1996 to 2000 (up to 36 months post-transplant). 265 (30.5%) pediatric patients had either inpatient or outpatient claims for UTI out of total 870 pediatric patients who qualified for the study. The authors found that early UTI (less than 6 months after transplant) was significantly [ = 0.007 upon multivariable Cox regression] associated with higher adjusted hazard ratio of graft loss, and late UTI was not associated with such an outcome. Risk for post-transplantation death was not increased significantly after either early UTI (AHR 1.23;

Pelle, et al. as well as Giral et al. reported that acute pyelonephritis of the graft is accompanied by renal failure and is an independent risk factor for impaired renal function as well as graft loss [47, 48]. Bodro et al. reported 1-year mortality rate of 3% in patients who developed worsening of graft function secondary to graft acute pyelonephritis. They further discovered that in patients with UTI due to a resistant strain of bacteria, the impairment of graft function is more frequent than in patients who develop UTI due to nonresistant strain bacteria [13]. Several hypotheses have been put forward to explain the negative impact of UTI on graft function. It has been postulated that bacterial infection activated the immune system, which can trigger the rejection cascades leading to acute or chronic rejections, causing deterioration of the graft function. Some authors propose that inflammation secondary to infection can cause scarring of the renal tissue, leading to loss of the functioning nephron mass causing impairment of renal function [49–51]. Reduction in the immunosuppressive agents following an episode of infection may accentuate the

*The patient was treated with oral antifungal agent, fluconazole, 100 mg/day for 21 days along with conventional Tacrolimus-based immunosuppressive regimen. Urine routine and culture sensitivity studies were performed on tenth day. There was reduction in the total leucocyte count to 6.35 x 10 <sup>6</sup> /μl, with normal differential count. The serum creatinine level dropped to 1.6 mg/dL. Urine examination and culture studies were negative thereafter. The patient responded well to the treatment and is on regular follow-up. Her present serum creatinine is 1.76 mg/dL, 4 months after the episode of urinary tract infection.*

**Figure 2.** Hematoxylin and eosin stained urine deposit reveals budding fungi along with pseudohyphae. (a) Creamy and smooth colonies of candida on Sabouraud's dextrose agar (red arrow). (b) Lactophenol cotton blue (wet preparation) reveals budding fungi (LCB, X 400)with chlamydospores (LCB, X 1000).

## **4. UTI and effect on renal allograft function**

## **4.1. Negative impact of urinary tract infections in renal transplant recipients**

It has been well documented that development of UTI in renal transplant recipients is associated with increased rates of health resource utilization, which includes length of stay as well as more economic burden. Longer hospital stay exposes these individuals to increased risk of development of nosocomial infection [2, 8].

## **4.2. Effect on graft function**

*after the episode of urinary tract infection.Case 2:The microscopic examination of the urine sediment revealed clusters of pus cells, scattered epithelial cells and fungal buds and pseudohyphae. (***Figure 2***) Urine culture study was performed on Sabouraud's dextrose agar. 65 g of the media was suspended in distilled water, mixed to form a uniform suspension, heated, boiled and then sterilized at 118–121°C for 15 min. The urine sample was streaked using inoculating loop and incubated in 37°C for 48 hours. The growth appeared in 48 hours as cream/white colored, smooth and pasty colonies. (***Figure 2a***). A drop of inoculated broth media was placed onto the slide and a drop of lactophenol cotton blue stain was added and examined under the microscope which revealed the presence of chlamydospores. (***Figure 2b***).*

54 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

*The patient was treated with oral antifungal agent, fluconazole, 100 mg/day for 21 days along with conventional Tacrolimus-based immunosuppressive regimen. Urine routine and culture sensitivity studies* 

*mal differential count. The serum creatinine level dropped to 1.6 mg/dL. Urine examination and culture studies were negative thereafter. The patient responded well to the treatment and is on regular follow-up. Her present serum creatinine is 1.76 mg/dL, 4 months after the episode of urinary tract infection.*

**Figure 2.** Hematoxylin and eosin stained urine deposit reveals budding fungi along with pseudohyphae. (a) Creamy and smooth colonies of candida on Sabouraud's dextrose agar (red arrow). (b) Lactophenol cotton blue (wet preparation)

reveals budding fungi (LCB, X 400)with chlamydospores (LCB, X 1000).

*/μl, with nor-*

*were performed on tenth day. There was reduction in the total leucocyte count to 6.35 x 10 <sup>6</sup>*

Mohan et al., in their prospective study of 31 patients who underwent renal transplantation, found that infections in the immediate post-transplant period adversely affected the graft survival. Mortality rate in patients with UTI was reported as 12.9% [9].

Abbott and colleagues undertook a retrospective cohort study of 28,942 Medicare primary renal transplant recipients in the U.S. Renal Data System database from 1996 through 2000, assessing Medicare claims for UTI occurring later than 6 months after transplantation based on ICD-9 codes, and found that the cumulative incidence of UTI during the first 6 months after renal transplantation was 17% (equivalent for both men and women) and at 3 years was 60% for women and 47% for men ( < 0.001 in Cox regression analysis). Late UTI was significantly associated with an increased risk of subsequent death and graft loss [45].

In a study by Dhamidharka et al., who analyzed US Renal Data System database over the period of 1996 to 2000 (up to 36 months post-transplant). 265 (30.5%) pediatric patients had either inpatient or outpatient claims for UTI out of total 870 pediatric patients who qualified for the study. The authors found that early UTI (less than 6 months after transplant) was significantly [ = 0.007 upon multivariable Cox regression] associated with higher adjusted hazard ratio of graft loss, and late UTI was not associated with such an outcome. Risk for post-transplantation death was not increased significantly after either early UTI (AHR 1.23; 95% CI 0.37 to 4.08) or late UTI (relative risk 2.22; 95% CI 0.90 to 5.44) [46].

Pelle, et al. as well as Giral et al. reported that acute pyelonephritis of the graft is accompanied by renal failure and is an independent risk factor for impaired renal function as well as graft loss [47, 48]. Bodro et al. reported 1-year mortality rate of 3% in patients who developed worsening of graft function secondary to graft acute pyelonephritis. They further discovered that in patients with UTI due to a resistant strain of bacteria, the impairment of graft function is more frequent than in patients who develop UTI due to nonresistant strain bacteria [13]. Several hypotheses have been put forward to explain the negative impact of UTI on graft function. It has been postulated that bacterial infection activated the immune system, which can trigger the rejection cascades leading to acute or chronic rejections, causing deterioration of the graft function. Some authors propose that inflammation secondary to infection can cause scarring of the renal tissue, leading to loss of the functioning nephron mass causing impairment of renal function [49–51]. Reduction in the immunosuppressive agents following an episode of infection may accentuate the rejection process [13].

Various studies like the one by Ostaszewska et al., have found out no significant difference related to UTI and graft survival [28]. Fiorante et al. also in their study of 189 renal allograft recipients, over a follow-up of 36 months, did not find an association between asymptomatic and symptomatic bacteriuria with graft dysfunction. They also did not report statistically significant association between graft dysfunction and acute pyelonephritis of the graft [42]. Similarly, Ariza et al. and Lee et al. did not report any significant graft survival and UTI [52].

**5.2. Symptomatic UTI**

**5.3. Candiduria**

mended [55, 56].

**6. Prevention**

out possibility of any infections.

Symptomatic bacteriuria is classified further as mild, moderate and severe. Any predisposing conditions have to be treated. For mild cases empirical therapy with oral antibiotics, preferably ciprofloxacin with or without amoxicillin for a period of 5–7 days is recommended. For moderate infections, treatment with ciprofloxacin or ceftriaxone or ampicillin-salbactum is advised for 14 days after the culture sensitivity reports are obtained. For severe symptomatic UTI empirical treatment with pipercillin-tazobactum or cefepime is recommended over a period of 14–21 days following culture sensitivity report. Multi-drug resistant organisms need to be kept in mind before starting the empirical therapy. Carbapenem is the drug of

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 57

In patients with asymptomatic candiduria, there is no recommended treatment. In cases of symptomatic candiduria fluconazole, 200–400 mg, orally per day for 14 days is the treatment of choice. Fluconazole may have drug interactions with Calcineurin inhibitor, hence dose adjustment is recommended. Disseminated cases would require treatment by intravenous amphotericin B, 0.3–1 mg/kg/day for 1–7 days. Flucytosine [25 mg/kg every 6 h for 7–10 days] can also be used, but with caution, especially in cases of renal dysfunction. Monitoring for cytopenias, rash, gastrointestinal symptoms and hepatotoxicity is recom-

Although the data from various studies does not provide a concrete evidence for posttransplant UTI to have a profound effect on graft dysfunction, but overall it is necessary to control infection related mortality. It is quite obvious from certain studies that UTI or any infection leads to increase in duration of stay at hospital as well as it adds to economic burden as discussed in this review. Infection of any sort can have a psychological effect on the transplant recipient too. With advent of wide range of antimicrobials available as well as vast advancement in the field of transplantation medicine, losing graft function to infections should not be acceptable. Hence it is important to identify the various risk factors and employ strategies to prevent the development of infections in these subset of patients. Individuals with high risk factors like those having structural anomalies of the urinary tract, old age patients, females, presence of comorbid conditions like diabetes, hypertension should be kept under proper surveillance. In case of living donors a thorough screening for infections before transplantation though serological tests, urine analysis and hematology is advisable to rule

Certain studies have emphasized the role of antimicrobial prophylaxis with trimethoprimsulfamethoxazole (TMP-SMZ) for prevention of UTI. TMP-SMZ is a broad spectrum

choice for such cases. For recurrent UTI the treatment is extended to 6 weeks.

## **5. Management of UTI**

Definitive diagnostic and treatment protocols for renal transplant patients are not well-defined. The current treatment protocols depend mainly on the severity of the infection, the local epidemiological data and the results of the culture reports. Complete urinalysis with microscopy along with culture studies is recommended. It has been proposed that bactericidal antibiotics should be preferred to bacteriostatic ones, which might be insufficient to cure the infection since the immune system cannot eradicate the dormant bacteria. Managing the predisposing factors is equally essential. The need for adequate immunosuppression and dose adjustment is also important. Various pharmacological interactions exist between antibiotics used to treat post-transplant UTI and immunosuppressant drugs. Ciprofloxacin and erythromycin are implicated in raising Calcineurin inhibitor (CNI) levels. Levofloxacin and ofloxacin usually do not interfere with CNI levels. Antifungal agents inhibit cytochrome P450 and increase CNI levels. Rifampin, imipenem and cephalosporin can reduce CNI levels. Nephrotoxic antibiotics (e.g., aminoglycosides, amphotericin) may have synergistic effects with CNIs, increasing renal damage.

UTI can co-exist with CMV, BKV and other viral and fungal diseases.

## **5.1. Management of asymptomatic bacteriuria**

No definitive consensus or management is available for treatment of asymptomatic bacteriuria. However many of the researchers agree that there is no need to subject patients with asymptomatic bacteriuria to antibiotics as there are not enough studies that prove that asymptomatic bacteriuria heralds a negative outcome. Also studies have shown that treatment of this entity does not prevent occurrence of significant bacteriuria in the later posttransplant period [39]. Few studies have demonstrated that use of antimicrobials in patients with asymptomatic bacteriuria is usually unsuccessful in removing the offending agent; also it does not prevent the occurrence of subsequent UTI [53]. Study by Goya et al. proposed that considering asymptomatic bacteriuria as a precursor for symptomatic bacteriuria and subsequent development of pyelonephritis and high risk of developing symptomatic UTI in early transplant period that may affect the graft function it is recommended to keep patients with asymptomatic bacteriuria under screening schedules. Treatment with narrow-spectrum antibiotics of short duration of 5–7 days following culture report is recommended [54].

## **5.2. Symptomatic UTI**

Various studies like the one by Ostaszewska et al., have found out no significant difference related to UTI and graft survival [28]. Fiorante et al. also in their study of 189 renal allograft recipients, over a follow-up of 36 months, did not find an association between asymptomatic and symptomatic bacteriuria with graft dysfunction. They also did not report statistically significant association between graft dysfunction and acute pyelonephritis of the graft [42]. Similarly, Ariza et al. and Lee et al. did not report any significant graft survival

56 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Definitive diagnostic and treatment protocols for renal transplant patients are not well-defined. The current treatment protocols depend mainly on the severity of the infection, the local epidemiological data and the results of the culture reports. Complete urinalysis with microscopy along with culture studies is recommended. It has been proposed that bactericidal antibiotics should be preferred to bacteriostatic ones, which might be insufficient to cure the infection since the immune system cannot eradicate the dormant bacteria. Managing the predisposing factors is equally essential. The need for adequate immunosuppression and dose adjustment is also important. Various pharmacological interactions exist between antibiotics used to treat post-transplant UTI and immunosuppressant drugs. Ciprofloxacin and erythromycin are implicated in raising Calcineurin inhibitor (CNI) levels. Levofloxacin and ofloxacin usually do not interfere with CNI levels. Antifungal agents inhibit cytochrome P450 and increase CNI levels. Rifampin, imipenem and cephalosporin can reduce CNI levels. Nephrotoxic antibiotics (e.g., aminoglycosides, amphotericin) may have synergistic effects with CNIs, increasing renal

No definitive consensus or management is available for treatment of asymptomatic bacteriuria. However many of the researchers agree that there is no need to subject patients with asymptomatic bacteriuria to antibiotics as there are not enough studies that prove that asymptomatic bacteriuria heralds a negative outcome. Also studies have shown that treatment of this entity does not prevent occurrence of significant bacteriuria in the later posttransplant period [39]. Few studies have demonstrated that use of antimicrobials in patients with asymptomatic bacteriuria is usually unsuccessful in removing the offending agent; also it does not prevent the occurrence of subsequent UTI [53]. Study by Goya et al. proposed that considering asymptomatic bacteriuria as a precursor for symptomatic bacteriuria and subsequent development of pyelonephritis and high risk of developing symptomatic UTI in early transplant period that may affect the graft function it is recommended to keep patients with asymptomatic bacteriuria under screening schedules. Treatment with narrow-spectrum antibiotics of short duration of 5–7 days following culture report is recommended [54].

UTI can co-exist with CMV, BKV and other viral and fungal diseases.

**5.1. Management of asymptomatic bacteriuria**

and UTI [52].

damage.

**5. Management of UTI**

Symptomatic bacteriuria is classified further as mild, moderate and severe. Any predisposing conditions have to be treated. For mild cases empirical therapy with oral antibiotics, preferably ciprofloxacin with or without amoxicillin for a period of 5–7 days is recommended. For moderate infections, treatment with ciprofloxacin or ceftriaxone or ampicillin-salbactum is advised for 14 days after the culture sensitivity reports are obtained. For severe symptomatic UTI empirical treatment with pipercillin-tazobactum or cefepime is recommended over a period of 14–21 days following culture sensitivity report. Multi-drug resistant organisms need to be kept in mind before starting the empirical therapy. Carbapenem is the drug of choice for such cases. For recurrent UTI the treatment is extended to 6 weeks.

## **5.3. Candiduria**

In patients with asymptomatic candiduria, there is no recommended treatment. In cases of symptomatic candiduria fluconazole, 200–400 mg, orally per day for 14 days is the treatment of choice. Fluconazole may have drug interactions with Calcineurin inhibitor, hence dose adjustment is recommended. Disseminated cases would require treatment by intravenous amphotericin B, 0.3–1 mg/kg/day for 1–7 days. Flucytosine [25 mg/kg every 6 h for 7–10 days] can also be used, but with caution, especially in cases of renal dysfunction. Monitoring for cytopenias, rash, gastrointestinal symptoms and hepatotoxicity is recommended [55, 56].

## **6. Prevention**

Although the data from various studies does not provide a concrete evidence for posttransplant UTI to have a profound effect on graft dysfunction, but overall it is necessary to control infection related mortality. It is quite obvious from certain studies that UTI or any infection leads to increase in duration of stay at hospital as well as it adds to economic burden as discussed in this review. Infection of any sort can have a psychological effect on the transplant recipient too. With advent of wide range of antimicrobials available as well as vast advancement in the field of transplantation medicine, losing graft function to infections should not be acceptable. Hence it is important to identify the various risk factors and employ strategies to prevent the development of infections in these subset of patients. Individuals with high risk factors like those having structural anomalies of the urinary tract, old age patients, females, presence of comorbid conditions like diabetes, hypertension should be kept under proper surveillance. In case of living donors a thorough screening for infections before transplantation though serological tests, urine analysis and hematology is advisable to rule out possibility of any infections.

Certain studies have emphasized the role of antimicrobial prophylaxis with trimethoprimsulfamethoxazole (TMP-SMZ) for prevention of UTI. TMP-SMZ is a broad spectrum

symptoms of UTI. This type of screening will be helpful in early diagnosis and treatment and preventing infection related mortality. Culture studies should be advised as and when required, and the treatment should be planned according to the organisms identified in the culture studies. Antibiotic prophylaxis should be given to patients who are at high risk for developing UTI. Urine examination should be advised during every follow-up. This practice will definitely help in early diagnosis of infection and help in preventing morbidity associated

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 59

Urinary tract infections in the post-transplant period are quite common, more so during the early period of first 3 months. There are various risk factors attributed to development of UTI like female sex, delayed graft function, old age, anatomical anomalies and organs from the deceased donors being more common. Although few studies have identified UTI in post-transplant period as a negative predictor for graft function, further studies are still required to establish this relationship. The criteria to define asymptomatic bacteriuria and UTI are the same as that for general population. However in view of studies that show that post-transplant UTI has deleterious effect on graft function, it is necessary to design standard definitions, protocols for surveillance, prevention and management of UTI in renal transplant

However our protocol for renal transplant recipients involves regular follow-up by urine routine and microscopic examination and renal function tests, which helps in early detection of infections leading to prompt management. Thus, early intervention in both the patients led to

restoration of the renal function with proper graft function.

None of the authors report any conflict of interest.

TMP-SMZ trimethoprim-sulfamethoxazole

with UTI.

recipients.

**Conflict of interest**

**Abbreviations**

RT renal transplant

UTI urinary tract infection. CFU colony forming units. DGF delayed graft function. CNI calcineurin inhibitors.

**8. Conclusion**

**Figure 3.** Scheme for evaluating a case of recurrent UTI.

antimicrobial agent, with relatively low cost and is mostly used for prevention of *Pneumocystis carinii* infection [2, 14, 51]. Ariza-Heredia et al. have reported the effect of TMP-SMZ prophylaxis offers great protection to prevent UTI in the first year. Four patients who were not offered this prophylaxis due to certain reasons developed UTI in first year of transplant as against those who received the prophylaxis [14].

In cases with recurrent UTI anatomical and functional abnormalities like vesicoureteral reflux and neurogenic bladder need to be addressed and managed accordingly. The patients should be educated for basic preventive measures like hydration and frequent voiding. Radiological studies should be implicated to rule out the anatomical defects, obstruction, calculi and retained foreign bodies. Prostatitis should be considered as an important differential diagnosis in men who present with recurrent post-transplant UTI. Mitra et al. have proposed a scheme for evaluating a case of recurrent UTI (**Figure 3**) [57].

## **7. Recommendations**

As the risk of UTI is very high in the first week of transplantation, we recommend that every renal transplant recipient should undergo urine routine examination with microscopy for first 10 days in the post-operative period irrespective of the fact that the patient has any symptoms of UTI. This type of screening will be helpful in early diagnosis and treatment and preventing infection related mortality. Culture studies should be advised as and when required, and the treatment should be planned according to the organisms identified in the culture studies. Antibiotic prophylaxis should be given to patients who are at high risk for developing UTI. Urine examination should be advised during every follow-up. This practice will definitely help in early diagnosis of infection and help in preventing morbidity associated with UTI.

## **8. Conclusion**

Urinary tract infections in the post-transplant period are quite common, more so during the early period of first 3 months. There are various risk factors attributed to development of UTI like female sex, delayed graft function, old age, anatomical anomalies and organs from the deceased donors being more common. Although few studies have identified UTI in post-transplant period as a negative predictor for graft function, further studies are still required to establish this relationship. The criteria to define asymptomatic bacteriuria and UTI are the same as that for general population. However in view of studies that show that post-transplant UTI has deleterious effect on graft function, it is necessary to design standard definitions, protocols for surveillance, prevention and management of UTI in renal transplant recipients.

However our protocol for renal transplant recipients involves regular follow-up by urine routine and microscopic examination and renal function tests, which helps in early detection of infections leading to prompt management. Thus, early intervention in both the patients led to restoration of the renal function with proper graft function.

## **Conflict of interest**

antimicrobial agent, with relatively low cost and is mostly used for prevention of *Pneumocystis carinii* infection [2, 14, 51]. Ariza-Heredia et al. have reported the effect of TMP-SMZ prophylaxis offers great protection to prevent UTI in the first year. Four patients who were not offered this prophylaxis due to certain reasons developed UTI in first year of transplant as

58 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

In cases with recurrent UTI anatomical and functional abnormalities like vesicoureteral reflux and neurogenic bladder need to be addressed and managed accordingly. The patients should be educated for basic preventive measures like hydration and frequent voiding. Radiological studies should be implicated to rule out the anatomical defects, obstruction, calculi and retained foreign bodies. Prostatitis should be considered as an important differential diagnosis in men who present with recurrent post-transplant UTI. Mitra et al. have proposed a

As the risk of UTI is very high in the first week of transplantation, we recommend that every renal transplant recipient should undergo urine routine examination with microscopy for first 10 days in the post-operative period irrespective of the fact that the patient has any

against those who received the prophylaxis [14].

**Figure 3.** Scheme for evaluating a case of recurrent UTI.

**7. Recommendations**

scheme for evaluating a case of recurrent UTI (**Figure 3**) [57].

None of the authors report any conflict of interest.

## **Abbreviations**


## **Author details**

Lovelesh Kumar Nigam\*, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and Kamlesh S. Suthar

[10] Silva M, Marra AR, Pereira CA, Medina-Pestana JO, Camargo LF. Bloodstream infection after kidney transplantation: Epidemiology, microbiology, associated risk factors, and

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 61

[11] Vidal E, Torre-Cisneros J, Blanes M, et al. Bacterial urinary tract infection after solid organ transplantation in the RESITRA cohort. Transplant Infectious Disease. 2012;**14**:595-603

[12] Fontserè S, Chacón N, Cordero E. Review of bacterial urinary tract infection in kidney transplant recipients: Incidence, risk factors and impact on the graft survival. International Journal of Transplantation Research and Medicine 2017;**3**:026. doi.org/10.23937/

[13] Bodro M, Sanclemente G, Lipperheide I, Allali M, Marco F, Bosch J, et al. Impact of urinary tract infections on short-term kidney graft outcome. Clinical Microbiology and

[14] Ariza-Heredia EJ, Beam EN, Lesnick TG, Kremers WK, Cosio FG, Razonable RR. Urinary tract infections in kidney transplant recipients: Role of gender, urologic abnormalities, and antimicrobial prophylaxis. Annals of Transplantation. 2013;**18**:195-204. DOI:

[15] Brown PD. Urinary tract infections in renal transplant recipients. Current Infectious

[16] Elkehili IM, Kekli AB, Zaak AS, Salem EL. Urinary tract infections in renal transplant recipients. Arabian Journal of Nephrology and Transplantation. 2010;**3**(2):53-55

[17] Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Gar nick J, et al. Infectious complications after kidney transplantation: Current epidemiology and associated risk

[18] Khosravi AD, Montazeri EA, Ghorbani A, Parhizgari N. Bacterial urinary tract infection in renal transplant recipients and their antibiotic resistance pattern: A four-year study.

[19] Origüen J, López-Medrano F, Fernández-Ruiz M, Polanco N, Gutiérrez E, et al. Should asymptomatic bacteriuria be systematically treated in kidney transplant recipients? Results from a randomized controlled trial. American Journal of Transplantation.

[20] Papasotiriou M, Savvidaki E, Kalliakmani P, Papachristou E, Marangos M, et al. Predisposing factors to the development of urinary tract infections in renal transplant recipients and the impact on the long-term graft function. Renal Failure. 2011;**33**:405-410

[21] Albert X, Huertas I, Pereiro II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in nonpregnant women. Cochrane Database

[22] Pourmand MR, Keshtvarz M, Talebi M, Mashhadi R. Incidence of recurrent urinary tract infection after renal transplantation. Medical Bacteriology. 2012;**1**(2 [2013]):27-34

outcome. Transplantation 2010;**90**:581-587

Infection 2015;**21**:1104.e1-1101104.e8

2572-4045.1510026

10.12659/AOT.883901

2016;**16**:2943-2953

Disease Reports. 2002;**4**:525-528

factors. Clinical Transplantation. 2006;**20**:401-409

Iran Journal of Microbiology. 2014;**6**:74-78

Systematic Review. 2004 CD001209

\*Address all correspondence to: drloveleshnigam@gmail.com

Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology, Institute of Kidney Disease and Research Sciences, BJ Medical College Campus, Ahmedabad, Gujarat, India

## **References**


[10] Silva M, Marra AR, Pereira CA, Medina-Pestana JO, Camargo LF. Bloodstream infection after kidney transplantation: Epidemiology, microbiology, associated risk factors, and outcome. Transplantation 2010;**90**:581-587

**Author details**

Kamlesh S. Suthar

**References**

Ahmedabad, Gujarat, India

Lovelesh Kumar Nigam\*, Aruna V. Vanikar, Rashmi D. Patel, Kamal V. Kanodia and

Department of Pathology, Lab Medicine, Transfusion Services and Immunohematology,

[1] Tawab KA, Gheith O, Otaibi TA, Nampoory N, Mansour H, Halim AH, et al. Recurrent urinary tract infection among renal transplant recipients: Risk factors and long-term

[2] Parasuraman R, Julian K. Urinary tract infections in solid organ transplantation.

[3] Anastasopoulos NA, Duni A, Peschos D, Agnantis N, Dounousi E. The Spectrum of infectious diseases in kidney transplantation: A review of the classification, pathogens and clinical manifestations. Infectious Diseases in Kidney Transplantation. 2015;**29**:415-422

[4] Karuthu S, Blumberg EA. Common infections in kidney transplant recipients. Clinical

[5] Umesh L, Mahesh E, Kumar A, Punith K, Lalitha K, Suman G. Infections in renal transplant recipients. Journal, Indian Academy of Clinical Medicine. 2007;**8**(4):316-323

[6] Gondos AS, Al-Moyed KA, Al-Robasi ABA, Al-Shamahy HA, Alyousefi NA. Urinary tract infection among renal transplant recipients in Yemen. PLoS One. December 2015.

[7] Espinar MJ, Miranda IM, Costa-de-Oliveira S, Rocha R, Rodrigues AG, Pina-Vaz C. Urinary tract infections in kidney transplant patients due to *Escherichia coli* and *Klebsiella pneumoniae*-producing extended-spectrum β-Lactamases: Risk factors and

[8] Becerra BJ, Becerra MB, Safdar N. A Nationwide assessment of the burden of urinary tract infection among renal transplant recipients. Journal of Transplantation. 2015 Article

[9] Mohan M, Neeraja M, Sudhaharan S, Raju SB, Gangadhar T, Lakshmi V. Risk factors for urinary tract infections in renal allograft recipients: Experience of a tertiary care center in Hyderabad, South India. Indian Journal of Nephrology. 2017;**27**:372-376. DOI: 10.4103/

molecular epidemiology. PLoS One. 2015. DOI: 10.1371/journal.pone.0134737

ID 854640, 8 pages:http://dx.doi.org/10.1155/2015/854640

Institute of Kidney Disease and Research Sciences, BJ Medical College Campus,

outcome. Experimental and Clinical Transplantation. 2017;**2**:157-163

Journal of the American Society of Nephrology. 2012;**7**:2058-2070

American Journal of Transplantation. 2013;**13**:327-336

DOI: 10.1371/journal.pone.0144266

ijn.IJN\_331\_16

\*Address all correspondence to: drloveleshnigam@gmail.com

60 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host


[23] Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology. 2012;**10**:162-168

[37] Camargo LF, Esteves ABA, Ulisses LRS, Rivelli GG, Mazzali M. Urinary tract infection in renal transplant recipients: Incidence, risk factors, and impact on graft function. Transplantation Proceedings.**46**:1757e1759 http://dx.doi.org/10.1016/j.transproceed.2014.05.006

Urinary Tract Infection in Renal Allograft Recipents http://dx.doi.org/10.5772/intechopen.77171 63

[38] Kara OD, Dincel N, Bulut IK, Ozdemir K, Yilmaz E, Gun ZH, et al. Infectious complications in pediatric renal transplant patients. World Journal of Nephrology and Urology.

[39] Moradi M, Abbasi M, Moradi A, Boskabadi A, Jalali A. Effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients. Urology Journal. 2005;**2**(1):32-35

[40] Satish R. Gokulnath. Intractable urinary tract infection in a renal transplant recipient.

[41] Korth J, Kukalla J, Rath PM, Dolff S, Krull M, Guberina H, et al. Increased resistance of gram-negative urinary pathogens after kidney transplantation. BMC Nephrology.

[42] Fiorante S, Lopez-Medrano F, Lizasoain M, Lalueza A, Juan RS, et al. Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients. Kidney

[43] Lopez-Medrano F, Aguado JM. Urinary Tract Infection in a Renal Transplant Recipients.

[44] Shams SF, Eidgahi ES, Lotfi Z, Khaledi A, Shakeri S, Sheikh M, et al. Urinary tract infection in a kidney transplant recipients 1st year after transplantation. Journal of Research

[45] Abbott KC, Swanson SJ, Richter ER, et al. Late urinary tract infection after renal transplantation in the United States. *American Journal of Kidney Diseases*. 2004;**44**(2):353-362

[46] Dharnidharka VR, Agoda LY, Abbott KC. Effects of urinary tract infection on outcomes after transplantation in children. Clinical Journal of the American Society of Nephrology.

[47] Pellé G, Vimont S, Levy PP, Hertig A, Ouali N, et al. Acute pyelonephritis represents a risk factor impairing longterm kidney graft function. American Journal of Transplantation.

[48] Giral M, Pascuariello G, Karam G, Hourmant M, Cantarovich D, et al. Acute graft pyelonephritis and long-term kidney allograft outcome. Kidney International. 2000;**61**:1880-1886

[49] Audard V, Amor M, Desvaux D, Pastural M, Baron C, Philippe R, et al. Acute graft pyelonephritis: A potential cause of acute rejection in renal transplant. Transplantation.

[50] Dupont PJ, Psimenou E, Lord R, Buscombe JR, Hilson AJ, Sweny P. Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symp-

toms or vesicoureteric reflux. Transplantation. 2007;**84**:351-355

Saudi Journal of Kidney Disease Transplantation. 2009;**20**(3):458-461

Monograph in Infectious Disease and Antimicrobial Agents

2014;**3**(2):92-99

2017;**18**:164

International. 2010;**78**:774-781

in Medical Sciences;**2016**

2007;**2**:100-106

2007;**7**:899-907

2005;**80**:1128-1130


[37] Camargo LF, Esteves ABA, Ulisses LRS, Rivelli GG, Mazzali M. Urinary tract infection in renal transplant recipients: Incidence, risk factors, and impact on graft function. Transplantation Proceedings.**46**:1757e1759 http://dx.doi.org/10.1016/j.transproceed.2014.05.006

[23] Giessing M. Urinary tract infection in renal transplantation. Arab Journal of Urology.

62 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

[24] Smelov V, Naber K, Johansen TEB. Improved classification of urinary tract infection: Future considerations. European Urology Supplements. 2016;**15**:71-80 http://dx.doi.

[25] Hooton TM, Bradley SF, Cardenas DD, et al. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clinical Infectious Diseases.

[26] Alkatheri AM. Urinary tract infections in Saudi renal transplant recipients. Journal of

[27] Menegueti MG, Pereira MF, Bellissimo-Rodrigues F, Pisi Garcia TM, Saber LTS, Papini Nardim ME, et al. Study of the risk factors related to acquisition of urinary tract infections in patients submitted to renal transplant. Revista da Sociedade Brasileira de Medicina

[28] Ostaszewska A, Wszoła M, Kuthan R, Domagała P, Góralski P, Diuwe P, et al. Urinary tract infection in patients after renal transplantation: Evaluation of risk factors. MEDtube

[29] Dantas SR, Kuboyama RH, Mazzali M, Moretti ML. Nosocomial infections in renal transplant patients: Risk factors and treatment implications associated with urinary tract

[31] Fayek SA, Keenan J, Haririan A, et al. Ureteral stents are associated with reduced risk of ureteral complications after kidney transplantation: A large single center experience.

[32] Giral M, Pascuariello G, Karam G, et al. Acute graft pyelonephritis and long-term kidney

[33] Almond PS, Matas A, Gillingham K, et al. Risk factors for chronic rejection in renal

[34] Memikoglu KO, Keven K, Sengul S, Soypacaci Z, Erturk S, Erbay B. Urinary tract infections following renal transplantation: A single-center experience. Transplantation

[35] Munoz P. Management of urinary tract infections and lymphocele in renal transplant

[36] Taminato M, Fram D, Grothe C, Pereira RRF, Belasco A, Barbosa D. Prevalence of infection in kidney transplantation from living versus deceased donor: Systematic review and meta-analysis. Revista Da Escola De Enfermagem Da U S P. 2015;**49**(3):502-507

allograft recipients. Transplantation. 1993;**55**(4):752-756 discussion 756-757

and surgical site infections. The Journal of Hospital Infection. 2006;**63**(2):117-123 [30] Stamm WE. Catheter-associated urinary tract infections: Epidemiology, pathogenesis,

and prevention. The American Journal of Medicine. 1991;**91**(3B):65S-71S

allograft outcome. Kidney International. 2002;**61**:1880-1886

recipients. Clinical Infectious Diseases. 2001;**33**(Suppl 1):S53-S57

Infectious Diseases and Immunity. 2013;**5**(2):18-23. DOI: 10.5897/JIDI12.026

Tropical. 2015;**48**(3):285-290 http://dx.doi.org/10.1590/0037-8682-0098-2015

2012;**10**:162-168

2010;**50**:625-663

Science. 2014;**2**:22-29

Transplantation. 2012;**93**:304-308

Proceedings. 2007;**39**:3131-3134

org/10.1016/j.eursup.2016.04.002


[51] Lorenz EC, Cosio FG. The impact of urinary tract infection in a renal transplant recipients. Kidney International. 2010;**78**:719-721. DOI: 10.1038/ki.2010.219

**Chapter 5**

**Provisional chapter**

**Uropathogenic** *Escherichia coli* **and Fimbrial Adhesins**

Urinary tract infections (UTIs) rank second among infectious diseases around the world, and this makes them significant. There are many microbial agents which may cause UTIs. *Enterobacteriaceae* family members are recognized as important UTI bacterial causative agents. Among them, uropathogenic *Escherichia coli* (UPEC) pathotypes are considered as the most important bacterial agents of UTIs. Today, genomics and bioinformatics explain us why UPEC strains are so considerable pathogens regarding UTIs. There is a diversity of *E. coli* strains involving commensal and pathogenic strains. Genomics shows that commensal strains of *E. coli* encompass the minimal amount of genome and genetic elements among *E. coli* populations, whereas the pathotypes of *E. coli* possess the maximal or a big portion of genomic elements. Previous studies confirm the presence of a vast range of virulence genes within the pool of *E. coli* pathotypes like UPEC. So, the pool of virulence genes (virulome) belonging to UPEC enables UPEC pathotypes to have huge genomes with the ability of different levels of pathogenesis. The more virulence factors, the more pathogenicity. Due to the presence of a mass of virulence factors within UPEC cellular structures,

well-known fimbrial adhesins in UPEC pathotypes are discussed in this chapter.

**Keywords:** uropathogenic *Escherichia coli*, genomics, fimbriae, adhesins, virulence

**Uropathogenic** *Escherichia coli* **and Fimbrial Adhesins** 

DOI: 10.5772/intechopen.71374

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Every year, several million people suffer from urinary tract infections (UTIs), and of course it

UTIs with second ranking are one of the most dominant infectious diseases around the world. Although UTIs include vast etiological microbial agents, two pathogenic microorganisms

costs expensive for governments and healthcare medicine centres [1, 2].

**Virulome**

**Virulome**

Payam Behzadi

**Abstract**

Payam Behzadi

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71374

factors, urinary tract infections

**1. Introduction**


**Provisional chapter**

## **Uropathogenic** *Escherichia coli* **and Fimbrial Adhesins Virulome Virulome**

**Uropathogenic** *Escherichia coli* **and Fimbrial Adhesins** 

DOI: 10.5772/intechopen.71374

#### Payam Behzadi Additional information is available at the end of the chapter

Payam Behzadi

[51] Lorenz EC, Cosio FG. The impact of urinary tract infection in a renal transplant recipi-

[52] Chacon-Mora N, Diaz JP, Matia EC. Urinary tract infection in a renal transplant recipi-

[53] Green H, Rahamimov R, Goldberg E, et al. Consequences of treated versus untreated asymptomatic bacteriuria in the first year following kidney transplantation: Retrospective observational study. European Journal of Clinical Microbiology & Infectious Diseases.

[54] Goya N, Takahashi K, Tanabe K, et al. Clinical studies of bacteriuria in renal transplantation recipients. Correlation with pyuria and symptomatic genitourinary tract infection.

[55] Pappas PG, Silveira FP. *Candida* in solid organ transplant recipients. American Journal of

[56] Pappas PG, Rex JH, Sobel JD, et al. Guidelines for treatment of candidiasis. Clinical

[57] Mitra S, Alangaden GJ. Recurrent urinary tract infections in kidney transplant recipi-

ents. Enfermedades Infecciosas y Microbiología Clínica. 2017;**35**(4):255-259

ents. Kidney International. 2010;**78**:719-721. DOI: 10.1038/ki.2010.219

64 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Nihon Hinyokika Gakkai Zasshi. 1991;**82**:947-954

ents. Current Infectious Disease Reports. 2011;**13**:579-587

Transplantation. 2009;**9**(4):173-179

Infectious Diseases. 2004;**38**:161-189

2012

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71374

#### **Abstract**

Urinary tract infections (UTIs) rank second among infectious diseases around the world, and this makes them significant. There are many microbial agents which may cause UTIs. *Enterobacteriaceae* family members are recognized as important UTI bacterial causative agents. Among them, uropathogenic *Escherichia coli* (UPEC) pathotypes are considered as the most important bacterial agents of UTIs. Today, genomics and bioinformatics explain us why UPEC strains are so considerable pathogens regarding UTIs. There is a diversity of *E. coli* strains involving commensal and pathogenic strains. Genomics shows that commensal strains of *E. coli* encompass the minimal amount of genome and genetic elements among *E. coli* populations, whereas the pathotypes of *E. coli* possess the maximal or a big portion of genomic elements. Previous studies confirm the presence of a vast range of virulence genes within the pool of *E. coli* pathotypes like UPEC. So, the pool of virulence genes (virulome) belonging to UPEC enables UPEC pathotypes to have huge genomes with the ability of different levels of pathogenesis. The more virulence factors, the more pathogenicity. Due to the presence of a mass of virulence factors within UPEC cellular structures, well-known fimbrial adhesins in UPEC pathotypes are discussed in this chapter.

**Keywords:** uropathogenic *Escherichia coli*, genomics, fimbriae, adhesins, virulence factors, urinary tract infections

## **1. Introduction**

Every year, several million people suffer from urinary tract infections (UTIs), and of course it costs expensive for governments and healthcare medicine centres [1, 2].

UTIs with second ranking are one of the most dominant infectious diseases around the world. Although UTIs include vast etiological microbial agents, two pathogenic microorganisms

> Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

such as *Escherichia coli* (*E. coli*) (as a predominant pioneer bacterial agent) and Candida albicans (C. albicans) (as a predominant pioneer fungal agent) are the most recognized UTI etiologic pathogens [3–6].

and create its own colony, the 10<sup>5</sup>

pathotypes [4, 7, 23–30].

CFUs/ml [3, 6, 10–14].

**1.2. The genus of** *Escherichia***: A great bacterial empire**

clades, which are branched into five strains of C-I to C-V [15–18].

than 10<sup>5</sup>

cells can be construed as 10<sup>5</sup>

But we have to notice that, in some cases, the aforementioned threshold must be counted less

The genus of *Escherichia* includes *E. albertii*, *E. coli*, *E*. *fergusonii*, *E*. *hermannii*, *E. marmotae* and *E*. *vulneris*. The familiarity of these species is shown in **Figure 1**. In addition to these species, there are some *Escherichia* strains which have no differences in their phenotypes; but from the genotypic aspects, they have different characteristics. These strains are named as cryptic

*E. coli* is the most famous member of Gram-negative bacterial family of *Enterobacteriaceae* which was identified by Theodor *Escherich*. This non-spore forming and generally motile (with a peritrichous flagellated arrangement) facultative anaerobic rod-shaped bacterium was named *E. coli* by the suggestion of Castellani and Chalmers in 1919 [7, 19, 20]. There are a diversity of *E. coli* strains which are divided into commensal types (intra-intestinal non-pathogenic strains) and pathotypes (intra-intestinal pathogenic *E. coli* (InPEC) and extra-intestinal pathogenic *E. coli* (ExPEC)). The commensal types of *E. coli* are able to be settled within the infants' alimentary canal just in some hours after birth as beneficial normal flora populations [21, 22]. The *E. coli* pathotypes are divided into a vast range of strains which may cause different types of infectious diseases. **Table 1** indicates the pathotypes and their related infections. In accordance with the table, the pathotypes have been divided into three groups: ExPEC, InPEC and ShiToPInPEC. Phylogenetic studies show a close relationship between *Shigella* spp. and *E. coli*. A close genetic similarity is recognized between *Shigella* spp. and enteroinvasive *E. coli* (EIEC)

**Figure 1.** The genome of uropathogenic *E. coli* (UPEC) has been compared with *E. albertii*, *E*. *fergusonii*, *E. marmotae* and *E*. *vulneris* by the online GView Server system. The figure indicates genomic familiarities between the *Escherichia* species. As shown, the species of *E. marmotae* and *E*. *vulneris* have very close genomic similarities with UPEC, whereas there is some dissimilarity between genomic treasures of *E. albertii*, *E*. *fergusonii* and UPEC (GView Server; https://server.gview.ca/).

colony-forming units (CFUs).

67

http://dx.doi.org/10.5772/intechopen.71374

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

The pangenomic and phylogenetic studies have revealed five different categories within the species of *E. coli*. These five categories involve A, B1, B2, D and E, which depending on their strains can cause extra- and intra-intestinal infections. The extra-intestinal pathogenic *E. coli* (ExPEC) may lead to a vast range of infectious diseases. So, uropathogenic *E. coli* (UPEC) represents one of the most important causative bacterial pathotypes of UTIs. Three phylogroups of A, B1 and E encompass intra-intestinal commensal and/or pathotypes of *E. coli*, whereas the B2 and D phylogroups involve, respectively, the most and the least numbers of UPEC pathotypes [7, 8].

## **1.1. Biology of urinary tract infections**

There are different types of UTIs with a diversity of clinical demonstrations. Today, we know that the UTI syndromes are completely in association with hosts' immune system activities, type of causative microbial agent and the contributed microbial virulence factors. UTIs may be appeared as acute or chronic lower (typically known as cystitis) and/or upper (typically known as pyelonephritis) urinary tract infections, with symptomatic or asymptomatic manifestations and complicated or uncomplicated demonstrations. So, asymptomatic bacteriuria and simple cystitis with some ignorable irritations may be recognized as light and mild UTIs, respectively; while the urosepsis is known as a serious deathful type of UTI. Generally, the uncomplicated UTIs are recognized in patients with no previous background for UTIs, whereas the complicated UTIs normally happen in patients with previous problems in their urinary tracts. The remarkable point of view is the association between predisposing factors of diabetes, sexual intercourse, gender, catheterization, pregnancy, overweight, genetic factors, host's immune system responses and the type of UTIs and their severities [3, 5, 8–12].

In accordance with previous surveys, there are several numbers of microbial pathogens which can be identified as UTI pathogenic microorganisms. The microbial pathogens depending on the type of UTIs involve a vast number of pathogenic causative agents including Gramnegative bacteria, e.g. UPEC, *Klebsiella* spp., *Enterobacter* spp., *Proteus* spp., *Citrobacter* spp., *Morganella morganii*, *Acinetobacter* spp., *Salmonella* spp. and *Pseudomonas aeruginosa*; Grampositive bacteria such as Staphylococcus aureus *(methicillin-sensitive* S. aureus (*MSSA*) and/ or *methicillin-resistant* S. aureus (*MRSA*)), Staphylococcus epidermidis (*methicillin-sensitive* S. epidermidis (*MSSE*) *and/or methicillin-resistant* S. epidermidis (*MRSE*)), *Staphylococcus saprophyticus*, *Streptococcus* spp., *Enterococcus faecium*, *Enterococcus faecalis*, diphtheroids and *Corynebacterium urealyticum* and fungal agents like C. albicans, Candida glabrata and Candida tropicalis. As aforementioned, some pathogens are predominant in complicated UTIs, and some others are responsible for uncomplicated UTIs; however, the UPEC strains are common causative agents in both types of complicated and uncomplicated UTIs. Moreover, the presence of living microbial cells determines the condition of UTIs. The usual threshold for UTI pathogens is estimated ≥10<sup>5</sup> living cells per urine millilitre (ml). As each living cell can grow and create its own colony, the 10<sup>5</sup> cells can be construed as 10<sup>5</sup> colony-forming units (CFUs). But we have to notice that, in some cases, the aforementioned threshold must be counted less than 10<sup>5</sup> CFUs/ml [3, 6, 10–14].

## **1.2. The genus of** *Escherichia***: A great bacterial empire**

such as *Escherichia coli* (*E. coli*) (as a predominant pioneer bacterial agent) and Candida albicans (C. albicans) (as a predominant pioneer fungal agent) are the most recognized UTI etio-

66 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The pangenomic and phylogenetic studies have revealed five different categories within the species of *E. coli*. These five categories involve A, B1, B2, D and E, which depending on their strains can cause extra- and intra-intestinal infections. The extra-intestinal pathogenic *E. coli* (ExPEC) may lead to a vast range of infectious diseases. So, uropathogenic *E. coli* (UPEC) represents one of the most important causative bacterial pathotypes of UTIs. Three phylogroups of A, B1 and E encompass intra-intestinal commensal and/or pathotypes of *E. coli*, whereas the B2 and D phylogroups involve, respectively, the most and the least numbers of UPEC pathotypes

There are different types of UTIs with a diversity of clinical demonstrations. Today, we know that the UTI syndromes are completely in association with hosts' immune system activities, type of causative microbial agent and the contributed microbial virulence factors. UTIs may be appeared as acute or chronic lower (typically known as cystitis) and/or upper (typically known as pyelonephritis) urinary tract infections, with symptomatic or asymptomatic manifestations and complicated or uncomplicated demonstrations. So, asymptomatic bacteriuria and simple cystitis with some ignorable irritations may be recognized as light and mild UTIs, respectively; while the urosepsis is known as a serious deathful type of UTI. Generally, the uncomplicated UTIs are recognized in patients with no previous background for UTIs, whereas the complicated UTIs normally happen in patients with previous problems in their urinary tracts. The remarkable point of view is the association between predisposing factors of diabetes, sexual intercourse, gender, catheterization, pregnancy, overweight, genetic factors, host's immune

In accordance with previous surveys, there are several numbers of microbial pathogens which can be identified as UTI pathogenic microorganisms. The microbial pathogens depending on the type of UTIs involve a vast number of pathogenic causative agents including Gramnegative bacteria, e.g. UPEC, *Klebsiella* spp., *Enterobacter* spp., *Proteus* spp., *Citrobacter* spp., *Morganella morganii*, *Acinetobacter* spp., *Salmonella* spp. and *Pseudomonas aeruginosa*; Grampositive bacteria such as Staphylococcus aureus *(methicillin-sensitive* S. aureus (*MSSA*) and/ or *methicillin-resistant* S. aureus (*MRSA*)), Staphylococcus epidermidis (*methicillin-sensitive* S. epidermidis (*MSSE*) *and/or methicillin-resistant* S. epidermidis (*MRSE*)), *Staphylococcus saprophyticus*, *Streptococcus* spp., *Enterococcus faecium*, *Enterococcus faecalis*, diphtheroids and *Corynebacterium urealyticum* and fungal agents like C. albicans, Candida glabrata and Candida tropicalis. As aforementioned, some pathogens are predominant in complicated UTIs, and some others are responsible for uncomplicated UTIs; however, the UPEC strains are common causative agents in both types of complicated and uncomplicated UTIs. Moreover, the presence of living microbial cells determines the condition of UTIs. The usual threshold for UTI

living cells per urine millilitre (ml). As each living cell can grow

system responses and the type of UTIs and their severities [3, 5, 8–12].

logic pathogens [3–6].

**1.1. Biology of urinary tract infections**

pathogens is estimated ≥10<sup>5</sup>

[7, 8].

The genus of *Escherichia* includes *E. albertii*, *E. coli*, *E*. *fergusonii*, *E*. *hermannii*, *E. marmotae* and *E*. *vulneris*. The familiarity of these species is shown in **Figure 1**. In addition to these species, there are some *Escherichia* strains which have no differences in their phenotypes; but from the genotypic aspects, they have different characteristics. These strains are named as cryptic clades, which are branched into five strains of C-I to C-V [15–18].

*E. coli* is the most famous member of Gram-negative bacterial family of *Enterobacteriaceae* which was identified by Theodor *Escherich*. This non-spore forming and generally motile (with a peritrichous flagellated arrangement) facultative anaerobic rod-shaped bacterium was named *E. coli* by the suggestion of Castellani and Chalmers in 1919 [7, 19, 20]. There are a diversity of *E. coli* strains which are divided into commensal types (intra-intestinal non-pathogenic strains) and pathotypes (intra-intestinal pathogenic *E. coli* (InPEC) and extra-intestinal pathogenic *E. coli* (ExPEC)). The commensal types of *E. coli* are able to be settled within the infants' alimentary canal just in some hours after birth as beneficial normal flora populations [21, 22].

The *E. coli* pathotypes are divided into a vast range of strains which may cause different types of infectious diseases. **Table 1** indicates the pathotypes and their related infections. In accordance with the table, the pathotypes have been divided into three groups: ExPEC, InPEC and ShiToPInPEC. Phylogenetic studies show a close relationship between *Shigella* spp. and *E. coli*. A close genetic similarity is recognized between *Shigella* spp. and enteroinvasive *E. coli* (EIEC) pathotypes [4, 7, 23–30].

**Figure 1.** The genome of uropathogenic *E. coli* (UPEC) has been compared with *E. albertii*, *E*. *fergusonii*, *E. marmotae* and *E*. *vulneris* by the online GView Server system. The figure indicates genomic familiarities between the *Escherichia* species. As shown, the species of *E. marmotae* and *E*. *vulneris* have very close genomic similarities with UPEC, whereas there is some dissimilarity between genomic treasures of *E. albertii*, *E*. *fergusonii* and UPEC (GView Server; https://server.gview.ca/).

#### 68 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host


each strain comprises core genome, accessory genome (extra genome and/or flexible genome) and some unique genes which are specific for each strain. Furthermore, the accessory genomic pool which is flexible may contain integrons, pathogenicity islands (PAIs), phages, plasmids, prophages and transposons. The presence of these genomic elements is related to the nature of the environment in which bacterial cells exist. So, the size of genome is completely dependent on the habitat of bacteria. In another word, the condition of genomic pool and sequence of the genome determine the biological characteristics of the bacteria. Therefore, genomics of *E. coli*

The reported results from previous studies show that the commensal strains of *E. coli* bear the smallest pangenome (with no virulence genes or with minimal capacity), whereas the pathogenic strains of *E. coli* like UPEC pathotypes encompass large pangenomes (because of the presence of a mass of virulence genes). So, the added genes in pathotype pangenomes are recognized as virulence genes (virulome). It is estimated that UPEC pathotypes carry 10<sup>5</sup> bp much more than commensal strains within their pangenomes. This property gives a high plasticity to UPEC pathotype pangenomes. As shown in published reports, the pangenome of *E. coli* strains involve 4.6–5.9 Mbp and the chromosomal genomes are consisted of limited

**Table 2** shows a number of well-known databases in which the genomic data regarding *E. coli*

Genes, genomes, etc. http://www.genome.jp/kegg/

Genomes http://ensemblgenomes.org/ [43]

genbank/

https://ecocyc.org/ [37, 38]

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

69

https://shigen.nig.ac.jp/ecoli/pec/ [41]

http://www.ddbj.nig.ac.jp/ [44]

http://www.ncbi.nlm.nih.gov/

[40]

[45]

http://www.genome.jp/kegg/

**Database The main subject URL Reference**

EcoGene 3.0 *Escherichia coli* K-12 http://ecogene.org/ [39]

Pfam 31.0 Protein family database http://pfam.xfam.org/ [42]

The profiling of *Escherichia coli* chromosome (PEC) database

Nucleotide sequence

Nucleotide sequence

**Table 2.** Some useful and helpful databases which can be used for *Escherichia coli* pangenome.

database

database

strains reveal the needs of them in their own habitats [7, 23, 35].

number of genes [7, 23, 26, 36].

EcoCyc *E. coli* Database *Escherichia coli*

K-12 MG1655

genomes are accessible.

Kyoto Encyclopedia of Genes and Genomes

SHared Information of GENetic Resources

Ensembl Genomes (The European Bioinformatics Institute

The DNA Data Bank of Japan (DDBJ)

(National Center for Biotechnology Information

(EMBL-EBI))

GenBank

(NCBI))

(KEGG)

(SHIGEN)

**Table 1.** The categorization of *E. coli* pathotypes, the related infections and the condition of appearance.

## **2.** *Escherichia coli* **and pangenomics**

*E. coli* is a quite diverse genus which involves a vast range of strains with different metabolic properties, pathogenesis, genomic treasure, virulence factors and ecological varieties. These characteristics make *E. coli* an important case in association with infectious diseases. The *E. coli* strains range from commensal strains (useful normal flora) to AIEC, DAEC, EAEC, EHEC, EIEC, EPEC, ETEC, NEMEC, SEPEC and UPEC pathotypes. The characteristic diversities among *E. coli* strains are completely pertaining to their specific pangenomes. The type of genes and the gene pool of microorganisms determine the quality and the quantity of genetic evolutionary properties [4, 7, 22].

The term pangenome was applied by Sigaux for a database with the content of tissues and tumour genomic data; but the application of pangenome with its microbial content was used by Tettelin and colleagues for the first time, and this refers to a collection of genes and genetic elements in a family group which can be recognized among species of a genus. According to genomic studies, each microbial genus encompasses a main genomic pool which is known as core genome. The core genome contains all those vital genes belonging to different species of a microbial genus. In addition to core genome, there is a group of genomic materials pertaining to species members of a genus which is named as extra genome (flexible or accessory genome). Sometimes some accessory genome pools contain unique genes which are completely related to specific strain. The extra genome possesses genes that are vital but varies in different genome pools. Some genera bear closed pangenomes, whereas the others contain open pangenomes. The open pangenomic microbial organisms involve a vast range of strains. In parallel with molecular techniques, bioinformatics has a key role in pangenomics. Computational analyses give us brilliant information regarding chromosomal genes and motile genetic elements such as plasmids, transposons and phages. Today, the bacterial genus of *E. coli* is known as the most progressive prokaryote with the highest detected genomic sets [7, 31–34].

The complete genomic data regarding *E. coli* (K12 strain) was reported in 1997 for the first time. Due to the recent aforementioned information regarding *E. coli* genomics, we now know that each strain comprises core genome, accessory genome (extra genome and/or flexible genome) and some unique genes which are specific for each strain. Furthermore, the accessory genomic pool which is flexible may contain integrons, pathogenicity islands (PAIs), phages, plasmids, prophages and transposons. The presence of these genomic elements is related to the nature of the environment in which bacterial cells exist. So, the size of genome is completely dependent on the habitat of bacteria. In another word, the condition of genomic pool and sequence of the genome determine the biological characteristics of the bacteria. Therefore, genomics of *E. coli* strains reveal the needs of them in their own habitats [7, 23, 35].

The reported results from previous studies show that the commensal strains of *E. coli* bear the smallest pangenome (with no virulence genes or with minimal capacity), whereas the pathogenic strains of *E. coli* like UPEC pathotypes encompass large pangenomes (because of the presence of a mass of virulence genes). So, the added genes in pathotype pangenomes are recognized as virulence genes (virulome). It is estimated that UPEC pathotypes carry 10<sup>5</sup> bp much more than commensal strains within their pangenomes. This property gives a high plasticity to UPEC pathotype pangenomes. As shown in published reports, the pangenome of *E. coli* strains involve 4.6–5.9 Mbp and the chromosomal genomes are consisted of limited number of genes [7, 23, 26, 36].

**2.** *Escherichia coli* **and pangenomics**

**Entero -Hemorrhagic E.coli**

68 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

evolutionary properties [4, 7, 22].

**ExPEC** 

**InPEC**

**Shigella Toxin Producer InPEC (ShiToPInPEC)** 

*E. coli* is a quite diverse genus which involves a vast range of strains with different metabolic properties, pathogenesis, genomic treasure, virulence factors and ecological varieties. These characteristics make *E. coli* an important case in association with infectious diseases. The *E. coli* strains range from commensal strains (useful normal flora) to AIEC, DAEC, EAEC, EHEC, EIEC, EPEC, ETEC, NEMEC, SEPEC and UPEC pathotypes. The characteristic diversities among *E. coli* strains are completely pertaining to their specific pangenomes. The type of genes and the gene pool of microorganisms determine the quality and the quantity of genetic

**Table 1.** The categorization of *E. coli* pathotypes, the related infections and the condition of appearance.

**Category Pathotype Type of infection Appearance Phylogroup**

**Entero -Aggregative E.coli (EAEC) Diarrhoea (bloody) Pathogenic** 

**Entero -Toxigenic E.coli (ETEC) Diarrhoea (bloody) Pathogenic** 

**Neonatal Meningitis E.coli (NEMEC) Meningitis in neonates Opportunistic D, E Septic E.coli (SEPEC) Sepsis Opportunistic B1 Uropathogenic E.coli (UPEC) Urogenital tract infections Opportunistic B2, D** 

**A , B1 , D, E Entero -Pathogenic E.coli (EPEC) Diarrhoea (bloody) Pathogenic** 

**Entero -Invasive E.coli (EIEC) Bloody Diarrhoea Pathogenic A, B1, E Adhesive -Invasive E. coli (AIEC) Bloody Diarrhoea Pathogenic B2 Diffused -Adhesive E.coli (DAEC) Bloody Diarrhoea Pathogenic A, B2, D** 

**(EHEC) Bloody Diarrhoea Pathogenic B1, D, E** 

The term pangenome was applied by Sigaux for a database with the content of tissues and tumour genomic data; but the application of pangenome with its microbial content was used by Tettelin and colleagues for the first time, and this refers to a collection of genes and genetic elements in a family group which can be recognized among species of a genus. According to genomic studies, each microbial genus encompasses a main genomic pool which is known as core genome. The core genome contains all those vital genes belonging to different species of a microbial genus. In addition to core genome, there is a group of genomic materials pertaining to species members of a genus which is named as extra genome (flexible or accessory genome). Sometimes some accessory genome pools contain unique genes which are completely related to specific strain. The extra genome possesses genes that are vital but varies in different genome pools. Some genera bear closed pangenomes, whereas the others contain open pangenomes. The open pangenomic microbial organisms involve a vast range of strains. In parallel with molecular techniques, bioinformatics has a key role in pangenomics. Computational analyses give us brilliant information regarding chromosomal genes and motile genetic elements such as plasmids, transposons and phages. Today, the bacterial genus of *E. coli* is known as the most

The complete genomic data regarding *E. coli* (K12 strain) was reported in 1997 for the first time. Due to the recent aforementioned information regarding *E. coli* genomics, we now know that

progressive prokaryote with the highest detected genomic sets [7, 31–34].


**Table 2** shows a number of well-known databases in which the genomic data regarding *E. coli* genomes are accessible.

**Table 2.** Some useful and helpful databases which can be used for *Escherichia coli* pangenome.

The outcomes of several studies reveal the presence of a huge number of virulence factors which have been expanded among different strains of UPEC. Here, the most considerable virulence factors are mentioned and the most considerable filamentous adhesins are explained one by one.

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

71

The severity of UPEC pathogenesis is completely in association with diversity of virulence genes in their pangenomes. **Figure 3** shows the pangenome of UTI89. The virulence genes may be located on chromosomes (added through vertical gene transfer) or plasmids, transposons, integrons and phages (added via horizontal gene transfers). Previous studies indicate that the majority of virulence genes belonging to UPEC are located on pathogenicity islands (PAIs) where many of genes are transferred from other species rather than *E. coli* through the feature of horizontal genomic exchange. UPEC pathotypes are effective pathogens due to their high capacity of virulome. The diversity of virulence factors enables UPEC to manifest different types of UTIs in their human hosts. Adhesion, immune system escape mechanisms, iron uptake systems, protease enzymes and toxins are the most significant mechanisms that UPEC pathotypes should utilize them to survive in the human host urinary tract [22, 51–53]. Because of the vast variety of pathogenicity potentials in UPEC strains, only hair-like structures of afimbrial adhesins (including curli and Afa) and fimbrial adhesins (comprising Dr, Type 1 fimbriae, Type 3 fimbriae, F1C fimbriae, S fimbriae, P fimbriae, Auf and F9 fimbriae) are discussed in this chapter. There are some useful databases such as Center for Genomic Epidemiology (https://cge.cbs.dtu.dk/services/VirulenceFinder/) and Virulence Factors of Pathogenic Bacteria (http://www.mgc.ac.cn/VFs/) which may be used for detection and identi-

**4. Uropathogenic** *Escherichia coli* **(UPEC) virulome**

fication virulence genes within the *E. coli* strain populations' genomes [54].

**Figure 3.** The pangenome map (chromosomal and plasmid genomes) of UPEC (UTI89). The GC content and GC skew

are shown, too (GView Server; https://server.gview.ca/).

**Figure 2.** A chromosomal comparison between UPEC (UTI89), *Shigella* sp. and *Salmonella enterica*. The GC content and GC skew are shown, too (GView Server; https://server.gview.ca/).

The pangenomic studies reveal an interesting evolutionary relationship between *E. coli*, *Shigella* spp. and *Salmonella enterica*. It seems that *E. coli* is the ancestor of *Shigella* spp. The *Shigella* spp. have derivated from *E. coli* pathotypes within a duration of 270,000–35,000 years, whereas the origination of *E. coli* and *S*. *enterica* bacteria from a common progenitor goes back to 100,000,000 years ago [4, 46] (**Figure 2**).

## **3. Uropathogenic** *Escherichia coli* **(UPEC)**

The UTIs are divided into community-acquired and nosocomial infectious diseases. The UPEC pathotypes are the most dominant causative bacterial agents of UTIs. As previous investigations show, about 50% of nosocomial and up to 95% of community-acquired UTIs are occurred by UPEC strains. So, the UPEC pathotypes are one of the most considered UTI causative agents worldwide. These reports lead us to a wide variety of virulence factors in UPEC pathotypes. Besides, the bioinformatic approaches and pangenomics confirm the presence of a giant treasure of virulence genes within the pangenome of UPEC [7, 8, 35, 47].

The spread of virulence genes among UPEC pathotypes is quite different. The range of UTIs varies from ignorable cases like asymptomatic bacteriuria to deathful cases like urosepsis. The severity of UTIs is completely in association with the UPEC virulence gene pool (virulome). Sometimes, pathotypes undergo mutations in their hosts' bodies which may lead to lose their own virulence genes. It seems that the UPEC pathotypes, which may cause asymptomatic bacteriuria, have undergone virulence gene deletions. On the other hand, strong uropathogenic strains encompass a mass of virulence genes which enable them to occur severe UTIs within their hosts' bodies. The occurrence of UTIs is associated with the host's genetic predisposing factors, immune system, gender, hospitalization, catheterization, social behaviour, sexual activities, personal hygiene and the presence of virulence factors in uropathogenic microbial agents [3, 7, 11, 13, 22, 48–50].

The outcomes of several studies reveal the presence of a huge number of virulence factors which have been expanded among different strains of UPEC. Here, the most considerable virulence factors are mentioned and the most considerable filamentous adhesins are explained one by one.

## **4. Uropathogenic** *Escherichia coli* **(UPEC) virulome**

**Figure 2.** A chromosomal comparison between UPEC (UTI89), *Shigella* sp. and *Salmonella enterica*. The GC content and

The pangenomic studies reveal an interesting evolutionary relationship between *E. coli*, *Shigella* spp. and *Salmonella enterica*. It seems that *E. coli* is the ancestor of *Shigella* spp. The *Shigella* spp. have derivated from *E. coli* pathotypes within a duration of 270,000–35,000 years, whereas the origination of *E. coli* and *S*. *enterica* bacteria from a common progenitor goes back to 100,000,000 years

The UTIs are divided into community-acquired and nosocomial infectious diseases. The UPEC pathotypes are the most dominant causative bacterial agents of UTIs. As previous investigations show, about 50% of nosocomial and up to 95% of community-acquired UTIs are occurred by UPEC strains. So, the UPEC pathotypes are one of the most considered UTI causative agents worldwide. These reports lead us to a wide variety of virulence factors in UPEC pathotypes. Besides, the bioinformatic approaches and pangenomics confirm the presence of a giant treasure of virulence genes within the pangenome of UPEC [7, 8, 35, 47].

The spread of virulence genes among UPEC pathotypes is quite different. The range of UTIs varies from ignorable cases like asymptomatic bacteriuria to deathful cases like urosepsis. The severity of UTIs is completely in association with the UPEC virulence gene pool (virulome). Sometimes, pathotypes undergo mutations in their hosts' bodies which may lead to lose their own virulence genes. It seems that the UPEC pathotypes, which may cause asymptomatic bacteriuria, have undergone virulence gene deletions. On the other hand, strong uropathogenic strains encompass a mass of virulence genes which enable them to occur severe UTIs within their hosts' bodies. The occurrence of UTIs is associated with the host's genetic predisposing factors, immune system, gender, hospitalization, catheterization, social behaviour, sexual activities, personal hygiene and the presence of virulence factors in uropathogenic microbial

GC skew are shown, too (GView Server; https://server.gview.ca/).

70 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

**3. Uropathogenic** *Escherichia coli* **(UPEC)**

ago [4, 46] (**Figure 2**).

agents [3, 7, 11, 13, 22, 48–50].

The severity of UPEC pathogenesis is completely in association with diversity of virulence genes in their pangenomes. **Figure 3** shows the pangenome of UTI89. The virulence genes may be located on chromosomes (added through vertical gene transfer) or plasmids, transposons, integrons and phages (added via horizontal gene transfers). Previous studies indicate that the majority of virulence genes belonging to UPEC are located on pathogenicity islands (PAIs) where many of genes are transferred from other species rather than *E. coli* through the feature of horizontal genomic exchange. UPEC pathotypes are effective pathogens due to their high capacity of virulome. The diversity of virulence factors enables UPEC to manifest different types of UTIs in their human hosts. Adhesion, immune system escape mechanisms, iron uptake systems, protease enzymes and toxins are the most significant mechanisms that UPEC pathotypes should utilize them to survive in the human host urinary tract [22, 51–53].

Because of the vast variety of pathogenicity potentials in UPEC strains, only hair-like structures of afimbrial adhesins (including curli and Afa) and fimbrial adhesins (comprising Dr, Type 1 fimbriae, Type 3 fimbriae, F1C fimbriae, S fimbriae, P fimbriae, Auf and F9 fimbriae) are discussed in this chapter. There are some useful databases such as Center for Genomic Epidemiology (https://cge.cbs.dtu.dk/services/VirulenceFinder/) and Virulence Factors of Pathogenic Bacteria (http://www.mgc.ac.cn/VFs/) which may be used for detection and identification virulence genes within the *E. coli* strain populations' genomes [54].

**Figure 3.** The pangenome map (chromosomal and plasmid genomes) of UPEC (UTI89). The GC content and GC skew are shown, too (GView Server; https://server.gview.ca/).

## **4.1. Filamentous adhesin virulome**

Each microorganism either pathogen or non-pathogen needs to be adhered for colonization. Indeed, colonization of pathogenic microorganisms results in pathogenesis within human body's host. For this reason, UPEC has a range of superficial proteins and adhesins (**Table 3**). However the hair-like structured fimbriae are invaluable virulence factors which enable UPEC pathotypes to have successful attachment, colonization, biofilm formation and virulence [7, 22, 53, 55–65].

proteins, whereas the *draE* genes with lower conserved sequences are responsible for adhesin structural subunits. Moreover, the AFA adhesins are encoded by a five-member gene operon including *afaA*, *afaE*, *afaD*, *afaB* and *afaC*. The proteins of AFAI and AFAIII are known as Dr family members. In accordance with previous studies, some of Dr and AFA adhesins have close similarities with chaperone-usher pathway adhesins. The AFA adhesins are recognized in up to 65% of UPEC pathotypes causing cystitis, 26% causing pyelonephritis and 6% asymp-

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

73

There are varieties of fimbriae which are produced by Gram-negative bacteria such as *Enterobacteriaceae* family members. The subunits of these fimbriae are assembled by different pathways like CU pathway. Those fimbriae produced via CU pathway are the most frequent filamentous organelles among Gram-negative bacteria populations. The CU pathway is a kind of common bacterial secretion system with a high conservancy. In a fimbrial CU pathway, chaperone (a periplasmic protein molecule) together with a pore-forming protein of usher (situated within bacterial outer membrane) orchestrate this secretion system. So through the CU pathway, the usher protein plays its role as platform assembler by employing a chaperone to produce and secrete subunits of CU fimbriae class. F1C, P, S, Auf, Type 1, Type 3 and F9 fimbriae in UPEC pathotypes are known as CU pathway proteinaceous adhes-

Type 1 fimbriae as mannose-sensitive adhesins (belonging to chaperone-usher class) are able to attach to those receptors with mannose residues. Uroplakin molecules with high frequency in human urine bladder are known as one of the most important Type 1 fimbriae receptors. Furthermore, there are different types of Type 1 fimbriae receptors which are located on human ureter and Henle's tubules. These fimbriae are encoded in 99% of commensal and pathogenic strains of *E. coli* including UPEC pathotypes. As important virulence factors, Type 1 fimbriae have peripheral arrangement upon the microorganisms' surfaces with a number of 1–5 hundred. Type 1 fimbriae with up to 10 nm width and up to 2 μm length are able to perform haemagglutination. The Type 1 fimbriae are encoded by the highly conserved gene operon consisted of nine genes of *fimBEAICDFGH*. The FimH protein which is located on the top of Type 1 fimbria is recognized as the main adhesin. FimG, Fim F and FimA protein molecules are, respectively, situated under the FimH molecule. FimC and FimD play their roles as chaperone and usher proteins, respectively. The recombinase enzymes of FimB and FimE activate as bidirectional switching molecules for turning on and/or turning off the cluster gene expression. The activities of FimB and FimE are directly associated with environmental

Type 3 fimbriae are encoded by *mrk* gene operon of *mrkABCDEF* in UPEC and other members of *Enterobacteriaceae* family such as Klebsiella pneumoniae. The highly conserved gene

tomatic bacteriuria (ABU) [7, 8, 22, 55, 61, 70, 71] (**Table 3**).

factors [7, 22, 50, 53, 55, 60, 62, 68, 71, 74, 76, 77] (**Table 3**).

**4.2. Chaperone-usher fimbrial adhesins**

ins [62, 66, 72–75] (**Table 3**).

*4.2.1. Type 1 fimbriae*

*4.2.2. Type 3 fimbriae*

Fimbrial adhesins are superficial peritrichous arranged exterior proteinaceous appendages which target special motifs upon the cell surface receptors to join them in the manner of key-and-lock operation. These adhesins are able to attach onto biotic (e.g. host cells) and abiotic (e.g. catheter) surfaces. The aforementioned characteristics make UPEC bacteria functional and effective pathogenic microorganisms. The attachment of bacterial cells of UPEC onto the host cells is a complicated process which may be caused by important proteinaceous molecules of adhesins. Adhesins prepare suitable condition for a successful signalling controlled communication between UPEC cells and human body cells. In other words, the fimbrial adhesins act as signal molecules. As shown in **Table 3**, the most studied and recognized superficial filamentous adhesins are Curli, Dr, AFA, Type 1 fimbriae, Type 3 fimbriae, F1C fimbriae, S fimbriae, P fimbriae, F9 fimbriae and Auf. Some of these superficial fimbrial organelles involving F1C, P, S, Auf, Type 1, Type 3 and F9 fimbriae are categorized into chaperoneusher (CU) proteins [8, 27, 53, 59, 62, 66].

## *4.1.1. Curli adhesins*

Curli adhesins of UPEC are known as types of fragile exterior proteinous coiled fibrous appendages which contribute in linking the UPEC cells onto related receptors situated upon the human body cells such as endothelial cells, epithelial cells, matrix proteins, urothelial cells, mucosal cells, blood cells, etc. In addition to UPEC pathotypes, curli adhesins are recognized in *Salmonella* spp. too. The affinity between curli organelles and Congo red makes it easy to observe these tiny adhesins by microscope. Curli adhesins with up to 12 nm width and 1 μm length are made of CsgA (curlin as major content with amyloid property) and CsgB (as minor content with amyloid property and nucleator activity) proteins. The highly conserved curli gene clusters in UPEC pathotypes are organized into *csgBAC* and *csgDEFG* operons. Curli molecules are effective structures to adhere UPEC cells onto the urine bladder and kidney urothelial cells within human bodies [50, 52, 53, 57, 67–69] (**Table 3**).

#### *4.1.2. Dr/Afa adhesins*

The Dr and Afa adhesins are the members of DR family. Dr adhesins (with a homology rate of ≥70%) and Afa molecules are able to bind to the Dr<sup>a</sup> blood group antigen molecules situated onto the decay-accelerating factors (DAFs). The DAF molecules are located upon the surface of different types of cells such as urothelial cells. The Dr gene operons consisted of five genes, including *draA–draE*, which are detectable in 7% of the UPEC populations. The *draE* gene is responsible for Dr haemagglutinin production, which is contributed in type IV collagen attachment. *draA–draG* genes are highly conserved and produce the accessory proteins, whereas the *draE* genes with lower conserved sequences are responsible for adhesin structural subunits. Moreover, the AFA adhesins are encoded by a five-member gene operon including *afaA*, *afaE*, *afaD*, *afaB* and *afaC*. The proteins of AFAI and AFAIII are known as Dr family members. In accordance with previous studies, some of Dr and AFA adhesins have close similarities with chaperone-usher pathway adhesins. The AFA adhesins are recognized in up to 65% of UPEC pathotypes causing cystitis, 26% causing pyelonephritis and 6% asymptomatic bacteriuria (ABU) [7, 8, 22, 55, 61, 70, 71] (**Table 3**).

#### **4.2. Chaperone-usher fimbrial adhesins**

There are varieties of fimbriae which are produced by Gram-negative bacteria such as *Enterobacteriaceae* family members. The subunits of these fimbriae are assembled by different pathways like CU pathway. Those fimbriae produced via CU pathway are the most frequent filamentous organelles among Gram-negative bacteria populations. The CU pathway is a kind of common bacterial secretion system with a high conservancy. In a fimbrial CU pathway, chaperone (a periplasmic protein molecule) together with a pore-forming protein of usher (situated within bacterial outer membrane) orchestrate this secretion system. So through the CU pathway, the usher protein plays its role as platform assembler by employing a chaperone to produce and secrete subunits of CU fimbriae class. F1C, P, S, Auf, Type 1, Type 3 and F9 fimbriae in UPEC pathotypes are known as CU pathway proteinaceous adhesins [62, 66, 72–75] (**Table 3**).

#### *4.2.1. Type 1 fimbriae*

**4.1. Filamentous adhesin virulome**

usher (CU) proteins [8, 27, 53, 59, 62, 66].

ies [50, 52, 53, 57, 67–69] (**Table 3**).

of ≥70%) and Afa molecules are able to bind to the Dr<sup>a</sup>

*4.1.2. Dr/Afa adhesins*

lence [7, 22, 53, 55–65].

*4.1.1. Curli adhesins*

Each microorganism either pathogen or non-pathogen needs to be adhered for colonization. Indeed, colonization of pathogenic microorganisms results in pathogenesis within human body's host. For this reason, UPEC has a range of superficial proteins and adhesins (**Table 3**). However the hair-like structured fimbriae are invaluable virulence factors which enable UPEC pathotypes to have successful attachment, colonization, biofilm formation and viru-

72 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Fimbrial adhesins are superficial peritrichous arranged exterior proteinaceous appendages which target special motifs upon the cell surface receptors to join them in the manner of key-and-lock operation. These adhesins are able to attach onto biotic (e.g. host cells) and abiotic (e.g. catheter) surfaces. The aforementioned characteristics make UPEC bacteria functional and effective pathogenic microorganisms. The attachment of bacterial cells of UPEC onto the host cells is a complicated process which may be caused by important proteinaceous molecules of adhesins. Adhesins prepare suitable condition for a successful signalling controlled communication between UPEC cells and human body cells. In other words, the fimbrial adhesins act as signal molecules. As shown in **Table 3**, the most studied and recognized superficial filamentous adhesins are Curli, Dr, AFA, Type 1 fimbriae, Type 3 fimbriae, F1C fimbriae, S fimbriae, P fimbriae, F9 fimbriae and Auf. Some of these superficial fimbrial organelles involving F1C, P, S, Auf, Type 1, Type 3 and F9 fimbriae are categorized into chaperone-

Curli adhesins of UPEC are known as types of fragile exterior proteinous coiled fibrous appendages which contribute in linking the UPEC cells onto related receptors situated upon the human body cells such as endothelial cells, epithelial cells, matrix proteins, urothelial cells, mucosal cells, blood cells, etc. In addition to UPEC pathotypes, curli adhesins are recognized in *Salmonella* spp. too. The affinity between curli organelles and Congo red makes it easy to observe these tiny adhesins by microscope. Curli adhesins with up to 12 nm width and 1 μm length are made of CsgA (curlin as major content with amyloid property) and CsgB (as minor content with amyloid property and nucleator activity) proteins. The highly conserved curli gene clusters in UPEC pathotypes are organized into *csgBAC* and *csgDEFG* operons. Curli molecules are effective structures to adhere UPEC cells onto the urine bladder and kidney urothelial cells within human bod-

The Dr and Afa adhesins are the members of DR family. Dr adhesins (with a homology rate

ated onto the decay-accelerating factors (DAFs). The DAF molecules are located upon the surface of different types of cells such as urothelial cells. The Dr gene operons consisted of five genes, including *draA–draE*, which are detectable in 7% of the UPEC populations. The *draE* gene is responsible for Dr haemagglutinin production, which is contributed in type IV collagen attachment. *draA–draG* genes are highly conserved and produce the accessory

blood group antigen molecules situ-

Type 1 fimbriae as mannose-sensitive adhesins (belonging to chaperone-usher class) are able to attach to those receptors with mannose residues. Uroplakin molecules with high frequency in human urine bladder are known as one of the most important Type 1 fimbriae receptors. Furthermore, there are different types of Type 1 fimbriae receptors which are located on human ureter and Henle's tubules. These fimbriae are encoded in 99% of commensal and pathogenic strains of *E. coli* including UPEC pathotypes. As important virulence factors, Type 1 fimbriae have peripheral arrangement upon the microorganisms' surfaces with a number of 1–5 hundred. Type 1 fimbriae with up to 10 nm width and up to 2 μm length are able to perform haemagglutination. The Type 1 fimbriae are encoded by the highly conserved gene operon consisted of nine genes of *fimBEAICDFGH*. The FimH protein which is located on the top of Type 1 fimbria is recognized as the main adhesin. FimG, Fim F and FimA protein molecules are, respectively, situated under the FimH molecule. FimC and FimD play their roles as chaperone and usher proteins, respectively. The recombinase enzymes of FimB and FimE activate as bidirectional switching molecules for turning on and/or turning off the cluster gene expression. The activities of FimB and FimE are directly associated with environmental factors [7, 22, 50, 53, 55, 60, 62, 68, 71, 74, 76, 77] (**Table 3**).

#### *4.2.2. Type 3 fimbriae*

Type 3 fimbriae are encoded by *mrk* gene operon of *mrkABCDEF* in UPEC and other members of *Enterobacteriaceae* family such as Klebsiella pneumoniae. The highly conserved gene of *mrkB* encodes chaperone protein of MrkB, whereas the MrkC plays role as usher protein. MrkA and MrkF are the major and minor subunits in Type 3 fimbriae, respectively. The adhesin molecule of Type 3 fimbria is recognized as MrkD and MrkE plays its role as a regulator protein. It seems that *mrk* gene cluster originally belongs to K. pneumoniae which has been horizontally transferred into UPEC pathotypes by plasmids. The role of Type 3 fimbriae in biofilm formation regarding catheter-associated urinary tract infections (CAUTs) is significantly considered [53, 56] (**Table 3**).

*4.2.6. Auf fimbriae*

*4.2.7. F9 fimbriae*

samples [80–86].

**6. Conclusion**

briae receptors [22, 53, 59, 60] (**Table 3**).

specific, sensitive and reliable outcome.

cific, flexible and rapid with high accuracy [4, 7, 8, 87–93].

Auf (acronym for another UPEC fimbria) fimbriae are detected in 67% of isolated UPEC pathotypes. The Auf fimbriae are encoded by the gene operon of *aufABCDEFG*. AufA protein is predominant subunit in Auf fimbria, whereas AufC is known as an usher protein. The Auf

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

75

The F9 fimbriae encoded by *f9* gene operon including *c1931–c1936* are detectable in 78% of UPEC populations. The C1931 protein is the major subunit identified in F9 fimbriae. The genetic and structural characteristics of F9 fimbriae are very close to Type 1, F1C and S fimbriae. Gal-beta-(1-3)-Glc-NAc and lacto-N-tetraose glycans are recognized as the main F9 fim-

Detection and identification of genes such as virulence genes of filamentous adhesins may be achieved by a vast range of molecular techniques. PCR tools from conventional and multiplex to real time are the commonest molecular diagnostic techniques which can be used for limited

Furthermore there are advanced pangenomic techniques like microarray technology which can be applied for detection and identification of different types of genes, when there are huge numbers of specimens. Microarray technology is divided into three types of DNA, protein and RNA microarray tools. The outcome of microarray technology is reliable, sensitive, spe-

UPEC strains are expanded pathogenic microorganisms which are able to carry a mass of virulence genes within their genomes. The environmental condition and the genomic abilities and capacity determine the expression of virulence genes and factors. The UPEC strains bear different types of virulence factors in different parts of their cellular structures. These properties make UPEC pathotypes interesting pathogenic microorganisms which can appear a vast range of UTIs: from acute to chronic, from light to severe, from complicated to uncomplicated, from lower to upper and from asymptomatic to symptomatic signs and syndromes. So, knowing the genotypic and phenotypic characteristics of UPEC strains in different regions of world helps us to recognize the probable UPEC strains with their local clinical demonstrations. This enables us to have an accurate diagnosis with a definite treatment to reduce the healthcare costs around the world. Moreover, equipped microbiology laboratories with normal molecular tools and techniques like PCR or advanced pangenomic technologies support us to have

protein receptors are still unknown in human body cells [7, 22, 53, 62, 74] (**Table 3**).

**5. Diagnostic methods for virulence genes of filamentous adhesins**

#### *4.2.3. F1C fimbriae*

The F1C fimbriae are encoded by a gene operon consisting of seven genes of *focAICDFGH*. F1C fimbriae are expressed by up to 30% of UPEC pathotypes. The F1C fimbria is composed of FocA (major fimbrin subunits), FocF and FocG (minor fimbrin subunits) proteins. On the top of F1C fimbria, FocH monomer is located which acts as an adhesin. So, F1C fimbriae adhere onto the receptors with galactosylceramide (situated on the surfaces of urothelial cells of the urinary bladder, kidneys and ureters) and globotriaosylceramide (located in kidneys) residues. Previous surveys indicate a strong attraction between F1C fimbriae and Gal-NAcbeta-1-4-Gal-beta structure of glycolipids. FocC and FocD proteins are recognized as chaperone and usher molecules, respectively. Due to prior scientific investigations, the F1C fimbriae are able to bind to their specific receptors upon the whole zone of the urinary tract. There is a close homology between F1C and S fimbriae [7, 53, 55, 62, 66, 78] (**Table 3**).

#### *4.2.4. S fimbriae*

In addition to FIC, the S fimbriae organelles have also a close morphology to F9, P and Type 1 fimbriae and are detected in ≥22% of the UPEC pathotypes. The S fimbriae are encoded by *sfa* gene operon with nine genes. SfaA, SfaS and SfaH proteins contribute in S fimbrial adhesion. The SfaA protein is a dominant subunit, and the minor subunits are composed of SfaG, SfaH and SfaS. SfaS is located on the top of S fimbriae and adhere to alpha-sialyl-2,3-alphagalactose residues upon the glycoproteins of urothelial tissues of the urinary bladder and kidneys. The presence or absence of S fimbriae is determined by environmental factors. The related regulations and phase variations are done by SfaB and SfaC [7, 22, 35, 50, 53, 55, 62, 66, 71, 77, 79] (**Table 3**).

#### *4.2.5. P fimbriae*

P fimbriae as considerable adhesins are encoded by 11 genes within a gene operon of *papA-K* in up to 70% of UPEC pathotypes. The predominant subunit in P fimbria is PapA fimbrin placed in the basis of the fimbrial stalk. PapG is known as the main adhesin which is linked to the stalk by PapE, PapF and PapK proteins. PapD and PapC have chaperone and usher roles, respectively. There are some isoclasses for PapG (PapGI, PapGII (major isoclass in UPEC strains) and PapGIII) in different UPEC pathotypes. The related receptor epitopes of P fimbriae are alpha-D-galactopyranosyl-(1-4)-beta-D-galactopyranoside which are located on the surface of entire urothelial cells covering the human urinary tract. P fimbriae are recognized as significant virulence factors in UPEC virulome [7, 22, 50, 53, 62, 66, 71, 77] (**Table 3**).

## *4.2.6. Auf fimbriae*

of *mrkB* encodes chaperone protein of MrkB, whereas the MrkC plays role as usher protein. MrkA and MrkF are the major and minor subunits in Type 3 fimbriae, respectively. The adhesin molecule of Type 3 fimbria is recognized as MrkD and MrkE plays its role as a regulator protein. It seems that *mrk* gene cluster originally belongs to K. pneumoniae which has been horizontally transferred into UPEC pathotypes by plasmids. The role of Type 3 fimbriae in biofilm formation regarding catheter-associated urinary tract infections (CAUTs) is signifi-

74 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The F1C fimbriae are encoded by a gene operon consisting of seven genes of *focAICDFGH*. F1C fimbriae are expressed by up to 30% of UPEC pathotypes. The F1C fimbria is composed of FocA (major fimbrin subunits), FocF and FocG (minor fimbrin subunits) proteins. On the top of F1C fimbria, FocH monomer is located which acts as an adhesin. So, F1C fimbriae adhere onto the receptors with galactosylceramide (situated on the surfaces of urothelial cells of the urinary bladder, kidneys and ureters) and globotriaosylceramide (located in kidneys) residues. Previous surveys indicate a strong attraction between F1C fimbriae and Gal-NAcbeta-1-4-Gal-beta structure of glycolipids. FocC and FocD proteins are recognized as chaperone and usher molecules, respectively. Due to prior scientific investigations, the F1C fimbriae are able to bind to their specific receptors upon the whole zone of the urinary tract. There is a

In addition to FIC, the S fimbriae organelles have also a close morphology to F9, P and Type 1 fimbriae and are detected in ≥22% of the UPEC pathotypes. The S fimbriae are encoded by *sfa* gene operon with nine genes. SfaA, SfaS and SfaH proteins contribute in S fimbrial adhesion. The SfaA protein is a dominant subunit, and the minor subunits are composed of SfaG, SfaH and SfaS. SfaS is located on the top of S fimbriae and adhere to alpha-sialyl-2,3-alphagalactose residues upon the glycoproteins of urothelial tissues of the urinary bladder and kidneys. The presence or absence of S fimbriae is determined by environmental factors. The related regulations and phase variations are done by SfaB and SfaC [7, 22, 35, 50, 53, 55, 62,

P fimbriae as considerable adhesins are encoded by 11 genes within a gene operon of *papA-K* in up to 70% of UPEC pathotypes. The predominant subunit in P fimbria is PapA fimbrin placed in the basis of the fimbrial stalk. PapG is known as the main adhesin which is linked to the stalk by PapE, PapF and PapK proteins. PapD and PapC have chaperone and usher roles, respectively. There are some isoclasses for PapG (PapGI, PapGII (major isoclass in UPEC strains) and PapGIII) in different UPEC pathotypes. The related receptor epitopes of P fimbriae are alpha-D-galactopyranosyl-(1-4)-beta-D-galactopyranoside which are located on the surface of entire urothelial cells covering the human urinary tract. P fimbriae are recognized as significant viru-

lence factors in UPEC virulome [7, 22, 50, 53, 62, 66, 71, 77] (**Table 3**).

close homology between F1C and S fimbriae [7, 53, 55, 62, 66, 78] (**Table 3**).

cantly considered [53, 56] (**Table 3**).

*4.2.3. F1C fimbriae*

*4.2.4. S fimbriae*

66, 71, 77, 79] (**Table 3**).

*4.2.5. P fimbriae*

Auf (acronym for another UPEC fimbria) fimbriae are detected in 67% of isolated UPEC pathotypes. The Auf fimbriae are encoded by the gene operon of *aufABCDEFG*. AufA protein is predominant subunit in Auf fimbria, whereas AufC is known as an usher protein. The Auf protein receptors are still unknown in human body cells [7, 22, 53, 62, 74] (**Table 3**).

## *4.2.7. F9 fimbriae*

The F9 fimbriae encoded by *f9* gene operon including *c1931–c1936* are detectable in 78% of UPEC populations. The C1931 protein is the major subunit identified in F9 fimbriae. The genetic and structural characteristics of F9 fimbriae are very close to Type 1, F1C and S fimbriae. Gal-beta-(1-3)-Glc-NAc and lacto-N-tetraose glycans are recognized as the main F9 fimbriae receptors [22, 53, 59, 60] (**Table 3**).

## **5. Diagnostic methods for virulence genes of filamentous adhesins**

Detection and identification of genes such as virulence genes of filamentous adhesins may be achieved by a vast range of molecular techniques. PCR tools from conventional and multiplex to real time are the commonest molecular diagnostic techniques which can be used for limited samples [80–86].

Furthermore there are advanced pangenomic techniques like microarray technology which can be applied for detection and identification of different types of genes, when there are huge numbers of specimens. Microarray technology is divided into three types of DNA, protein and RNA microarray tools. The outcome of microarray technology is reliable, sensitive, specific, flexible and rapid with high accuracy [4, 7, 8, 87–93].

## **6. Conclusion**

UPEC strains are expanded pathogenic microorganisms which are able to carry a mass of virulence genes within their genomes. The environmental condition and the genomic abilities and capacity determine the expression of virulence genes and factors. The UPEC strains bear different types of virulence factors in different parts of their cellular structures. These properties make UPEC pathotypes interesting pathogenic microorganisms which can appear a vast range of UTIs: from acute to chronic, from light to severe, from complicated to uncomplicated, from lower to upper and from asymptomatic to symptomatic signs and syndromes. So, knowing the genotypic and phenotypic characteristics of UPEC strains in different regions of world helps us to recognize the probable UPEC strains with their local clinical demonstrations. This enables us to have an accurate diagnosis with a definite treatment to reduce the healthcare costs around the world. Moreover, equipped microbiology laboratories with normal molecular tools and techniques like PCR or advanced pangenomic technologies support us to have specific, sensitive and reliable outcome.


[5] Behzadi E, Behzadi P. The role of toll-like receptors (TLRs) in urinary tract infections (UTIs). Central European Journal of Urology. 2016;**69**:404-410. DOI: 10.5173/

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

77

[6] Behzadi P, Behzadi E, Ranjbar R. Urinary tract infections and *Candida albicans*. Central

[7] Jahandeh N, Ranjbar R, Behzadi P, Behzadi E. Uropathogenic *Escherichia coli* virulence genes: Invaluable approaches for designing DNA microarray probes. Central European

[8] Behzadi P, Behzadi E.Uropathogenic *Escherichia coli*: An Ideal Resource for DNA Microarray Probe Designing. In: Rojas I, Ortuño F, editors. Bioinformatics and Biomedical Engineering. 5th IWBBIO 2017. Lecture notes in computer science part II, vol 10209. Cham: Springer; 2017.

[9] Schwab S, Jobin K, Kurts C. Urinary tract infection: recent insight into the evolutionary arms race between uropathogenic *Escherichia coli* and our immune system. Nephrol Dial

[10] Johansen TB, Bonkat G, Cai T, Tandogdu Z, Wagenlehner F, Grabe M. Grey zones in the field of urinary tract infections. European Urology Focus. 2016;**2**:460-462. DOI: 10.1016/j.

[11] Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nature Reviews. Micro-

[12] Kline KA, Lewis AL. Gram-positive uropathogens, polymicrobial urinary tract infection, and the emerging microbiota of the urinary tract. Microbiology spectrum. 2016;**4**(2). DOI:

[13] Behzadi P, Behzadi E, Yazdanbod H, Aghapour R, Cheshmeh MA, Omran DS. A survey on urinary tract infections associated with the three most common uropathogenic bacteria.

[14] Brubaker L, Wolfe AJ. The female urinary microbiota/microbiome: Clinical and research implications. Rambam Maimonides Medical Journal. 2017;**8**:e0015. DOI: 10.5041/RMMJ.

[15] Liu S, Jin D, Lan R, Wang Y, Meng Q, Dai H, et al. *Escherichia marmotae* sp. nov., isolated from faeces of Marmota Himalayana. International Journal of Systematic and Evolutionary

[16] Clermont O, Gordon DM, Brisse S, Walk ST, Denamur E. Characterization of the cryptic Escherichia lineages: Rapid identification and prevalence. Environmental Microbiology.

[17] Ooka T, Ogura Y, Katsura K, Seto K, Kobayashi H, Kawano K, et al. Defining the genome features of *Escherichia albertii*, an emerging enteropathogen closely related to *Escherichia coli*.

Genome Biology and Evolution. 2015;**7**:3170-3179. DOI: 10.1093/gbe/evv211

European Journa of Urology. 2015;**68**:96-101. DOI: 10.5173/ceju.2015.01.474

Journal of Urology. 2015;**68**:452-458. DOI: 10.5173/ceju.2015.625

pp. 12-19. DOI: 10.1007/978-3-319-56154-7\_2

Transplant. 2017;**gfx022**:1-7. DOI: 10.1093/ndt/gfx022

biology. 2015;**13**:269-284. DOI: 10.1038/nrmicro3432

Microbiology. 2015;**65**:2130-2134. DOI: 10.1099/ijs.0.000228

2011;**13**:2468-2477. DOI: 10.1111/j.1462-2920.2011.02519.x

10.1128/microbiolspec.UTI-0012-2012

ceju.2016.871

euf.2016.03.012

Maedica. 2010;**5**:111-5

10292

**Table 3.** The UPEC fimbrial and afimbrial adhesins and their characteristics within human bodies [7, 22, 53, 55–64, 71**]**.

## **Author details**

Payam Behzadi

Address all correspondence to: behzadipayam@yahoo.com

Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran

## **References**


**Author details**

Adhesins Type of

**Dr** Fimbrial adhesin

Fimbrial adhesin (sensitive to mannose)

Fimbrial adhesin Resistance to mannose

**Type 1 fimbriae** 

**Type 3** 

**P fimbriae** 

**Auf fimbriae (Another UPEC Fimbriae)**

**Curli** Afimbrial adhesin *csgA, csgB,csgC, csgD,* 

**fimbriae** Fimbrial adhesin *mrk gene familyincluding: mrkA,* 

**F1C fimbriae** Fimbrial adhesin *focA, focC, focD, focf, focG, focH,* 

**S fimbriae** Fimbrial adhesin *sfaA, sfaB, sfaC, sfaD, sfaE, sfaF,* 

**F9 fimbriae** Fimbrial adhesin *c1931, c1932, c1933, c1934,* 

Fimbrial adhesin *aufA, aufB, aufC, aufD, aufE,* 

*csgE,csgF,csgG* 

*dra* gene family including: *draA, draB, draC, draD, draE,* 

*afaII, afaIII ,afaIV,nfaI ,drII*

*fim* gene family including: *fimA, fimB, fimC, fimD, fimE,*

*focI*

*papa, papB, papC, papD, papE, papF, papG, papH, papI, papJ, papK*

*c1935, c1936*

*aufF, aufG*

Payam Behzadi

**References**

University, Tehran, Iran

013-0069-x

pgmj.2004.023036

Address all correspondence to: behzadipayam@yahoo.com

2016;**69**:105-111. DOI: 10.5173/ceju.2016.654

Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad

**Table 3.** The UPEC fimbrial and afimbrial adhesins and their characteristics within human bodies [7, 22, 53, 55–64, 71**]**.

adhesins Genes Role Target structure Type of UTIs

Matrix Proteins like Fibronectin, Laminin and Plasminogen, Mucosal cells

A vast range of cells with Dr blood group antigen on their surfaces like urothelia, Neutrophil cells, Connective tissues in upper part of human urinary tract

Red Blood Cells (RBCs), Mucosal membrane and Epithelium cells, Uroplakin receptors in urine bladder

Glycolipids of endothelia, Mucosal membrane and Glomeruli

Sial icacid molecules on kidneys and glomeruli endothelial, epithelial and mucosal cells

vascular epithelia, urothelia and Mucosal cells

formation) ? Urothelial cells ? UTIs ?

formation) unknown UTIs

Severe UTIs; Cystitis in particular

(Recurrent and/or chronic) Cystitis and pyelonephritis (mostly in pregnant women),

UTIs

UTIs, Pyelonephritis in particular

Upper UTIs in most cases

Acute forms of UTIs (particularly Pyelonephritis), ABU in few cases

Adhesion for colonization (biofilm formation) and invasion

invasion

formation), invasion

Adhesion for colonization (biofilm formation)

Adhesion and colonization

Adhesion for colonization (biofilm

Adhesion for colonization (biofilm

Asymptomatic Bacteriuria (ABU) in few cases **AFA** Afimbrial adhesin *afa* gene family including: *afaI,* 

*mrkB, mrkC, mrkD, mrkE, mrkF* UTIs in catheterized patients

*draP* Adhesion for colonization, Preparing

*fimF, fimG, fimH, fimI* Adhesion for colonization (biofilm

76 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

*sfaG, sfaH, sfaS, sfaX, sfaY* Adhesion and colonization

[1] Ciani O, Grassi D, Tarricone R. An economic perspective on urinary tract infection: The "costs of resignation". Clinical Drug Investigation. 2013;**33**:255-261. DOI: 10.1007/s40261-

[2] Kucheria R, Dasgupta P, Sacks S, Khan M, Sheerin N.Urinary tract infections: New insights into a common problem. Postgraduate Medical Journal. 2005;**81**:83-86. DOI: 10.1136/

[3] Behzadi P, Behzadi E. The microbial agents of urinary tract infections at central laboratory of Dr. Shariati hospital, Tehran, Iran. Turkiye Kliniklire Tip Bilim. 2008;**28**:445-449 [4] Behzadi P, Najafi A, Behzadi E, Ranjbar R. Microarray long oligo probe designing for *Escherichia coli*: An in-silico DNA marker extraction. Central European Journal of Urology.


[18] NCBI > Genomes & Maps > Genome > *Escherichia* [Internet]. NCBI.Available from: https:// www.ncbi.nlm.nih.gov/genome/?term=Escherichia [Accessed: 2017-08-23]

[31] McInerney JO, McNally A, O'Connell MJ. Why prokaryotes have pangenomes. Natural

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

79

[32] Snipen L-G, Ussery DW. A domain sequence approach to pangenomics: Applications to

[33] Rouli L, Merhej V, Fournier P-E, Raoult D. The bacterial pangenome as a new tool for analysing pathogenic bacteria. NMNI. 2015;**7**:72-85. DOI: 10.1016/j.nmni.2015.06.005 [34] Marschall T, Marz M, Abeel T, Dijkstra L, Dutilh BE, Ghaffaari A, et al. Computational pan-genomics: Status, promises and challenges. BioRxiv. 2016;**043430**. DOI: 10.1101/

[35] Lo AW, Moriel DG, Phan M-D, Schulz BL, Kidd TJ, Beatson SA, et al. 'Omic'Approaches to study Uropathogenic *Escherichia coli* virulence. Trends in Microbiology. 2017;**25**:729-

[36] Terlizzi ME, Gribaudo G, Maffei ME. UroPathogenic *Escherichia coli* (UPEC) infections: Virulence factors, bladder responses, antibiotic, and non-antibiotic antimicrobial strate-

[37] Karp P, Weaver D, Paley S, Fulcher C, Kubo A, Kothari A, et al. The EcoCyc Database. EcoSal Plus. 2014;**6**:10.1128/ecosalplus.ESP-0009-2013. DOI: 10.1128/ecosalplus.ESP-0009-2013

[38] Keseler IM, Collado-Vides J, Santos-Zavaleta A, Peralta-Gil M, Gama-Castro S, Muñiz-Rascado L, et al. EcoCyc: A comprehensive database of *Escherichia coli* biology. Nucleic

[39] Zhou J, Rudd KE. EcoGene 3.0. Nucleic Acids Research. 2013;**41**:D613-D624. DOI:

[40] Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Research. 2017;**45**:D353-D361.

[41] Yamazaki Y, Niki H, Kato J. Profiling of *Escherichia coli* Chromosome Database. In: Osterman AL, Gerdes SY. (eds) Microbial Gene Essentiality: Protocols and Bioinformatics. Methods in Molecular Biology™. 1st ed. Humana Press, New Jersey, USA; 2008;**416**:

[42] Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, et al. The Pfam protein families database: Towards a more sustainable future. Nucleic Acids Research. 2016;**44**:

[43] Kersey PJ, Allen JE, Armean I, Boddu S, Bolt BJ, Carvalho-Silva D, et al. Ensembl genomes 2016: More genomes, more complexity. Nucleic Acids Research. 2015;**44**:D574-D580. DOI:

[44] Mashima J, Kodama Y, Fujisawa T, Katayama T, Okuda Y, Kaminuma E, et al. DNA data bank of Japan. Nucleic Acids Res. 2017;**45**:D25-D31. DOI: 10.1093/nar/gkw1001

gies. Frontiers in Microbiology. 2017;**8**:1566. DOI: 10.3389/fmicb.2017.01566

Acids Research. 2010;**39**:D583-DD90. DOI: 10.1093/nar/gkq1143

*Escherichia coli*. F1000Res. 2012;**1**:19. DOI: 10.12688/f1000research.1-19.v2

Microbiology. 2017;**2**:17040. DOI: 10.1038/nmicrobiol.2017.40

043430

740. DOI: 10.1016/j.tim.2017.04.006

10.1093/nar/gks1235

10.1093/nar/gkv1209

DOI: 10.1093/nar/gkw1092

385-389. DOI: 10.1007/978-1-59745-321-9\_26

D279-D285. DOI: 10.1093/nar/gkv1344


[31] McInerney JO, McNally A, O'Connell MJ. Why prokaryotes have pangenomes. Natural Microbiology. 2017;**2**:17040. DOI: 10.1038/nmicrobiol.2017.40

[18] NCBI > Genomes & Maps > Genome > *Escherichia* [Internet]. NCBI.Available from: https://

[19] Etymologia: *Escherichia coli*. Emerging Infectious Disease Journal. 2015;**21**:1310. DOI:

[20] Schaechter M Editor. Desk Encyclopedia of Microbiology. 2nd ed. Academic press,

[21] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews. Micro-

[22] Donnenberg M. *Escherichia coli*: Pathotypes and principles of pathogenesis. 2nd ed.

[23] Robins-Browne RM, Holt KE, Ingle DJ, Hocking DM, Yang J, Tauschek M. Are *Escherichia coli* Pathotypes still relevant in the era of whole-genome sequencing? Frontiers in Cellular

[24] Rossi E, Cimdins A, Lüthje P, Brauner A, Sjöling Å, Landini P, et al. "It's a gut feeling"– *Escherichia coli* biofilm formation in the gastrointestinal tract environment. Critical

[25] Leimbach A, Hacker J, Dobrindt U. *E. coli* as an all-rounder: The thin line between commensalism and pathogenicity. In: Dobrindt U, Hacker J, Svanborg C. (eds) Between Pathogenicity and Commensalism. Current Topics in Microbiology and Immunology, 1st ed.

[26] Croxen MA, Finlay BB. Molecular mechanisms of *Escherichia coli* pathogenicity. Nature

[27] Servin AL. Pathogenesis of human diffusely adhering *Escherichia coli* expressing Afa/Dr adhesins (Afa/Dr DAEC): Current insights and future challenges. Clinical Microbiology

[28] da Silva LC, de Mello Santos AC, Silva RM. Uropathogenic *Escherichia coli* pathogenicity islands and other ExPEC virulence genes may contribute to the genome variability of enteroinvasive *E. coli*. BMC Microbiology. 2017;**17**:68. DOI: 10.1186/s12866-

[29] Nash JH, Villegas A, Kropinski AM, Aguilar-Valenzuela R, Konczy P, Mascarenhas M, et al. Genome sequence of adherent-invasive Escherichia coli and comparative genomic analysis with other *E. coli* pathotypes. BMC Genomics. 2010;**11**:667. DOI: 10.1186/

[30] O'brien CL, Bringer M-A, Holt KE, Gordon DM, Dubois AL, Barnich N, et al. Comparative genomics of Crohn9s disease-associated adherent-invasive *Escherichia coli*. Gut 2016;**0**:

and Infection Microbiology. 2016;**6**:141. DOI: 10.3389/fcimb.2016.00141

Reviews in Microbiology. 2017:1-30. DOI: 10.1080/1040841X.2017.1303660

Springer, Berlin, Heidelberg; 2013;**358**:3-32. DOI: 10.1007/82\_2012\_30

Reviews. Microbiology. 2010;**8**:26-38. DOI: 10.1038/nrmicro2265

Reviews. 2014;**27**:823-869. DOI: 10.1128/CMR.00036-14

www.ncbi.nlm.nih.gov/genome/?term=Escherichia [Accessed: 2017-08-23]

78 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

10.3201/eid2108.ET2108

biology. 2004;**2**:123-140. DOI: 10.1038/nrmicro818

Academic press, Elsevier, UK; 2013

Elsevier, UK; 2010

017-0979-5

1471-2164-11-667

1-8. DOI: 10.1136/gutjnl-2015-311059


[45] Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, et al. GenBank. Nucleic Acids Research. 2017;**45**:D37-D42. DOI: 10.1093/nar/gkw1070

[57] Cordeiro MA, Werle CH, Milanez GP, Yano T. Curli fimbria: An *Escherichia coli* adhesin associated with human cystitis. Brazilian Journal of Microbiology. 2016;**47**:414-416. DOI:

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

81

[58] Klemm P, Schembri M. Type 1 fimbriae, Curli, and antigen 43: Adhesion, colonization,

[59] Ulett GC, Mabbett AN, Fung KC, Webb RI, Schembri MA. The role of F9 fimbriae of uropathogenic *Escherichia coli* in biofilm formation. Microbiology. 2007;**153**:2321-2331. DOI:

[60] Wurpel DJ, Totsika M, Allsopp LP, Hartley-Tassell LE, Day CJ, Peters KM, et al. F9 fimbriae of uropathogenic *Escherichia coli* are expressed at low temperature and recognise Galβ1-3GlcNAc-containing glycans. PLoS One. 2014;**9**:e93177. DOI: 10.1371/journal.

[61] Emo L, Kerenyi M, Nagy G. Virulence factors of uropathogenic *Escherichia coli*. International Journal of Antimicrobial Agents. 2003;**22**:29-33. DOI: 10.1016/S0924-8579(03)0

[62] Spurbeck RR, Stapleton AE, Johnson JR, Walk ST, Hooton TM, Mobley HL. Fimbrial profiles predict virulence of uropathogenic *Escherichia coli* strains: Contribution of ygi and yad fimbriae. Infection and immunity. 2011;**79**:4753-4763. DOI: 10.1128/IAI.

[63] Profiling of *Escherichia coli* chromosome (PEC) database; Japan: National Institute of Genetics. 1998-2016 ed. Availabl from: https://shigen.nig.ac.jp/ecoli/pec/ [Accessed:

[64] Fernández-Romero N, Romero-Gómez MP, Mora-Rillo M, Rodríguez-Baño J, López-Cerero L, Pascual Á, et al. Uncoupling between core genome and virulome in extraintestinal pathogenic *Escherichia coli*. Canadian Journal of Microbiology. 2015;**61**:647-652. DOI: 10.1139/

[65] Behzadi P, Behzadi E. Environmental Microbiology. 1st ed. Tehran: Niktab Publisher; 2007

[66] Wurpel DJ, Beatson SA, Totsika M, Petty NK, Schembri MA. Chaperone-usher fimbriae of *Escherichia coli*. PLoS One. 2013;**8**:e52835. DOI: 10.1371/journal.pone.0052835

[67] Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, et al. Role of *Escherichia coli* curli operons in directing amyloid fiber formation. Science. 2002;**295**:851-855.

[68] Van Houdt R, Michiels CW. Role of bacterial cell surface structures in *Escherichia coli* biofilm formation. Research in Microbiology. 2005;**156**:626-633. DOI: 10.1016/j.resmic.2005.

[69] Barnhart MM, Chapman MR. Curli biogenesis and function. Annual Review of Microbiology. 2006;**60**:131-147. DOI: 10.1146/annurev.micro.60.080805.142106

and biofilm formation. EcoSal Plus. 2004;**1**. DOI: 10.1128/ecosalplus.8.3.2.6

10.1016/j.bjm.2016.01.024

10.1099/mic.0.2006/004648-0

pone.0093177

0236-X

05621-11

2017-08-23]

cjm-2014-0835

02.005

DOI: 10.1126/science.1067484


[57] Cordeiro MA, Werle CH, Milanez GP, Yano T. Curli fimbria: An *Escherichia coli* adhesin associated with human cystitis. Brazilian Journal of Microbiology. 2016;**47**:414-416. DOI: 10.1016/j.bjm.2016.01.024

[45] Benson DA, Cavanaugh M, Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, et al. GenBank. Nucleic Acids Research. 2017;**45**:D37-D42. DOI: 10.1093/nar/gkw1070

80 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

[46] Gordienko EN, Kazanov MD, Gelfand MS. Evolution of pan-genomes of *Escherichia coli*, *Shigella* spp., and *Salmonella enterica*. Journal of Bacteriology. 2013;**195**:2786-2792. DOI:

[47] Wiles TJ, Kulesus RR, Mulvey MA. Origins and virulence mechanisms of uropathogenic *Escherichia coli*. Experimental and Molecular Pathology. 2008;**85**:11-19. DOI: 10.1016/j.

[48] Salvador E, Wagenlehner F, Köhler C-D, Mellmann A, Hacker J, Svanborg C, et al. Comparison of asymptomatic bacteriuria *Escherichia coli* isolates from healthy individuals versus those from hospital patients shows that long-term bladder colonization selects for attenuated virulence phenotypes. Infection and Immunity. 2012;**80**:668-678. DOI:

[49] Zdziarski J, Brzuszkiewicz E, Wullt B, Liesegang H, Biran D, Voigt B, et al. Host imprints on bacterial genomes—Rapid, divergent evolution in individual patients. PLoS patho-

[50] Kot B. Virulence factors and innovative strategies for the treatment and control of uropathogenic *Escherichia coli*. In: Samie A. *Escherichia coli*-Recent Advances on Physiology, Pathogenesis and Biotechnological Applications. 1st ed. InTech, Rijeka, Croatia; 2017.

[51] Torres AG. *Escherichia coli* in the Americas. 1st ed. Springer, Switzerland; 2016. DOI:

[52] Subashchandrabose S, Mobley HLT. Virulence and fitness determinants of uropathogenic *Escherichia coli*. Microbiology spectrum. 2015;**3**:10.1128/microbiolspec.UTI-0015-

[53] Klemm P, Hancock V, Schembri MA. Fimbrial adhesins from extraintestinal *Escherichia coli*. Environmental Microbiology Reports. 2010;**2**:628-640. DOI: 10.1111/j.1758-2229.

[54] Quainoo S, Coolen JP, van Hijum SA, Huynen MA, Melchers WJ, van Schaik W, et al. Whole-genome sequencing of bacterial pathogens: The future of nosocomial outbreak analysis. Clinical Microbiology Reviews 2017;**30**:1015-1063. DOI: 10.1128/

[55] Virulence Factors of Pathogenic Bacteria: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, CAMS&PUMC, Bejing, China; [Internet]. 2017. Available from: http://www.mgc.ac.cn/cgi-bin/VFs/genus.cgi?Genus=Escherichia

[56] Ong C-LY, Ulett GC, Mabbett AN, Beatson SA, Webb RI, Monaghan W, et al. Identification of type 3 fimbriae in uropathogenic *Escherichia coli* reveals a role in biofilm formation.

Journal of Bacteriology. 2008;**190**:1054-1063. DOI: 10.1128/JB.01523-07

gens. 2010;**6**(8):e1001078). DOI: 10.1371/journal.ppat.1001078

2012. DOI: 10.1128/microbiolspec.UTI-0015-2012

10.1128/JB.02285-12

yexmp.2008.03.007

10.1128/IAI.06191-11

DOI: 10.5772/67778

2010.00166.x

CMR.00016-17

[Accessed: 2017-08-23]

10.1007/978-3-319-45092-6


[70] Van Loy CP, Sokurenko EV, Moseley SL. The major structural subunits of Dr and F1845 fimbriae are adhesins. Infection and Immunity. 2002;**70**:1694-1702. DOI: 10.1128/IAI.70. 4.1694-1702.2002

[83] Munkhdelger Y, Gunregjav N, Dorjpurev A, Juniichiro N, Sarantuya J. Detection of virulence genes, phylogenetic group and antibiotic resistance of uropathogenic *Escherichia coli* in Mongolia. Journal of Infection in Developing Countries. 2017;**11**:51-57. DOI: 10.3855/

Uropathogenic *Escherichia coli* and Fimbrial Adhesins Virulome

http://dx.doi.org/10.5772/intechopen.71374

83

[84] Ebadi M, Askari N, Jajarmi M, Ghanbarpour R. Detection of fimbrial genes, antibiotic resistance profile and phylogenetic background of uropathogenic *E. coli* isolated from clinical samples in Karaj City, Iranian Journal of Medical Bacteriology. 2017;**6**:15-20

[85] Paniagua-Contreras GL, Hernández-Jaimes T, Monroy-Pérez E, Vaca-Paniagua F, Díaz-Velásquez C, Uribe-García A, et al. Comprehensive expression analysis of pathogenicity genes in uropathogenic *Escherichia coli* strains. Microbial Pathogenesis. 2017;**103**:1-7.

[86] Yun KW, Kim HY, Park HK, Kim W, Lim IS. Virulence factors of uropathogenic *Escherichia coli* of urinary tract infections and asymptomatic bacteriuria in children. Journal of Microbiology, Immunology, and Infection. 2014;**47**:455-461. DOI: 10.1016/j.

[87] Behzadi P, Behzadi E, Ranjbar R. IL-12 family cytokines: General characteristics, pathogenic microorganisms, receptors, and signalling pathways. Acta Microbiologica et Immunologica

[88] Behzadi P, Behzadi E, Ranjbar R. Microarray probe set: Biology, bioinformatics and bio-

[89] Behzadi P, Ranjbar R. Microarray long oligo probe designing for Bacteria: An in silico pan-

[90] Ranjbar R, Behzadi P, Mammina C.Respiratory tularemia: *Francisella tularensis* and microarray probe designing. The Open Microbiology Journal. 2016;**10**:176-182. DOI: 10.2174/

[91] Behzadi P, Ranjbar R, Alavian SM. Nucleic acid-based approaches for detection of viral hepatitis. Jundishapur Journal of Microbiol. 2015;**8**:e17449. DOI: 10.5812/jjm.17449 [92] Behzadi P, Behzadi E, Alavian SM. DNA microarray technology in HBV genotyping.

[93] Ranjbar R, Behzadi P, Farshad S. Advances in diagnosis and treatment of *Helicobacter pylori* infection. Acta Microbiologica et Immunologica Hungarica. 2017;**64**:273-292. DOI:

Minerva Medica. 2017;**108**:473-476. DOI: 10.23736/S0026-4806.17.05059-5

jidc.7903

jmii.2013.07.010

1874285801610010176

10.1556/030.64.2017.008

DOI: 10.1016/j.micpath.2016.12.008

Hungarica. 2016;**63**:1-25. DOI: 10.1556/030.63.2016.1.1

genomic research. Albanian Medical Journal. 2016;**2**:5-11

physics. Albanian Medical Journal. 2015;**2**:78-83


[83] Munkhdelger Y, Gunregjav N, Dorjpurev A, Juniichiro N, Sarantuya J. Detection of virulence genes, phylogenetic group and antibiotic resistance of uropathogenic *Escherichia coli* in Mongolia. Journal of Infection in Developing Countries. 2017;**11**:51-57. DOI: 10.3855/ jidc.7903

[70] Van Loy CP, Sokurenko EV, Moseley SL. The major structural subunits of Dr and F1845 fimbriae are adhesins. Infection and Immunity. 2002;**70**:1694-1702. DOI: 10.1128/IAI.70.

82 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

[71] Baby S, Karnaker VK, Geetha R. Adhesins of Uropathogenic *Escherichia coli* (UPEC). Int

[72] Stubenrauch C, Belousoff MJ, Hay ID, Shen H-H, Lillington J, Tuck KL, et al. Effective assembly of fimbriae in *Escherichia coli* depends on the translocation assembly module nanomachine. Natural Microbiology. 2016;**1**:16064. DOI: 10.1038/

[73] Waksman G, Hultgren SJ. Structural biology of the chaperone–usher pathway of pilus biogenesis. Nature Reviews. Microbiology. 2009;**7**:765. DOI: 10.1038/nrmicro2220 [74] Nuccio S-P, Bäumler AJ. Evolution of the chaperone/usher assembly pathway: Fimbrial classification goes Greek. Microbiology and Molecular Biology Reviews. 2007;**71**:

[75] Busch A, Waksman G. Chaperone–usher pathways: Diversity and pilus assembly mechanism. Philosophical Transactions of Royal Society B. 2012;**367**:1112-1122. DOI: 10.1098/

[76] Matuszewski MA, Tupikowski K, Dołowy Ł, Szymańska B, Dembowski J, Zdrojowy R. Uroplakins and their potential applications in urology. Central European Journal of

[77] Bien J, Sokolova O, Bozko P. Role of uropathogenic *Escherichia Coli* virulence factors in development of urinary tract infection and kidney damage. International Journla of

[78] Khan AS, Kniep B, Oelschlaeger TA, Van Die I, Korhonen T, Hacker J.Receptor structure for F1C fimbriae of uropathogenic *Escherichia coli*. Infection and Immunity. 2000;**68**:3541-3547.

[79] Ejrnæs K. Bacterial characteristics of importance for recurrent urinary tract infections

[80] Ranjbar R, Bolandian M, Behzadi P. Virulotyping of *Shigella* spp. isolated from pediatric patients in Tehran, Iran. Acta Microbiologica et Immunologica Hungarica. 2017;**64**:71-80.

[81] Ranjbar R, Tabatabaee A, Behzadi P, Kheiri R. Enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) genotyping of *Escherichia coli* strains isolated from different animal stool specimens. Iranian Journal of Pathology.

[82] Behzadi E, Behzadi P, Sirmatel F. Identification of 30-kDa heat shock protein gene in *Trichophyton rubrum*. Mycoses. 2009;**52**:234-238. DOI: 10.1111/j.1439-0507.2008.01561.x

4.1694-1702.2002

nmicrobiol.2016.64

rstb.2011.0206

J Med Microbiol Trop Dis. 2016;**2**:10-18

551-575. DOI: 10.1128/MMBR.00014-07

DOI: 10.1128/IAI.68.6.3541-3547.2000

DOI: 10.1556/030.64.2017.007

2017;**12**:25-34

Urology. 2016;**69**:252. DOI: 10.5173/ceju.2016.638

Nephrology. 2012;**2012**:1-15. DOI: 10.1155/2012/681473

caused by *Escherichia coli*. Dan Med Bull. 2011;**58**:B4187


**Chapter 6**

**Provisional chapter**

**Resistant Gram-Negative Urinary Tract Bacterial**

**Resistant Gram-Negative Urinary Tract Bacterial** 

DOI: 10.5772/intechopen.71872

Urinary tract infection (UTI) is one of the most common infections in both the community as well in hospital settings. It is mostly caused by Gram-negative bacteria (GNBs). Over the past two decades, GNBs have developed complex mechanisms of resistance against most of the potent antibiotics. This has been a global challenge which has been identified by the World Health Organization as "one of the greatest threats to human health." This crisis is mostly attributed to the overuse and misuse of these medications, as well as lack of new drug antimicrobials by the pharmaceutical industry. This resulted in prolonged hospital stay, marked increase in the cost as well as increase in morbidity and mortality. Furthermore, it increases the risks and complications of urological procedures. In this chapter, we review the management of the most common and challenging group of resistant Gram-negative organisms, the extended-spectrum β-lactamases producing organisms (ESBL) and the carbapenem-resistant organisms (CRE/CRP). The latter group includes carbapenem-resistant *Enterobacteriaceae* (CRE), as well as *Pseudomonas aeruginosa* carbapenemases (CRP). When treating these infections, clinicians have few effective antimicrobials options. A critical step in managing these organisms is the early recognition and appropriate empiric therapy. Both showed mor-

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Urinary tract infection is the second most common infectious presentation in community as well as in hospital settings. It has been estimated that 150 million people are diagnosed with

**Keywords:** urinary tract infection (UTI), Gram-negative bacteria (GNBs), complicated urinary tract infections (CUTIs), extended-spectrum β-lactamases producing organisms

(ESBL), carbapenem-resistant organisms (CRE/CRP), carbapenems, ceftazidime-avibactam, colistin, fosfomycin, *Enterobacteriaceae*

**Infections**

**Abstract**

**Infections**

Nashaat S. Hamza and Abdalla Khalil

Nashaat S. Hamza and Abdalla Khalil

http://dx.doi.org/10.5772/intechopen.71872

bidity and mortality benefits.

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Provisional chapter**

## **Resistant Gram-Negative Urinary Tract Bacterial Infections Infections**

**Resistant Gram-Negative Urinary Tract Bacterial** 

DOI: 10.5772/intechopen.71872

Nashaat S. Hamza and Abdalla Khalil

Nashaat S. Hamza and Abdalla Khalil Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71872

#### **Abstract**

Urinary tract infection (UTI) is one of the most common infections in both the community as well in hospital settings. It is mostly caused by Gram-negative bacteria (GNBs). Over the past two decades, GNBs have developed complex mechanisms of resistance against most of the potent antibiotics. This has been a global challenge which has been identified by the World Health Organization as "one of the greatest threats to human health." This crisis is mostly attributed to the overuse and misuse of these medications, as well as lack of new drug antimicrobials by the pharmaceutical industry. This resulted in prolonged hospital stay, marked increase in the cost as well as increase in morbidity and mortality. Furthermore, it increases the risks and complications of urological procedures. In this chapter, we review the management of the most common and challenging group of resistant Gram-negative organisms, the extended-spectrum β-lactamases producing organisms (ESBL) and the carbapenem-resistant organisms (CRE/CRP). The latter group includes carbapenem-resistant *Enterobacteriaceae* (CRE), as well as *Pseudomonas aeruginosa* carbapenemases (CRP). When treating these infections, clinicians have few effective antimicrobials options. A critical step in managing these organisms is the early recognition and appropriate empiric therapy. Both showed morbidity and mortality benefits.

**Keywords:** urinary tract infection (UTI), Gram-negative bacteria (GNBs), complicated urinary tract infections (CUTIs), extended-spectrum β-lactamases producing organisms (ESBL), carbapenem-resistant organisms (CRE/CRP), carbapenems, ceftazidime-avibactam, colistin, fosfomycin, *Enterobacteriaceae*

## **1. Introduction**

Urinary tract infection is the second most common infectious presentation in community as well as in hospital settings. It has been estimated that 150 million people are diagnosed with

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

UTI each year worldwide [1]. It is mostly caused by GNBs. Over the past two decades, GNBs have developed complex mechanisms of resistance against most of the potent antibiotics. This has been a global challenge which has been identified by the World Health Organization as "one of the greatest threats to human health" [2]. This crisis is mostly man-made as it is attributed to the overuse and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry seeking better profitable agents.

identified from a Medline search (2000–2017), in addition to laboratory data and abstracts

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

87

The term ESBL was originally applied to plasmid-encoded β-lactamases that are capable of inactivating extended-spectrum cephalosporins and are inhibited by β-lactamase inhibitors, such as clavulanic acid. *Enterobacteriaceae*, primarily *Escherichia coli* and *Klebsiella pneumoniae*,

ESBLs are plasmid-encoded or chromosomally encoded β-lactamases with broad activity against penicillins and cephalosporins. They are a diverse group of bacterial enzymes that break down and inactivate most β-lactam antibiotics. They are inhibited by the available β-lactamase inhibitors (clavulanic acid, sulbactam, avibactam, and tazobactam) and do not affect cephamycins (e.g., cefoxitin and cefotetan) or carbapenems. β-Lactamases are divided into A, B, C, and D classes according to their amino acid sequence homology (Ambler classification) [14].

These bacteria are usually multi-resistant, as they are frequently capable of resisting other antibiotics, such as the aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole though other mechanisms, leaving few treatment options [3]. As these resistant genes are plasmid-mediated, they can be easily disseminated to other bacterial species [15–17]. UTIs caused by these organisms are seen at alarming rates in both hospital infection and in the

Although 95–100% ESBL organisms are still considered sensitive to carbapenems, rapid emergence of carbapenem resistance has been documented globally, and was linked to the over

Surveillance in Asia, Latin America, and Europe revealed dramatically increasing resistance to cephalosporins among *E. coli* and *Klebsiella* spp. [21]. In a large study in Turkey (SMART), the rate of ESBL in *E. coli* isolated from urine samples was high (50% hospital isolates and 38%

In one study, 21,414 positive urine cultures were collected from a University hospital in the UK. There were 1420 ESBL-positive specimens. There were a 44% increase, from 4.6 to 6.6%,

Multidrug resistance were detected in 75% of ESBL + *Klebsiella* spp. against >6 antibiotic

In the CHINET surveillance system data from 2005 to 2014, ESBL production among *E. coli*

The spreading of such isolates in the community is well documented, so containment of this type of bacterial infection will be real challenging [23]. There were many outbreaks caused by

these organisms all over the globe with high morbidity and mortalities [17].

from international Conferences.

**2.1. Definition: ESBL organisms**

community settings [15, 18, 19].

community acquired isolates) [22, 23].

of the ESBL-positive organisms over 2 years.

isolates was between 51.7 and 55.8% [25].

usage of these agents [20].

**2.2. Epidemiology**

classes [24].

are among the most frequently producing bacteria [9].

This resulted in prolonged hospital stay, marked increases in the cost as well as increase in morbidity and mortality [3–6]. Furthermore, bloodstream infections associated with severe complicated urinary tract infections (CUTIs) are associated with high mortality rates of 20–50% among critically ill patients. Many urological procedures are complicated with such infectious manse, frustrating the surgeons and the patients [7].

Multiple mechanisms that enable the organism to become resistant include enzymatic transformation, modification of site of action, active efflux from the cell interior and, the prevention of entry of the molecules into the cell [8].

There are different confusing terminologies in addressing this process. An international panel of experts developed the following definitions: multidrug-resistant (MDROs) means acquiring nonsusceptibility to at least one agent in three or more antimicrobial categories, extensively drug-resistant (XDR) is nonsusceptible to at least one agent in all, but two or fewer antimicrobial categories, and pan-drug-resistant (PDR) isolates are nonsusceptible to any of the available antimicrobial classes [1, 9, 10].

The term "ESKAPE" was one of the former descriptions of pathogens that cause the majority of hospital infections while effectively "escaping" the effects of available therapeutics. Other terms include "SPICE organisms" which include many Gram-negative bacteria that have inducible, chromosomal AmpC β-lactamase genes. The resistance to antibiotics may not be detectable initially, but appears after a period of exposure to β-lactam antibiotics (during therapy or after).

We are focusing in this review on the most common and challenging groups of resistant Gram-negative organisms, the ESBL, and the CRE, as well as CRP. The other highly resistant organism, such as *Acinetobacter baumannii*, less frequently causes urinary tract infection and its therapy is even more complicated [11–13].

When treating these infections, clinicians have a few effective antimicrobials to choose from and many are associated with significant adverse effects. A critical step in managing these organisms is the early recognition and appropriate empiric therapy. Both showed morbidity and mortality benefits. In this chapter we will review the available data on managing UTIs caused by ESBL and the CRE/CRP.

## **2. Materials and methods**

The purpose of this chapter is to review the available data on managing UTIs caused by resistant Gram-negative bacteria. Clinical trials and review articles (in English) were identified from a Medline search (2000–2017), in addition to laboratory data and abstracts from international Conferences.

## **2.1. Definition: ESBL organisms**

UTI each year worldwide [1]. It is mostly caused by GNBs. Over the past two decades, GNBs have developed complex mechanisms of resistance against most of the potent antibiotics. This has been a global challenge which has been identified by the World Health Organization as "one of the greatest threats to human health" [2]. This crisis is mostly man-made as it is attributed to the overuse and misuse of these medications, as well as a lack of new drug develop-

This resulted in prolonged hospital stay, marked increases in the cost as well as increase in morbidity and mortality [3–6]. Furthermore, bloodstream infections associated with severe complicated urinary tract infections (CUTIs) are associated with high mortality rates of 20–50% among critically ill patients. Many urological procedures are complicated with such

Multiple mechanisms that enable the organism to become resistant include enzymatic transformation, modification of site of action, active efflux from the cell interior and, the prevention

There are different confusing terminologies in addressing this process. An international panel of experts developed the following definitions: multidrug-resistant (MDROs) means acquiring nonsusceptibility to at least one agent in three or more antimicrobial categories, extensively drug-resistant (XDR) is nonsusceptible to at least one agent in all, but two or fewer antimicrobial categories, and pan-drug-resistant (PDR) isolates are nonsusceptible to any of

The term "ESKAPE" was one of the former descriptions of pathogens that cause the majority of hospital infections while effectively "escaping" the effects of available therapeutics. Other terms include "SPICE organisms" which include many Gram-negative bacteria that have inducible, chromosomal AmpC β-lactamase genes. The resistance to antibiotics may not be detectable initially, but appears after a period of exposure to β-lactam antibiotics (during

We are focusing in this review on the most common and challenging groups of resistant Gram-negative organisms, the ESBL, and the CRE, as well as CRP. The other highly resistant organism, such as *Acinetobacter baumannii*, less frequently causes urinary tract infection and

When treating these infections, clinicians have a few effective antimicrobials to choose from and many are associated with significant adverse effects. A critical step in managing these organisms is the early recognition and appropriate empiric therapy. Both showed morbidity and mortality benefits. In this chapter we will review the available data on managing UTIs

The purpose of this chapter is to review the available data on managing UTIs caused by resistant Gram-negative bacteria. Clinical trials and review articles (in English) were

ment by the pharmaceutical industry seeking better profitable agents.

86 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

infectious manse, frustrating the surgeons and the patients [7].

of entry of the molecules into the cell [8].

the available antimicrobial classes [1, 9, 10].

its therapy is even more complicated [11–13].

caused by ESBL and the CRE/CRP.

**2. Materials and methods**

therapy or after).

The term ESBL was originally applied to plasmid-encoded β-lactamases that are capable of inactivating extended-spectrum cephalosporins and are inhibited by β-lactamase inhibitors, such as clavulanic acid. *Enterobacteriaceae*, primarily *Escherichia coli* and *Klebsiella pneumoniae*, are among the most frequently producing bacteria [9].

ESBLs are plasmid-encoded or chromosomally encoded β-lactamases with broad activity against penicillins and cephalosporins. They are a diverse group of bacterial enzymes that break down and inactivate most β-lactam antibiotics. They are inhibited by the available β-lactamase inhibitors (clavulanic acid, sulbactam, avibactam, and tazobactam) and do not affect cephamycins (e.g., cefoxitin and cefotetan) or carbapenems. β-Lactamases are divided into A, B, C, and D classes according to their amino acid sequence homology (Ambler classification) [14].

These bacteria are usually multi-resistant, as they are frequently capable of resisting other antibiotics, such as the aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole though other mechanisms, leaving few treatment options [3]. As these resistant genes are plasmid-mediated, they can be easily disseminated to other bacterial species [15–17]. UTIs caused by these organisms are seen at alarming rates in both hospital infection and in the community settings [15, 18, 19].

Although 95–100% ESBL organisms are still considered sensitive to carbapenems, rapid emergence of carbapenem resistance has been documented globally, and was linked to the over usage of these agents [20].

## **2.2. Epidemiology**

Surveillance in Asia, Latin America, and Europe revealed dramatically increasing resistance to cephalosporins among *E. coli* and *Klebsiella* spp. [21]. In a large study in Turkey (SMART), the rate of ESBL in *E. coli* isolated from urine samples was high (50% hospital isolates and 38% community acquired isolates) [22, 23].

In one study, 21,414 positive urine cultures were collected from a University hospital in the UK. There were 1420 ESBL-positive specimens. There were a 44% increase, from 4.6 to 6.6%, of the ESBL-positive organisms over 2 years.

Multidrug resistance were detected in 75% of ESBL + *Klebsiella* spp. against >6 antibiotic classes [24].

In the CHINET surveillance system data from 2005 to 2014, ESBL production among *E. coli* isolates was between 51.7 and 55.8% [25].

The spreading of such isolates in the community is well documented, so containment of this type of bacterial infection will be real challenging [23]. There were many outbreaks caused by these organisms all over the globe with high morbidity and mortalities [17].

## **2.3. Risk factors**

Many studies have implicated broad-spectrum cephalosporins as the major class associated with ESBL production; others considered fluoroquinolone and β-lactam-β-lactamase inhibitor combinations, as the main risk factors for ESBL infections [26]. Other risk factors include nursing home residence, diabetes, recurrent UTIs, male gender, prolonged hospitalization, intensive care admission, and urinary catheterization [19, 24, 27–29].

The detection of specific genes by PCR and sequencing are commonly used for final confirmation of ESBL producers. A commercially available multiplex real-time PCR can detect the predominant class A β-lactamase genes *bla*CTX-M, *bla*SHV, *bla*TEM, and CIT-type AmpCs with high

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

89

The carbapenems are the most potent agents with wide spectra of coverage. They are the most dependent agents in critical infectious syndromes. However, resistance to these agents has increasingly been reported worldwide, rendering them increasingly ineffective. These organisms are also capable of resisting other classes of antibiotics (aminoglycosides, fluoroquinolone, and co-trimoxazole), due to the frequent coexistence of other resistance genes on the same mobile genetic elements, rendering them superbugs. The most recent example is the emergence of colistin resistant genes in isolates which are already resistant to the

*K. pneumoniae* carbapenemase (KPC-class A) was the first CRE enzyme to be reported in 2001. New Delhi metallo-β-lactamase (NDM-class B) is one of the most recently reported metallo-enzymes. It has spread widely in the Indian sub-continent and now worldwide. The oxacillinase-48 type (OXA-48-class C) has been identified mostly in Mediterranean and southern European countries. Other mechanisms of resistance include efflux pump over activity (pumping the antibiotics out of the bacterial cell), hyper production of AmpC β-lactamase in the already highly resistant ESBL organisms, and changes in porin perme-

Infections with such resistant isolates resulted in high morbidity, prolonged hospital stay, and mortality [37, 38]. In a pooled analysis of the 9 studies (985 patients), the mortality rate was higher among CRE-infected than carbapenem susceptible *Enterobacteriaceae*infected patients (RR 2.05, 95% CI 1.56–2.69). The authors calculated 26–44% of deaths from 7 studies attributable to carbapenem resistance [39]. The rate was even higher (61%) in patients infected with KPC-expressing *K. pneumoniae* who received initially ineffective

A multicenter observational study in 11 hospitals from 7 Latin American countries that included 255 patients with bacteremia was reported. Twenty-three percent of the isolates

According to the latest data collected by the European Antimicrobial Resistance Surveillance

CRE are more prevalent in Italy and Greece. In an active surveillance study, rectal swabs (and clinical samples) were collected from 15,104 hospitalized patients (over 2 years). *K. pneumoniae*

Network (EARS-Net), the rate of CRE rose from 6.2% in 2012 to 8.1% in 2015 [41].

CRE was detected in 496 consecutive non-replicated samples [42].

sensitivity and it is much faster than routine cultures [36].

**2.6. Carbapenem resistant organisms**

carbapenems.

ability [8].

therapy [40].

**2.7. Epidemiology**

were CRE/CRP [38].

Prospective cohort study of 225 healthy German volunteers traveling to 53 different countries (mostly in Asia, Africa, and S. America) evaluated the risk of ESBL colonization. Stool samples were collected before and after traveling. The isolates were examined phenotypically and by PCR amplification sequencing. Among 191 participants that were ESBL-negative before travel, 30% were colonized by ESBL-producing *E. coli* after returning home [29, 30].

The use of antibiotics in farm animals as growth promoters is linked to this global disaster. In a recent study from India, 18 poultry farms were surveyed, 16 of them reported using antimicrobials for growth promotion. There were 1556 *E. coli* isolates, collected and tested. The prevalence of ESBL-positive strains in broiler farms was 87% [31]. Multiple studies have shown the benefit of early identifications of this organism, to offer the appropriate empiric therapy. A simple predicting score for early recognition was recently published. Four risk factors were identified; each was given a score of one. Scores above 2 had a sensitivity of (84%) and a specificity of (92%). These variables include recent antimicrobial use (OR, 15.29), recent invasive procedures (OR, 12.33), nursing home residents (OR, 27.77), and frequent emergency department visits (OR, 9.98) [32].

#### **2.4. Mechanism of resistance**

The most common mechanisms include enzymatic inactivation, target modification, reduced permeability, and active efflux. Antibiotic resistance can be intrinsic to specific microorganisms, which can be explained by their inherent characteristics. Point mutations on β-lactamase genes are responsible for emergence of ESBLs. These new genes could be transmitted through small mobile genetic element DNA (plasmid, transposons) to other bacteria from same or other species [5, 8].

A more distinct type of ESBL including CTX-M-type, AmpC, and carbapenemase, can confer phenotypic resistance that widens the resistance abilities against more antibiotics than the classical isolates [33].

#### **2.5. Detection**

These organisms are capable of resisting most of the third-generation cephalosporins but they are inhibited by clavulanate. This is the basis of detecting these organisms using routine laboratory tests such as double disk diffusion test or E-test. The size of zone of inhibition around one or more of the β-lactam-containing discs toward the clavulanic acid-containing disc is indicative of some ESBL producers [34, 35].

The detection of specific genes by PCR and sequencing are commonly used for final confirmation of ESBL producers. A commercially available multiplex real-time PCR can detect the predominant class A β-lactamase genes *bla*CTX-M, *bla*SHV, *bla*TEM, and CIT-type AmpCs with high sensitivity and it is much faster than routine cultures [36].

## **2.6. Carbapenem resistant organisms**

**2.3. Risk factors**

department visits (OR, 9.98) [32].

**2.4. Mechanism of resistance**

other species [5, 8].

classical isolates [33].

indicative of some ESBL producers [34, 35].

**2.5. Detection**

Many studies have implicated broad-spectrum cephalosporins as the major class associated with ESBL production; others considered fluoroquinolone and β-lactam-β-lactamase inhibitor combinations, as the main risk factors for ESBL infections [26]. Other risk factors include nursing home residence, diabetes, recurrent UTIs, male gender, prolonged hospitalization,

Prospective cohort study of 225 healthy German volunteers traveling to 53 different countries (mostly in Asia, Africa, and S. America) evaluated the risk of ESBL colonization. Stool samples were collected before and after traveling. The isolates were examined phenotypically and by PCR amplification sequencing. Among 191 participants that were ESBL-negative before

The use of antibiotics in farm animals as growth promoters is linked to this global disaster. In a recent study from India, 18 poultry farms were surveyed, 16 of them reported using antimicrobials for growth promotion. There were 1556 *E. coli* isolates, collected and tested. The prevalence of ESBL-positive strains in broiler farms was 87% [31]. Multiple studies have shown the benefit of early identifications of this organism, to offer the appropriate empiric therapy. A simple predicting score for early recognition was recently published. Four risk factors were identified; each was given a score of one. Scores above 2 had a sensitivity of (84%) and a specificity of (92%). These variables include recent antimicrobial use (OR, 15.29), recent invasive procedures (OR, 12.33), nursing home residents (OR, 27.77), and frequent emergency

The most common mechanisms include enzymatic inactivation, target modification, reduced permeability, and active efflux. Antibiotic resistance can be intrinsic to specific microorganisms, which can be explained by their inherent characteristics. Point mutations on β-lactamase genes are responsible for emergence of ESBLs. These new genes could be transmitted through small mobile genetic element DNA (plasmid, transposons) to other bacteria from same or

A more distinct type of ESBL including CTX-M-type, AmpC, and carbapenemase, can confer phenotypic resistance that widens the resistance abilities against more antibiotics than the

These organisms are capable of resisting most of the third-generation cephalosporins but they are inhibited by clavulanate. This is the basis of detecting these organisms using routine laboratory tests such as double disk diffusion test or E-test. The size of zone of inhibition around one or more of the β-lactam-containing discs toward the clavulanic acid-containing disc is

travel, 30% were colonized by ESBL-producing *E. coli* after returning home [29, 30].

intensive care admission, and urinary catheterization [19, 24, 27–29].

88 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

The carbapenems are the most potent agents with wide spectra of coverage. They are the most dependent agents in critical infectious syndromes. However, resistance to these agents has increasingly been reported worldwide, rendering them increasingly ineffective. These organisms are also capable of resisting other classes of antibiotics (aminoglycosides, fluoroquinolone, and co-trimoxazole), due to the frequent coexistence of other resistance genes on the same mobile genetic elements, rendering them superbugs. The most recent example is the emergence of colistin resistant genes in isolates which are already resistant to the carbapenems.

*K. pneumoniae* carbapenemase (KPC-class A) was the first CRE enzyme to be reported in 2001. New Delhi metallo-β-lactamase (NDM-class B) is one of the most recently reported metallo-enzymes. It has spread widely in the Indian sub-continent and now worldwide. The oxacillinase-48 type (OXA-48-class C) has been identified mostly in Mediterranean and southern European countries. Other mechanisms of resistance include efflux pump over activity (pumping the antibiotics out of the bacterial cell), hyper production of AmpC β-lactamase in the already highly resistant ESBL organisms, and changes in porin permeability [8].

Infections with such resistant isolates resulted in high morbidity, prolonged hospital stay, and mortality [37, 38]. In a pooled analysis of the 9 studies (985 patients), the mortality rate was higher among CRE-infected than carbapenem susceptible *Enterobacteriaceae*infected patients (RR 2.05, 95% CI 1.56–2.69). The authors calculated 26–44% of deaths from 7 studies attributable to carbapenem resistance [39]. The rate was even higher (61%) in patients infected with KPC-expressing *K. pneumoniae* who received initially ineffective therapy [40].

## **2.7. Epidemiology**

A multicenter observational study in 11 hospitals from 7 Latin American countries that included 255 patients with bacteremia was reported. Twenty-three percent of the isolates were CRE/CRP [38].

According to the latest data collected by the European Antimicrobial Resistance Surveillance Network (EARS-Net), the rate of CRE rose from 6.2% in 2012 to 8.1% in 2015 [41].

CRE are more prevalent in Italy and Greece. In an active surveillance study, rectal swabs (and clinical samples) were collected from 15,104 hospitalized patients (over 2 years). *K. pneumoniae* CRE was detected in 496 consecutive non-replicated samples [42].

In a Greek study, 3449 *K. pneumoniae* isolates were recovered over 10 years. Among them, 1668 (48%) were CRE-producing. Sixteen percent of the isolates were resistant to colistin [43].

Studies of the pharmacokinetic/pharmacodynamics data also showed superiority of this class of antibiotic in achieving the proper concentration above the bacterial minimal inhibitory

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

91

In vitro activities against many ESBL isolates are well documented against large collections of

For treating CRE/CRP, limited data on combination regimens involving carbapenems (if MICs ≥ 8  mg/L) adding colistin or high-dose tigecycline or aminoglycoside or even triple combinations, seem to confer decent therapeutic advantage over monotherapy. For organisms with

In a recent meta-analysis of 22 studies of using, the most common regimen, carbapenems plus

On the other hand, a retrospective study of 436 patients were recruited in the INCREMENT study-cohort (26 tertiary hospitals from 10 countries). The main outcome variable was 30 day all-cause mortality in patients with CRE/CRP bloodstream infection. Overall mortality was not different between those receiving combination therapy and monotherapy (35%

Tigecycline with colistin, colistin with a carbapenem, fosfomycin with a carbapenem, fosfomycin with an aminoglycoside, and a carbapenem with an aminoglycoside have been reported as antibiotic combinations effectively administered to series of patients infected with

Efforts have been exerted to limit the usage of their precious agents by using alternative regi-

PTZ is a broad-spectrum drug combination used in serious infections. However, the extensive

Some ESBL *E. coli* producers' isolates might have high in vitro susceptibility to PTZ; however, its clinical utility in serious UTIs, especially when associated with bacteremia, has been controversial. In a prospective, randomized, open-label comparison of the therapeutic efficacy of (PTZ), cefepime, and ertapenem in nosocomial UTIs with ESBL producers, 66 participants were evenly randomized to the PTZ and ertapenem treatment groups (cefepime arm was eliminated because of high treatment failure rate). The clinical and microbiological responses

Similar non-inferiority of PTZ to carbapenems was shown in a retrospective analysis of blood-

In a post hoc analysis of patients with bloodstream infections due to ESBL producing isolates from 6 published prospective cohorts, the effect of amoxicillin-clavulanic acid, PTZ, and

stream infection by an ESBL-producing organism, if susceptible in vitro [61].

Synergy is another potential benefit arising from the use of antibiotic combinations.

ESBL producing *Enterobacteriaceae* and *P. aeruginosa* isolates [57].

colistin or polymyxin had mortality advantages [38].

carbapenemase-producing *Enterobacteriaceae* [4].

to both antibiotics were similar around 94% [60].

usage of this agent accelerated the emergence of resistance [48, 59].

higher MIC, a combination of two or even three antibiotics may be needed.

concentrations (MICs) [56].

vs. 41%) [58].

mens whenever [46].

*2.9.2.2. Piperacillin-tazobactam (PTZ)*

#### **2.8. Detection**

These include antimicrobial susceptibility testing, modified Hodge testing, and inhibitorbased testing. In 2015, the CDC-CRE surveillance definition was revised to one of two criteria: (1) resistance to any carbapenem according to current CLSI breakpoints (MIC ≥ 2 for ertapenem or ≥4 for doripenem, meropenem, or imipenem) or (2) demonstration of carbapenemase production. Several phenotypic assays are available commercially detecting carbapenemase production from bacterial culture within hours. The Carba NP test has high sensitivity and specificity that can differentiate between class A, B, and C CRE. In one study, its specificity and sensitivity were almost 96% [44].

There are many commercially available PCR-based testing for early recognition and confirmation.

## **2.9. Therapy of urinary tract infections caused by MDROs**

#### *2.9.1. ESBL-producing β-lactamases*

In general and for serious life threatening infections, the carbapenems are the drugs of choice for infections caused by these organisms [12, 35]. However, the surge in using the carbapenems, resulted in the evolution of CRE/CRP, so there were multiple recent trials evaluating, carbapenem-sparing are regimens, mostly for less severe infections [12, 45–48].

#### *2.9.2. CRE/CRP*

In general, there is no clear consensus on managing these organisms. The available data are drawn from expert opinion or from small trials. There are few controlled trials that determined the best therapeutic so far [49, 50].

In the following sections, we will review the available data on different classes of antibiotics that have been used in managing ESBL, and then if applicable, will discuss their roles in treating CRE/CRP.

#### *2.9.2.1. Carbapenems*

They have a broad spectrum of antimicrobial activity more than any other classes of antimicrobials, and are potent bactericidal (ertapenem lakes anti-pseudomonas activities) [51–54].

In multiple non-randomized studies that included large number of patients with bacteremia, sepsis, and other serious infections, they showed high cure-improvement rates with great safety profile [54, 55].

Studies of the pharmacokinetic/pharmacodynamics data also showed superiority of this class of antibiotic in achieving the proper concentration above the bacterial minimal inhibitory concentrations (MICs) [56].

In vitro activities against many ESBL isolates are well documented against large collections of ESBL producing *Enterobacteriaceae* and *P. aeruginosa* isolates [57].

For treating CRE/CRP, limited data on combination regimens involving carbapenems (if MICs ≥ 8  mg/L) adding colistin or high-dose tigecycline or aminoglycoside or even triple combinations, seem to confer decent therapeutic advantage over monotherapy. For organisms with higher MIC, a combination of two or even three antibiotics may be needed.

In a recent meta-analysis of 22 studies of using, the most common regimen, carbapenems plus colistin or polymyxin had mortality advantages [38].

On the other hand, a retrospective study of 436 patients were recruited in the INCREMENT study-cohort (26 tertiary hospitals from 10 countries). The main outcome variable was 30 day all-cause mortality in patients with CRE/CRP bloodstream infection. Overall mortality was not different between those receiving combination therapy and monotherapy (35% vs. 41%) [58].

Synergy is another potential benefit arising from the use of antibiotic combinations.

Tigecycline with colistin, colistin with a carbapenem, fosfomycin with a carbapenem, fosfomycin with an aminoglycoside, and a carbapenem with an aminoglycoside have been reported as antibiotic combinations effectively administered to series of patients infected with carbapenemase-producing *Enterobacteriaceae* [4].

Efforts have been exerted to limit the usage of their precious agents by using alternative regimens whenever [46].

## *2.9.2.2. Piperacillin-tazobactam (PTZ)*

In a Greek study, 3449 *K. pneumoniae* isolates were recovered over 10 years. Among them, 1668 (48%) were CRE-producing. Sixteen percent of the isolates were resistant to colistin [43].

90 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

These include antimicrobial susceptibility testing, modified Hodge testing, and inhibitorbased testing. In 2015, the CDC-CRE surveillance definition was revised to one of two criteria: (1) resistance to any carbapenem according to current CLSI breakpoints (MIC ≥ 2 for ertapenem or ≥4 for doripenem, meropenem, or imipenem) or (2) demonstration of carbapenemase production. Several phenotypic assays are available commercially detecting carbapenemase production from bacterial culture within hours. The Carba NP test has high sensitivity and specificity that can differentiate between class A, B, and C CRE. In one study, its specificity

There are many commercially available PCR-based testing for early recognition and

In general and for serious life threatening infections, the carbapenems are the drugs of choice for infections caused by these organisms [12, 35]. However, the surge in using the carbapenems, resulted in the evolution of CRE/CRP, so there were multiple recent trials evaluating,

In general, there is no clear consensus on managing these organisms. The available data are drawn from expert opinion or from small trials. There are few controlled trials that deter-

In the following sections, we will review the available data on different classes of antibiotics that have been used in managing ESBL, and then if applicable, will discuss their roles in treat-

They have a broad spectrum of antimicrobial activity more than any other classes of antimicrobials, and are potent bactericidal (ertapenem lakes anti-pseudomonas activities)

In multiple non-randomized studies that included large number of patients with bacteremia, sepsis, and other serious infections, they showed high cure-improvement rates with great

carbapenem-sparing are regimens, mostly for less severe infections [12, 45–48].

**2.8. Detection**

confirmation.

*2.9.2. CRE/CRP*

ing CRE/CRP.

[51–54].

*2.9.2.1. Carbapenems*

safety profile [54, 55].

and sensitivity were almost 96% [44].

*2.9.1. ESBL-producing β-lactamases*

mined the best therapeutic so far [49, 50].

**2.9. Therapy of urinary tract infections caused by MDROs**

PTZ is a broad-spectrum drug combination used in serious infections. However, the extensive usage of this agent accelerated the emergence of resistance [48, 59].

Some ESBL *E. coli* producers' isolates might have high in vitro susceptibility to PTZ; however, its clinical utility in serious UTIs, especially when associated with bacteremia, has been controversial. In a prospective, randomized, open-label comparison of the therapeutic efficacy of (PTZ), cefepime, and ertapenem in nosocomial UTIs with ESBL producers, 66 participants were evenly randomized to the PTZ and ertapenem treatment groups (cefepime arm was eliminated because of high treatment failure rate). The clinical and microbiological responses to both antibiotics were similar around 94% [60].

Similar non-inferiority of PTZ to carbapenems was shown in a retrospective analysis of bloodstream infection by an ESBL-producing organism, if susceptible in vitro [61].

In a post hoc analysis of patients with bloodstream infections due to ESBL producing isolates from 6 published prospective cohorts, the effect of amoxicillin-clavulanic acid, PTZ, and carbapenems were compared. The mortality rates at day 30 were much higher with the first 2 antibiotics than with carbapenems [62].

There is few data from limited studies (with small number of participants) that showed cefepime is effective if used against in vitro susceptible ESBL-producing *Enterobacteriaceae*

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

93

There are less robust data for the efficacy of other cephalosporins, cefmetazole (a cephamycins),

Aminoglycosides are very potent antibiotics; however, their use is associated with significant renal and auditory toxicities. They have been successful in treating ESBL-UTIs as a monotherapy or in combinations with other agents. Combinations with other agents were effective in the treatment of CRE/CRP infections if the strain is susceptible to aminoglycosides [69].

Many of the plasmids that carry ESBL-producing genes also carry genes encodes resistant to aminoglycosides, mostly against tobramycin and gentamicin. In contrast, amikacin has

In a small study of UTI caused by highly resistant ESBL (also resistant to nitrofurantoin, fosfomycin, and quinolones and trimethoprim/sulfamethoxazole), amikacin intramuscular injections for 10 days achieved clinical success in 97.2%. Overall bacteriological success rate was

In a review of 20 studies evaluating CRE infections therapy, combination of aminoglycosides

In many parts of the world, *E. coli* fluoroquinolone resistance rates are >20% among patients with community-acquired uncomplicated UTI and 50% among patients with complicated infections. The rate of resistance is even higher against *Klebsiella* spp. up to 70% in one recent

The co-existing of ESBL and fluoroquinolone resistant is extremely high in some areas of the world, in those who uses quinolones prophylaxis and in returned travelers to theses endemic areas [73]. Therefore, they are in general not recommended in the setting of high

Sitafloxacin is the newest member (fourth generation) of the fluoroquinolone family of antibiotics which has a broad-spectrum activity including many anaerobes [75]. In a recent prospective randomized controlled trial, comparing the clinical and bacteriological efficacy of sitafloxacin and ertapenem for non-bacteremic acute pyelonephritis caused by ESBL-EC was evaluated. Carbapenems were initially given to all patients, and then were randomized to one of the study drugs. The 2 arms were equal in the rates of clinical and microbiological cure [76]. These data suggest that fluoroquinolones may no longer be effective as first-line therapy for Gram-negative UTI in hospitalized patients and definitely in ESBL-producing organisms.

and as a de-escalation therapy in patients with uncomplicated UTIs [53, 67].

in treating patients with extended-spectrum β-lactamase producing [68].

retained high susceptibility rates, particularly against *E. coli.*

and carbapenems displayed the lowest mortality rate (11.1%) [71].

94.1% on the 7–10 days after treatment [70].

international surveillance study [8, 72].

*2.9.2.4. Aminoglycosides*

*2.9.2.5. Fluoroquinolones*

ESBL isolates [74].

In a retrospective observational study, 331 patients with ESBL bacteremias were evaluated. Empiric therapy with PTZ was used in 48% while 52% received carbapenems. The adjusted risk of death (14-day mortality) was 1.92 times higher for patients receiving empiric PTZ compared with carbapenem therapy (95% confidence interval, 1.07–3.45) [63].

In an editorial that tried to explain these controversial results, the authors mentioned various variables including the inoculum of the bacteria in the bloodstream, the sources of bacteremia (less fatal if from UTIs than central line infections), selection bias inherent to observational studies, and the presence of different genetic and virulence of the included bacteria [35].

A large recent multicenter randomized controlled open-label non-inferiority trial, MERINO trial, comparing meropenem (standard arm) against PTZ in adult patients with bacteremia caused by *E. coli* or *Klebsiella* spp., is ongoing, and hopefully, it will provide better answer to these conflicting data [61].

## *2.9.2.3. Cephalosporins*

Cephalosporins have been less effective than comparative regimens in treating severe/serious infections with ESBL-producing bacteria. They are rapidly hydrolyzed by many ESBLs stains [60].

In many clinical studies, it was associated with a trend toward clinical and microbiological failure, as well as a trend of increased mortality [64, 65].

Despite their in vitro activities, there are reports of mutations and/or acquiring plasmids encoding AmpC-resistant genes during therapy with these agents. Others concerns about this agent failure include the decreased activity with high bacterial load (inoculum effect) and the failure to meet necessary pharmacodynamics targets due to inadequate dosing and/or interval schedules [50].

The most studied agent in this class is the cefepime. In the above-mentioned recent prospective, randomized, open-label that compared (PTZ), cefepime, and ertapenem in nosocomial UTIs, the microbiological and therapeutic efficacies of cefepime in febrile nosocomial urinary tract infection with ESBL *E. coli* were much less than the other competitors at 33% [60].

Data is more clear in patients with serious infections associated with ESBL-producing organisms' bloodstream infections. In a recent study, the mortality risk was 2.87 times higher for patients receiving cefepime compared with carbapenems (95% confidence interval (0.88–9.41) [66].

Another retrospective study included adult patients with BSI due to ESBL-producing *K. pneumoniae* or *E. coli*. In multivariate analysis, using cefepime as empirical therapy was associated with a trend toward an increased mortality risk, while empirical carbapenem therapy was associated with a trend toward decreased mortality [65].

There is few data from limited studies (with small number of participants) that showed cefepime is effective if used against in vitro susceptible ESBL-producing *Enterobacteriaceae* and as a de-escalation therapy in patients with uncomplicated UTIs [53, 67].

There are less robust data for the efficacy of other cephalosporins, cefmetazole (a cephamycins), in treating patients with extended-spectrum β-lactamase producing [68].

## *2.9.2.4. Aminoglycosides*

carbapenems were compared. The mortality rates at day 30 were much higher with the first

In a retrospective observational study, 331 patients with ESBL bacteremias were evaluated. Empiric therapy with PTZ was used in 48% while 52% received carbapenems. The adjusted risk of death (14-day mortality) was 1.92 times higher for patients receiving empiric PTZ com-

In an editorial that tried to explain these controversial results, the authors mentioned various variables including the inoculum of the bacteria in the bloodstream, the sources of bacteremia (less fatal if from UTIs than central line infections), selection bias inherent to observational studies, and the presence of different genetic and virulence of the included bacteria [35].

A large recent multicenter randomized controlled open-label non-inferiority trial, MERINO trial, comparing meropenem (standard arm) against PTZ in adult patients with bacteremia caused by *E. coli* or *Klebsiella* spp., is ongoing, and hopefully, it will provide better answer to

Cephalosporins have been less effective than comparative regimens in treating severe/serious infections with ESBL-producing bacteria. They are rapidly hydrolyzed by many ESBLs

In many clinical studies, it was associated with a trend toward clinical and microbiological

Despite their in vitro activities, there are reports of mutations and/or acquiring plasmids encoding AmpC-resistant genes during therapy with these agents. Others concerns about this agent failure include the decreased activity with high bacterial load (inoculum effect) and the failure to meet necessary pharmacodynamics targets due to inadequate dosing and/or

The most studied agent in this class is the cefepime. In the above-mentioned recent prospective, randomized, open-label that compared (PTZ), cefepime, and ertapenem in nosocomial UTIs, the microbiological and therapeutic efficacies of cefepime in febrile nosocomial urinary tract infection with ESBL *E. coli* were much less than the other competitors at 33% [60].

Data is more clear in patients with serious infections associated with ESBL-producing organisms' bloodstream infections. In a recent study, the mortality risk was 2.87 times higher for patients receiving cefepime compared with carbapenems (95% confidence inter-

Another retrospective study included adult patients with BSI due to ESBL-producing *K. pneumoniae* or *E. coli*. In multivariate analysis, using cefepime as empirical therapy was associated with a trend toward an increased mortality risk, while empirical carbapenem therapy was

failure, as well as a trend of increased mortality [64, 65].

associated with a trend toward decreased mortality [65].

pared with carbapenem therapy (95% confidence interval, 1.07–3.45) [63].

92 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

2 antibiotics than with carbapenems [62].

these conflicting data [61].

*2.9.2.3. Cephalosporins*

interval schedules [50].

val (0.88–9.41) [66].

stains [60].

Aminoglycosides are very potent antibiotics; however, their use is associated with significant renal and auditory toxicities. They have been successful in treating ESBL-UTIs as a monotherapy or in combinations with other agents. Combinations with other agents were effective in the treatment of CRE/CRP infections if the strain is susceptible to aminoglycosides [69].

Many of the plasmids that carry ESBL-producing genes also carry genes encodes resistant to aminoglycosides, mostly against tobramycin and gentamicin. In contrast, amikacin has retained high susceptibility rates, particularly against *E. coli.*

In a small study of UTI caused by highly resistant ESBL (also resistant to nitrofurantoin, fosfomycin, and quinolones and trimethoprim/sulfamethoxazole), amikacin intramuscular injections for 10 days achieved clinical success in 97.2%. Overall bacteriological success rate was 94.1% on the 7–10 days after treatment [70].

In a review of 20 studies evaluating CRE infections therapy, combination of aminoglycosides and carbapenems displayed the lowest mortality rate (11.1%) [71].

## *2.9.2.5. Fluoroquinolones*

In many parts of the world, *E. coli* fluoroquinolone resistance rates are >20% among patients with community-acquired uncomplicated UTI and 50% among patients with complicated infections. The rate of resistance is even higher against *Klebsiella* spp. up to 70% in one recent international surveillance study [8, 72].

The co-existing of ESBL and fluoroquinolone resistant is extremely high in some areas of the world, in those who uses quinolones prophylaxis and in returned travelers to theses endemic areas [73]. Therefore, they are in general not recommended in the setting of high ESBL isolates [74].

Sitafloxacin is the newest member (fourth generation) of the fluoroquinolone family of antibiotics which has a broad-spectrum activity including many anaerobes [75]. In a recent prospective randomized controlled trial, comparing the clinical and bacteriological efficacy of sitafloxacin and ertapenem for non-bacteremic acute pyelonephritis caused by ESBL-EC was evaluated. Carbapenems were initially given to all patients, and then were randomized to one of the study drugs. The 2 arms were equal in the rates of clinical and microbiological cure [76].

These data suggest that fluoroquinolones may no longer be effective as first-line therapy for Gram-negative UTI in hospitalized patients and definitely in ESBL-producing organisms.

## *2.9.2.6. Trimethoprim/sulfamethoxazole*

Although treatment with trimethoprim/sulfamethoxazole was traditionally effective in treating UTIS, the evolution of resistance is a current major concern. The Infectious Diseases Society of America guideline recommends against using it if local bacterial resistance rate is ≥20% [77]. Genes that encode for ESBLs are usually found on large plasmids accompanied by genetic determinants of resistance against multiple classes of antibiotics, such as aminoglycosides, sulfonamides, and fluoroquinolones. TMP-SMX is not recommended as an empiric treatment option of UTIs caused by resistant strains of *E. coli* or *K. pneumoniae* that reaches 40–66% in some areas in the world [78].

Currently, they are the backbone of most of the regimens used against the CRE/CRP organisms. Common combination regimens include tigecycline, carbapenem, minocycline, rifampicin, aminoglycosides, ampicillin/sulbactam, and piperacillin-tazobactam. Large clinical trials

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

95

Polymyxin B is administered directly as the active antibiotic, whereas colistin methanesulfonate is converted in vivo to colistin. The optimal dosing of these agents is still controversial. Higher doses of colistin were proposed for managing serious CRE/CRP associated infections. A recent systematic review that included 22 studies (observational studies as well as randomized controlled trials) of polymyxin-based combination therapy in adult patients with infections caused by CRE/CRP was published. The primary outcome was a 30-day mortality. Mortality was significantly higher with polymyxin monotherapy compared with combination therapy of polymyxin with tigecycline, aminoglycosides or fosfomycin, of 1.57 (95% CI = 1.06−2.32).

The mechanism of colistin resistance can be generally classified intrinsic or acquired by a

In November 2015, plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China. As of September 2016, the mcr-1 gene was detected in 35 countries worldwide in human sources in 22 countries [88]. This created a real lethal

This agent has gained attention, as it has activities against both Gram-positive and Gramnegative MDR and XDR bacteria [89, 90–94]. It exhibits bactericidal activity against many Gram-positive and Gram-negative pathogens including many of the ESBL-producing *E. coli* and *K. pneumoniae* [91]. Fosf achieves very high concentrations within the urine and is therefore an excellent agent for cystitis, but it is not recommended for treating pyelonephritis or bacteremias due to inadequate concentrations in the blood. However, small studies have shown great results in using Fosf in complicated UTIs [95]. It is currently approved by the American Food and Drug Administration for the treatment of uncomplicated cystitis as a onetime dose of 3 g. Several studies have shown clinical efficacy in the treatment of ESBL cystitis

A meta-analysis that evaluated the antimicrobial activity, or the clinical effectiveness of Fosf, reviewed 17 studies. Out of a total of 5057 clinical isolates of *Enterobacteriaceae*, 4448 were ESBL producers. Almost 90% of the isolates were susceptible to Fosf. Eighty percent of 748 *K.* 

In a prospective study of 47 patients with UTI caused by *E. coli*-ESBL-producing organisms, the outcome was evaluated. Fosfomycin was used in 27 patients and 20 patients received meropenem. The clinical and microbiological success was similar in 2 groups; however, the

are underway to clarify the use of polymyxin different combinations [85].

However, the authors caution about the low quality of the evidence [86].

recently recognized plasmid-mediated resistance gene [87].

when the dosing is extended to 3 g every 48–72 h for 3 doses [96].

*pneumoniae* isolates produced ESBL and were susceptible to Fosf [94].

superbug.

*2.9.2.9. Fosfomycin (Fosf)*

## *2.9.2.7. Tigecycline*

Tigecycline has potent activity against a vast majority of organisms including Gram-negatives, Gram-positives, and anaerobes. It has almost susceptibility rates of 100% against ESBLproducing *E. coli*, however less potency against *K. pneumoniae* isolates producing. However, its use has concerning safety issues [11, 79]. Insufficient urinary excretion of the unchanged drug (15–22% of the dose) has prompted recommendations to avoid tigecycline for UTIs therapy [80, 81].

In a systematic review of the literature, 14 patients received tigecycline for UTIs caused by MDR Gram-negative bacilli. In 12 patients, there were initial microbiological clearance. Eleven patients had evidence of clinical response. However, there were post-therapy growth of tigecycline-resistant organisms in 2 cases [81].

Few studies tried to overcome this obstacle by using higher than the recommended dose for highly resistant organisms *(*initial dose of 200 mg one time followed by 100 mg every 24 h) [82].

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for bloodstream or urinary tract infections [83].

This agent has no activity against *Pseudomonas*, *Proteus*, *Providencia*, and *Morganella.*

#### *2.9.2.8. The polymyxins*

The polymyxins are antibacterial agents that are produced from different strains of *Bacillus polymyxa*. Colistin and polymyxin B are available commercially; both have similar chemical structures and antibacterial activity in vitro, however they differ in their pharmacokinetic profiles. They can cause significant nephrotoxicity (reported in 20–60%) and neurotoxicity [69]. However, the spreading of extensively resistant Gram-negative bacteria as well as the paucity of newer effective antimicrobials let to the extensive usage of these agents as a last resort [84]. The vast majority of ESBL-producing *E. coli* and *K. pneumoniae* are susceptible to these drugs.

Currently, they are the backbone of most of the regimens used against the CRE/CRP organisms. Common combination regimens include tigecycline, carbapenem, minocycline, rifampicin, aminoglycosides, ampicillin/sulbactam, and piperacillin-tazobactam. Large clinical trials are underway to clarify the use of polymyxin different combinations [85].

Polymyxin B is administered directly as the active antibiotic, whereas colistin methanesulfonate is converted in vivo to colistin. The optimal dosing of these agents is still controversial.

Higher doses of colistin were proposed for managing serious CRE/CRP associated infections.

A recent systematic review that included 22 studies (observational studies as well as randomized controlled trials) of polymyxin-based combination therapy in adult patients with infections caused by CRE/CRP was published. The primary outcome was a 30-day mortality. Mortality was significantly higher with polymyxin monotherapy compared with combination therapy of polymyxin with tigecycline, aminoglycosides or fosfomycin, of 1.57 (95% CI = 1.06−2.32). However, the authors caution about the low quality of the evidence [86].

The mechanism of colistin resistance can be generally classified intrinsic or acquired by a recently recognized plasmid-mediated resistance gene [87].

In November 2015, plasmid-borne colistin resistance gene mcr-1 was initially identified in animal and clinical samples from China. As of September 2016, the mcr-1 gene was detected in 35 countries worldwide in human sources in 22 countries [88]. This created a real lethal superbug.

## *2.9.2.9. Fosfomycin (Fosf)*

*2.9.2.6. Trimethoprim/sulfamethoxazole*

40–66% in some areas in the world [78].

of tigecycline-resistant organisms in 2 cases [81].

as monotherapy for bloodstream or urinary tract infections [83].

*2.9.2.7. Tigecycline*

apy [80, 81].

[82].

*2.9.2.8. The polymyxins*

these drugs.

Although treatment with trimethoprim/sulfamethoxazole was traditionally effective in treating UTIS, the evolution of resistance is a current major concern. The Infectious Diseases Society of America guideline recommends against using it if local bacterial resistance rate is ≥20% [77]. Genes that encode for ESBLs are usually found on large plasmids accompanied by genetic determinants of resistance against multiple classes of antibiotics, such as aminoglycosides, sulfonamides, and fluoroquinolones. TMP-SMX is not recommended as an empiric treatment option of UTIs caused by resistant strains of *E. coli* or *K. pneumoniae* that reaches

94 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Tigecycline has potent activity against a vast majority of organisms including Gram-negatives, Gram-positives, and anaerobes. It has almost susceptibility rates of 100% against ESBLproducing *E. coli*, however less potency against *K. pneumoniae* isolates producing. However, its use has concerning safety issues [11, 79]. Insufficient urinary excretion of the unchanged drug (15–22% of the dose) has prompted recommendations to avoid tigecycline for UTIs ther-

In a systematic review of the literature, 14 patients received tigecycline for UTIs caused by MDR Gram-negative bacilli. In 12 patients, there were initial microbiological clearance. Eleven patients had evidence of clinical response. However, there were post-therapy growth

Few studies tried to overcome this obstacle by using higher than the recommended dose for highly resistant organisms *(*initial dose of 200 mg one time followed by 100 mg every 24 h)

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline

The polymyxins are antibacterial agents that are produced from different strains of *Bacillus polymyxa*. Colistin and polymyxin B are available commercially; both have similar chemical structures and antibacterial activity in vitro, however they differ in their pharmacokinetic profiles. They can cause significant nephrotoxicity (reported in 20–60%) and neurotoxicity [69]. However, the spreading of extensively resistant Gram-negative bacteria as well as the paucity of newer effective antimicrobials let to the extensive usage of these agents as a last resort [84]. The vast majority of ESBL-producing *E. coli* and *K. pneumoniae* are susceptible to

This agent has no activity against *Pseudomonas*, *Proteus*, *Providencia*, and *Morganella.*

This agent has gained attention, as it has activities against both Gram-positive and Gramnegative MDR and XDR bacteria [89, 90–94]. It exhibits bactericidal activity against many Gram-positive and Gram-negative pathogens including many of the ESBL-producing *E. coli* and *K. pneumoniae* [91]. Fosf achieves very high concentrations within the urine and is therefore an excellent agent for cystitis, but it is not recommended for treating pyelonephritis or bacteremias due to inadequate concentrations in the blood. However, small studies have shown great results in using Fosf in complicated UTIs [95]. It is currently approved by the American Food and Drug Administration for the treatment of uncomplicated cystitis as a onetime dose of 3 g. Several studies have shown clinical efficacy in the treatment of ESBL cystitis when the dosing is extended to 3 g every 48–72 h for 3 doses [96].

A meta-analysis that evaluated the antimicrobial activity, or the clinical effectiveness of Fosf, reviewed 17 studies. Out of a total of 5057 clinical isolates of *Enterobacteriaceae*, 4448 were ESBL producers. Almost 90% of the isolates were susceptible to Fosf. Eighty percent of 748 *K. pneumoniae* isolates produced ESBL and were susceptible to Fosf [94].

In a prospective study of 47 patients with UTI caused by *E. coli*-ESBL-producing organisms, the outcome was evaluated. Fosfomycin was used in 27 patients and 20 patients received meropenem. The clinical and microbiological success was similar in 2 groups; however, the costs were significantly lower in the Fosf group (p < 0.001). Fosfomycin was used orally 3 g sachet every other night total of 3 doses, while meropenem was used as a dose for 14 days [95].

β-lactamases, and *CRE.* Currently, Cef-Avb is approved for complicated UTIs (limited to patients without other treatment options in the empiric and documented treatment of

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

97

In an in vitro study, it was tested against collection of international urinary isolates (1797 isolates were collected from 159 medical centers). All ESBL isolates as well as meropenem-non-

In another study, 34,062 isolates of *Enterobacteriaceae* from patients (with mostly UTIs) were collected (International Network for Optimal Resistance Monitoring, surveillance from 39 countries). Overall, 99.5% of isolates were susceptible to Cef-Avb. It was also active (99.9%) against molecularly confirmed ESBL-producing, plasmid-mediated AmpC-producing (100%), and ESBL- and AmpC-producing (100%). It lacks activity against the metallo-β-lactamase

The REPRISE, an international, randomized, open-label trial, recruited 333 patients from 16 countries worldwide. The study recruited patients mostly with complicated UTIs caused by ceftazidime-resistant *Enterobacteriaceae* or *P. aeruginosa*. They were randomly assigned, 165 to Cef-Avb and 168 to best available therapy. The overall proportions of patients with a clinical

In another clinical study, Cef-Avb was compared to imipenem-cilastatin in hospitalized adults with serious complicated UTI due to Gram-negative pathogens. Patients were allowed to switch to oral ciprofloxacin after at least 4 days on the study drug. Patients in the Cef-Avb

The RECAPTURE study recruited 033 patients, who were randomized in 2 arms, 393 received Cef-Avb and 417 received doripenem, with possible oral antibiotic switch (total duration was 10–14 days). Combined symptomatic resolution/microbiological were similar in the 2 arms

In a recent study, the outcome of therapy with ceftazidime-avibactam (38 patients) was compared to the outcome of therapy with colistin (99 patients) with CRE infections. Most patients received additional anti-CRE agents as part of their treatment. All-cause hospital mortality at

Salvage therapy: in a case series of 36 patients, mostly with life-threatening infections received Cef-Avb as a salvage therapy. The causative organisms were CRE (2 were CRP). In 65.8% of patients, other concurrent antibiotics were used. More than 70% of the patients experienced

Resistance: in less than 2 years since its approval, resistant strains have been isolated. Cef-Avb-resistant *K. pneumoniae* emerged in 3 patients after using Cef-Avb for 10–19 days [109].

This agent was approved in 2015 for the treatment of complicated urinary tract infections (adults with limited or no other therapeutic options) [110]. There are many in vitro studies that

group had a better microbiological response (70% vs. 71%) [105].

30 days and after were 9% vs. 32%, respectively [107].

susceptible *E. coli* and *K. pneumoniae* isolates were susceptible to Cef-Avb [102].

MDROs).

producers (NDM-1 enzyme) [103].

cure were similar in the 2 arms [104].

(70.2% vs. 66.2%, respectively) [106].

clinical and/or microbiological cure [108].

*2.9.2.13. Ceftolozane-tazobactam (Cef-Taz)*

In a retrospective study, 60 patients were treated for MDR UTI. There were cases infected with *Enterobacteriaceae*, *P. aeruginosa*, and *VRE*. The clinical response rate was 55%. Chronic kidney disease was associated clinical failure (p = 0.04) [92].

For the carbapenem-producing organisms, a very few clinical data on using this agent are available.

In Europe, an intravenous Fosf formulation is available. In a small (in 11 ICU patients) European study, intravenous Fosf (2–4 g q6 h) in combination with other antibiotics was associated with good bacteriological and clinical outcomes in all patients with carbapenemresistant *K. pneumoniae* infections [96].

In an in vitro study, 365 isolates out of 2229 urine samples were evaluated. ESBL producers were detected in 65% were, 16% were carbapenem-resistant *Enterobacteriaceae*, almost 95% of the total isolates were susceptible to Fosf [97].

A recent, albeit pessimistic, data came from China. A study collected 233 clinical isolates CRE/ CRP *Carbapenem Resistant Enterobacteriaceae*/*Carbapenem Resistant Pseudomonas* at four different hospitals. Forty-five percent of the strains (105/233) were resistant to Fosf. Plasmid-mediated fosfomycin-modifying enzymes fosA, fosA2, fosA3, and fosA5 genes were identified [98].

#### *2.9.2.10. Nitrofurantoin*

Another oral antimicrobial agent that can be considered for the treatment of ESB cystitis is nitrofurantoin. One study showed clinical cure rates of 69% in patients with ESBL cystitis in which all isolates were also resistant to SMX/TMP and ciprofloxacin [99].

Nitrofurantoin should only be used for lower UTI and should be avoided in patients with a creatinine clearance less than 60 (few studies accepted GFR more than 40) mL/min as reduced renal function results in decreased active drug within the urine [100]. It is contraindicated in pregnancy.

#### *2.9.2.11. Cefoperazone-sulbactam*

In a larger in vitro study, against the GNBs, a total of 18,386 organisms including 13,224 *Enterobacteriaceae* and 3536 *Pseudomonas* were collected (2013–2014) as part of the SENTRY Antimicrobial Surveillance Program. Cefoperazone/sulbactam inhibited 94% of *Enterobacteriaceae* [101]. There are limited clinical data on the usefulness of this agent against ESBL or CRE/CRP organisms in the urinary tract.

#### *2.9.2.12. Ceftazidime-avibactam (Cef-Avb)*

Ceftazidime, a third-generation cephalosporin, when combined with avibactam has potent activities against β-lactamase-producing Gram-negative pathogens including ESBL, AmpC β-lactamases, and *CRE.* Currently, Cef-Avb is approved for complicated UTIs (limited to patients without other treatment options in the empiric and documented treatment of MDROs).

In an in vitro study, it was tested against collection of international urinary isolates (1797 isolates were collected from 159 medical centers). All ESBL isolates as well as meropenem-nonsusceptible *E. coli* and *K. pneumoniae* isolates were susceptible to Cef-Avb [102].

In another study, 34,062 isolates of *Enterobacteriaceae* from patients (with mostly UTIs) were collected (International Network for Optimal Resistance Monitoring, surveillance from 39 countries). Overall, 99.5% of isolates were susceptible to Cef-Avb. It was also active (99.9%) against molecularly confirmed ESBL-producing, plasmid-mediated AmpC-producing (100%), and ESBL- and AmpC-producing (100%). It lacks activity against the metallo-β-lactamase producers (NDM-1 enzyme) [103].

The REPRISE, an international, randomized, open-label trial, recruited 333 patients from 16 countries worldwide. The study recruited patients mostly with complicated UTIs caused by ceftazidime-resistant *Enterobacteriaceae* or *P. aeruginosa*. They were randomly assigned, 165 to Cef-Avb and 168 to best available therapy. The overall proportions of patients with a clinical cure were similar in the 2 arms [104].

In another clinical study, Cef-Avb was compared to imipenem-cilastatin in hospitalized adults with serious complicated UTI due to Gram-negative pathogens. Patients were allowed to switch to oral ciprofloxacin after at least 4 days on the study drug. Patients in the Cef-Avb group had a better microbiological response (70% vs. 71%) [105].

The RECAPTURE study recruited 033 patients, who were randomized in 2 arms, 393 received Cef-Avb and 417 received doripenem, with possible oral antibiotic switch (total duration was 10–14 days). Combined symptomatic resolution/microbiological were similar in the 2 arms (70.2% vs. 66.2%, respectively) [106].

In a recent study, the outcome of therapy with ceftazidime-avibactam (38 patients) was compared to the outcome of therapy with colistin (99 patients) with CRE infections. Most patients received additional anti-CRE agents as part of their treatment. All-cause hospital mortality at 30 days and after were 9% vs. 32%, respectively [107].

Salvage therapy: in a case series of 36 patients, mostly with life-threatening infections received Cef-Avb as a salvage therapy. The causative organisms were CRE (2 were CRP). In 65.8% of patients, other concurrent antibiotics were used. More than 70% of the patients experienced clinical and/or microbiological cure [108].

Resistance: in less than 2 years since its approval, resistant strains have been isolated. Cef-Avb-resistant *K. pneumoniae* emerged in 3 patients after using Cef-Avb for 10–19 days [109].

## *2.9.2.13. Ceftolozane-tazobactam (Cef-Taz)*

costs were significantly lower in the Fosf group (p < 0.001). Fosfomycin was used orally 3 g sachet every other night total of 3 doses, while meropenem was used as a dose for 14 days [95]. In a retrospective study, 60 patients were treated for MDR UTI. There were cases infected with *Enterobacteriaceae*, *P. aeruginosa*, and *VRE*. The clinical response rate was 55%. Chronic kidney

96 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

For the carbapenem-producing organisms, a very few clinical data on using this agent are

In Europe, an intravenous Fosf formulation is available. In a small (in 11 ICU patients) European study, intravenous Fosf (2–4 g q6 h) in combination with other antibiotics was associated with good bacteriological and clinical outcomes in all patients with carbapenem-

In an in vitro study, 365 isolates out of 2229 urine samples were evaluated. ESBL producers were detected in 65% were, 16% were carbapenem-resistant *Enterobacteriaceae*, almost 95% of

A recent, albeit pessimistic, data came from China. A study collected 233 clinical isolates CRE/ CRP *Carbapenem Resistant Enterobacteriaceae*/*Carbapenem Resistant Pseudomonas* at four different hospitals. Forty-five percent of the strains (105/233) were resistant to Fosf. Plasmid-mediated fosfomycin-modifying enzymes fosA, fosA2, fosA3, and fosA5 genes were identified [98].

Another oral antimicrobial agent that can be considered for the treatment of ESB cystitis is nitrofurantoin. One study showed clinical cure rates of 69% in patients with ESBL cystitis in

Nitrofurantoin should only be used for lower UTI and should be avoided in patients with a creatinine clearance less than 60 (few studies accepted GFR more than 40) mL/min as reduced renal function results in decreased active drug within the urine [100]. It is contraindicated in

In a larger in vitro study, against the GNBs, a total of 18,386 organisms including 13,224 *Enterobacteriaceae* and 3536 *Pseudomonas* were collected (2013–2014) as part of the SENTRY Antimicrobial Surveillance Program. Cefoperazone/sulbactam inhibited 94% of *Enterobacteriaceae* [101]. There are limited clinical data on the usefulness of this agent against

Ceftazidime, a third-generation cephalosporin, when combined with avibactam has potent activities against β-lactamase-producing Gram-negative pathogens including ESBL, AmpC

which all isolates were also resistant to SMX/TMP and ciprofloxacin [99].

disease was associated clinical failure (p = 0.04) [92].

resistant *K. pneumoniae* infections [96].

*2.9.2.10. Nitrofurantoin*

*2.9.2.11. Cefoperazone-sulbactam*

ESBL or CRE/CRP organisms in the urinary tract.

*2.9.2.12. Ceftazidime-avibactam (Cef-Avb)*

pregnancy.

the total isolates were susceptible to Fosf [97].

available.

This agent was approved in 2015 for the treatment of complicated urinary tract infections (adults with limited or no other therapeutic options) [110]. There are many in vitro studies that

demonstrated activity against Gram-negative and Gram-positive microorganisms, including *E. cloacae*, *E. coli*, *K. oxytoca*, *K. pneumoniae*, *Proteus mirabilis*, *P. aeruginosa* as well as coverage of most ESBL-producing organisms and some anaerobes [110, 111].

Higher rates have been reported in other countries: 5.4% in Argentina and 15% in India [117]. In India, 47% in *E. coli*-related UTIs in pregnant patients were ESBL-producing *E. coli*

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

99

Peripartum maternal transmission of ESBL organism to newborn infants was documented

Recently, first outbreak of a CTX-M ESBL-producing *E. coli* in an Irish neonatal intensive care unit was reported. This outbreak was mediated by mother to neonate transmission [121].

Carbapenem are the drugs of choice for treating complicated UTIs and pyelonephritis due to ESBL pathogens in pregnancy [122]. In small studies, orally administered fosfomycin have

A case control study compared outcomes in pregnant women with ESBL-UTIs. Suboptimal treatment was noted in the majority of cases involving ESBL-UTIs (89%, n = 40), which was far more likely than what was observed for non-ESBL infections. Data support the importance of more aggressive treatment and follow-up of pregnant women with ESBL-UTIs to prevent

There are very limited data on CRE/CRP UTI in pregnancy. A case report of communityacquired pyelonephritis caused by KPC-producing isolate was reported in Australia [124].

Authors were refrained from using colistin, because of its toxicity in pregnancy (category C). Tigecycline was not considered either (category D). Rather, they added cefepime, which is regarded as safe in pregnancy (category B) and offers potential synergistic activity with fosfomycin, which is also an inhibitor of cell wall synthesis. In that study, the isolate was resistant to cefepime in vitro. By using 6 g/day as a continuous infusion, they estimated that levels in plasma of 20–30 μg/mL were maintained; moreover, cefepime achieved a very high concentration in the urine. Therefore, it has been reasoned that concentrations of cefepime sufficient to inhibit the growth of *K. pneumoniae* (MIC >32 μg/mL) would be maintained in the urine and genitourinary tract. This approach was successful, as proven by sterile urine cultures (obtained weekly while the patient was on cefepime and 6 weeks after the end of therapy) and

For these challenging cases, a new drug (see above), ceftazidime-avibactam, has shown great activities against most of the ESBL and many of the CRE/CRP organisms. This novel agent is safe during pregnancy. However, there are no randomized trials to show this activity, and it

The optimal length of treatment UTI with highly resistant organisms has not been extensively studied. As there are many different causes of underlying abnormality, a simple recommendation cannot be made. 10 to 14 days of antibiotics are usually recommended for patients with bacteremia, hypotension, and other signs of severe sepsis. Recent clinical trials included

been used to treat cystitis with ESBL pathogens with good success.

secondary clinical pyelonephritis [123].

the absence of symptoms.

**2.11. Duration of therapy**

should be considered as a salvage therapy [125].

[117–119].

[120].

Cef-Taz was tested in vitro against 3851 *P. aeruginosa* isolates collected from 32 U.S. hospitals. It was active against 97.0% of the isolates, which was better than 7 other broad spectra antibiotics. A total of 363 isolates were classified as extensively drug resistant; Cef-Taz was active against 76.9% of these isolates [112].

The ASPECT is a randomized, double-blind, double-dummy, non-inferiority trial over 25 countries. 1083 patients enrolled, of whom 82% had pyelonephritis. Patients were randomly assigned to receive Cef-Taz or intravenous high-dose levofloxacin for 7 days. Overall, the composite cure rates were higher in the Cef-Taz group than in the levofloxacin. In a subgroup analysis, clinical cure was seen in 90% compared with 73% in patients with ESBL-producing uropathogens [113].

## *2.9.2.14. Ceftaroline/avibactam*

Ceftaroline is a cephalosporin with broad-spectrum activity against Gram-positive and Gram-negative organisms. When Ceftaroline combined with avibactam, it gains activities against many ESBL-producing organisms in vitro. It was tested in one study against 272 ESBL *Enterobacteriaceae* strains. All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/mL; however, it exhibited limited activity against *Acinetobacter* spp. and *P. aeruginosa* [114].

There are no clinical studies that tested the activity of this agent on UTIs caused by any MDROs.

#### *2.9.2.15. Ceftriaxone + sulbactam + disodium edetate (Elores)*

It is a novel molecule, which combines β-lactam plus β-lactamase inhibitor. It has shown activities against many resistant Gram-negative bacterial infections. There is a limited data on its spectrum, usage (mostly in India), and its role in urinary tract infections in specific.

In one study, Elores activity was compared to other comparators (including carbapenems) in treating various infectious syndromes. There were 2500 patients enrolled in the study, in which 24% of the patients had UTIs (no specifics on severity or the causative organisms). The clinical cure/improvement was achieved in 98%. There was no clear description on the types or the incidence of resistant organisms in the study [115].

#### **2.10. ESBL and CRE urinary tract infections with pregnancy**

Few studies have been conducted regarding the prevalence of ESBL-producing organisms in pregnant women. In Ireland, a low figure of 1.63% of pregnant patients was colonized with ESBL organisms (perianal). Similar rates were seen in a Norwegian study (2.9%) [116].

Higher rates have been reported in other countries: 5.4% in Argentina and 15% in India [117]. In India, 47% in *E. coli*-related UTIs in pregnant patients were ESBL-producing *E. coli* [117–119].

Peripartum maternal transmission of ESBL organism to newborn infants was documented [120].

Recently, first outbreak of a CTX-M ESBL-producing *E. coli* in an Irish neonatal intensive care unit was reported. This outbreak was mediated by mother to neonate transmission [121].

Carbapenem are the drugs of choice for treating complicated UTIs and pyelonephritis due to ESBL pathogens in pregnancy [122]. In small studies, orally administered fosfomycin have been used to treat cystitis with ESBL pathogens with good success.

A case control study compared outcomes in pregnant women with ESBL-UTIs. Suboptimal treatment was noted in the majority of cases involving ESBL-UTIs (89%, n = 40), which was far more likely than what was observed for non-ESBL infections. Data support the importance of more aggressive treatment and follow-up of pregnant women with ESBL-UTIs to prevent secondary clinical pyelonephritis [123].

There are very limited data on CRE/CRP UTI in pregnancy. A case report of communityacquired pyelonephritis caused by KPC-producing isolate was reported in Australia [124].

Authors were refrained from using colistin, because of its toxicity in pregnancy (category C). Tigecycline was not considered either (category D). Rather, they added cefepime, which is regarded as safe in pregnancy (category B) and offers potential synergistic activity with fosfomycin, which is also an inhibitor of cell wall synthesis. In that study, the isolate was resistant to cefepime in vitro. By using 6 g/day as a continuous infusion, they estimated that levels in plasma of 20–30 μg/mL were maintained; moreover, cefepime achieved a very high concentration in the urine. Therefore, it has been reasoned that concentrations of cefepime sufficient to inhibit the growth of *K. pneumoniae* (MIC >32 μg/mL) would be maintained in the urine and genitourinary tract. This approach was successful, as proven by sterile urine cultures (obtained weekly while the patient was on cefepime and 6 weeks after the end of therapy) and the absence of symptoms.

For these challenging cases, a new drug (see above), ceftazidime-avibactam, has shown great activities against most of the ESBL and many of the CRE/CRP organisms. This novel agent is safe during pregnancy. However, there are no randomized trials to show this activity, and it should be considered as a salvage therapy [125].

## **2.11. Duration of therapy**

demonstrated activity against Gram-negative and Gram-positive microorganisms, including *E. cloacae*, *E. coli*, *K. oxytoca*, *K. pneumoniae*, *Proteus mirabilis*, *P. aeruginosa* as well as coverage of

Cef-Taz was tested in vitro against 3851 *P. aeruginosa* isolates collected from 32 U.S. hospitals. It was active against 97.0% of the isolates, which was better than 7 other broad spectra antibiotics. A total of 363 isolates were classified as extensively drug resistant; Cef-Taz was active

The ASPECT is a randomized, double-blind, double-dummy, non-inferiority trial over 25 countries. 1083 patients enrolled, of whom 82% had pyelonephritis. Patients were randomly assigned to receive Cef-Taz or intravenous high-dose levofloxacin for 7 days. Overall, the composite cure rates were higher in the Cef-Taz group than in the levofloxacin. In a subgroup analysis, clinical cure was seen in 90% compared with 73% in patients with ESBL-producing

Ceftaroline is a cephalosporin with broad-spectrum activity against Gram-positive and Gram-negative organisms. When Ceftaroline combined with avibactam, it gains activities against many ESBL-producing organisms in vitro. It was tested in one study against 272 ESBL *Enterobacteriaceae* strains. All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/mL; however, it exhibited limited activity against *Acinetobacter* spp. and *P. aeruginosa* [114].

There are no clinical studies that tested the activity of this agent on UTIs caused by any

It is a novel molecule, which combines β-lactam plus β-lactamase inhibitor. It has shown activities against many resistant Gram-negative bacterial infections. There is a limited data on its spectrum, usage (mostly in India), and its role in urinary tract infections in

In one study, Elores activity was compared to other comparators (including carbapenems) in treating various infectious syndromes. There were 2500 patients enrolled in the study, in which 24% of the patients had UTIs (no specifics on severity or the causative organisms). The clinical cure/improvement was achieved in 98%. There was no clear description on the types

Few studies have been conducted regarding the prevalence of ESBL-producing organisms in pregnant women. In Ireland, a low figure of 1.63% of pregnant patients was colonized with ESBL organisms (perianal). Similar rates were seen in a Norwegian study (2.9%) [116].

most ESBL-producing organisms and some anaerobes [110, 111].

98 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

*2.9.2.15. Ceftriaxone + sulbactam + disodium edetate (Elores)*

or the incidence of resistant organisms in the study [115].

**2.10. ESBL and CRE urinary tract infections with pregnancy**

against 76.9% of these isolates [112].

uropathogens [113].

MDROs.

specific.

*2.9.2.14. Ceftaroline/avibactam*

The optimal length of treatment UTI with highly resistant organisms has not been extensively studied. As there are many different causes of underlying abnormality, a simple recommendation cannot be made. 10 to 14 days of antibiotics are usually recommended for patients with bacteremia, hypotension, and other signs of severe sepsis. Recent clinical trials included complicated urinary tract infections with resistant organisms that have used the study drugs for 10–14 days [93, 105, 106].

On the other hand, our (and others) clinical exercise with monotherapy and single dose of fosfomycin was also associated with high rates of relapse. We also have great concerns about

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

101

Meanwhile, we are proposing fosfomycin 3 g oral sachets twice a week for 3–4 doses with

**B.** For complicated UTIs: monotherapy with carbapenems, piperacillin-tazobactam, amino-

Treatment of carbapenem-resistant organisms is a real challenge because of limited choices for effective reliable regimens. There are no randomized controlled trials evaluating different antibiotic options for carbapenemase producers. There are many observational studies; combination therapy appears to be superior to single-drug therapy. Combinations of a polymyxin, tigecycline, and meropenem have met with the greatest success. Meropenem has been used in these combinations despite a lack of in vitro susceptibility. Recently ceftazidimeavibactam is showing promising results. It has good activity against (nearly) all class A and class C β-lactamases as well as OXA-48 carbapenemases. However, it lacks activity against

the rapid progression of fosfomycin resistance. This will require further research.

nitrofurantoin 100 mg twice a day for 10 days (if susceptible).

glycosides or ceftazidime-avibactam would be effective.

*2.14.2. CRE/CRP producing organisms*

If we can summarize the data above:

**2.** Ceftazidime-avibactam (single agent).

**2.15. For complicated UTIs/critically ill patients**

**1.** Aminoglycosides (amikacin or gentamicin) or colistin.

and polymyxin do not have good clearance in the urine.

**3.** Tigecycline plus colistin or aminoglycosides: have been tried in few trials.

**4.** Triple combinations including aminoglycoside, carbapenem, colistin, rifampicin, tigecycline, and fosfomycin have demonstrated synergistic or bactericidal effects in few small

Even with the above-mentioned regimens, failure of therapy is very common, as tigecycline

The rapid and global spread of antimicrobial-resistant organisms in recent years is a global challenge. The overuse of antimicrobial use in humans and animals coupled with increased

the metallo enzymes.

Plus: a carbapenem or

studies.

**3. Conclusion**

## **2.12. Infection-control**

A successful infection program should be able to recognize, screen, and isolate both colonized and infected patients. Standard and transmission-based precautions are strictly applied at all times. Other basic measures including hand hygiene, use of personal protective barriers, and aggressive environmental cleaning are very beneficial. Implementation of simple itemsbundles (multiple-drug resistant bundles MDROs) have shown to be very effective in controlling outbreaks.

Hospital-wide vs. high risk areas (ICU, dialysis centers) (routine vs. on outbreaks based) and clinical and bacteriological surveillance have been useful in early identifications and isolation of index cases. The use of molecular technologies including polymerase chain reaction (PCR) optimized the surveillance process [14].

A strict protocol including the above-mentioned interventions showed a great success in reducing the nosocomial spreading of the highly resistant organisms. During the intervention, nosocomial CRE acquisition in acute care declined from a monthly high of 55.5 to an annual low of 4.8 cases per 100,000 patient-days (p < 0.001) [126].

## **2.13. Antimicrobial stewardship**

Multidisciplinary program including physicians, pharmacists, and microbiologists that aims to control the usage of antimicrobial is mandatory. In one study, carbapenem use was strictly restricted through antimicrobial stewardship in an effort to control MDROs spreading in an ICU setting. The study protocol also included strict environmental cleaning and disinfection in addition to basic infection control measures. The rate of hospital acquired MDRO *Acinetobacter* decreased from 22.82 cases per 1000 patient-days to 2.68 cases per 1000 patientdays after the protocol implementation (p < 0.001) [127].

## **2.14. Summary of recommended therapy**

## *2.14.1. ESBL producing organisms*

In general, carbapenems are the most reliable treatment for infections caused by ESBLproducing bacteria. As shown above, the over usage of these agents resulted in the emergence of the CRE. Multiple trials have shown other effective-carbapenem sparing regimens.

We proposed the following:

**A.** Uncomplicated cystitis caused by ESBL producing *E. coli* and without any indwelling catheters or obstruent: fosfomycin would be effective (and approved) therapy. In cystitis caused by other ESBL producing organism, fosfomycin alone was associated with significant clinical and microbiological failures.

On the other hand, our (and others) clinical exercise with monotherapy and single dose of fosfomycin was also associated with high rates of relapse. We also have great concerns about the rapid progression of fosfomycin resistance. This will require further research.

Meanwhile, we are proposing fosfomycin 3 g oral sachets twice a week for 3–4 doses with nitrofurantoin 100 mg twice a day for 10 days (if susceptible).

**B.** For complicated UTIs: monotherapy with carbapenems, piperacillin-tazobactam, aminoglycosides or ceftazidime-avibactam would be effective.

## *2.14.2. CRE/CRP producing organisms*

complicated urinary tract infections with resistant organisms that have used the study drugs

100 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

A successful infection program should be able to recognize, screen, and isolate both colonized and infected patients. Standard and transmission-based precautions are strictly applied at all times. Other basic measures including hand hygiene, use of personal protective barriers, and aggressive environmental cleaning are very beneficial. Implementation of simple itemsbundles (multiple-drug resistant bundles MDROs) have shown to be very effective in control-

Hospital-wide vs. high risk areas (ICU, dialysis centers) (routine vs. on outbreaks based) and clinical and bacteriological surveillance have been useful in early identifications and isolation of index cases. The use of molecular technologies including polymerase chain reaction (PCR)

A strict protocol including the above-mentioned interventions showed a great success in reducing the nosocomial spreading of the highly resistant organisms. During the intervention, nosocomial CRE acquisition in acute care declined from a monthly high of 55.5 to an

Multidisciplinary program including physicians, pharmacists, and microbiologists that aims to control the usage of antimicrobial is mandatory. In one study, carbapenem use was strictly restricted through antimicrobial stewardship in an effort to control MDROs spreading in an ICU setting. The study protocol also included strict environmental cleaning and disinfection in addition to basic infection control measures. The rate of hospital acquired MDRO *Acinetobacter* decreased from 22.82 cases per 1000 patient-days to 2.68 cases per 1000 patient-

In general, carbapenems are the most reliable treatment for infections caused by ESBLproducing bacteria. As shown above, the over usage of these agents resulted in the emergence

**A.** Uncomplicated cystitis caused by ESBL producing *E. coli* and without any indwelling catheters or obstruent: fosfomycin would be effective (and approved) therapy. In cystitis caused by other ESBL producing organism, fosfomycin alone was associated with signifi-

of the CRE. Multiple trials have shown other effective-carbapenem sparing regimens.

for 10–14 days [93, 105, 106].

optimized the surveillance process [14].

**2.13. Antimicrobial stewardship**

annual low of 4.8 cases per 100,000 patient-days (p < 0.001) [126].

days after the protocol implementation (p < 0.001) [127].

**2.14. Summary of recommended therapy**

cant clinical and microbiological failures.

*2.14.1. ESBL producing organisms*

We proposed the following:

**2.12. Infection-control**

ling outbreaks.

Treatment of carbapenem-resistant organisms is a real challenge because of limited choices for effective reliable regimens. There are no randomized controlled trials evaluating different antibiotic options for carbapenemase producers. There are many observational studies; combination therapy appears to be superior to single-drug therapy. Combinations of a polymyxin, tigecycline, and meropenem have met with the greatest success. Meropenem has been used in these combinations despite a lack of in vitro susceptibility. Recently ceftazidimeavibactam is showing promising results. It has good activity against (nearly) all class A and class C β-lactamases as well as OXA-48 carbapenemases. However, it lacks activity against the metallo enzymes.

If we can summarize the data above:

## **2.15. For complicated UTIs/critically ill patients**

**1.** Aminoglycosides (amikacin or gentamicin) or colistin.

Plus: a carbapenem or


Even with the above-mentioned regimens, failure of therapy is very common, as tigecycline and polymyxin do not have good clearance in the urine.

## **3. Conclusion**

The rapid and global spread of antimicrobial-resistant organisms in recent years is a global challenge. The overuse of antimicrobial use in humans and animals coupled with increased global connectivity facilitated the transmission of Gram-negative infections harboring extended-spectrum β-lactamases. When treating these infections, clinicians have a few effective antimicrobials to choose from and many are associated with significant adverse effects. Definitive therapy should always be guided by susceptibility testing. Expert consultation with an infectious disease specialist is recommended.

[6] Tumbarello M, Viale P, Viscoli C. Predictors of mortality in bloodstream infections caused by *Klebsiella pneumoniae* carbapenemase-producing *K. pneumoniae*: Importance of combination therapy. Clinical Infectious Diseases. 2012;**55**:943-950. DOI: 10.1093/cid/

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

103

[7] Zowawi HM, Harris PN, Roberts MJ. The emerging threat of multidrug-resistant Gramnegative bacteria in urology. Nature Reviews Urology. 2015;**12**:570-584. DOI: 10.1038/

[8] Ruppe E, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gramnegative bacilli. Annals of Intensive Care. 2015;**5**:61. DOI: 10.1186/s13613-015-0061-0

[9] Magiorakos AP, Srinivasan A, Carey RB. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection. 2012;**18**:268-281.

[10] Kallen AJ, Srinivasan A. Current epidemiology of multidrug-resistant gram-negative bacilli in the United States. Infection Control and Hospital Epidemiology. 2010;**31**(Suppl 1):S51-

[11] Pallett A, Hand K. Complicated urinary tract infections: Practical solutions for the treatment of multiresistant Gram-negative bacteria. Journal of Antimicrobial Chemotherapy.

[12] Bader MS, Loeb M, Brooks AA. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgraduate Medicine. 2017;**129**:242-258.

[13] Ena J, Arjona F, Martinez-Peinado C. Epidemiology of urinary tract infections caused by extended-spectrum beta-lactamase-producing *Escherichia coli*. Urology. 2006;**68**:1169-

[14] van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacte-

[15] Padmini N, Ajilda AA, Sivakumar N. Extended spectrum beta-lactamase producing *Escherichia coli* and *Klebsiella pneumoniae*: Critical tools for antibiotic resistance pattern.

[16] Bradford PA. Extended-spectrum beta-lactamases in the 21st century: Characterization, epidemiology, and detection of this important resistance threat. Clinical Microbiology

Reviews. 2001;**14**:933-951, table of contents. DOI: 10.1128/CMR.14.4.933-951.2001

[17] Rupp ME, Fey PD. Extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae: Considerations for diagnosis, prevention and drug treatment. Drugs. 2003;

riaceae. Virulence. 2017;**8**:460-469. DOI: 10.1080/21505594.2016.1222343

Journal of Basic Microbiology. 2017;**57**. DOI: 10.1002/jobm.201700008

cis588

nrurol.2015.199

DOI: 10.1111/j.1469-0691.2011.03570.x

DOI: 10.1080/00325481.2017.1246055

1174. DOI: 10.1016/j.urology.2006.08.1075

2010;**65**(Suppl 3):iii25-iii33. DOI: 10.1093/jac/dkq298

S54. DOI: 10.1086/655996

**63**:353-365

## **Declaration of interest**

The authors report no conflicts of interest.

## **Author details**

Nashaat S. Hamza\* and Abdalla Khalil

\*Address all correspondence to: nashaat11@hotmail.com

The International Medical Center, Jeddah, KSA

## **References**


[6] Tumbarello M, Viale P, Viscoli C. Predictors of mortality in bloodstream infections caused by *Klebsiella pneumoniae* carbapenemase-producing *K. pneumoniae*: Importance of combination therapy. Clinical Infectious Diseases. 2012;**55**:943-950. DOI: 10.1093/cid/ cis588

global connectivity facilitated the transmission of Gram-negative infections harboring extended-spectrum β-lactamases. When treating these infections, clinicians have a few effective antimicrobials to choose from and many are associated with significant adverse effects. Definitive therapy should always be guided by susceptibility testing. Expert consultation

[1] Flores-Mireles AL, Walker JN, Caparon M. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nature Reviews. Microbiology. 2015;**13**:269-284.

[2] Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence.

[3] de Kraker ME, Wolkewitz M, Davey PG. Burden of antimicrobial resistance in European hospitals: Excess mortality and length of hospital stay associated with bloodstream infections due to *Escherichia coli* resistant to third-generation cephalosporins. The Journal of

[4] Falagas ME, Lourida P, Poulikakos P. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: Systematic evaluation of the available evidence. Antimicrobial Agents and Chemotherapy. 2014;**58**:654-663. DOI: 10.1128/AAC.

[5] Majeed A, Alarfaj S, Darouiche R. An update on emerging therapies for urinary tract infections. Expert Opinion on Emerging Drugs. 2017;**22**:53-62. DOI: 10.1080/1472

Antimicrobial Chemotherapy. 2011;**66**:398-407. DOI: 10.1093/jac/dkq412

with an infectious disease specialist is recommended.

102 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

\*Address all correspondence to: nashaat11@hotmail.com

2016;**7**:1-14. DOI: 10.1080/21505594.2016.1207834

The International Medical Center, Jeddah, KSA

**Declaration of interest**

**Author details**

**References**

01222-13

8214.2017.1293650

The authors report no conflicts of interest.

Nashaat S. Hamza\* and Abdalla Khalil

DOI: 10.1038/nrmicro3432


[18] Peirano G, Costello M, Pitout JD. Molecular characteristics of extended-spectrum betalactamase-producing *Escherichia coli* from the Chicago area: High prevalence of ST131 producing CTX-M-15 in community hospitals. International Journal of Antimicrobial Agents. 2010;**36**:19-23. DOI: 10.1016/j.ijantimicag.2010.02.016

[28] Suarez CJ, Lolans K, Villegas MV. Mechanisms of resistance to beta-lactams in some common Gram-negative bacteria causing nosocomial infections. Expert Review of Anti-

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

105

[29] Soraas A, Sundsfjord A, Sandven I. Risk factors for community-acquired urinary tract infections caused by ESBL-producing enterobacteriaceae—A case-control study in a low prevalence country. PLoS One. 2013;**8**:e69581. DOI: 10.1371/journal.pone.0069581 [30] Lubbert C, Straube L, Stein C. Colonization with extended-spectrum beta-lactamaseproducing and carbapenemase-producing Enterobacteriaceae in international travelers returning to Germany. International Journal of Medical Microbiology. 2015;**305**:148-156.

[31] Brower CH, Mandal S, Hayer S. The prevalence of extended-spectrum beta-lactamase-producing multidrug-resistant *Escherichia coli* in poultry chickens and variation according to farming practices in Punjab, India. Environmental Health Perspectives.

[32] Dickstein Y, Geffen Y, Andreassen S. Predicting antibiotic resistance in urinary tract infection patients with prior urine cultures. Antimicrobial Agents and Chemotherapy.

[33] Zowawi HM, Balkhy HH, Walsh TR. Beta-lactamase production in key gram-negative pathogen isolates from the Arabian peninsula. Clinical Microbiology Reviews. 2013;**26**:

[34] Singh RM, Singh HL. Comparative evaluation of six phenotypic methods for detecting extended-spectrum beta-lactamase-producing Enterobacteriaceae. Journal of Infection

[35] Perez F, Bonomo RA. Editorial commentary: Bloodstream infection caused by extendedspectrum beta-lactamase-producing Gram-negative bacteria: How to define the best treatment regimen? Clinical Infectious Diseases. 2015;**60**:1326-1329. DOI: 10.1093/cid/

[36] Chavda KD, Satlin MJ, Chen L. Evaluation of a multiplex PCR assay to rapidly detect Enterobacteriaceae with a broad range of beta-lactamases directly from perianal swabs. Antimicrobial Agents and Chemotherapy. 2016;**60**:6957-6961. DOI: 10.1128/

[37] Ben-David D, Kordevani R, Keller N. Outcome of carbapenem resistant *Klebsiella pneumoniae* bloodstream infections. Clinical Microbiology and Infection. 2012;**18**:54-60. DOI:

[38] Villegas MV, Pallares CJ, Escandon-Vargas K. Characterization and clinical impact of bloodstream infection caused by Carbapenemase-producing Enterobacteriaceae in seven Latin American countries. PLoS One. 2016;**11**:e0154092. DOI: 10.1371/journal.

in Developing Countries. 2014;**8**:408-415. DOI: 10.3855/jidc.4052

infective Therapy. 2005;**3**:915-922. DOI: 10.1586/14787210.3.6.915

DOI: 10.1016/j.ijmm.2014.12.001

2017;**125**:077015. DOI: 10.1289/EHP292

361-380. DOI: 10.1128/CMR.00096-12

civ007

AAC.01458-16

pone.0154092

10.1111/j.1469-0691.2011.03478.x

2016;**60**:4717-4721. DOI: 10.1128/AAC.00202-16


[28] Suarez CJ, Lolans K, Villegas MV. Mechanisms of resistance to beta-lactams in some common Gram-negative bacteria causing nosocomial infections. Expert Review of Antiinfective Therapy. 2005;**3**:915-922. DOI: 10.1586/14787210.3.6.915

[18] Peirano G, Costello M, Pitout JD. Molecular characteristics of extended-spectrum betalactamase-producing *Escherichia coli* from the Chicago area: High prevalence of ST131 producing CTX-M-15 in community hospitals. International Journal of Antimicrobial

[19] Briongos-Figuero LS, Gomez-Traveso T, Bachiller-Luque P. Epidemiology, risk factors and comorbidity for urinary tract infections caused by extended-spectrum betalactamase (ESBL)-producing enterobacteria. International Journal of Clinical Practice.

[20] Fernando MM, Luke WA, Miththinda JK. Extended spectrum beta lactamase producing organisms causing urinary tract infections in Sri Lanka and their antibiotic susceptibility pattern—A hospital based cross sectional study. BMC Infectious Diseases. 2017;**17**:138.

[21] Zhang J, Zhou K, Zheng B. High prevalence of ESBL-producing *Klebsiella pneumoniae* causing community-onset infections in China. Frontiers in Microbiology. 2016;**7**:1830.

[22] Koksal I, Yilmaz G, Unal S. Epidemiology and susceptibility of pathogens from SMART 2011-12 Turkey: Evaluation of hospital-acquired versus community-acquired urinary tract infections and ICU- versus non-ICU-associated intra-abdominal infections. The Journal of Antimicrobial Chemotherapy. 2017;**72**:1364-1372. DOI: 10.1093/jac/dkw574

[23] Castillo-Tokumori F, Irey-Salgado C, Malaga G. Worrisome high frequency of extendedspectrum beta-lactamase-producing *Escherichia coli* in community-acquired urinary tract infections: A case-control study. International Journal of Infectious Diseases. 2017;**55**:16-

[24] Toner L, Papa N, Aliyu SH. Extended-spectrum beta-lactamase-producing Enterobacteriaceae in hospital urinary tract infections: Incidence and antibiotic susceptibility profile over 9 years. World Journal of Urology. 2016;**34**(7):1031. DOI: 10.1007/s00345-

[25] Hu FP, Guo Y, Zhu DM. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014. Clinical Microbiology and

[26] Wener KM, Schechner V, Gold HS. Treatment with fluoroquinolones or with beta-lactam-beta-lactamase inhibitor combinations is a risk factor for isolation of extended-spectrum-beta-lactamase-producing Klebsiella species in hospitalized patients. Antimicrobial

[27] Azap OK, Arslan H, Serefhanoglu K. Risk factors for extended-spectrum beta-lactamase positivity in uropathogenic *Escherichia coli* isolated from community-acquired urinary tract infections. Clinical Microbiology and Infection. 2010;**16**:147-151. DOI:

Agents and Chemotherapy. 2010;**54**:2010-2016. DOI: 10.1128/AAC.01131-09

Infection. 2016;**22**(Suppl 1):S9-14. DOI: 10.1016/j.cmi.2016.01.001

Agents. 2010;**36**:19-23. DOI: 10.1016/j.ijantimicag.2010.02.016

104 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

2012;**66**:891-896. DOI: 10.1111/j.1742-1241.2012.02991.x

DOI: 10.1186/s12879-017-2250-y

DOI: 10.3389/fmicb.2016.01830

19. DOI: 10.1016/j.ijid.2016.12.007

10.1111/j.1469-0691.2009.02941.x

015-1718-x


[39] Falagas ME, Tansarli GS, Karageorgopoulos DE. Deaths attributable to carbapenemresistant Enterobacteriaceae infections. Emerging Infectious Diseases. 2014;**20**:1170- 1175. DOI: 10.3201/eid2007.121004

[50] Tamma PD, Rodriguez-Bano J. The use of Noncarbapenem beta-lactams for the treatment of extended-spectrum beta-lactamase infections. Clinical Infectious Diseases.

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

107

[51] Breilh D, Texier-Maugein J, Allaouchiche B. Carbapenems. Journal of Chemotherapy.

[52] Carbapenems for Multi-Drug Resistant Infections: A Review of Guidelines. CADTH Rapid Response Reports. Ottawa (ON): Canadian Agency for Drugs and Technologies

[53] Golan Y. Empiric therapy for hospital-acquired, Gram-negative complicated intraabdominal infection and complicated urinary tract infections: A systematic literature review of current and emerging treatment options. BMC Infectious Diseases. 2015;**15**:313.

[54] Kaniga K, Flamm R, Tong SY. Worldwide experience with the use of doripenem against extended-spectrum-beta-lactamase-producing and ciprofloxacin-resistant Enterobacteriaceae: Analysis of six phase 3 clinical studies. Antimicrobial Agents and Chemotherapy.

[55] Gutierrez-Gutierrez B, Bonomo RA, Carmeli Y. Ertapenem for the treatment of bloodstream infections due to ESBL-producing Enterobacteriaceae: A multinational pre-registered cohort study. The Journal of Antimicrobial Chemotherapy. 2016;**71**:1672-1680.

[56] Watanabe A, Fujimura S, Kikuchi T. Evaluation of dosing designs of carbapenems for severe respiratory infection using Monte Carlo simulation. Journal of Infection and

[57] Betriu C, Gomez M, Lopez-Fabal F. Activity of doripenem against extended-spectrum beta-lactamase-producing Enterobacteriaceae and *Pseudomonas aeruginosa* isolates. European Journal of Clinical Microbiology & Infectious Diseases. 2010;**29**:1179-1181.

[58] Gutierrez-Gutierrez B, Salamanca E, de Cueto M. Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemaseproducing Enterobacteriaceae (INCREMENT): A retrospective cohort study. The Lancet

[59] Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clinical

[60] Seo YB, Lee J, Kim YK. Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing *Escherichia coli*. BMC Infectious Diseases. 2017;**17**:404. DOI:

Infectious Diseases. 2017;**17**:726-734. DOI: 10.1016/S1473-3099(17)30228-1

Microbiology Reviews. 2010;**23**:160-201. DOI: 10.1128/CMR.00037-09

Chemotherapy. 2007;**13**:332-340. DOI: 10.1007/s10156-007-0562-3

2017;**64**:972-980. DOI: 10.1093/cid/cix034

DOI: 10.1186/s12879-015-1054-1

DOI: 10.1093/jac/dkv502

DOI: 10.1007/s10096-010-0974-3

10.1186/s12879-017-2502-x

in Health; 2016

2013;**25**:1-17. DOI: 10.1179/1973947812Y.0000000032

2010;**54**:2119-2124. DOI: 10.1128/AAC.01450-09


[50] Tamma PD, Rodriguez-Bano J. The use of Noncarbapenem beta-lactams for the treatment of extended-spectrum beta-lactamase infections. Clinical Infectious Diseases. 2017;**64**:972-980. DOI: 10.1093/cid/cix034

[39] Falagas ME, Tansarli GS, Karageorgopoulos DE. Deaths attributable to carbapenemresistant Enterobacteriaceae infections. Emerging Infectious Diseases. 2014;**20**:1170-

106 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

[40] Tumbarello M, Sanguinetti M, Montuori E. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: Importance of inadequate initial antimicrobial treatment. Antimicrobial Agents and Chemotherapy. 2007;**51**:1987-1994. DOI: 10.1128/AAC.01

[41] Weist K, Hogberg LD. ECDC publishes 2015 surveillance data on antimicrobial resistance and antimicrobial consumption in Europe. Euro Surveillance. 2016;**21**. DOI:

[42] Parisi SG, Bartolini A, Santacatterina E. Prevalence of *Klebsiella pneumoniae* strains producing carbapenemases and increase of resistance to colistin in an Italian teaching hospital from January 2012 to December 2014. BMC Infectious Diseases. 2015;**15**:244. DOI:

[43] Spyropoulou A, Papadimitriou-Olivgeris M, Bartzavali C. A ten-year surveillance study of carbapenemase-producing *Klebsiella pneumoniae* in a tertiary care Greek university hospital: Predominance of KPC- over VIM- or NDM-producing isolates. Journal of

[44] Poirel L, Nordmann P. Rapidec Carba NP test for rapid detection of Carbapenemase producers. Journal of Clinical Microbiology. 2015;**53**:3003-3008. DOI: 10.1128/JCM.00977-15

[45] Yoon YK, Kim JH, Sohn JW. Role of piperacillin/tazobactam as a carbapenem-sparing antibiotic for treatment of acute pyelonephritis due to extended-spectrum betalactamase-producing *Escherichia coli*. International Journal of Antimicrobial Agents.

[46] Gibble AM, Gross AE, Huang AM. Examining the clinical effectiveness of non-carbapenem beta-lactams for the treatment of extended-Spectrum beta-lactamase-producing Enterobacteriaceae. Antibiotics (Basel). 2015;**4**:653-666. DOI: 10.3390/antibiotics4040653

[47] Pilmis B, Parize P, Zahar JR. Alternatives to carbapenems for infections caused by ESBLproducing Enterobacteriaceae. European Journal of Clinical Microbiology & Infectious

[48] D'Angelo RG, Johnson JK, Bork JT. Treatment options for extended-spectrum beta-lactamase (ESBL) and AmpC-producing bacteria. Expert Opinion on Pharmacotherapy.

[49] Lee CH, Chu FY, Hsieh CC. A simple scoring algorithm predicting extended-spectrum beta-lactamase producers in adults with community-onset monomicrobial Enterobacteriaceae bacteremia: Matters of frequent emergency department users.

Medicine (Baltimore). 2017;**96**:e6648. DOI: 10.1097/MD.0000000000006648

Medical Microbiology. 2016;**65**:240-246. DOI: 10.1099/jmm.0.000217

2017;**49**:410-415. DOI: 10.1016/j.ijantimicag.2016.12.017

Diseases. 2014;**33**:1263-1265. DOI: 10.1007/s10096-014-2094-y

2016;**17**:953-967. DOI: 10.1517/14656566.2016.1154538

1175. DOI: 10.3201/eid2007.121004

10.2807/1560-7917.ES.2016.21.46.30399

10.1186/s12879-015-0996-7

509-06


[61] Harris PN, Peleg AY, Iredell J. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible *Escherichia coli* and Klebsiella spp (the MERINO trial): Study protocol for a randomised controlled trial. Trials. 2015;**16**:24. DOI: 10.1186/s13063-014-0541-9

[72] Talan DA, Takhar SS, Krishnadasan A. Fluoroquinolone-resistant and extended-spectrum beta-lactamase-producing *Escherichia coli* infections in patients with pyelonephritis, United States (1). Emerging Infectious Diseases. 2016;**22**:1594-1603. DOI: 10.3201/eid2209.

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

109

[73] Kantele A, Mero S, Kirveskari J. Fluoroquinolone antibiotic users select fluoroquinolone-resistant ESBL-producing Enterobacteriaceae (ESBL-PE)—Data of a prospective traveller study. Travel Medicine and Infectious Disease. 2017;**16**:23-30. DOI: 10.1016/j.

[74] Someshwaran R, Prakash KG, Deshpande SA. Adherence to hospital antibiotic policy for treatment of *Escherichia coli* ESBL in urine. Journal of Clinical and Diagnostic Research.

[75] Tiengrim S, Phiboonbanakit D, Thunyaharn S. Comparative in vitro activity of sitafloxacin against bacteria isolated from Thai patients with urinary tract infections and lower respiratory tract infections. Journal of the Medical Association of Thailand.

[76] Malaisri C, Phuphuakrat A, Wibulpolprasert A. A randomized controlled trial of sitafloxacin vs. ertapenem as a switch therapy after treatment for acute pyelonephritis caused by extended-spectrum beta-lactamase-producing *Escherichia coli*: A pilot study.

Journal of Infection and Chemotherapy. 2017;**23**. DOI: 10.1016/j.jiac.2017.05.005

[77] Gupta K, Hooton TM, Naber KG. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clinical Infectious Diseases. 2011;**52**:e103-e120. DOI: 10.1093/

[78] Karlowsky JA, Denisuik AJ, Lagace-Wiens PR. In vitro activity of fosfomycin against *Escherichia coli* isolated from patients with urinary tract infections in Canada as part of the CANWARD surveillance study. Antimicrobial Agents and Chemotherapy. 2014;**58**:1252-

[79] Kaewpoowat Q, Ostrosky-Zeichner L. Tigecycline: A critical safety review. Expert Opinion on Drug Safety. 2015;**14**:335-342. DOI: 10.1517/14740338.2015.997206

[80] Drekonja DM, Johnson JR. Tigecycline treatment for urinary tract infections: Case report and literature review. Journal of Chemotherapy. 2011;**23**:168-170. DOI: 10.1179/

[81] Brust K, Evans A, Plemmons R. Tigecycline in treatment of multidrug-resistant Gram-negative bacillus urinary tract infections: A systematic review. The Journal of

[82] Cunha BA. Pharmacokinetic considerations regarding tigecycline for multidrug-resistant (MDR) *Klebsiella pneumoniae* or MDR *Acinetobacter baumannii* urosepsis. Journal of

Antimicrobial Chemotherapy. 2014;**69**(10):2606. DOI: 10.1093/jac/dku189

Clinical Microbiology. 2009;**47**:1613. DOI: 10.1128/JCM.00404-09

2016;**10**:DC01-4. DOI: 10.7860/JCDR/2016/16084.7382

160148

tmaid.2017.01.003

2012;**95**(Suppl 2):S6-17

cid/ciq257

joc.2011.23.3.168

1256. DOI: 10.1128/AAC.02399-13


[72] Talan DA, Takhar SS, Krishnadasan A. Fluoroquinolone-resistant and extended-spectrum beta-lactamase-producing *Escherichia coli* infections in patients with pyelonephritis, United States (1). Emerging Infectious Diseases. 2016;**22**:1594-1603. DOI: 10.3201/eid2209. 160148

[61] Harris PN, Peleg AY, Iredell J. Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible *Escherichia coli* and Klebsiella spp (the MERINO trial): Study protocol for a randomised controlled trial.

[62] Rodriguez-Bano J, Navarro MD, Retamar P. Beta-lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing *Escherichia coli*: A post hoc analysis of prospective cohorts. Clinical Infectious

[63] Tamma PD, Han JH, Rock C. Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum betalactamase bacteremia. Clinical Infectious Diseases. 2015;**60**:1319-1325. DOI: 10.1093/cid/

[64] Dewar S, Reed LC, Koerner RJ. Emerging clinical role of pivmecillinam in the treatment of urinary tract infection in the context of multidrug-resistant bacteria. The Journal of

[65] Chopra T, Marchaim D, Veltman J. Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing *Klebsiella pneumoniae* and *Escherichia coli*. Antimicrobial Agents and

[66] Lee NY, Lee CC, Huang WH. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clinical Infectious Diseases. 2013;**56**:488-495. DOI: 10.1093/cid/cis916 [67] Guet-Revillet H, Emirian A, Groh M. Pharmacological study of cefoxitin as an alternative antibiotic therapy to carbapenems in treatment of urinary tract infections due to extended-spectrum-beta-lactamase-producing *Escherichia coli*. Antimicrobial Agents and

[68] Matsumura Y, Yamamoto M, Nagao M. Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-beta-lactamase-producing *Escherichia coli* bacteremia. Antimicrobial Agents and Chemotherapy. 2015;**59**:5107-5113. DOI:

[69] Kaye KS, Gales AC, Dubourg G. Old antibiotics for multidrug-resistant pathogens: From in vitro activity to clinical outcomes. International Journal of Antimicrobial Agents.

[70] Ipekci T, Seyman D, Berk H. Clinical and bacteriological efficacy of amikacin in the treatment of lower urinary tract infection caused by extended-spectrum beta-lactamase-producing *Escherichia coli* or *Klebsiella pneumoniae*. Journal of Infection and Chemotherapy.

[71] Tzouvelekis LS, Markogiannakis A, Piperaki E. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clinical Microbiology and Infection. 2014;**20**:862-

Antimicrobial Chemotherapy. 2014;**69**:303-308. DOI: 10.1093/jac/dkt368

Chemotherapy. 2012;**56**:3936-3942. DOI: 10.1128/AAC.05419-11

Chemotherapy. 2014;**58**:4899-4901. DOI: 10.1128/AAC.02509-14

2017;**49**:542-548. DOI: 10.1016/j.ijantimicag.2016.11.020

2014;**20**:762-767. DOI: 10.1016/j.jiac.2014.08.007

872. DOI: 10.1111/1469-0691.12697

Trials. 2015;**16**:24. DOI: 10.1186/s13063-014-0541-9

108 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Diseases. 2012;**54**:167-174. DOI: 10.1093/cid/cir790

civ003

10.1128/AAC.00701-15


[83] van Duin D, Cober ED, Richter SS. Tigecycline therapy for carbapenem-resistant *Klebsiella pneumoniae* (CRKP) bacteriuria leads to tigecycline resistance. Clinical Microbiology and Infection. 2014;**20**:O1117-O1120. DOI: 10.1111/1469-0691.12714

[96] Michalopoulos A, Virtzili S, Rafailidis P. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant *Klebsiella pneumoniae* in critically ill patients: A prospective evaluation. Clinical Microbiology and Infection. 2010;**16**:184-

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

111

[97] Banerjee S, Sengupta M, Sarker TK. Fosfomycin susceptibility among multidrug-resistant, extended-spectrum beta-lactamase-producing, carbapenem-resistant uropatho-

[98] Huang L, Hu YY, Zhang R. Prevalence of fosfomycin resistance and plasmid-mediated fosfomycin-modifying enzymes among carbapenem-resistant Enterobacteriaceae in Zhejiang, China. Journal of Medical Microbiology. 2017;**66**:1332-1334. DOI: 10.1099/

[99] Tasbakan MI, Pullukcu H, Sipahi OR. Nitrofurantoin in the treatment of extendedspectrum beta-lactamase-producing *Escherichia coli*-related lower urinary tract infection. International Journal of Antimicrobial Agents. 2012;**40**(6):554. DOI: 10.1016/j.

[100] Oplinger M, Andrews CO. Nitrofurantoin contraindication in patients with a creatinine clearance below 60 mL/min: Looking for the evidence. The Annals of Pharmacotherapy.

[101] Pfaller MA, Flamm RK, Duncan LR. Antimicrobial activity of tigecycline and cefoperazone/sulbactam tested against 18,386 Gram-negative organisms from Europe and the Asia-Pacific region (2013-2014). Diagnostic Microbiology and Infectious Disease.

[102] Flamm RK, Sader HS, Farrell DJ. Ceftazidime-avibactam and comparator agents tested against urinary tract isolates from a global surveillance program (2011). Diagnostic Microbiology and Infectious Disease. 2014;**80**:233-238. DOI: 10.1016/j.

[103] Karlowsky JA, Biedenbach DJ, Kazmierczak KM. Activity of ceftazidime-avibactam against extended-spectrum- and AmpC beta-lactamase-producing Enterobacteriaceae collected in the INFORM global surveillance study from 2012 to 2014. Antimicrobial

[104] Carmeli Y, Armstrong J, Laud PJ. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and *Pseudomonas aeruginosa* complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): A randomised, pathogen-directed, phase 3 study. The Lancet Infectious

[105] Vazquez JA, Gonzalez Patzan LD, Stricklin D. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: Results of a prospective, investigator-blinded, randomized study. Current Medical Research and Opinion.

Agents and Chemotherapy. 2016;**60**:2849-2857. DOI: 10.1128/AAC.02286-15

Diseases. 2016;**16**:661-673. DOI: 10.1016/S1473-3099(16)30004-4

2012;**28**:1921-1931. DOI: 10.1185/03007995.2012.748653

gens. Indian Journal of Urology. 2017;**33**:149-154. DOI: 10.4103/iju.IJU\_285\_16

186. DOI: 10.1111/j.1469-0691.2009.02921.x

2013;**47**:106-111. DOI: 10.1345/aph.1R352

2017;**88**:177-183. DOI: 10.1016/j.diagmicrobio.2017.02.020

jmm.0.000578

ijantimicag.2012.08.003

diagmicrobio.2014.07.005


[96] Michalopoulos A, Virtzili S, Rafailidis P. Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant *Klebsiella pneumoniae* in critically ill patients: A prospective evaluation. Clinical Microbiology and Infection. 2010;**16**:184- 186. DOI: 10.1111/j.1469-0691.2009.02921.x

[83] van Duin D, Cober ED, Richter SS. Tigecycline therapy for carbapenem-resistant *Klebsiella pneumoniae* (CRKP) bacteriuria leads to tigecycline resistance. Clinical Microbiology and

[84] Zavascki AP, Nation RL. Nephrotoxicity of Polymyxins: Is there any difference between Colistimethate and Polymyxin B? Antimicrobial Agents and Chemotherapy. 2017;**61**:

[85] Lenhard JR, Nation RL, Tsuji BT. Synergistic combinations of polymyxins. International Journal of Antimicrobial Agents. 2016;**48**:607-613. DOI: 10.1016/j.ijantimicag.2016.09.014

[86] Zusman O, Altunin S, Koppel F. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: Systematic review and meta-analysis. The Journal of

[87] Liu YY, Wang Y, Walsh TR. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study. The Lancet Infectious Diseases. 2016;**16**:161-168. DOI: 10.1016/

[88] Giamarellou H. Epidemiology of infections caused by polymyxin-resistant pathogens. International Journal of Antimicrobial Agents. 2016;**48**:614-621. DOI: 10.1016/j.

[89] Falagas ME, Vouloumanou EK, Samonis G. Fosfomycin. Clinical Microbiology Reviews.

[90] Jacobson S, Junco Noa L, Ahmed S. Efficacy and safety of oral fosfomycin for urinary tract infections in hospitalized patients. Antimicrobial Agents and Chemotherapy.

[91] Sastry S, Doi Y. Fosfomycin: Resurgence of an old companion. Journal of Infection and

[92] Seroy JT, Grim SA, Reid GE. Treatment of MDR urinary tract infections with oral fosfomycin: A retrospective analysis. The Journal of Antimicrobial Chemotherapy.

[93] Linsenmeyer K, Strymish J, Weir S. Activity of Fosfomycin against extended-spectrum-beta-lactamase-producing uropathogens in patients in the community and hospitalized patients. Antimicrobial Agents and Chemotherapy. 2016;**60**:1134-1136. DOI:

[94] Falagas ME, Kastoris AC, Kapaskelis AM. Fosfomycin for the treatment of multidrugresistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: A systematic review. The Lancet Infectious Diseases. 2010;**10**:43-50. DOI:

[95] Senol S, Tasbakan M, Pullukcu H. Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing *Escherichia coli*-related complicated lower urinary tract infection. Journal of Chemotherapy. 2010;**22**:355-357. DOI:

Chemotherapy. 2016;**22**:273-280. DOI: 10.1016/j.jiac.2016.01.010

Antimicrobial Chemotherapy. 2017;**72**:29-39. DOI: 10.1093/jac/dkw377

Infection. 2014;**20**:O1117-O1120. DOI: 10.1111/1469-0691.12714

110 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

e02319-16. DOI: 10.1128/AAC.02319-16

S1473-3099(15)00424-7

ijantimicag.2016.09.025

10.1128/AAC.02614-15

10.1016/S1473-3099(09)70325-1

10.1179/joc.2010.22.5.355

2016;**29**:321-347. DOI: 10.1128/CMR.00068-15

2016;**60**:1952. DOI: 10.1128/AAC.02971-15

2016;**71**:2563-2568. DOI: 10.1093/jac/dkw178


[106] Roberts MJ, Bennett HY, Harris PN. Prostate biopsy-related infection: A systematic review of risk factors, prevention strategies, and management approaches. Urology. 2017;**104**:11-21. DOI: 10.1016/j.urology.2016.12.011

[116] Rettedal S, Lohr IH, Bernhoff E. Extended-spectrum beta-lactamase-producing Enterobacteriaceae among pregnant women in Norway: Prevalence and maternal-neonatal

Resistant Gram-Negative Urinary Tract Bacterial Infections

http://dx.doi.org/10.5772/intechopen.71872

113

transmission. Journal of Perinatology. 2015;**35**:907-912. DOI: 10.1038/jp.2015.82 [117] Pathak A, Chandran SP, Mahadik K. Frequency and factors associated with carriage of multi-drug resistant commensal Escherichia Coli among women attending antenatal clinics in central India. BMC Infectious Diseases. 2013;**13**:199. DOI:

[118] Villar HE, Aubert V, Baserni MN. Maternal carriage of extended-spectrum beta-lactamase-producing *Escherichia coli* isolates in Argentina. Journal of Chemotherapy.

[119] Rizvi M, Khan F, Shukla I. Rising prevalence of antimicrobial resistance in urinary tract infections during pregnancy: Necessity for exploring newer treatment options. Journal

[120] Peretz A, Skuratovsky A, Khabra E. Peripartum maternal transmission of extendedspectrum beta-lactamase organism to newborn infants. Diagnostic Microbiology and

[121] O'Connor C, Philip RK, Kelleher J. The first occurrence of a CTX-M ESBL-producing *Escherichia coli* outbreak mediated by mother to neonate transmission in an Irish neonatal intensive care unit. BMC Infectious Diseases. 2017;**17**:16. DOI: 10.1186/

[122] Hutley EJ, Chand MA, Hounsome G. Fosfomycin: An oral agent for urinary infection caused by extended spectrum beta-lactamase producing organisms. The Journal of

[123] Eppes CS, Clark SL. Extended-spectrum beta-lactamase infections during pregnancy: A growing threat. American Journal of Obstetrics and Gynecology. 2015;**213**:650-652.

[124] Khatri A, Naeger Murphy N, Wiest P. Community-acquired pyelonephritis in pregnancy caused by KPC-producing *Klebsiella pneumoniae*. Antimicrobial Agents and

[125] van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation beta-lactam/beta-lactamase inhibitor combinations. Clinical Infec-

[126] Schwaber MJ, Carmeli Y. An ongoing national intervention to contain the spread of carbapenem-resistant enterobacteriaceae. Clinical Infectious Diseases. 2014;**58**:697-703.

[127] Cheon S, Kim MJ, Yun SJ. Controlling endemic multidrug-resistant *Acinetobacter baumannii* in intensive care units using antimicrobial stewardship and infection control. The Korean Journal of Internal Medicine. 2016;**31**:367-374. DOI: 10.3904/kjim.2015.178

Infectious Disease. 2017;**87**:168-171. DOI: 10.1016/j.diagmicrobio.2016.11.004

of Laboratory Physicians. 2011;**3**:98-103. DOI: 10.4103/0974-2727.86842

2013;**25**:324-327. DOI: 10.1179/1973947813Y.0000000081

Infection. 2010;**60**:308-309. DOI: 10.1016/j.jinf.2010.01.006

Chemotherapy. 2015;**59**(8):4375. DOI: 10.1128/AAC.00553-15

tious Diseases. 2016;**63**:234-241. DOI: 10.1093/cid/ciw243

10.1186/1471-2334-13-199

s12879-016-2142-6

DOI: 10.1016/j.ajog.2015.03.020

DOI: 10.1093/cid/cit795


[116] Rettedal S, Lohr IH, Bernhoff E. Extended-spectrum beta-lactamase-producing Enterobacteriaceae among pregnant women in Norway: Prevalence and maternal-neonatal transmission. Journal of Perinatology. 2015;**35**:907-912. DOI: 10.1038/jp.2015.82

[106] Roberts MJ, Bennett HY, Harris PN. Prostate biopsy-related infection: A systematic review of risk factors, prevention strategies, and management approaches. Urology.

[107] van Duin D, Lok JJ, Earley M. Colistin vs. Ceftazidime-avibactam in the treatment of infections due to Carbapenem-resistant Enterobacteriaceae. Clinical Infectious

[108] Temkin E, Torre-Cisneros J, Beovic B. Ceftazidime-Avibactam as salvage therapy for infections caused by Carbapenem-resistant organisms. Antimicrobial Agents and

[109] Shields RK, Chen L, Cheng S. Emergence of Ceftazidime-Avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of Carbapenem-resistant *Klebsiella pneumoniae* infections. Antimicrobial Agents and Chemotherapy. 2017;**61**:e02097-16

[110] Pfaller MA, Bassetti M, Duncan LR. Ceftolozane/tazobactam activity against drugresistant Enterobacteriaceae and *Pseudomonas aeruginosa* causing urinary tract and intraabdominal infections in Europe: Report from an antimicrobial surveillance programme (2012-15). The Journal of Antimicrobial Chemotherapy. 2017;**72**:1386-1395.

[111] Scott LJ. Ceftolozane/tazobactam: A review in complicated intra-abdominal and urinary tract infections. Drugs. 2016;**76**:231-242. DOI: 10.1007/s40265-015-0524-5

[112] Shortridge D, Castanheira M, Pfaller MA. Ceftolozane-tazobactam activity against *Pseudomonas aeruginosa* clinical isolates from U.S. Hospitals: Report from the PACTS Antimicrobial Surveillance Program, 2012 to 2015. Antimicrobial Agents and

[113] Wagenlehner FM, Umeh O, Steenbergen J. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: A randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet.

[114] Castanheira M, Sader HS, Farrell DJ. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant *Staphylococcus aureus* carrying various staphylococcal cassette chromosome mec types. Antimicrobial Agents and Chemotherapy. 2012;**56**:4779-

[115] Chaudhary M, Mir MA, Ayub SG. Safety and efficacy of a novel drug elores (ceftriaxone+sulbactam+disodium edetate) in the management of multi-drug resistant bacterial infections in tertiary care centers: A post-marketing surveillance study. The Brazilian Journal of Infectious Diseases. 2017;**21**:408-417. DOI: 10.1016/j.bjid.2017.

Chemotherapy. 2017;**61**:e01964-16. DOI: 10.1128/AAC.01964-16

Chemotherapy. 2017;**61**:e0465-17. DOI: 10.1128/AAC.00465-17

2015;**385**:1949-1956. DOI: 10.1016/S0140-6736(14)62220-0

4785. DOI: 10.1128/AAC.00817-12

02.007

2017;**104**:11-21. DOI: 10.1016/j.urology.2016.12.011

112 Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Diseases. 2017;**65**. DOI: 10.1093/cid/cix783

DOI: 10.1128/AAC.02097-16

DOI: 10.1093/jac/dkx009


*Edited by Tomas Jarzembowski, Agnieszka Daca and Maria Alicja Dębska-Ślizień*

Urinary tract infection (UTI) is a problem so common and so significant in routine clinical practice that accurate diagnostics are especially important. In particular, complicated UTI is associated with an increased rate of therapy failures, as a result of possible biofilm formation on foreign elements and antibiotic resistance, as well as the increased possibility of an infection recurrence. These are the arguments for the constant search for novel diagnostic tools and techniques. These and many other vital topics regarding UTI complications, management, and treatment, in addition to antibiotic resistance and bacterial virulence traits allowing us to mitigate or avoid antibiotic action, are presented in this book.

Published in London, UK © 2018 IntechOpen © Dr\_Microbe / iStock

Urinary Tract Infection - The Result of the Strength of the Pathogen, or the Weakness of the Host

Urinary Tract Infection

The Result of the Strength of the Pathogen,

or the Weakness of the Host

*Edited by Tomas Jarzembowski,* 

*Agnieszka Daca and Maria Alicja Dębska-Ślizień*