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## Meet the editors

Tomasz Jarzembowski is an assistant professor in the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. He obtained a Ph.D. from the Department of Biology, University of Gdańsk (UG), in 2000, and a DSc from the Faculty of Medicine, GUMed, in 2015. After obtaining a specialization in clinical microbiology in 2003, Dr. Jarzembowski began studying biofilm formation and heterogeneity of antibiotic

resistance. The latter research, which he conducted in cooperation with experts in nephrology and immunology, resulted in the designation of a new diagnostic method for UTIs, which was patented in 2017. Currently, his interests are focused on the proteomic study of virulence biomarkers of species of microbiome. Dr. Jarzembowski has been a leader of several projects of the Ministry of Education and Science, Poland, and a grant from Applied Microbiology International. He is a member of the Main Audit Committee of the Polish Society of Microbiologists (PTM), the Steering Committee of the Gdańsk branch of PTM, Applied Microbiology International, and the editorial board of several international journals. He is an author and editor of more than sixty scientific publications and book chapters.

Agnieszka Daca obtained her Ph.D. from the Medical University of Gdańsk, Poland, in 2011. Her thesis discussed immunological changes observed in the blood of patients with systemic lupus erythematosus (SLE). After her Ph.D., Dr. Daca divided her work into two aspects. The first is the widely understood interaction between bacteria and the innate immune system (especially monocytes) in cooperation with Tomasz Jarzem-

bowski. For this, she researches virulence traits of bacteria (especially Enterococcus faecalis) and their impact on monocytes' behavior. The main aspect is the monocytes' ability to phagocytose bacteria and their impact on the human body's ability to eradicate bacteria, especially in immunocompromised patients. The second branch of her scientific activity is the immunology of autoimmune diseases, mainly SLE and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in cooperation with Prof. Alicja Dębska-Ślizień and her co-workers from the Medical University of Gdańsk.

### Contents


#### **Chapter 7 121** Usefulness of Urine Tests in the Prevention, Diagnosis, Treatment and Prognosis of Pathologies Present during Pregnancy *by Noren Villalobos*

## Preface

Urinalysis is one of the most useful laboratory techniques that provides an abundance of information regarding one's health. In most circumstances, it is non-invasive and safe. Aside from its obvious benefits, urinalysis reflects not only urinary tract functioning but also the functioning of other parts of the body such as the digestive system or circulatory system. The various biomarkers and metabolites detected in urine can provide information about ongoing processes and currently developing problems in the body. Given the wide range of possible applications for data received from urine analysis in everyday home and hospital care, it is not unexpected that urinalysis history is particularly long and interesting.

The first glimpse into rudimental urine analysis, known at the time as uroscopy, comes from ancient history. Back then, sages were aware of urine's unique ability to represent the human body condition and were able to link features of urine such as color, consistency, sediment, odor, and volume with, for example, the state of hydration or the diet of the urine donor. The drawn findings became more sophisticated and better reflected the state of homeostasis of the human body as understanding about the functioning of the urinary system in general and each of its parts independently increased.

The advancement of understanding the human body's functioning in health and disease was matched by the development of increasingly precise and accurate diagnostic tools. The data acquired from correctly collected urine is now astounding. However, it is worth noting that the increasing specificity, susceptibility, and diversity of urine analysis techniques corresponds to the growing demand for such procedures. It no longer simply reflects the body's volemia state, it also indicates numerous diseases, pharmacokinetics, and many other factors.

The advancement of renal transplants has created a demand for accurate monitoring of kidney functioning without the use of invasive procedures. The patients' near-constant monitoring necessitates both swift and sensitive approaches for assessing the current state of the transplanted organ as well as the entire body. This includes, for example, normally difficult-to-discover asymptomatic inflammations, which, due to their insidious nature, can lead to transplant rejection.

We cordially welcome you to read this book. It highlights the history of urinalysis and its significance in daily practice as well as in the case of patients with unique needs and requirements. We hope you will find it informative and stimulating.

> **Agnieszka Daca and Tomasz Jarzembowski** Departamet of Medical Microbiology, Medical University of Gdańsk, Gdańsk, Poland

Foreword

Urine was the first body fluid to be examined in order to find associations between its changed properties (looks, odor, and taste) and various human ailments. Urinoscopy, and then urinalysis in its most rudimentary form, was already known more than 6000 years ago. Modern urinalysis started in the 17th century and progress is ongoing. This book

Chapter 1 by Dr. Agnieszka Daca and D.Sc. Tomasz Jarzembowski reviews the history of

Chapter 2 by Prof. Chandrasekhar Nagaraj discusses catheter-associated urinary tract infections (CAUTIs). UTIs are of great clinical importance and often arise as nosocomial infections, originating in the hospital setting. In cases of hospital-acquired UTIs (HAUTIs), patients' hospital stays are often prolonged and costly. Even worse, microorganisms that cause HAUTIs are more virulent and resistant to antibiotics than those causing other UTIs. The ability of such microorganisms to form biofilm on catheters often leads to catheter-associated UTIs (CAUTIs), which are the second most common hospital-acquired infection (HAI). This chapter describes the CAUTI condition itself, as well as procedures preceding catheterization, catheterization itself, and other

Chapter 3 by Dr. Laura Cristina Nocua-Báez and Dr. Jorge Alberto Cortés also reviews UTIs. Apart from obvious microbiological approaches, there are non-microbiological tests for characterizing the microorganisms that cause UTIs. Some of these tests can be used in the doctor's office or emergency room, whereas others require more sophisticated instruments. Some of the goals of using non-microbiological approaches are to bypass the difficulties of diagnosis in some patients (e.g., older patients or those who are cognitively impaired) and to more quickly diagnose UTIs, enabling quicker introduction of therapy.

Chapter 4 by Dr. Lovelesh K. Nigam discusses patients undergoing renal transplants. These patients may develop UTIs, cystitis, nephrolithiasis, cancers, and other conditions that can be traced and diagnosed by modern urinalysis. One of the important groups of conditions for which transplant patients are at risk, and for which urinalysis may help with early detection, is viral nephropathies. Furthermore, modern urinalysis may indicate upcoming graft rejection as well as the condition of the graft itself, reducing the need for renal biopsy and related risks. Finally, urinalysis in this group of patients may show the

Chapter 5 by Dr. Abraham Joseph Pellissery, Dr. Poonam Gopika Vinayamohan, Ms. Leya Susan Viju, Ms. Divya Joseph, and Prof. Kumar Venkitanarayanan discuss urine metabolomics. By discovering novel biomarkers, the metabolomics approach helps to develop new avenues of clinical diagnosis not only for diseases of the urinary system, but also for infectious, metabolic, and inflammatory diseases and malignancies. It is also invaluable in monitoring health status, both in healthy and diseased individuals. In the former, it may give early warning, while in the latter it may show the progression of the disease or the

relapse of the disease underlying kidney failure prior to transplantation.

progression and efficacy of treatment.

provides a comprehensive overview of urinalysis.

urinalysis and highlights its progress over the years.

preventive measures.

## Foreword

Urine was the first body fluid to be examined in order to find associations between its changed properties (looks, odor, and taste) and various human ailments. Urinoscopy, and then urinalysis in its most rudimentary form, was already known more than 6000 years ago. Modern urinalysis started in the 17th century and progress is ongoing. This book provides a comprehensive overview of urinalysis.

Chapter 1 by Dr. Agnieszka Daca and D.Sc. Tomasz Jarzembowski reviews the history of urinalysis and highlights its progress over the years.

Chapter 2 by Prof. Chandrasekhar Nagaraj discusses catheter-associated urinary tract infections (CAUTIs). UTIs are of great clinical importance and often arise as nosocomial infections, originating in the hospital setting. In cases of hospital-acquired UTIs (HAUTIs), patients' hospital stays are often prolonged and costly. Even worse, microorganisms that cause HAUTIs are more virulent and resistant to antibiotics than those causing other UTIs. The ability of such microorganisms to form biofilm on catheters often leads to catheter-associated UTIs (CAUTIs), which are the second most common hospital-acquired infection (HAI). This chapter describes the CAUTI condition itself, as well as procedures preceding catheterization, catheterization itself, and other preventive measures.

Chapter 3 by Dr. Laura Cristina Nocua-Báez and Dr. Jorge Alberto Cortés also reviews UTIs. Apart from obvious microbiological approaches, there are non-microbiological tests for characterizing the microorganisms that cause UTIs. Some of these tests can be used in the doctor's office or emergency room, whereas others require more sophisticated instruments. Some of the goals of using non-microbiological approaches are to bypass the difficulties of diagnosis in some patients (e.g., older patients or those who are cognitively impaired) and to more quickly diagnose UTIs, enabling quicker introduction of therapy.

Chapter 4 by Dr. Lovelesh K. Nigam discusses patients undergoing renal transplants. These patients may develop UTIs, cystitis, nephrolithiasis, cancers, and other conditions that can be traced and diagnosed by modern urinalysis. One of the important groups of conditions for which transplant patients are at risk, and for which urinalysis may help with early detection, is viral nephropathies. Furthermore, modern urinalysis may indicate upcoming graft rejection as well as the condition of the graft itself, reducing the need for renal biopsy and related risks. Finally, urinalysis in this group of patients may show the relapse of the disease underlying kidney failure prior to transplantation.

Chapter 5 by Dr. Abraham Joseph Pellissery, Dr. Poonam Gopika Vinayamohan, Ms. Leya Susan Viju, Ms. Divya Joseph, and Prof. Kumar Venkitanarayanan discuss urine metabolomics. By discovering novel biomarkers, the metabolomics approach helps to develop new avenues of clinical diagnosis not only for diseases of the urinary system, but also for infectious, metabolic, and inflammatory diseases and malignancies. It is also invaluable in monitoring health status, both in healthy and diseased individuals. In the former, it may give early warning, while in the latter it may show the progression of the disease or the progression and efficacy of treatment.

Chapter 6 by Assistant Prof. Hiroko Furo, Dr. Tony Lin, Dr. Yi Yuan Zhou and Dr. Sarah Abdelsayed discusses the application of quantitative gas chromatography–mass spectrometry (GC–MS) for tracing opiates in urine. Findings from GC–MS may help clinicians monitor the results of treatment for opioid use disorder, as well as facilitate interpretation of urine drug test results.

Finally, in Chapter 7, which examines UTIs in pregnant women, Ph.D. Noren Villalobos shows that the use of non-microbiological tests assessing the possibility of UTIs in this vulnerable group of patients may facilitate diagnosis (including the identification of involved microorganisms) and thus allow for proper, timely, and targeted treatment.

In conclusion, modern urinalysis is a relatively easy, multimodal, and fairly inexpensive tool in health and disease monitoring, as excellently described and discussed in this book.

> **Jacek Witkowski** Professor, Head of the Department of Physiopathology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland

Section 1

Urinalysis in Everyday

Practice

Section 1

## Urinalysis in Everyday Practice

#### **Chapter 1**

## Introductory Chapter: Modern Diagnostics with the Ancient History

*Agnieszka Daca and Tomasz Jarzembowski*

#### **1. Introduction**

Urinary tract (UT), in its entirety, has a long and interesting history extending far beyond modern times. The first written mention of UT and especially kidneys reaches ancient Egypt, as kidneys together with the heart, were the only organs not removed from the mummified bodies [1]. It was believed that the kidneys are the means of judgment in the afterlife, the proverbial guide for the heart's decisions. The fundamental role of kidneys and heart for humans' afterlife fate was not only Egyptian domain as it was also a common belief among other ancient civilizations and religions, such as Semitic Tradition and Old Testament [2, 3].

The fact that the kidneys were not removed from dead bodies before mummification and burial has been the reason for today's existence of the archaic samples of those organs with, e.g., renal cysts and stones [1, 4]. As such, the knowledge of urinary tract infections (UTIs) also reaches ancient times. They were not called UTIs but were well defined nonetheless, together with very specific ways of treatment (e.g. [1]). The first written mention of UTI dates back again to ancient Egypt and the Ebers Papyrus from 1550 BC, where UTI is described as 'sending forth heat from bladder' [5]. It is worth underlining that the actual role of UT was far from correct in those ancient times, but still, the aforementioned Ebers Papyrus contains interesting descriptions of maladies such as urethritis, prostatitis, or cystitis and procedures such as uroscopy, which will be the modern urinalysis [1]. Later on, but still, in Antiquity, despite very limited and often quite erroneous knowledge of urinary tract functioning, Hippocrates and his successors were able to perform a rudimental urinalysis, noting such features as color, consistency, sediment, odor, and volume [6]. Corpus Hippocraticum presented many known renal afflictions today, such as renal colic, chronic renal infection, renal tuberculosis, and UTI symptoms, e.g., urinary incontinence and urinary retention [4].

The historical breakthrough for the UT elements and their role in physiology dates back to the brilliant scientist Galen of Pergamon, who was the first to claim and prove that the main role of kidneys, not the bladder, is to produce urine [7]. Even though the exact mechanism of urine formation remained a mystery to this scientist because the function was described as 'the separation of excess and poorly concocted bodily humors', the impact of Galen on nephrology cannot be diminished both in the case of uroscopy and the structure of the kidneys [7]. What is even more important, when it comes to Galen's impact on nephrology, is his contribution to its pathology. Galen is,

e.g., credited for the first differential diagnosis and work-up of anuria and oliguria. His work also details the approach to a patient with such conditions as diabetes mellitus and diabetes insipidus, even though the exact pathomechanisms of those diseases themselves were a mystery at that time [8].

An even more detailed description of kidneys and UT was created by Oribasius from Pergamum, the Byzantine scholar who, apart from his impact on nephrology development, was remembered as the writer of *Collectiones Medicae* [4, 9], preserving the ancient medical knowledge. His descriptions of the nephron structure, together with a detailed illustration of its blood circulation, were the most detailed at the time. His proposed treatment options for hematuria, both acute and chronic nephritis and nephrolithiasis, even though they are not on par with today's practice, emphasized the role of physiotherapy and phytotherapy in nephropathology of that time [9]. Another Byzantine scholar – Avicenna – preserved the at the time known practices and knowledge from Greek and Far Eastern regarding urinalysis [10]. He said that 'urine is a faithful guide for the knowledge of the illness', which is a succinct description of the idea standing behind urinalysis.

#### **2. Postantiquity advances in nephrology**

Beginning from the Renaissance, the modern history of nephrology started. It still greatly drew from the knowledge of ancient scientists and physicians, in part mentioned above, but the new equipment allowed the previously unattainable precision in human anatomy and physiology observation [4]. Andreas Vesalius, the Belgian anatomist, and Roman Bartolomeo Eustachio working separately at more or less the same time, based their discoveries on direct observations of humans' and dogs' kidneys. Their meticulous work allowed them to correct many of the mistakes of their predecessors (and still, they had different results regarding some of the anatomical features of analyzed kidneys, e.g., the position of the right and left one in the human body) when it comes to the anatomy of the kidney [11]. Where Vesalius and Eustachio were quite ignorant of the function of the kidney itself [12], Neapolitan physicist and mathematician Giovanni Borelli was vitally interested in mechanisms explaining the mechanics of the body, among them kidney functioning, stating that the kidneys play the role of sieve filtering blood and excreting the elements which need to be eliminated [11]. Marcello Malpighi and Lorenzo Bellini, other renowned physicians, who were additionally armed with magnifying lenses and microscopes, were able to perform even more detailed observations of renal structure and function, especially Malpighians' body of the kidney [13]. Bellini, Borello, and Malpighi though, even with all the advances in their observations, still believed that urine is created in purely mechanistic or hydraulic ways [11, 14]. The concept of ultrafiltration as the means of urine formation was first described by Archibald Pitcairne, even though it was properly termed almost 150 years later [11]. The final touches to the kidney anatomy and function were added by William Bowman, who, armed with a microscope far better than Malpighi's and Bellini's described the existence of Bowman capsule surrounding the Malpighi's body. That in itself added the missing element to the urine formation hypothesis [15].

Richard Bright is considered the father of modern clinical nephrology. Together with other famous physicians, Thomas Hodgkin and Thomas Addison, they developed knowledge about specific pathologies; some were even named after them [4]. Bright discovered that the presence of albuminuria and edema is always linked with kidney disease [16]. He described such conditions as acute nephritis, nephrotic syndrome, and uremia. Additionally, he found and explained the link between kidney disease and enlarged ventricles of the heart [17].

Urinalysis remained largely unchanged at the time. As a visual science, it linked the observed changes in color, consistency, sediment, odor, and taste with specific diseases. And diabetes mellitus and diabetes insipidus are the best in proving the need for tasting the sample as the first means 'sweet as honey' and the second 'without taste or perceptible flavor' [18]. What is worth mentioning, though, is that with uroscopy becoming more and more popular, there were regions around the world where uromancy developed [19]. Many of those not knowledgeable enough made it a practice to diagnose various diseases based on information from pamphlets containing elaborate charts allowing comparing the color of the urine to diagnose assorted diseases [20]. Later on, it led to the need for uroscopy regulation, and some statutes were formulated trying to regulate the art of uroscopy [21].

#### **3. The dawn of modern urinalysis**

Together with the anatomical and functional advances of nephrology, also nephropathology and diagnostics started to develop. The autopsies of dead bodies brought many pathologies to light. Interesting results were revealed by, e.g., Malpighi's body autopsy [22]. He suffered from chronic kidney disease and supposedly hypertension, and his autopsy results were published together with over 2000 others in Theophile Bonet's *Sepulchretum sive anatomia practica ex cadaveribus morbo denatis*. The first such extensive collection of postmortem reports [22]. In turn *De Sedibus et Causis Morborum per anatomen indigatis* published almost 100 years later by Giovanni Morgagni, is considered the foundation for the classification of kidney diseases based on gross anatomy and clinical symptoms [23].

The development of physiology and pathology was accompanied by the advances in chemistry of urine. The first ones mentioning the exact parameters of urine, such as specific gravity, hematuria, or proteinuria, were Paracelsus and his two followers, Joan Baptista van Helmont and Herman Boerhaave [24, 25]. The chemistry knowledge in those days was not on par with physiology development though [26]. The dominant role of alchemy at the time had some impact on that. The beginning of actual urinalysis based on actual chemical structure is set in the seventeenth century. It was then that chemistry was freed from the influences of mystic alchemy and started to make headways. Many manuals were published about the principles of basic chemical methods, such as distillation and sublimation but also many others. Christofle Glaser, Nicolas Lemery, and aforementioned Herman Boerhaave should probably be mentioned as the ones (but not the only ones) who impacted chemistry the most at the time [25, 27]. The chemicals in the urine were divided into nonvolatile acidic residues, identified as chloride salts later on, and 'volatile alkali', ammonium carbonate, or urea. The aforementioned Bellini and Thomas Willis should probably be credited to be the ones of first authors of quite extensive descriptions of changes in urine (its' color, taste, and odor) depending on the urine's composition and clinical condition [18]. Willis was also the one involved in regulating uroscopy, mentioned earlier, by clearly stating that the observed changes in urine's color, taste, and odor reflect those of the blood, not mystic humors [28]. The link between blood and urine and the need to analyze them both to get a clear picture of various illnesses was also later underlined by others, e.g., Robert Boyle and Browne Langrish [25, 29]. The last

one even said 'the study of the proportions of several principles of blood and urine, both in sound and disease state, will be highly useful in investigating the causes and the phenomenon of disease' [29].

The inauguration of biochemistry is dated to the beginning of the nineteenth century. Probably the most important milestone from that time is the identification of a vital element of urine – urea. It was identified and characterized by William Prout and synthesized by Friedrich Wöhler [30, 31]. Quite quickly, urea was linked with several pathologies, and the term 'uremia' was coined. The first disease in which an elevated level of serum urea was noted was mentioned earlier Bright's disease (or nephritis), but soon the urea level started to get measured in many other kidney diseases [32]. But what is most important about the research regarding urea is its role in the development of the concept of dialysis and artificial kidney [33].

The first complete compendium about the analysis of urine, *Quantitative Clinical Chemistry*, was published at the beginning of the twentieth century by John P. Peters and Donald D. Van Slyke [34]. It contained a detailed description of blood and urine chemical composition and the rules for standardized measurement of such parameters as electrolytes concentration, especially K+ , and Na+ . That allowed for assessing conditions such as hyponatremia, respiratory and metabolic acidosis, and effective osmotic pressure [35, 36]. As all of them are linked with renal state, Peters insisted on combining clinical laboratory and clinical investigation. That way, laboratory diagnostics became vital to clinical diagnosis [34]. By the end of the 30s of the 20th century, urinalysis started to become a common routine in medical examinations [37].

Almost 100 years later, urinalysis is still considered one of the most important tools implemented in standard medical examination. This period was filled with an intense development of that branch of the diagnostic laboratory. Many new techniques were developed, increasing the sensitivity and specificity of performed tests and making it easier to interpret obtained results even in specific and demanding groups of patients, e.g., pregnant women.

#### **Author details**

Agnieszka Daca1 \* and Tomasz Jarzembowski<sup>2</sup>

1 Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdansk, Poland

2 Deparment of Microbiology, Medical University of Gdansk, Gdansk, Poland

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

© 2023 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.

### **References**

[1] Salem ME, Eknoyan G. The kidney in ancient Egyptian medicine: Where does it stand? American Journal of Nephrology. 1999;**19**(2):140-147

[2] Diamandopoulos A, Goudas P. The role of the kidney as a religious, cultural and sexual symbol. American Journal of Nephrology. 2002;**22**(2-3):107-111

[3] Maio G. The metaphorical and mythical use of the kidney in antiquity. American Journal of Nephrology. 1999;**19**(2):101-106

[4] Greydanus D, Kadochi M. Reflections on the medical history of the kidney: From Alcmaeon of Croton to Richard bright – standing on the shoulders of giants. Journal of Integrative Nephrology and Andrology. 2016;**3**(4):101

[5] Easmon CFS. Topley & Wilson's principles of bacteriology, virology and immunity. Immunology. 1984;**52**(4):780

[6] Hippocrates AF. The Genuine Works of Hippocrates; translated from the Greek with a preliminary discourse and annotations [Internet]. New York: W. Wood; 2023. p. 416. Available from: http://archive.org/details/ genuineworksofhi00tran

[7] Eknoyan G. The origins of nephrology – Galen, the founding father of experimental renal physiology. American Journal of Nephrology. 1989;**9**(1):66-82

[8] Temkin O. A Galenic model for quantitative physiological reasoning? Bulletin of the History of Medicine. 1961;**35**(5):470-475

[9] Eftychiadis AChr. Renal and glomerular circulation according to Oribasius (4th century). American Journal of Nephrology. 2002;**22**(2-3):136-138

[10] Abdel-Halim RES. The role of Ibn Sina (Avicenna)'s medical poem in the transmission of medical knowledge to medieval Europe. Urology Annals. 2014;**6**(1):1-12

[11] Eknoyan G. The scientific revolution—The kidney and nephrology in and about the seventeenth century (part 1). Seminars in Dialysis. 2015;**28**(3):282-292

[12] DeBroe ME, Sacreacute D, Snelders ED, De Weerdt DL. The Flemish anatomist Andreas Vesalius (1514-1564) and the kidney. American Journal of Nephrology. 1997;**17**(3-4):252-260

[13] McVaugh MR. Losing ground. The disappearance of attraction from the kidneys. The changing concepts of physiology from antiquity into Early Modern Europe. In: Blood, Sweat and Tears. The Netherlands: Brill; 2012. (Intersections; vol. 25)

[14] Brown TM. Medicine in the shadow of the principia. Journal of the History of Ideas. 1987;**48**(4):629-648

[15] Eknoyan G. Sir William Bowman: His contributions to physiology and nephrology. Kidney International. 1996;**50**(6):2120-2128

[16] Dock W. Proteinuria: The story of 280 years of trials, errors, and rectifications. Bulletin of the New York Academy of Medicine. 1974;**50**(6):659-666

[17] Young RH. Dr Richard bright – Father of medical renal disease. Archives of Pathology & Laboratory Medicine. 2009;**133**(9):1365

[18] Eknoyan G. Looking at the urine: The renaissance of an unbroken

tradition. American Journal of Kidney Diseases. 2007;**49**(6):865-872

[19] Armstrong JA. Urinalysis in Western culture: A brief history. Kidney International. 2007;**71**(5):384-387

[20] Wellcome HS et al. The Evolution of Urine Analysis: An Historical Sketch of the Clinical Examination of Urine: Lecture Memoranda. Los Angeles: American Medical Association; 1911. Available from: https://onlinebooks. library.upenn.edu/webbin/book/ lookupid?key=ha002083175

[21] Pelling M, White F, Pelling M, White F. Medical Conflicts in Early Modern London: Patronage, Physicians, and Irregular Practitioners 1550-1640. Oxford, New York: Oxford University Press; 2003. p. 428. Oxford Studies in Social History

[22] Hajdu SI. The first printed treatise in pathology. Annals of Clinical and Laboratory Science. 2009;**39**(1):92-93

[23] Antonello A, Calò L, Bonfante L, Mennella G, Abaterusso C, Spinello M, et al. Giovan Battista Morgagni, a Pioneer of clinical nephrology. American Journal of Nephrology. 1999;**19**(2):222-225

[24] Bernoulli R. Paracelsus – physician, reformer, philosopher, scientist|SpringerLink. Experientia. 1999;**50**(4):334-338

[25] Fruton JS. The emergence of biochemistry. Science. 1976;**192**(4237): 327-334

[26] Moran BT. Distilling Knowledge. USA: Harvard University Press; 2005. Available from: https://www.jstor.org/ stable/j.ctvjz83pp

[27] Neville RG. Christophle Glaser and the 'Traité de la Chymie,' 1663. Chymia. 1965;**10**:25-52

[28] Eknoyan G, Nagy J. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease. Advances in Chronic Kidney Disease. 2005;**12**(2):223-229

[29] Foster WD. The early history of clinical pathology in Great Britain. Medical History. 1959;**3**(3):173-187

[30] Kinne-Saffran E, Kinne RKH. Vitalism and synthesis of urea: From Friedrich Wöhler to Hans a Krebs. American Journal of Nephrology. 1999;**19**(2):290-294

[31] Rosenfeld L. William Prout: Early 19th century physician-chemist. Clinical Chemistry. 2003;**49**(4):699-705

[32] Cameron J. Sir Robert Christison (1797-1882): The man, his times, and his contributions to nephrology. The Journal of the Royal College of Physicians of Edinburgh. 2007

[33] Gottschalk CW, Fellner SK. History of the science of dialysis. American Journal of Nephrology. 2008;**17**(3-4):289-298

[34] Seldin DW. Scientific achievements of John P. Peters. American Journal of Nephrology. 2002;**22**(2-3):192-196

[35] Bruckman FS, Peters JP. The plasma proteins in relation to blood hydration. The Journal of Clinical Investigation. 1930;**8**(4):591-595

[36] Peters JP, Wakeman AM, Eisenman AJ, Lee C. Total acid-base equilibrium of plasma IN health and disease. The Journal of Clinical Investigation. 1929;**6**(4):517-549

[37] Free AH, Free HM. Urinalysis, critical discipline of clinical science. CRC Critical Reviews in Clinical Laboratory Sciences. 1972;**3**(4):481-531

#### **Chapter 2**

## Hospital-Acquired Urinary Tract Infections

*Chandrasekhar Nagaraj*

#### **Abstract**

Hospital-Acquired Infection (HAI/nosocomial infections) nosocomial infections, is gaining importance due to prolonged hospital stays and increased cost of hospital care as a result of infections acquired within the hospital. Organisms are more virulent and drug-resistant responsible for increased morbidity and mortality. Professor (Dr) Ignaz Phillip Semmelweis a Hungarian obstetrician, in 1847 observed this phenomenon. Catheter-associated Urinary Tract Infection (CAUTI) is the second most common infection (most common is Central Line-Associated bloodstream Infection–CLABSI). Development of CAUTI as an outcome, are discussed as precatheterization, input and output variable factors, and catheter maintenance. Careful monitoring is needed to understand these processes. **Pre-catheterization process** starts from the selection of the patient until catheterization is done. **Input variables** are catheter material, different types of urinary catheters, organisms causing these infections, and mechanism of infection. **Catheterization processes variables** include the need for catheterization, methods of catheterization, patient preparation, aseptic precautions, steps of catheterization, duration of catheterization, use of antibiotics, and the process of catheter removal. Final analysis of the cost involved makes it a comprehensive approach to the topic. Prevention of CAUTI as part of surveillance serves as an indicator to monitor the quality of services provided by the health care facility.

**Keywords:** hospital-acquired infection (HAI), nosocomial infections, urinary tract infection (UTI), catheter-associated urinary tract infection (CAUTI), asymptomatic bacteriuria, care bundle, health education, long-term catheter care, economic burden of hospitalization

#### **1. Introduction**

Catheter is a device used to drain urine from the bladder under different conditions. In the hospital, urinary catheters are used extensively on a variety of patient populations. During the process, the patient may get an infection other than for which he was admitted. In the hospital setup, urinary tract infection could follow the insertion of the urinary catheter. These infections following urinary catheterization are referred to as Catheter-associated urinary tract infection (CAUTI). CAUTI is a device (catheter) associated infection.

#### **1.1 Urinary tract infections (UTIs)**

Urinary tract infections (UTIs) are bacterial infections affecting nearly 150 million people around the world annually [1]. It is estimated that among all ambulatory patients (0.9%), 10.5 million persons have UTI symptoms and 2–3 million persons report to the emergency department in the United States alone [2–4]. In Infant boys, older men, and females of all ages, significant morbidity is due to UTIs. Frequent recurrences of pyelonephritis with sepsis, renal damage in young, preterm babies, and complications due to frequent antimicrobial use with high-level antibiotic resistance and Clostridium difficile colitis are the common complications of UTI. In the United States, approximately US\$3.5 billion per year is spent on societal costs for UTI infections (includes health care costs and time missed from work).

Urinary catheterization is used to evacuate urine by passing a hollow catheter. Catheter is passed through the urethra or sometimes through the suprapubic region. Indwelling urinary catheterization is classified as short-term (*in situ* less than 28 days), or long-term (*in situ* greater than 28 days) based on the time interval the catheter is in place.

Clinically, UTIs are classified as uncomplicated or complicated. Uncomplicated UTIs affect individuals who are otherwise healthy with no structural or neurological urinary tract abnormalities [5, 6]. Uncomplicated UTI infections are again classified as cystitis (lower UTIs) and pyelonephritis (upper UTIs) [5, 7]. Risk factors associated with cystitis include female gender, a prior UTI, sexual activity, vaginal infection, diabetes, obesity, and genetic susceptibility [3, 7]. Complicated UTIs are associated with factors that compromise the urinary tract or host defense mechanisms, such as urinary obstruction, urinary retention (associated with neurological disease, immunosuppression, renal failure, renal transplantation, pregnancy and the presence of foreign bodies, including calculi, indwelling catheters or other drainage devices) [8, 9]. Indwelling catheters can be attributed to 70–80% of complications of UTIs [10], which translates to 1 million cases per year in the United States [4].

UTIs are caused by gram-negative bacteria, gram-positive bacteria, and by some fungi [11]. Uropathogenic *Escherichia coli* (UPEC) is the most common agent causing both uncomplicated and complicated UTIs. Other agents involved, in order of prevalence, causing uncomplicated UTIs are *Klebsiella pneumoniae*, *Staphylococcus saprophyticus*, *Enterococcus faecalis*, group B *Streptococcus* (GBS), *Proteus mirabilis*, *Pseudomonas aeruginosa*, *Staphylococcus aureus,* and *Candida spp* [3, 6, 11–13]. Similarly, complicated UTIs are caused by Enterococcus spp., *K. pneumoniae*, *Candida spp*., *S. aureus*, *P. mirabilis*, *Ps. aeruginosa,* and GBS in order of prevalence following UPEC [9, 11, 14–16].

#### **1.2 Health care-associated infections (HCAI)**

By definition, "an infection that was not incubating at the time of admission is considered nosocomial if it develops in a patient who has been hospitalized for 48 to 72 hours or more." Health care-associated infections (HCAIs) are acquired by patients during their hospital stay [17]. Initially, the term HCAIs was referred only to the infections acquired by patients admitted to an acute-care hospital. At present, HCAI includes infections contracted in various healthcare settings, such as long-term care, family medicine clinics, home care, and ambulatory care, where patients get treated. HCAIs are infections that first appear 48 hours or more or within 30 days following hospitalization (can go up to 90 days for orthopedic implants) [18]. Adverse drug

events (ADE), HCAIs and surgical complications are the most common types of complications seen in hospitalized patients [19–23].

Estimates of the Center for Disease Control and Prevention (CDC) nosocomial infections contribute 0.7 to 10.1% of deaths and cause 0.1 to 4.4% of all deaths occurring in hospitals. US Center for Disease Control and Prevention project a figure of 1.7 million hospitalized patients to acquire HCAIs annually and more than 98,000 of them die [24]. HCAIs are the common complications associated with hospital care and one of the top ten leading causes of death in the USA [25]. Seven out of the 100 hospitalized patients in advanced countries and ten in emerging countries acquire an HCAI [26]. In high-income countries, of the 5–15% hospitalized HCAI patients, 9–37% are admitted to intensive care units (ICUs) [27, 28]. Around 0.5 million episodes of HCAIs are diagnosed every year in ICUs alone [23, 29, 30]. ICU patients are critically ill, immuno-compromised, and susceptible to HCAIs [31, 32]. Nosocomial infections affect more than 1.6 million patients annually costing about \$ 4.5 billion in the United States.

Hungarian obstetrician Professor (Dr) Ignaz Phillip Semmelweis, visualized that healthcare providers could transmit disease among themselves or to the patients. He was working in a Maternity Hospital in Vienna when he identified the mode of transmission and spread of puerperal sepsis. In 1847, he observed higher rates of maternal deaths among patients treated by obstetricians and medical students compared to those cared for by midwives. At that time, he found a pathologist while carrying out an autopsy on a patient with puerperal sepsis accidentally wounded with the scalpel and died of sepsis. Semmelweis wrote that "both scalpel and physician's contaminated hands could transmit organisms to mothers during labor." He introduced hand washing with chlorinated lime to be used by every staff working in that obstetric hospital. This practice brought a large improvement in maternal mortality rates [33]. Koch's postulates published in 1890, "the germ theory of disease" gave validity to Semmelweis' theory of transmission of disease from doctor to patient. Thus, Semmelweis became the first to describe HCAI and also provide intervention through hand hygiene [34].

The 2021 National and State HAI Progress Report [35] provided a detailed classification of different HAIs – "Central Line-Associated Blood Stream Infections (CLABSI), Catheter-Associated Urinary Tract Infections (CAUTI), Ventilator-Associated Events (VAE), Surgical Site Infections (SSI), Methicillin-Resistant *S. aureus* (MRSA) bloodstream events, and *Clostridioides difficile* (*C. difficile*) events." The report provided details in the form of technical tables with additional statistics about HAIs.

The report included infection-specific standardized infection ratios (SIRs) to measure progress in reducing HAIs compared to the 2015 baseline time period [36]. SIR is the ratio of the observed number of infections (events) to the number of predicted infections for a summarized time period. The report also included the standardized utilization ratios (SURs), which measure the use of a device by comparing the number of observed device days to the number of predicted device days [37]. The risk adjustment methodology of 2015 national baseline is used to calculate the SIR and SUR metrics.

#### *1.2.1 Catheter-associated urinary tract infection (CAUTI)*

CAUTI risk factors include catheterization for long periods, female gender, older age, and diabetes [38]. High recurrence rates of antimicrobial resistance among

uropathogens that resulted in increased economic burden to the patients were noted in patients suffering from CAUTI. Increased morbidity and mortality of catheterassociated UTIs (CAUTIs) are the common cause of secondary bloodstream infections.

Hospital-acquired infections (HAIs) are associated with the use of devices such as catheters, ventilators, central lines, etc. Major causes of HAIs is due to prolonged hospitalization, use of invasive devices, such as catheters and irrational use of antibiotics [39]. More than 30% of annual infections are seen in the critical care area of the hospital [24]. Among the device-associated hospital-acquired infections, Central lineassociated bloodstream infections (CLABSIs) are the most common [40]. It is followed by catheter-associated urinary tract infections (CAUTIs) and ventilatorassociated pneumonia (VAP) [41].

Indwelling urethral catheters account for about 80% of UTI [40]. Catheters may facilitate colonization of the urinary bladder due to poor catheter placement, prolonged catheterization, poor aseptic technique, poor hand hygiene, and poor asepsis of the urethral orifice opening. Hence, catheters are a common source of urinary tract infections [42]. Catheter placement is not directly associated with the development of UTIs.

Each patient, depending on age, comorbidities, and socioeconomic status the test result and frequency of a UTI can differ significantly. Gram-negative bacteria, such as *E. coli*, *Klebsiella spp*., *P. mirabilis*, *Ps. aeruginosa*, and *Citrobacter spp*., are the predominant isolates in urinary tract infections. Gram-positive bacteria, such as *S. aureus* and *Enterococcus species,* are the most common [43, 44].

A secondary hospital-acquired bloodstream infection may occur as post-catheter-associated urinary tract infection, (17% of nosocomial bacteremia from urinary tract infections) with an associated mortality of 10% [45]. Asymptomatic bacteriuria is the presence of a significant bacterial count, that is, >10<sup>5</sup> CFU/mL (Colony Forming Units/mL). In a well-collected urine sample with aseptic precautions from a patient who has asymptomatic, bacteriuria is commonly seen in clinical practice [46]. It is associated with low sequelae and low morbidity. In the majority of cases, it is self-limiting. In pregnant women, asymptomatic bacteriuria needs to be treated.

The urinary tract is usually sterile except for the distal urethra. The infection mostly follows instrumentation of the urinary tract, particularly catheterization (66– 88%). Each case of hospital-acquired urinary tract infection adds approximately \$675 to the cost of hospitalization, which increases to \$2800 when bacteremia develops [47]. Patient mortality may be high (30%) [48]. The incidence of hospital-acquired urinary tract infection can be reduced by decreasing the use of inappropriate indwelling urinary catheters, using closed drainage and ensuring the removal of the catheter when it is not required [49].

Leaving a urinary catheter for a long time *in situ* contributes to the development of a catheter-associated urinary tract infection (CAUTI) [50]. Risk of development of CAUTI increases by 5% per day in relation to the length of catheter *in situ*. Twenty-five percent of hospitalized patients are catheterized at some stage of their admission. It is critical to follow proper practices and procedures to minimize the risk of infection [51, 52].

A history of long-term hospitalization attributable to device-related infections should alert the possibility of CAUTI. Common symptoms are dysuria, fever (>38°C), urgency, frequency, dysuria without any cause, flank pain, supra-pubic pain, urinary urgency, and hematuria. Positive urinary cultures are expected if the patient has not

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

consumed antibiotics prior to the sample collection. The presence of bacteria in the urine without these symptoms is due to colonization [49]. An increase in treatment costs and risk of lethality for patients are observed.

Bacteriuria signifies either colonization (asymptomatic bacteriuria) or infection. Bacteriuria can be found both in catheterized and non-catheterized patients. Of the patients with catheter *in situ* for more than 30 days, 10–30% will develop bacteriuria compared to 1% of non-catheterized patients [53, 54]. Colonization rather than infection is associated with bacteriuria accounting for more than 90% of patients who are on the urinary catheter [55]. Diagnosis of CAUTI is not evidence-based [56]. Established laboratory criteria to differentiate between CAUTI and asymptomatic bacteriuria are not available. Clinicians rely on a combination of clinical signs and symptoms in addition to laboratory-confirmed bacteriuria to reach the diagnosis of CAUTI [57]. Clinical signs and symptoms of CAUTI are fever, new-onset confusion, loin, or suprapubic pain [56, 58]. Fever is the most frequently encountered symptom. However, the absence of fever does not rule out infection [57].

#### *1.2.2 Morbidity and mortality associated with CAUTI*

An increased morbidity, mortality, and length of hospitalization are associated with CAUTI [59–64]. In hospital-acquired bloodstream infection, CAUTI is the primary source of infection (8.5%) [65]. Bacteremia surveillance revealed 3.8% of cases to have resulted from CAUTI [66].

#### **1.3 Etiology**

Noncomplicated cystitis (86%) and up to 90% of noncomplicated pyelonephritis are mainly associated with *E. coli infection* [67]. Though *E. coli* is the most common infection, complicated UTIs have a more varied etiology. Other gram-negative bacilli like *Klebsiella*, *Citrobacter,* and *Enterobacter spp*. cause 11%; and *Ps. aeruginosa*, 8%. Gram-positive bacteria also are encountered in catheter-associated urinary tract infections (CAUTI) with D-group *Streptococci* causing 19% of them, and *S. aureus*, 4% associated with complications. Polymicrobial UTI cases represent 30% of complicated CAUTI. Other microorganisms such as yeasts cause 18% of UTIs. The significant appearance of *Ps. aeruginosa* in those of nosocomial origin along with extendedspectrum beta-lactamase (ESBL) and quinolone-resistant Enterobacteriaceae are encountered in those having healthcare-associated acquisition and secondary bloodstream infections [68].

Scottish Intercollegiate Guidelines Network (SIGN) recommends careful recording of associated localizing (loin or supra pubic tenderness) or systemic features of CAUTI. We have to exclude the possibility of other sources of infection. An appropriate sample of urine is to be sent for culture and the antimicrobial susceptibility of the organisms identified. An empiric antimicrobial therapy has to be considered based on the severity of the presentation, comorbid factors, and the local antimicrobial susceptibility patterns and antimicrobial prescribing guidelines [56].

#### **1.4 Pathogenesis**

Urethral catheterization interferes with the local natural defense mechanisms of the urinary tract. The length of the urethra and urine flow washes microorganisms

away from the bladder. Most organisms that cause CAUTI have to enter the bladder by migrating along the internal (intraluminal) and external (extraluminal) catheter surfaces. Intraluminal migration occurs when there is contamination of the catheter lumen that can occur due to the failure of a closed drainage system or from contaminated urine in the drainage bag. Extra luminal migration of microorganisms occurs from the perineum that can occur at the time after insertion of the catheter or later by capillary action *via* the outer surface of the catheter [58]. Patient's flora in the perineum region or the hands of HCWs provides the common pathogens associated with CAUTI, which include *E. coli*, *Enterococcus spp*., *Pseudomonas spp*., *Klebsiella spp*., *Enterobacter spp*., or *Candida spp* [69]. Risk factors of CAUTI are the duration of catheterization [59, 70, 71], underlying predisposing neurological disease, [61] female gender, [71, 72] and diabetes mellitus [71]. The importance of virulence surface proteins such as Type 1 and Type 2 fimbriae and surface attachment proteins such as FimH has been shown to be important in UPEC organisms which have come to light in recent days [72]. Similarly, pathogenicity islands (PAIs) designated ICEPm1, papAH, papEF, fimH, fyuA, and traT genes contribute to genomic variability and virulence that have also been identified and studied [73].

#### **2. Factors to be considered prior to the insertion of a urinary catheter**

Catheterization is done to drain the urine from the bladder. The main cause of hospital-acquired urinary tract infection revolves around the process of insertion to removal of the catheter. Draining of the urine can be done not only by transurethral catheterization but also by other routes, such as suprapubic or external drainage, by using a condom. With catheter being a central point of infection, it is important to prioritize the need of catheterization and if it is possible to avoid catheterization. The above facts suggest the need to understand conditions where catheterization is required, and when it can be avoided. There is a need to understand the methods of catheterization for use in different situations. These factors are discussed with the help of available literature on each variable factor.

#### **2.1 Indications for catheterization and can catheterization be avoided?**

Urinary catheterization is indicated [74–77] to relieve acute urinary retention due to bladder outlet obstruction, for assessing the healing of an open sacral or perineum wounds, to assist in achieving patient immobilization due to unstable thoracic, lumbar spine, or pelvic fractures, to monitor urinary output in critically ill patients or when a patient is unable or unwilling to collect urine during prolonged surgical procedures with general or spinal anesthesia, during regional analgesia for labor and delivery, for instillation of drugs or during urology investigations and for patient comfort during end of life care. In spite of delineating the conditions requiring catheterization, a urinary catheter is inappropriate in 21–54% of catheterized patients [78–80].

CDC guideline highlights the importance of limiting the use of urinary catheters to reduce the risk of UTI [81]. European Prospective Investigation into Cancer and Nutrition (EPIC) guidelines also advocate the selected usage of urinary catheterization and highlight avoidance when possible [82].

The most important measure to prevent CAUTI is to limit the use of urinary catheters and leave them in place only for the period indications persist [75, 82]. Based on comprehensive risk assessment, evaluation and the expected duration of

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

catheterization a decision is to be made regarding whether to catheterize and what type of catheter should be used. Consideration should be given to alternative management methods (e.g., condom) [83].

Urinary catheters are to be used only when indicated and should be removed at the earliest possible time. Complications associated with catheterization are infection, bacteremia, urethritis, urethral strictures, hematuria, and bladder perforation [84–87]. In practice, it is noted that indwelling urethral catheters are used when it is not indicated or remain *in situ* for a longer period than necessary [78, 79, 88].

As an alternative, the use of an external catheter (e.g., condom system) should be considered if clinically appropriate and practical.

Urinary catheters should not be used for the convenience of patient care. It should not be used for obtaining urine samples to perform diagnostic tests. Alternative methods include the use of external catheter (e.g., condom system) or intermittent catheterization.

#### **2.2 Methods of catheterization**

Catheterization could be external (condom system), or indwelling catheter (a) inserted either in a health care facility or (b) by the patients themselves (selfcatheterization). Indwelling catheters are also further classified as (i) short-term (a duration of catheterization intended to be less than or equal to 14 days) or (ii) longterm (when a person uses a urinary catheter for at least four weeks, that is, for 28 days or more or (iii) intermittent indwelling catheters. The selection of method of catheterization should be decided on a patient basis.

Intermittent catheterization is advocated as a method of choice for patients with idiopathic or neurogenic bladder dysfunction due to residual urine in the bladder. Patients often experience urinary frequency, urgency, incontinence, and repeated urine infections [89]. Intermittent catheterization lower the rates of CAUTI as compared to urethral and suprapubic catheterization [75]. Greater patient independence, reduced interference with sexual activity and reduced need for equipment and appliances are the advantages [90].

Suprapubic catheterization is indicated for post-pelvic or urological surgery with difficulty in voiding, urethral trauma, chronic prostatitis, and post-gynecological surgery. Suprapubic catheterization is associated with lower rates of bacteriuria, recatheterization, and urethral stricture [75].

#### **3. Understanding the contributory factors OF CAUTI**

The number of factors associated with the process of catheterization. With the available literature, individual factors are considered in the causation of urinary tract infections. Discussion of the variable factors could be studied as the material or the type of catheter used as input variable factors or the process of insertion to final removal as a process variable factor.

#### **3.1 Input variable factors**

Knowledge of different materials has accumulated in the field of material science, which has contributed to the development of a variety of catheters. These could be the use of different metals or antibiotic-incorporated catheters, which could prevent

bacterial growth or nonirritant materials, which could prevent damage of the urethral epithelium, thus preventing breach of the surface of the urethral epithelial layer and thereby help in the retention of the catheter for a longer duration of time. These factors finally help the clinician to have a choice of the catheter to be used in different situations. Similarly, the length and size of the catheter are important factors to be considered.

#### *3.1.1 Type of catheter*

EPIC guidelines advocated the use of silver-coated catheters to reduce infection rates. This was not addressed in the earlier CDC guideline. A Cochrane Review concluded that the use of silver alloy indwelling catheters reduced the risk of CAUTI [91]. They recommended economic evaluation to confirm the reduction of infection.

Meta-analysis showed silver alloy-coated catheters to be significantly more effective in preventing bacteriuria [91–103]. Antimicrobial-coated catheters preventing catheter-associated bacteriuria/funguria during short-term catheterization were reported consistently [104]. However, no study demonstrated any clinical benefit for the use of different types of catheters.

#### *3.1.2 Selection of a urinary catheter*

Urinary catheters are of various types, sizes, and are made up of different materials. Foley's catheter is the most common type used. The Foley's catheter may have two or three lumens each of them with a different function to perform; one for the inflation of the balloon, second one for urine drainage of urine, and third one for irrigation.

#### *3.1.3 Catheter size*

Catheter size is measured by the diameter of the outer circumference (range from 6Fr-24Fr - French (Fr) metric scale). The smallest gauge that meets the needs of the patient should be the one to be given the choice of selection. It minimizes urethral trauma, reflux bladder spasm, and the amount of residual urine collected in the bladder. All these are predisposing factors to CAUTI [105, 106]. Catheters are manufactured in different lengths. The manufacturer's instructions are applicable [107].

#### *3.1.4 Catheter material*

Catheter material should be selected based on the patient's assessment and the clinician's preference. Duration of catheterization, patient comfort, patient history of allergies to the components (such as latex allergy), ease of insertion and removal, and the ability of the catheter material to reduce the likelihood of complications should decide the type of catheter material selected [108].

Commonly polyvinyl chloride (PVC), hydrogel, latex, silicone catheters, or a combination of these materials are used. Either latex or silicone-based catheters are the standard ones. Latex catheters are strong, elastic, and flexible and are common catheter types used for short-term catheterization. Silicone catheters (synthetic catheters) replace latex catheters in patients with latex sensitivity. There is no significant

#### *Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

difference between the latex and silicone catheters and their contribution when it comes to the incidence of bacteriuria [85, 88, 109, 110]. For long-term use of catheters, evidence is insufficient to draw conclusions [111]. CDC advises the use of silicone catheters to reduce the risk of encrustation in long-term catheterized patients [75]. For intermittent catheterization, single-use catheters are preferred and are designed to be cleaned and reused. Manufacturers' instructions are to be followed strictly.

Antiseptic or antimicrobial-coated catheters are available with a variety of antimicrobial agents, such as gentamicin, [110] silver hydrogel, [93, 112] minocycline, rifampicin, [113] chlorhexidine-silver, sulfadiazine, chlorhexidine-sulfadiazine-triclosan, nitrofurazone, [113] and nitrofuroxone incorporated into the catheters [114]. Antiseptic or antimicrobial-coated catheters significantly prevent or delay the onset of CAUTI [110]. The poor quality of the studies makes decision-making difficult. Silver alloy catheters appear to be associated with a reduced incidence of bacteriuria [74, 115–119]. A Cochrane Review suggests the use of silver-alloy catheters used for less than one week [93]. The review also showed that antibiotic-impregnated catheters had lower rates of asymptomatic bacteriuria at less than one week of catheterization. When catheterization exceeded one week, the results were not statistically significant. Studies are needed to evaluate cost–benefit effectiveness of antiseptic and antimicrobial-coated catheters [77, 110].

#### **3.2 Process variables**

#### *3.2.1 Use of aseptic (standard) precautions during urinary catheterization*

To minimize the risk, HCWs are to be trained to perform catheterization and have to be assessed. Their competency in technical aspects and application of the principles of aseptic technique should be documented [74, 110, 120, 121].

Standard precautions "*must be applied by all HCWs for all patients at all times*." They are useful to contain transmissible microorganisms that may be present in blood and body fluids, excretions, and secretions (except sweat). Standard precautions "*must be applied by all HCWs for all patients at all times*" while performing close activities with patients, patients'surroundings, and handling and disposing clinical waste [122]. HCWs should wear sufficient personal protective equipment (PPE) to prevent skin or clothing contamination. Contaminated body fluids may contain pathogenic microorganisms which may get transferred either to themselves or other patients. While performing urinary catheter insertion, a disposable plastic apron, and sterile gloves will usually be sufficient [110, 122]. Disposable plastic aprons and gloves are single-use items that are to be worn and then discarded after each procedure [122]. Hands should be decontaminated before the procedure, after the procedure, and also after removing PPE [123].

#### *3.2.2 Aseptic technique*

During the insertion of indwelling and intermittent urinary catheters, HCWs must practice strict aseptic techniques and use sterile equipment as per the expert opinion, clinical guidance, and principles of best practice [124–128].

The aseptic technique refers to the practices that help to reduce the risk of post-procedure infections. This decreases the likelihood of microorganisms entering the body during clinical procedures. The aseptic technique reduces the risk of infection by preventing the transmission of microorganisms either directly or

indirectly. Wide variations in the practice of aseptic techniques have been found in different surveys. A standardized aseptic non-touch technique (ANTT)™ has been developed [129].

#### *3.2.3 Hand decontamination*

Hand hygiene is the single most important procedure. The World Health Organization (WHO) advocates five situations (moments) of hand hygiene performance: [129] (a) Before touching the patient, (b) before a clean or aseptic procedure, (c) after body fluid exposure risk, which also includes emptying a urinary catheter drainage system [125, 130], (d) after touching the patient's surroundings, and (e) after touching the patient. Except when an aseptic procedure is being performed, non-sterile singleuse gloves should be worn. Hands should be decontaminated before and after removing PPE [124, 125, 130].

#### *3.2.4 Patient preparation*

Patients should be provided with adequate information regarding the need for catheter insertion, catheter maintenance, and removal of the catheter by the caregiver. The patient should be given the opportunity to discuss the implications of the procedure [120].

#### *3.2.4.1 Skin/meatus cleaning and disinfection*

Patient preparation to prevent infection during catheterization depends on the method of catheterization, skin or meatus cleaning and disinfection. This process is also carried out for daily maintenance of the catheter.

#### *3.2.4.1.1 Meatus cleaning prior to catheterization*

As infection can get transmitted *via* the external surface of the catheter during catheter insertion especially when an indwelling or intermittent catheter is used. Here, the urethral meatus should be cleaned prior to catheterization [77], which involves the mechanical removal of exudate and smegma washing the meatus area with soap and water [128]. The use of antiseptic solution versus sterile saline wash prior to catheter insertion needs more evidence [64, 108, 131–134].

The standard practice of cleansing the urethral meatus is to retract the foreskin (where possible), cleaning the glans penis, and return the foreskin to normal position after insertion of the catheter. A front-to-back cleaning technique should be adopted after the labia minora are separated for women. After a thorough cleaning, the urethral opening should be washed and cleaned with sterile water or sterile saline solution. The area should be wiped dry using sterile swabs. The gauze ball or swab should be discarded after a single use. The same procedure is to be performed before selfintermittent catheterization.

#### *3.2.4.1.2 Suprapubic catheterization*

The skin over the insertion site should be washed with soap and water. Then, the site is dried thoroughly. Then, it is cleaned with an aqueous or alcohol-based surgical site disinfectant solution (e.g., chlorhexidine or povidone-iodine) as per local guidelines [135].

#### *3.2.5 Maintaining a sterile field*

Before each procedure, environmental surfaces should be effectively cleaned and disinfected as practiced for any other minor surgical procedure [136]. Maintaining the integrity of the sterile field is important. HCWs should use sterile gloves and a drape to create a sterile field [74]. Sterile catheter packs, which contain all needed materials should be used [110].

#### *3.2.6 Steps of catheterization*

Steps of catheterization start from the process of insertion till the catheter is removed. Since infection could occur at any step of catheterization, each of them are analyzed with the available scientific data.

#### *3.2.6.1 Catheter insertion*

The CDC guideline stresses that catheters should be inserted using sterile equipment and an aseptic technique [81]. The use of aseptic technique was not shown to reduce CAUTI in a systematic review, [137] and following principles of good practice, clinical guidance [81, 138], and expert opinion [119, 139–142]. However, the EPIC guidelines concluded that urinary catheters must be inserted aseptically [82].

In a study focused on the influence of sterile versus clean technique for catheter insertion found no statistical difference between the two groups, while there was a considerable cost difference [143]. The sterile method was found to be more than twice as expensive as the clean method. It was concluded that strict sterility was not necessary for preoperative short-term urethral catheterization.

#### *3.2.6.2 Insertion procedure*

#### *3.2.6.2.1 Indwelling urethral catheterization*

The entry point for microorganisms into the blood and lymphatic system was a bruise or trauma to the urethral mucosa that occurred during catheterization [144]. To minimize urethral trauma and infection, it is recommended to apply sterile lubricant or anesthetic gel from a single-use container [110]. Once the catheter is inserted, urine is allowed to drain and the balloon is inflated to secure the catheter in place. The indwelling catheter is then connected to a closed sterile drainage bag, which is placed below the level of the bladder to facilitate drainage.

Documentation of the patient information is recorded, which includes an indication for catheter insertion, date and time of catheter insertion, type and size of catheter, amount of water used to inflate the balloon, any complications encountered, review date and name of HCW who inserted catheter [145].

#### *3.2.6.2.2 Intermittent catheterization*

Intermittent catheterization is affected by the use of sterile or clean technique, coated or uncoated catheters, single (sterile) or multiple-use (clean) catheters, selfcatheterization or catheterization by others, or by any other strategy that need further clarification [89]. Many guidelines recommend an aseptic technique and sterile

equipment for intermittent catheterization in a healthcare setting. A clean technique is recommended for self-intermittent catheterization [75, 110, 145].

#### *3.2.6.2.3 Suprapubic catheterization*

Suprapubic catheter is commonly done in a theater by a urologist/surgeon, with all sterile precautions. Some catheters are secured to the abdominal wall by a suture. A small sterile dressing may be placed over the site, which can be removed after 24 hours.

#### *3.2.6.3 Catheter maintenance and dwell time*

The CDC guideline addresses adherence to a sterile closed system as the cornerstone of infection control. Irrigation should be avoided unless there is a need to prevent or relieve the obstruction [81]. The EPIC guidelines state that a sterile, continuously closed urinary drainage system is central to the prevention of CAUTI [121]. The use of a closed urinary drainage system is effective [126, 140, 141, 146–150].

The CDC guidelines [82] stress the need to avoid meatus care using povidone-iodine. The EPIC guidelines, based on expert opinion [81, 140, 141] and one systematic reviews [74] recommend against vigorous meatus cleansing. The EPIC guideline recommends daily routine bathing or showering to maintain meatus hygiene [82, 117]. In three earlier studies that investigated meatus care to prevent bacteriuria, little or no benefit was found other than standard personal hygiene in patients with indwelling catheters [151–153].

The literature review concluded that flushing catheters and daily perineum care do not prevent infection [147].

Only one study which examined different types of catheters showed that substances in the latex urinary catheter were toxic to *E. coli* [88].

There is a direct relationship between dwell time and incidence of infection [81, 149, 154–156]. Urinary tract catheterization of at least 3 days was sufficient to increase the risk of urinary tract infection [97]. Early removal is key to the prevention of UTI [77, 151, 157, 158]. Early removal is also associated with shorter hospital stays [91, 155].

#### *3.2.6.4 Catheter removal*

Neither the CDC nor the EPIC guidelines discuss catheter removal. Best strategies for the removal of catheters were reviewed through 26 trials involving a total of 2933 participants [155]. Inconclusive evidence of the benefit for midnight removal of indwelling catheters and the need for re-catheterization have been noted. There is only a little evidence for the effectiveness of catheter clamping [91].

#### **4. Management of urinary catheters**

Care of drainage system needs proper care for infection prevention. Care of urinary bag, catheter position, and handling of the wound are important in infection prevention.

#### **4.1 Drainage systems**

Urinary drainage is done through a catheter connected to a drainage tube, which opens into a drainage bag. In a closed system, the catheter is to be connected to the

#### *Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

drainage tube and that is not disturbed. Urine is emptied into the bag through a valve or a port that reduces the risk of ascending infection from intraluminal transmission. Irrespective of the drainage system, daily care is needed to prevent infection. Its effectiveness is dependent on good catheter hygiene [77, 82, 109, 136, 159, 160]. Closed system is the best method to manage the drainage system to prevent CAUTI [110, 117].

#### *4.1.1 Drainage bags*

Four main types of drainage bags are used with indwelling catheterization. A leg drainage bag with a drainage tap directly attached to the catheter, a drainage bag with a drainage tap secured to a catheter stand, a non-drainable bag with no drainage tap which is secured to a catheter stand (useful for overnight drainage), and a combined drainage bag and urinary catheter, which is pre-connected to the catheter during the manufacturing process.

#### *4.1.2 Management of catheterized patients*

For catheterized patients with spinal cord injury and patients admitted to longterm care facilities advocate reusing drainage bags after cleaning and disinfection is advocated (Best practice guidelines) [160, 161]. It does not increase the risk of CAUTI [161–163]. This practice is an unacceptable procedure since it does not provide a validated method for decontamination [164, 165]. This practice is not discussed in other evidence-based guidelines [74, 76, 77, 110, 117]. The recommendation is for the use of single-use drainage bags.

Sterile and non-sterile (i.e., clean) drainage bags are available in the market. A sterile bag is used for directly connecting the bag to the catheter which is accepted by evidence-based guidelines [74, 75, 83, 110, 162]. Non-sterile Catheters are used in some healthcare settings [165]. No studies comparing the CAUTI rate with sterile and non-sterile night drainage bags were available in the literature and require further studies. The use of pre-connected urinary catheters and drainage bags reduces the risk of CAUTI [166]. However, there is no conclusive data [75, 77, 166–168].

A good practice is to maintain the bag below the level of the bladder, [136, 169] minimize contamination of the drainage bag outlet port by avoiding contact with the floor or other surfaces, [136, 159] access the catheter drainage system only when absolutely necessary (e.g., changing the drainage bag as per the manufacturer's instructions), [80] empty the drainage bag regularly to prevent reflux and use a separate clean container for each patient and prevent the container touching the drainage tap when emptying the drainage bag [80, 98].

#### **4.2 Collecting catheter specimens of urine (CSU)**

A sampling port is made available for the collection of urine samples. The sampling port should be disinfected with an appropriate disinfectant (e.g., 70% alcohol) and allowed to dry fully before collecting the sample. Manufacturer's instructions should be followed. Single-step, needle-free urine collection containers that are suitable for laboratory use should be used to reduce HCW exposure to urine splash and needle stick injuries [170].

#### **4.3 Catheter valves**

A catheter valve is a device connected to the end of the catheter and its value is being evaluated. The catheter valve allows urine to be stored in the bladder and eliminates the need for a urine drainage bag. The valve is released at regular intervals to prevent over-distension of the bladder or dilation of the renal tract. The catheter valves may reduce the risk of CAUTI, [171–173] reduce bladder irritation [172] and maintain bladder tone and capacity. This helps to improve the rehabilitation process after catheter removal.

Evidence suggests that patients prefer to use the catheter valves [157]. But the use of a catheter valve is contraindicated in patients with limited bladder capacity, [174] reflux or renal impairment, [173] detrusor muscle instability, [165, 166] mental disorientation, [171] impaired bladder sensation, [171] poor manual dexterity [175], and immobility.

#### **4.4 Securing indwelling urethral catheters**

Use of adhesive, nonadhesive devices (e.g., elastic/Velcro® straps) to secure the urinary catheter to the leg, or abdomen is recommended (best practice guidelines and expert opinion) [75, 169, 175, 176]. By securing the catheters, trauma and bleeding are reduced, dislodgement is prevented and bladder spasms, which may result from pressure and traction are also prevented. These are seen as advantages [177, 178]. A systematic literature review [178] has shown no evidence suggestive of cathetersecuring system capable of preventing CAUTI. Though no statistically significant differences were found, the clinical significance of 45% reduction in the rate of symptomatic UTI was noted in patients who received the securing device [179].

It is recommended to place the securement device at the stiffest part of the catheter (usually just below the bifurcation where the balloon is inflated) to prevent occlusion of the lumen. The securement device can be placed on the abdomen or thigh [176]. To prevent skin trauma from excess traction, a regular assessment is necessary. In addition, adhesive material may result in skin irritation and dermatitis and elasticized / Velcro® straps should be used with caution, especially in patients with peripheral vascular disease [176, 180]. The skin site used for the securing device should be regularly changed.

#### **4.5 Suprapubic catheters**

The suprapubic catheter emerges at right angles to the abdomen. It needs to be secured in this position. Dressing and tapes should only be used on the healed insertion site when it is absolutely necessary.

#### **4.6 Meatus and insertion site care**

#### *4.6.1 Indwelling urethral catheters*

There is no advantage in using antiseptic preparations for meatus care over routine bathing or showering [136, 144, 181, 182]. Vigorous meatus cleansing beyond normal hygiene practice is not recommended. It may increase the risk of infection. Washing the meatus with soap and water during daily routine bathing or showering is all that is required. If this forms part of a bed bath, the water

#### *Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

should be changed and a clean cloth should be used [183]. Prevention of contamination of the entry site of the catheter during cleaning is important. For women adopting a front-to-back approach, washing toward the anus is to be practiced. For uncircumcised men, the foreskin should be retracted before the area underneath is cleaned. This is often a reservoir for bacteria, particularly in the elderly [169].

#### *4.6.2 Suprapubic catheter*

An aseptic technique with a suitable cleansing solution and a sterile dressing should be used for wound care until the insertion site is healed [145]. Once healed, the site should be washed daily with warm water and soap.

#### **4.7 Catheter irrigation**

There is no evidence to suggest routine irrigation of a urinary catheter. Using antiseptic or antimicrobial agents to decrease CAUTI has no place in the management [10, 121]. A closed continuous irrigation system should be used if irrigation is required for other reasons (e.g., post-surgery). An aseptic technique should be used for intermittent irrigation (e.g., flushing or installation of drugs).

#### *4.7.1 Catheter blockage*

Each patient should have an individualized care regimen designed to minimize the problems of blockage and encrustation. The recurrent blockage is due to the encrustation of the catheter from mineral salt deposits. It is a complication in approximately 50% of all long-term catheterized patients [184]. Catheter blockage causes leakage, bypassing of urine and urinary retention. This condition results in the increased number of catheter changes. Encrustation on the external surface can cause trauma to the urethra during catheter removal.

Catheter maintenance solutions (CMS) are acidic washout solutions. CMS is commonly used to prolong catheter life by reducing pH, which helps in the dissolution of existing encrustations [82]. Disruption of the closed system increases the risk of infection. Frequent blockage leads to frequent re-catheterization. Potential infection risks associated with CMS use are outweighed by increased catheter life and reduced patient discomfort [185]. HCWs should be alert for the signs and symptoms of autonomic dysreflexia in patients with spinal cord injuries. Autonomic dysreflexia is a lifethreatening condition.

#### **4.8 Catheter removal**

The risk of acquiring bacteriuria has been estimated at 5% for each day of catheterization, accumulating to 100% in 4 weeks. The longer the catheter remains *in situ*, higher is the risk of infection [133]. Catheterization should be reviewed daily and removed as soon as possible [75, 121, 182]. Clamping urinary catheters prior to removal is not to be followed [75].

#### *4.8.1 Strategies for limiting the duration of short-term catheters*

Success strategy in limiting catheter use and duration of catheterization is achieved by implementing procedure-specific guidelines for postoperative catheter removal, and providing reminders to physicians to review and limit the duration of catheterization [186–190]. Providing guidelines to manage postoperative retention may include the use of bladder scanners [187]. Care plans/protocols directing nurses to remove catheters need to be developed [187, 189, 191].

The effectiveness of reminder systems has helped in reducing CAUTI and urinary catheter use. Rate of re-catheterization was reduced by 52% following the use of reminder or stop orders. Duration of catheterization decreased by 37% and re-catheterization rates were similar in control and intervention groups, respectively [192].

#### *4.8.2 Changing long-term catheters*

Long-term catheterization is defined as a catheter *in situ* for greater than 28 days. No consensus exists on how frequently such catheters need to be changed. Manufacturer's instructions should be followed in addition to individual patient's requirements (e.g., before blockage occurs or is likely to occur) [76].

#### *4.8.3 CAUTI preventive care bundles*

Care bundles are useful in identifying the cause of CAUTI in each patient due to a breach in the process of catheter care. It analyses the clinical, laboratory, bacteriological, and radiological data and through root cause analysis (RCA) suggest corrective and preventive actions (CAPA) needed to prevent CAUTI infection. It follows the surveillance activity.

"A care bundle is a group of evidence-based practices that improve the quality of care." Care bundles have been developed for a range of conditions and disease processes [193–196]. Implementation of care bundles is helpful in improving the care of all patients in both multidisciplinary teams and individual wards/units. The decrease is significant when adjusted for device utilization [197].

Compliance with a care bundle for an individual patient is measured as either 100% or 0%. To achieve 100%, all of the evidence-based components of the bundle must be implemented. If one of the components of the care bundle is not in place, a score of zero is allocated. The ward or team score is calculated as the percentage of all patients with a urinary catheter that achieved 100% compliance with the care bundle.

#### **4.9 Antimicrobial prophylaxis**

There is no role for routine antimicrobial prophylaxis. Prophylaxis after the change or instrumentation of urinary catheters (both short and long-term) is not indicated. Despite a lack of evidence, the use of prophylactic antimicrobial (aminoglycosides are commonly used). This has resulted in overuse and increased resistance to antibiotics. The benefits of antimicrobial prophylaxis must be balanced against possible adverse effects like selection pressure for the development of antibiotic-resistant bacteria. C. difficile infection and antimicrobial toxicity are the other two effects

of prophylactic overuse. Risk–benefit analysis cannot be reliably estimated. The effectiveness of prophylactic antimicrobials at the time of urinary catheter insertion, change, or removal is variable. There is a specific need for guidelines to be established [198].

All reviews showed limited evidence for the use of prophylactic antibiotics for both short-term and long-term catheters [155, 199]. Majority of best practice guidelines do not recommend the use of prophylactic antimicrobials before the removal of catheters. A comprehensive review also did not show any conclusion [200]. There is also little data regarding the patient with a previous episode of septicemia associated with catheter manipulations. The use of short-term catheterization to prevent bacteriuria appear to be a better strategy than the use of antimicrobials.

The asymptomatic bacteremia rate is approximately 10% per catheter change. It is unwise to recommend the use of prophylactic antimicrobials for long-term catheterized patients [200, 201]. Recently published guidelines from the US do not recommend the routine use of systemic antimicrobials at the time of catheter placement, removal, or replacement. According to CDC, unless clinical indications exist (e.g., in patients with bacteriuria upon catheter removal post-urologic surgery), routine use of systemic antimicrobials is not required.

UK National Institute for Health and Clinical Excellence (NICE) guidelines on antimicrobial prophylaxis against infective endocarditis also does not support the use of antibiotic prophylaxis to prevent endocarditis in patients undergoing urological procedures, including catheterization [202]. The British Society for Antimicrobial Chemotherapy state that the risk of bacteremia increases in presence of bacteriuria. Hence, treatment is recommended for pre-procedures [203]. US guidelines on the prevention of infective endocarditis, state that no published data is available to demonstrate a conclusive link between procedures of the gastrointestinal or genitourinary tract to be related to the development of endocarditis [204].

Prophylactic use of antimicrobials has no relation to change or instrumentation of urinary catheters (both short and long-term). In patients with bacteriuria, high risk of endocarditis or significantly immune compromised (e.g., patients with neutropenia, hematological malignancy, post solid organ transplantation), definitive randomizedcontrolled trials are needed.

#### **5. Surveillance for CAUTI**

Surveillance is "the ongoing systematic collection, analysis, and interpretation of data and the timely dissemination of the data to those who need to know to prevent and control infection" [205]. Prevalence studies are used to do surveillance of CAUTI [206–208]. Prospective CAUTI surveillance is useful for high-risk groups: (e.g., patients admitted to intensive care surgical or obstetric units) [10]. Rates of CAUTI range from 3.3 to 17.4/1000 catheter days among ICU patients [209–212]. Much lower infection rates (1.24–2.26/1000 catheter days) are reported in long-term care institutions [213]. Including CAUTI as part of the hospital's regular surveillance program should be considered by all hospitals depending on the risk profile of their patients and available resources. CAUTI rate should be reported as the number of CAUTI per 1000 urinary catheter days.

#### **5.1 CAUTI definition for surveillance**

The CDC or the HELICS definitions are most commonly used for HCAI surveillance [214, 215]. HELICS definition of urinary tract infection is specifically designed for use in intensive care units only. CDC definitions are to be used in acute facilities. CAUTI surveillance should only include symptomatic CAUTI, as the prevalence of asymptomatic bacteriuria is high among elderly care residents [216].

#### **5.2 Forms and protocol for data collection**

Data collectors should be trained in the definitions, surveillance, and protocols to be utilized. An example of data collection forms for CAUTI surveillance needs to be standardized and used.

**Calculation of the denominator**: Denominator value data is collected in this form. This is a daily count of all the urinary catheters in the area/patient group under surveillance. The number of patients with urinary catheter device *in situ* is known as urinary catheter days. Data should be collected at a specified time each day.

**Calculation of the numerator:** The numerator data is collected in this form. It represents the number of patients with CAUTI. This form is used to collect and report each suspected or confirmed CAUTI in the area/patient group under surveillance. Additional information that is to be collected includes patient demographics, signs and symptoms of infection, laboratory results if applicable and the presence or absence of a urinary catheter.

The CAUTI rate per 1000 catheter days is calculated by using the following formula:

No of CAUTIs No*:* of U*:* Catheter days ðdenominatorÞ � 1000

Example: Calculation of CAUTI rate per 1000 catheter days.


144 = denominator data (number of catheter days in the month of January in the ICU).

3.The CAUTI rate for the month of January in the ICU (per 1000 urinary catheter days) is thus:

$$\frac{1 \ge 1000}{144} = 6.9 \text{ CAUTIs} / 1000 \text{ catheter days}$$

CAUTI surveillance should be a part of routine hospital surveillance.

#### **5.3 Surveillance result feedback**

Regular CAUTI rate feedback to the relevant area(s) of the healthcare facility is very important along with any comments or suggestions for improvement. Ideally, it is monthly or at least once in a quarter. Feedback helps the healthcare facility to monitor the trends, identify outbreaks, and in addition to monitor the effectiveness of preventative programs.

#### **6. Clinical presentation**

Clinically, CAUTI presents with fever, new-onset confusion, loin, or suprapubic pain. Fever, though the most common symptom, absence of fever does not rule out infection. The Scottish Intercollegiate Guidelines Network (SIGN) recommends follow-up of catheterized patients with fever to be looked for associated localizing loin or suprapubic tenderness or systemic features, exclude other sources of infection, send an appropriate sample of urine for culture, consider empiric antimicrobial therapy as required by clinical presentation and severity and existing comorbid factors if any. Local antimicrobial susceptibility patterns and antimicrobial prescribing guidelines should be the guide for the suggestion of empirical treatment [56–58].

#### **7. Laboratory findings**

Bacteria in urine (bacteriuria) signifies either colonization (asymptomatic bacteriuria) or infection. Bacteriuria is detected in both catheterized and non-catheterized patients. An un-centrifuged sample of urine shows plenty of WBCs with motile or nonmotile bacteria on microscopic examination of urine. It is significant to note that in patients with catheter *in situ* greater than 30 days, 10–30% will develop bacteriuria compared to 1% of non-catheterized patients [53, 54]. More than 90% of catheterassociated bacteriuria are cases of colonization rather than infection [55]. Definitive diagnosis of CAUTI is not evidence-based [56]. Laboratory criteria for differentiating between CAUTI and asymptomatic bacteriuria have not been established. The use of molecular techniques for not only diagnosis of CAUTI but also for antibiotic sensitivity for treatment may become important in the present scenario. Multiplexed RTPCR probes can be prepared and would be used in these situations. LAMP is another technology that is useful. Pathogenic bacteria can be tested for virulence using specific PCR probes and by surface active proteins known as adhesion proteins [72, 73].

A UTI can be tested by routine urine examination for the presence of bacteria, and inflammatory cells. This could be followed by culture and sensitivity for testing their sensitivity to different antimicrobials. With modern tools, phenotypic and genotypic expressions could be analyzed. Same time secondary bloodstream infections with the same organism detected in the urine could be noted. Their phenotypic and genotypic expression would give the possibility of selection for antibiotic sensitivity or secondary infection with a hospital-acquired organism could be identified. Molecular tools could be helpful in HAI surveillance of CAUTI.

#### **8. Health education and training of HCWs**

All HCWs and caregivers require education regarding the insertion and the removal of urinary catheter to prevent infection in the hospital setup. This is a continuous process and should be conducted at regular intervals. A similar education regarding the urinary catheter is to be given to the relatives and patient carers regarding the need for catheterization, catheter maintenance, chance of patient developing CAUTI, and importance of catheter care and how long the patient needs catheterization. They also need to be trained in meatus care with bathing, use of soap and water, and aseptic procedures used. This is not only an education to maintain the catheter in home care, intermittent and self-catheterization but also to induce confidence among the care givers.

#### **8.1 Education for healthcare workers**

A number of studies have demonstrated staff education programs can reduce HCAI [217, 218]. Best practice guidelines recommend staff education as a key factor in preventing CAUTI [10, 75, 110, 117, 181]. Education is a continuous process. It is to be done compulsorily at the time of induction of new staff. It should also become a regular education for HCWs. An induction education program should provide information regarding indications for catheterization, safe insertion technique, catheter maintenance, catheter removal, obtaining a urine specimen, and signs and symptoms of urinary infection. Attendance records of education sessions should be maintained.

The retraining education program should include technical topics, such as indications for catheterization, management of catheters, and removal of catheters, when no longer required. Some deficits in the knowledge and practice of HCWs have been identified.

The deficits in knowledge form the need for the next training. Some of the training needs identified include inappropriate use of a drainage tap to collect urine samples, [219] inappropriate use of lubricants for insertion, [220] daily changing of catheter bags [220], and poor documentation of the process [82, 221].

#### **8.2 Education for patients/relatives/carers**

Appropriate education of patients, relatives, and carers should focus on the management of urinary catheters, so that they can take part during home care [10, 75, 110, 119]. They should be trained for intermittent catheterization, insertion technique, and care of reusable catheters where appropriate. Support should be available for the entire duration of the catheterization [83].

Well-designed and appropriately written patient educational materials can augment other educational efforts, which ultimately improve patient care [222, 223]. These patient information leaflets should have a description of catheter care, emptying the catheter bag, when the catheter and catheter bag requires to be changed, signs and symptoms of complications (e.g., infection, leakage, and blockage), and whom to contact should complications develop.

#### **9. CAUTI prevention**

Numerous guidelines to prevent CAUTI highlight the importance of educational measures for all healthcare professionals [51]. Hand hygiene is the most important

preventive step. If a patient is found to be colonized or infected, contact precautions along with a good environmental cleaning to avoid the Multi-Drug Resistant (MDR) organism transmission should be emphasized.

Unnecessary catheter insertion should not be encouraged. Reducing the period of catheterization is a relevant prevention strategy [78].

In a prospective study, initial indication was judged to be inappropriate in 21%, and continued catheterization was judged to be inappropriate for almost one-half of catheter days [80]. Surveillance is important [224]. A nationwide study showed 56% of hospitals were not having a system for monitoring and 74% did not monitor the duration of catheterization. A French prospective interventional study showed a reduction in CAUTI from 10.6 to 1.1 episodes per 100 patients when nurses and physicians were reminded daily to remove unnecessary urinary catheters four days after insertion [154]. It also decreased the incidence of CAUTI from 12.3 to 1.8 per 1000 catheter days. Alternative prevention strategies (use of antimicrobial-coated catheters, catheter irrigation with antimicrobials, antimicrobials in the drainage bag, or prophylaxis with cranberry products) can also be considered but they need more studies. In conclusion, simple practices, such as hand hygiene, limited and judicious use of catheters, and the use of some preventive additive procedures, can prevent CAUTI.

#### **10. Treatment**

Treatment of asymptomatic bacteriuria is needed only in pregnant women, before transurethral resection of the prostate or any traumatic genitourinary procedures associated with mucosal bleeding, in immunosuppressed patients, or after the first year of renal transplantation [225]. Treating nonpregnant women is to be considered if there is asymptomatic bacteriuria in the first 48 hours after urinary catheterization. In other cases, antibiotics only eliminate bacteriuria transitorily. Antibiotic administration neither decreases the frequency of symptomatic infection nor prevents further episodes of asymptomatic bacteriuria. Drug pressure could select MDR microorganisms.

Symptomatic bacteriuria needs withdrawal or replacement of the urinary catheter before initiating antibiotics [226]. To choose an empirical treatment, underlying conditions and the local epidemiology should be considered (risk of MDR). Carbapenems should be used in patients with high-risk Multi-Drug Resistant empirical treatment. It is important not to recommend or administer empirical antimicrobial treatment where antibiotics have more than 20% of resistant strains for noncomplicated UTIs or 10% for complicated ones (Ex.: Quinolones). Treatment must be adjusted once an antimicrobial susceptibility report is available. Other antimicrobial agents are used in accordance with the aetiological agent involved (yeasts or other bacterial species). Fluconazole is the first-line antifungal agent recommended. Amphotericin B is to be used only when fluconazole resistance is suspected. The optimal treatment duration has been classically 14 days, but this can be shortened up to 5 days if there is an adequate clinical response. Follow-up urine cultures are not needed except if there is no clinical improvement 72 hours after the treatment is started.

MDR microorganisms have emerged as a potential threat to infection control. Piperacillin/tazobactam is not recommended in monotherapy as empirical treatment of CAUTI if Multi-Drug Resistant microorganism is suspected. Carbapenems can be used in monotherapy although higher dose regimens have

fosfomycin [227]. Carbapenems with β-lactams/β-lactamase inhibitor combinations (BLBIC) for treatment of bacteremia due to ESBL infections. *E. coli* had no significant differences in urinary bacteremia or mortality when carbapenems with BLBIC was administered as definitive or empirical treatment. For the treatment of carbapenemases (CBP) Enterobacteriaceae; [228] *Klebsiella pneumonia*, combination therapy with at least two drugs displaying *in vitro* activity against the isolate is recommended. Combinations that included meropenem were associated with significantly higher survival rates when the meropenem MIC was ≤8 mg/L. Thus, for the treatment of UTI caused by MDR microorganisms, either monotherapy or bi-therapy should be decided considering the severity of infection, severity of underlying conditions, MIC values, and clinical response. Monotherapy can safely be used when no severity of signs is present. Quinolones and cotrimoxazole can be used safely as a definitive treatment only if MIC is optimal. New drugs like ceftazidime/avibactam and ceftolozane/tazobactam need further studies.

#### **11. Conclusion**

The chapter analyzes various aspects from causation to prevention and treatment of CAUTI with detailed literature for each factor involved. It addresses the various views of different researchers on each of the subtopic of catheterization keeping the cost factor also.

The final conclusion is that catheterization is inevitable but used only when it is needed. While using an appropriate method of catheterization, appropriate catheter, simple procedures of asepsis, and keeping it *in situ* only till the period that is needed are to be kept in mind. If an intermittent catheterization is needed, it should be accepted as the procedure that is needed for that particular patient (patientcentric). To keep patient care as an important priority, the HAI surveillance program is to be adopted by the hospital and carried out regularly and reviewed periodically. Appropriate corrective measures are required to prevent HAI in general and CAUTI in particular.

#### **Acknowledgements**

The author wishes to thank the Management of PESIMSR, Kuppam, Andhra Pradesh. India for their support and encouragement to bring out this chapter. The author is also thankful to Dr. Guru Vijay Kumar, Senior Resident, Community Medicine department, PESIMSR, Kuppam, AP for helping in editing the manuscript.

#### **Conflict of interest**

There is no conflict of interest in bringing out this chapter.

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

#### **Author details**

Chandrasekhar Nagaraj Department of Microbiology, PESIMSR, Kuppam, Andhra Pradesh, India

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

© 2023 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.

#### **References**

[1] Stamm WE, Norrby SR. Urinary tract infections: Disease panorama and challenges. The Journal of Infectious Diseases. 2001;**183**(Suppl. 1):S1-S4 11171002]

[2] Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2007. Vital and Health Statistics. 2011;**13**:1-38

[3] Foxman B. Urinary tract infection syndromes: Occurrence, recurrence, bacteriology, risk factors, and disease burden. Infectious Disease Clinics of North America. 2014;**28**:1-13

[4] Foxman B. The epidemiology of urinary tract infection. Nature Reviews. Urology. 2010;**7**:653-660

[5] Hooton TM. Uncomplicated urinary tract infection. New England Journal of Medicine. 2012;**366**:1028-1037

[6] Nielubowicz GR, Mobley HL. Host– pathogen interactions in urinary tract infection. Nature Reviews. Urology. 2010;**7**:430-441

[7] Hannan TJ et al. Host–pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiology Reviews. 2012;**36**:616-648

[8] Lichtenberger P, Hooton TM. Complicated urinary tract infections. Current Infectious Disease Reports 2008; 10:499–504 18945392]

[9] Levison ME, Kaye D. Treatment of complicated urinary tract infections with an emphasis on drug-resistant gramnegative uropathogens. Current Infectious Disease Reports. 2013;**15**: 109-115

[10] Lo E et al. Strategies to prevent catheter-associated urinary tract infections in acute care hospitals: 2014 update. Infection Control and Hospital Epidemiology. 2014;**35**:464-479

[11] Flores-Mireles AL et al. Urinary tract infections: Epidemiology, mechanisms of infection and treatment options. Nature Reviews. Microbiology. 2015;**13**(5): 269-284

[12] Kline KA, Schwartz DJ, Lewis WG, Hultgren SJ, Lewis AL. Immune activation and suppression by group B Streptococcus in a murine model of urinary tract infection. Infection and Immunity. 2011;**79**:3588-3595

[13] Ronald A. The etiology of urinary tract infection: Traditional and emerging pathogens. The American Journal of Medicine. 2002;**113**(Suppl. 1A):14S-19S

[14] Fisher JF, Kavanagh K, Sobel JD, Kauffman CA, Newman C. A Candida urinary tract infection: Pathogenesis. Clinical Infectious Diseases. 2011;**52** (Suppl. 6):S437-S451

[15] Chen YH, Ko WC, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opinion on Pharmacotherapy. 2013;**14**:587-596

[16] Jacobsen SM, Stickler DJ, Mobley HL, Shirtliff ME. Complicated catheter-associated urinary tract infections due to Escherichia coli and Proteus mirabilis. Clinical Microbiology Reviews. 2008;**21**:26-59

[17] Collins AS. Preventing health careassociated infections. In: Hughes RG, editor. Patient Safety and Quality: An

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

Evidence-Based Handbook for Nurses. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008

[18] Revelas A. Healthcare - associated infections: A public health problem. Nigerian Medical Journal. 2012;**53**(2): 59-64

[19] Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients: Results of the Harvard medical practice study I. The New England Journal of Medicine. 1991;**324**(6):370-376

[20] Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients: Results from the Harvard medical practice study II. The New England Journal of Medicine. 1991; **324**(6):377-384

[21] Garrouste-Orgeas M, Philippart F, Bruel C, Max A, Lau N, Misset B. Overview of medical errors and adverse events. Annals of Intensive Care. 2012; **2**(1):2

[22] Parameswaran Nair N, Chalmers L, Peterson GM, Bereznicki BJ, Castelino RL, Bereznicki LR. Hospitalization in older patients due to adverse drug reactions –the need for a prediction tool. Clinical Interventions in Aging. 2016;**11**:497-505

[23] Desikan R, Krauss MJ, Dunagan WC, et al. Reporting of adverse drug events: examination of a hospital incident reporting system. In: Henriksen K, Battles JB, Marks ES, et al., editors. Advances in Patient Safety: From Research to Implementation (Volume 1: Research Findings). Rockville (MD): Agency for Healthcare Research and Quality (US); 2005

[24] Klevens RM, Edwards JR, Richards CL Jr, Horan TC, Gaynes RP,

Pollock DA, et al. Estimating health careassociated infections and deaths in U.S. hospitals, 2002. Public Health Reports. 2007;**122**:160-166

[25] Agency for Healthcare Research and Quality [webpage on the Internet] Patient safety primers: Healthcareassociated infections. 2012

[26] Danasekaran R, Mani G, Annadurai K. Prevention of healthcareassociated infections: Protecting patients, saving lives. International Journal of Community Medical Public Health. 2014;**1**(1):67-68

[27] World Alliance for Patient Safety [webpage on the Internet] The Global Patient Safety Challenge 2005–2006 "Clean Care is Safer Care.". Geneva: WHO; 2005

[28] Vincent J-L. Nosocomial infections in adult intensive-care units. Lancet. 2003;**361**(9374):2068-2077

[29] Nuvials X, Palomar M, Alvarez-Lerma F, et al. Health-care associated infections. Patient characteristics and influence on the clinical outcome of patients admitted to ICU. Intensive Care Medical Experiment. 2015;**3**(Suppl. 1):A82

[30] Johnson NB, Hayes LD, Brown K, Hoo EC, Ethier KA. Centres for Disease Control and Prevention (CDC). CDC National Health Report: Leading causes of morbidity and mortality and associated behavioral risk and protective factors-United States, 2005-2013. MMWR Suppl.ements. 2014;**63**(4):3-27

[31] McDermid RC, Stelfox HT, Bagshaw SM. Frailty in the critically ill: A novel concept. Critical Care. 2011; **15**(1):301

[32] Chernow B. Variables affecting outcome in critically ill patients. Chest. 1999;**115**(Suppl. 5):S71-S76

[33] Noakes TD, Borresen J, Hew-Butler T, Lambert MI, Jordaan E. Semmelweis and the aetiology of puerperal sepsis 160 years on: An historical review. Epidemiology and Infection. 2008; **136**(1):1-9

[34] Sydnor ERM, Perl TM. Hospital epidemiology and Infection Control in acute-care settings. Clinical Microbiology Reviews. 2011;**24**(1): 141-173

[35] In: The 2021 National and State HAI Progress Report. https://www. cdc.gov/hai/data/portal/progress-report. html

[36] Guide to the SIR Updated April 2022 (In: The NHSN Standard Infection Ratio (SIR) – CDC), pp 1–50

[37] A Guide to the SUR Updated April 2022 (In: The NHSN Standard Utilization Ratio (SUR) – CDC), pp 1-28

[38] Chenoweth CE, Gould CV, Saint S. Diagnosis, management, and prevention of catheter-associated urinary tract infections. Infectious Disease Clinics of North America. 2014;**28**:105-119

[39] Al-Tafiq JA, Tambyah PA. Healthcare associated infections (HAI) perspectives. Journal of Infection and Public Health. 2014;**7**:339-344

[40] Obaid NA. Preventive measures and Management of Catheter-Associated Urinary Tract Infection in adult Intensive Care Units in Saudi Arabia. Journal of Epidemiology Global Health. 2021;**11**:164-168

[41] Rosenthal VD. Device-associated nosocomial infections in 55 intensive care units of 8 developing countries. Annals of Internal Medicine. 2006;**145**: 582-591

[42] Storme O, Tiran Saucedo J, Garcia-Mora A, Dehesa-Davila M, Naber KG. Risk factors and predisposing conditions for urinary tract infection. Therapeutic Advances in Urology. 2019;**11**:19-28

[43] Guneysel O, Onur O, Erdede M, Denizbasi A. Trimethoprim / sulfamethoxazole resistance in urinary tract infections. The Journal of Emergency Medicine. 2009;**36**:338-341

[44] Bagchi I, Jaitly NK, Thombare V. Microbiological evaluation of catheter associated urinary tract infection in a tertiary care hospital. People's Journal of Scientific Research. 2015;**8**:23-29

[45] Zahran F. Catheter associated Urinary tract Infection (Cauti) in MedicalWard, and Icu Kfhh during year 2017. International Journal of Advanced Research. 2018;**6**:997-1011

[46] Dalen DM, Zvonar RK, Jessamine PG. An evaluation of the management of asymptomatic catheterassociated bacteriuria and candiduria at the Ottawa Hospital. Canadian Journal of Infectious Diseases Medical Microbiology. 2005;**16**:166-170

[47] Martin CM, Bookrajian EN. Bacteruria prevention after indwelling urinary catheterization. Archives of Internal Medicine. 1962:703-711

[48] Saint S. Clinical and economic consequences of nosocomial catheter related bacteriuria. Journal of Infectious Control. 2000;**28**:68-75

[49] Paget G, Naicker S, Perovic O. Guidelines for the management of nosocomial urinary tract infections. The South Africa Journal of Epidemiological Infection. 2005;**20**(2):58-60

[50] Saint S, Chenoweth CE. Biofilms and catheter-associated urinary tract

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

infections. Infectious Disease Clinics of North America. 2003;**17**(2):411-432

[51] Saint S, Wiese J, Amory JK, Bernstein ML, Patel UD, Zemencuk JK, et al. Are physicians aware of which of their patients have indwelling urinary catheters? The American Journal of Medicine. 2000;**109**(6):476-480

[52] Humphreys H, Newcombe RG, Enstone J, Smyth ET, McIlvenny G, Fitzpatrick F, et al. Four country healthcare associated infection prevalence survey 2006: Risk factor analysis. The Journal of Hospital Infection. 2008;**69**(3):249-257

[53] Garibaldi RA, Burke JP, Dickman ML, Smith CB. Factors predisposing to bacteriuria during indwelling urethral catheterization. The New England Journal of Medicine. 1974; **291**(5):215-219

[54] Haley RW, Hooton TM, Culver DH, Stanley RC, Emori TG, Hardison CD, et al. Nosocomial infections in U.S. hospitals, 1975-1976: Estimated frequency by selected characteristics of patients. The American Journal of Medicine. 1981; **70**(4):947-959

[55] Tambyah PA, Maki DG. Catheterassociated urinary tract infection is rarely symptomatic: A prospective study of 1,497 catheterized patients. Archives of Internal Medicine. 2000;**160**(5): 678-682

[56] Scottish Intercollegiate Guideline Network. Management of Suspected Bacterial Urinary Tract Infection in Adults. A National Clinical Guideline; Edinburgh: SIGN; 2006

[57] Elvy J, Colville A. Catheterassociated urinary tract infection: What is it, what causes it and how can we

prevent it? Journal of Infection Prevention. 2009;**10**(2):36-41

[58] Maki DG, Tambyah PA. Engineering out the risk for infection with urinary catheters. Emerging Infectious Diseases. 2001;**7**(2):342-347

[59] Tissot E, Limat S, Cornette C, Capellier G. Risk factors for catheterassociated bacteriuria in a medical intensive care unit. European Journal of Clinical Microbiology & Infectious Diseases. 2001;**20**(4):260-262

[60] Tambyah PA, Halvorson KT, Maki DG. A prospective study of pathogenesis of catheter-associated urinary tract infections. Mayo Clinic Proceedings. 1999;**74**(2):131-136

[61] Platt R, Polk BF, Murdock B, Rosner B. Risk factors for nosocomial urinary tract infection. American Journal of Epidemiology. 1986;**124**(6):977-985

[62] Shapiro M, Simchen E, Izraeli S, Sacks TG. A multivariate analysis of risk factors for acquiring bacteriuria in patients with indwelling urinary catheters for longer than 24 hours. Infection Control. 1984;**5**(11):525-532

[63] Coello R, Charlett A, Ward V, Wilson J, Pearson A, Sedgwick J, et al. Device-related sources of bacteraemia in English hospitals–opportunities for the prevention of hospital-acquired bacteraemia. Journal of Hospital Infection. 2003 Jan;**53**(1):46-57

[64] Holroyd-Leduc JM, Sen S, Bertenthal D, Sands LP, Palmer RM, Kresevic DM, et al. The relationship of indwelling urinary catheters to death, length of hospital stay, functional decline, and nursing home admission in hospitalized older medical patients. Journal of the American Geriatrics Society. 2007 Feb;**55**(2):227-233

[65] Ovbiagele B, Hills N, Saver J, Claiborne JS. Frequency of determinates of pneumonia and Urinary tract Infection. Journal of Stroke and Cerebrovascular Diseases. 2006;**15**(5): 209-213

[66] Oza A, Cunney R. Enhanced bacteraemia surveillance in Ireland 2004 and 2005. Epi-Insight 7. 2006

[67] Andreu A, Cacho J, Coira A, Lepe JA. Microbiological diagnosis of urinary tract infections. Enfermedades Infecciosas y Microbiología Clínica. 2011;**29**:52-57

[68] Horcajada JP, Shaw E, Padilla B, Pintado V, Calbo E, Benito N, et al. Healthcare-associated, communityacquired and hospital-acquired bacteraemic urinary tract infections in hospitalized patients: A prospective multicentre cohort study in the era of antimicrobial resistance. Clinical Microbiology and Infection. 2013;**19**: 962-968

[69] Nicolle LE. The chronic indwelling catheter and urinary infection in longterm-care facility residents. Infection Control and Hospital Epidemiology. 2001 May;**22**(5):316-321

[70] Nguyen-Van-Tam SE, Nguyen-Van-Tam JS, Myint S, Pearson JC. Risk factors for hospital-acquired urinary tract infection in a large English teaching hospital: A case-control study. Infection. 1999 May;**27**(3):192-197

[71] Graves N, Tong E, Morton AP, Halton K, Curtis M, Lairson D, et al. Factors associated with health careacquired urinary tract infection. American Journal of Infection Control. 2007;**35**(6):387-392

[72] Govindarajan DK, Kandaswamy K. Virulence factors of uropathogens and

their role in host pathogen interactions. The Cell Surface. 2022;**8**:1-12

[73] Rezatofighi SE, Mirzarazi M. Virulence genes and phylogenetic groups of uropathogenic *Escherichia coli* isolates from patients with urinary tract infection and uninfected control subjects: a case control study. BMC Infectious Diseases. 2021;**21**:1-11

[74] Saint S, Lipsky B. Preventing catheter-related bacteriuria: Should we? Can we? How? Archives of Internal Medicine. 1999;**159**(8):800-808

[75] Gould CV, Umscheid CA, Agarwai RK, Kuntz G, Pesueo DA. Guideline for Prevention of Catheter Associated Urinary Tract Infections. 2010;**31**: 319-326

[76] Tenke P, Kovacs B, Bjerldund-Johansen T, Matsumoto T, Tambyah P, Naber K. European and Asian guidelines on management and prevention of catheter-associated urinary tract infections. International Journal of Antimicrobial Agents. 2007;**31**(S1):68-78

[77] Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, 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. 2010;**50**(5):625-663

[78] Gokula RR, Hickner JA, Smith MA. Inappropriate use of urinary catheters in elderly patients at a Midwestern community teaching hospital. American Journal of Infection Control. 2004;**32**(4): 196-199

[79] Jain P, Parada JP, David A, Smith LG. Overuse of the indwelling *Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

urinary tract catheter in hospitalized medical patients. Archives of Internal Medicine. 1995;**155**(13):1425-1429

[80] Munasinghe RL, Yazdani H, Siddique M, Hafeez W. Appropriateness of use of indwelling urinary catheters in patients admitted to the medical service. Infection Control and Hospital Epidemiology. 2001;**22**(10):647-649

[81] Wong ES. Guideline for prevention of catheter-associated urinary tract infections. American Journal of Infection Control. 1983;**11**(1):28-36

[82] Pratt RJ et al. Epic 2: National evidence-based guidelines for preventing healthcare associated infections in NHS hospitals in England. The Journal of Hospital Infection. 2007;**6** (Suppl. 1):S1-S64

[83] Pellowe CM, Pratt RJ, Harper P, Loveday HP, Robinson N, Jones SR, et al. Evidence-based guidelines for preventing healthcare-associated infections in primary and community care in England. The Journal of Hospital Infection. 2003;**55**(Suppl. 2):S2-S127

[84] Matlow AG, Wray RD, Cox PH. Nosocomial urinary tract infections in a paediatric intensive care unit: A followup after 10 years. Pediatric Critical Care Medicine. 2003;**4**(1):74-77

[85] Talja M, Korpela A, Jarvi K. Comparison of urethral reaction to full silicone, hydrogen-coated and siliconised latex catheters. British Journal of Urology. 1990;**66**(6):652-657

[86] Robertson GS, Everitt N, Burton PR, Flynn JT. Effect of catheter material on the incidence of urethral strictures. British Journal of Urology. 1991;**68**(6): 612-617

[87] Saint S, Kaufman SR, Rogers MA, Baker PD, Boyko EJ, Lipsky BA. Risk

factors for nosocomial urinary tract related bacteremia: A case-control study. American Journal of Infection Control. 2006;**34**(7):401-407

[88] Lopez-Lopez G, Pascual A, Martinez-Martinez L, Perea EJ. Effect of siliconized latex urinary catheter on bacterial adherence and human neutrophil activity. Diagnostic Microbiology and Infectious Disease. 1991;**14**(1):1-6

[89] Moore KN, Fader M, Getliffe K. Long-term bladder management by intermittent catheterization in adults and children. Cochrane Database of Systematic Reviews. 2007;**4**:CD006008

[90] Chai T, Chung AK, Belville WD, Faerber GJ. Compliance and complications of clean intermittent catheterization in the spinal cord injured patient. Paraplegia. 1995 Mar;**33**(3):161-163

[91] Schumm K, Lam TBL. Types of urethral catheters for management of short-term voiding problems in hospitalized adults: A systematic review (structured abstract). Cochrane Database of Abstracts of Reviews of Effects. 2008;**2008**:1-37

[92] Chaiban G, Hanna H, Dvorak T, Raad I. A rapid method of impregnating endotracheal tubes and urinary catheters with gendine: A novel antiseptic agent. Journal of Antimicrobial Chemotherapy. 2000;**55**(1):51-56

[93] Cho YW, Park JH, Kim SH, Cho YH, Choi JM, Shin HJ, et al. Gentamicinreleasing urethral catheter for short-term catheterization. Journal of Biomaterials Science, Polymer Edition. 2003;**14**(9): 963-972

[94] Gentry H, Cope S. Using silver to reduce catheter associated urinary tract infections. Nursing Standard. 2005; **19**(50):51-54

[95] Johnson JR, Kuskowski MA, Wilt TJ. Systematic review: Antimicrobial urinary catheters to prevent catheter associated urinary tract infection in hospitalized patients. Annals of Internal Medicine. 2006;**144**(2): 116-127

[96] Karchmer TB, Giannetta ET, Muto CA, Strain BA, Farr BM. A randomized crossover study of silvercoated urinary catheters in hospitalized patients. Archives of Internal Medicine. 2000;**160**(3):3294-3298

[97] Lai KK. Use of silver-hydrogel urinary catheters on the incidence of catheter associated urinary tract infections in hospitalized patients. American Journal of Infection Control. 2002;**30**(4):221-225

[98] Madeo M, Davies D, Johnson G, Owen E, Wadsworth P, Mmiin CR. The impact of using silver alloy urinary catheters in reducing the incidence of urinary tract infections in the critical care setting. British Journal of Infection Control. 2005;**5**(1):21-24

[99] Newton T, Still JM, Law EA. Comparison of the effect of early insertion of standard latex and silver impregnated latex Foley catheters on urinary tract infections in bum patients. Infection Control and Hospital Epidemiology. 2002;**23**(4): 217-218

[100] Niel-Weise BS, Arend SM, van den Broek PJ. Is there evidence for recommending silver-coated urinary catheters in guidelines? Journal of Hospital Infection. 2002;**52**(2):81-87

[101] Rupp ME, Fitzgerald T, Marion N, Helget V, Puumala S, Anderson JR, et al. Effect of silver-coated urinary catheters: Efficacy, cost-effectiveness, and antimicrobial resistance. American Journal of Infection Control. 2004;**32**(8): 445-450

[102] Saint S, Elmore J, Sullivan S. The efficacy of silver alloy-coated urinary catheters in preventing urinary tract infection: A metaanalysis. Journal of Urology. 1998; **162**(1):283-284

[103] Thibon P, Le Coutour X, Leroyer R, Fabry J. Randomized multi-Centre trial of the effects of a catheter coated with hydrogel and silver salts on the incidence of hospital acquired urinary tract infections. Journal of Hospital Infection. 2000;**45**(2):117-124

[104] Drekonja DM, Kuskowski MA, Wilt TJ, Johnson JR. Antimicrobial urinary catheters: A systematic review. Expert Review Medical Devices. 2008; **5**(4):495-506

[105] Dieckhaus KD, Garibaldi RA. Prevention of catheter-associated urinary tract infections. In: Abrutytn E, Goldman DA, Scheckler WE, editors. Saunders Infection Control Reference Service. Philadelphia: Saunders Co; 1998. pp. 167-174

[106] Roe BH, Brocklehurst JC. Study of patients with indwelling catheters. Journal of Advanced Nursing. 1987 Nov; **12**(6):713-718

[107] National Patient Safety Agency. Female urinary catheters causing trauma to adult males. 2009. Ref Type: Online Source

[108] Newman DK. Internal and external urinary catheters: A primer for clinical practice. Ostomy/Wound Management. 2008 Dec;**54**(12):18-35

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

[109] Nickel JC, Feero P, Costerton JW, Wilson E. Incidence and importance of bacteriuria in postoperative, short-term urinary catheterization. Canadian Journal of Surgery. 1989 Mar;**32**(2): 131-132

[110] Pratt RJ, Pellowe CM, Wilson JA, Loveday HP, Harper PJ, Jones SR, et al. epic2: National evidence-based guidelines for preventing healthcareassociated infections in NHS hospitals in England. Journal of Hospital Infection. 2007;**65**(Suppl. 1):S1-S64

[111] Jahn P, Beutner K, Langer G. Types of indwelling urinary catheters for longterm bladder drainage in adults. Cochrane Database Syst Rev. 2012 Oct 17;**10**:CD004997. DOI: 10.1002/ 14651858.CD004997. pub3. PMID: 23076911 Review

[112] Thibon P, Le C, Leroyer R, Fabry J. Randomized multi-Centre trial of the effects of a catheter coated with hydrogel and silver salts on the incidence of hospital-acquired urinary tract infections. The Journal of Hospital Infection. 2000 Jun;**45**(2):117-124

[113] Gaonkar TA, Sampath LA, Modak SM. Evaluation of the antimicrobial efficacy of urinary catheters impregnated with antiseptics in an in vitro urinary tract model. Infection Control and Hospital Epidemiology. 2003 Jul;**24**(7):506-513

[114] Darouiche RO, Smith JA Jr, Hanna H, Dhabuwala CB, Steiner MS, Babaian RJ, et al. Efficacy of antimicrobial impregnated bladder catheters in reducing catheter-associated bacteriuria: A prospective, randomized, multicentre clinical trial. Urology. 1999 Dec;**54**(6):976-981

[115] Al-Habdan I, Sadat-Ali M, Corea JR, Al-Othman A, Kamal BA, Shriyan DS.

Assessment of nosocomial urinary tract infections in orthopaedic patients: A prospective and comparative study using two different catheters. International Surgery. 2003 Jul;**88**(3):152-154

[116] Brosnahan J, Jull A, Tracy C. Types of urethral catheters for management of short-term voiding problems in hospitalised adults. Cochrane Database of Systematic Reviews. 2002;**1**: CD004013

[117] Pratt RJ, Pellowe C, Loveday HP, Robinson N, Smith GW, Barrett S, et al. The epic project: Developing national evidence based guidelines for preventing hospital-acquired infections. Phase 1: Guidelines for preventing hospitalacquired infections. Journal of Hospital Infection. 2022;**47**(Suppl. 1):S3-S82

[118] Riley DK, Classen DC, Stevens LE, Burke JP. A large randomized clinical trial of a silver-impregnated urinary catheter: Lack of efficacy and staphylococcal super infection. The American Journal of Medicine. 1995; **98**(4):349-356

[119] Health Information and Quality Authority. National Standards for the Prevention and Control of Healthcare Associated Infection. Dublin: Heath Information and Quality Authority; 2009

[120] Magnall J, Watterson L. Principles of aseptic technique in urinary catheterization. Nursing Standard. 2006; **21**(8):49-56

[121] Siegel JD, Rhinehart E, Jackson M, Chiarello L. 2007 guideline for isolation precautions: Preventing transmission of infectious agents in health care settings. American Journal of Infection Control. 2007;**35**(10 Suppl. 2):S65-S164

[122] Desautels RE, Walter CW, Graves RC, Harrison JH. Technical advances in the prevention of urinary tract infection. The Journal of Urology. 1962;**87**:487-490

[123] Kass EH, Schneiderman LJ. Entry of bacteria into the urinary tracts of patients with inlying catheters. The New England Journal of Medicine. 1957; **256**(12):556-557

[124] Kunin CM. Urinary Tract Infections: Detection, Prevention and Management. Baltimore: Williams and Wilkins; 1997

[125] Kunin CM, McCormack RC. Prevention of catheter-induced urinarytract infections by sterile closed drainage. The New England Journal of Medicine. 1966;**274**(21):1155-1161

[126] Rowley S. Aseptic on-touch technique. Nursing Times. 2001;**97**(7):6

[127] SARI Infection Control Subcommittee. Health Protection Surveillance Centre. Dublin. Guidelines for hand hygiene in Irish healthcare settings. 2005

[128] World Health Organisation. Guidelines on Hand Hygiene in Healthcare. 2009. Ref Type: Online Source

[129] Warren JW. Catheter-associated urinary tract infections. Infectious Disease Clinics of North America. 1997; **11**(3):609-622

[130] Association for Continence Advice. Notes on Good Practice. 2007. http:// www.notesongoodpractice.co.uk/

[131] Dunn S. Management of short-term indwelling urethral catheters to prevent urinary tract infections. A systematic review. 2000. The Joanna Briggs Institute for Evidence Based Nursing and Midwifery.

[132] Page LC, Conroy-Hiller T, T. Florence Z. Management of short-term indwelling urethral catheters to prevent urinary tract infections. International Journal of Evidence-Based Healthcare. 2004;**2**(8):271-291

[133] Australian Guidelines for the Prevention and Control of Infection in Healthcare Australian Guidelines for the Prevention and Control of Infection in Healthcare. National Health and Medical Research Council May 2019. 2020. Website Reference number CD34 ISBN online 978-1-86496-028-0

[134] Panknin HT, Althaus P. Guidelines for preventing infections associated with the insertion and maintenance of shortterm indwelling urethral catheters in acute care. The Journal of Hospital Infection. 2001;**49**(2):146-147

[135] National Collaborating Centre for Women's and Children's Health. Prevention and Treatment of Surgical Site Infection. London: RCOG Press; 2008

[136] Department of Health and Aging Austrialian Government. Infection control guidelines for the prevention of transmission of infectious diseases in the healthcare setting. 2004.

[137] Dmm S, Pretty L, Reid H, Evans D. Management of Short Term Indwelling Urethral Catheters to Prevent Urinary Tract Infections. A Systematic Review. Australia: The Joanna Briggs Institute for Evidence Based Nursing and Midwifery; 2000

[138] Ward V, Wilson J, Taylor L, Cookson B, Glynn A. Preventing Hospital-Acquired Infection: Clinical Guidelines. London: Public Health Laboratory Service; 1997

[139] Dieckhaus KD, Garibaldi RA. Prevention of catheter-associated

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

urinary tract infections. In: Abmtytn E, Goldmann DA, Scheckler WE, editors. Saunders Infection Control Reference Service. Philadelphia: Saunders; 1998. pp. 169-174

[140] Kunin CM. Urinary Tract Infections: Detection, Prevention and Management. 5th ed. Baltimore: Williams & Wilkins; 1997. pp. 228-229

[141] Stamm WE. Catheter-associated urinary tract infections: Epidemiology, pathogenesis, and prevention. American Journal of Medicine. 1991;**91**(Suppl. 3B): 65-71

[142] Stamm WE. Urinary tract infections. In: Bennett JV, Brachman PS, editors. Hospital Infection. 4th ed. Philadelphia: Lippincott-Raven; 1998. pp. 477-485

[143] Carpeti EA, Andrews SM, Bentley PG. Randomized study of sterile versus non-sterile urethral catheterization. Annals of the Royal College of Surgeons of England. 1996; **7**(1):59-60

[144] Bardsley A. Use of lubricant gels in urinary catheterization. Nursing Standard. 2005;**20**(8):41-46

[145] Dougherty L, Lister S. The Royal Marsden Hospital Manual of Clinical Nursing Procedures. 7th ed. London: Wiley-Blackwell; 2008

[146] Burke JP, Riley DK. Nosocomial urinary tract infection. In: Mayhall CG, editor. Hospital Epidemiology and Infection Control. Philadelphia: Lippincott Williams & Wilkins; 1996. pp. 139-153

[147] Gardam MA, Amihod B, Orenstein P, Consolacion N, Miller MA. Ovemtilization of indwelling catheters

and the development of nosocomial urinary tract infection. Clinical Pe1jormance Quality Health Care. 1998; **6**(3):99-102

[148] Niel-Weise BS, van den Broeck PJ. Antibiotic policies for short-term catheter bladder drainage in adults. Cochrane Database of Systematic Reviews. 2005;**3**:CD005428

[149] Saint S, Veenstra D, Sullivan S, Chenoweth C, Fendrick A. The potential clinical and economic benefits of silver alloy urinary catheters in preventing urinary tract infection. Archives of Internal Medicine. 2000;**160**(17): 2670-2675

[150] Van den Eijkel E, Griffiths P. Catheter valves for indwelling urinary catheters: A systematic review. British Journal of Community Nursing. 2006; **11**(3):111-114

[151] Burke JP, Garibaldi RA, Britt MR, Jacobson JA, Conti M, Alling DW. Prevention of catheter-associated urinary tract infections: Efficacy of daily meatal care regimens. American Journal of Medicine. 1981;**70**(3):655-658

[152] Burke JP, Jacobson JA, Garibaldi RA, Conti MT, Alling DW. Evaluation of daily meatal care with poly-antibiotic ointment in prevention of urinary catheter- associated bacteriuria. Journal of Urology. 1983; **129**(2):331-334

[153] Classen DC, Larsen RA, Burke JP, Alling DW, Stevens LE. Daily meatal care for prevention of catheterassociated bacteriuria: Results using frequent applications of polyantibiotic cream. Infection Control and Hospital Epidemiology. 1991;**12**(3):157-162

[154] Crouzet J, Bertrand X, Venier AG, Badoz M, Husson C, Talon D. Control of the duration of urinary catheterization: Impact on catheter associated urinary tract infection. The Journal of Hospital Infection. 2007;**67**(3):253-257

[155] Griffiths R, Fernandez R. Strategies for the removal of short-term indwelling urethral catheters in adults. Cochrane Database of Systematic Reviews. 2007;**2**: CD004011. DOI: 10.1002/14651858. CD00401l.pub3

[156] Phipps S, Lim YN, McClinton S, Barry C, Rane A, N'Dow J. Short term urinary catheter policies following urogenital surgery in adults. Cochrane Database of Systematic Reviews. 2006;**2**: CD004374. DOI: 10.10002/14651858. CD004374.pub2

[157] Apisarnthanarak A,

Thongphubeth K, Sirinvaravong S, Kitkangvan D, Yuekyen C, Warachan B, et al. Effectiveness of multifaceted hospital wide quality improvement programs featuring an intervention to remove unnecessary urinary catheters at a tertiary care center in Thailand. Infection Control and Hospital Epidemiology. 2007;**28**(7):791-798

[158] Nicolle LE. Catheter-related urinary tract infection. Drugs & Aging. 2005; **22**(8):627-639

[159] Agodi A, Barchitta M, Anzaldi A, Marchese F, Bonaccorsi A, Motta M. Active surveillance of nosocomial infections in urologic patients. European Urology. 2009;**51**(1):247-254

[160] Smith PW, Bennett G, Bradley S, Drinka P, Lautenbach E, Marx J, et al. SHEA/APIC guideline: Infection prevention and control in the long-term care facility. American Journal of Infection Control. 2008 Sep;**36**(7):504-535

[161] Consortium for Spinal Cord Medicine. Bladder management in adults with spinal cord injury: A clinical practice guideline for health-care providers. The Journal of Spinal Cord Medicine. 2006;**29**(5):527-573

[162] Dille CM, Kirchhoff KT. Decontamination of vinyl urinary drainage bags with bleach. Rehabilitation Nursing. 1993;**18**(5):292-295

[163] Hashisaki P, Swenson J, Mooney B, Epstein B, Bowcutt C. Decontamination of urinary bags for rehabilitation patients. Archives of Physical Medicine and Rehabilitation. 1984;**65**(8):474-476

[164] Rooney M. Impacting health care: Study of a reusable urinary drainage system. SCI Nursing. 1994;**11**(1):16-18

[165] Toughill E. Indwelling urinary catheters: Common mechanical and pathogenic problems. The American Journal of Nursing. 2005;**105**(5):35-37

[166] Wright D, Pomfret I. Urinary catheterization: The infection control aspects. Journal of Community Nursing. 2010;**23**(3):11-14

[167] Platt R, Polk BF, Murdock B, Rosner B. Reduction of mortality associated with nosocomial urinary tract infection. Lancet. 1983;**1**(8330): 893-897

[168] DeGroot-Kosolcharoen J, Guse R, Jones JM. Evaluation of a urinary catheter with a preconnected closed drainage bag. Infection Control and Hospital Epidemiology. 1988;**9**(2):72-76

[169] Leone M, Garnier F, Antonini F, Bimar MC, Albanese J, Martin C. Comparison of effectiveness of two urinary drainage systems in intensive care unit: A prospective, randomized clinical trial. Intensive Care Medicine. 2003;**29**(3):410-413

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

[170] Newman DK. The indwelling urinary catheter: Principles for best practice. Journal of Wound, Ostomy, and Continence Nursing. 2007;**34**(6): 655-661

[171] McCann M, Hennigan M, Hawshaw S. Nurse's knowledge of infection control measures preventing urinary tract infections in catheterised patients. In: Proceedings of the 26th International Nursing and Midwifery Research Conference. Dublin; 2007

[172] Addison R. Catheter valves: A special focus on the bard Flip-Flo catheter. The British Journal of Nursing. 1999;**8**(9):576-580

[173] Doherty W. The Sims Portex catheter valve: An alternative to the leg bag. The British Journal of Nursing. 1999;**8**(7):459-462

[174] Fader M, Pettersson L, Brooks R, Dean G, Wells M, Cottenden A, et al. A multicentre comparative evaluation of catheter valves. The British Journal of Nursing. 1997;**6**(7):359

[175] Pomfret I. Catheter care in the community. Nursing Standard. 2000; **14**(27):46-51

[176] Pettersson L, Fader M. Choosing a catheter valve that suits the patient. Community Nurse. 1997 May;**3**(4):9

[177] Gray ML. Securing the indwelling catheter. The American Journal of Nursing. 2008;**108**(12):44-50

[178] Senese V, Hendricks B, Morrison M, Harris J. Clinical practice guidelines: Care of the patient with an indwelling catheter. Urologic Nursing. 2006;**26**(1): 80-81

[179] Gray M. What nursing interventions reduce the risk of symptomatic urinary tract infection in the patient with an indwelling catheter? Journal of Wound, Ostomy, and Continence Nursing. 2004;**31**(1):3-13

[180] Darouiche RO, Goetz L, Kaldis T, Cerra-Stewart C, AlSharif A, Priebe M. Impact of stat lock securing device on symptomatic catheter-related urinary tract infection: A prospective, randomized, multicentre clinical trial. American Journal of Infection Control. 2006;**34**(9):555-560

[181] Pomfret IJ. Catheters: Design, selection and management. The British Journal of Nursing. 1996;**5**(4): 245-251

[182] Fraise AP, Bradley C. Ayliffe's Control of Hospital Infection - a Practical Handbook. 5th ed. London: Hodder Arnold; 2009

[183] Joanna Briggs Institute. Management of Indwelling Urethral Catheters to Prevent Urinary Tract Infection. 2000.

[184] Getliffe K. Catheter blockage in community patients. Nursing Standard. 1990;**5**(9):33-36

[185] McCarthy K, Hunter I. Importance of pH monitoring in the care of longterm catheters. The British Journal of Nursing. 2001;**10**(19):1240-1247

[186] Stephan F, Sax H, Wachsmuth M, Hoffmeyer P, Clergue F, Pittet D. Reduction of urinary tract infection and antibiotic use after surgery: A controlled, prospective, before-after intervention study. Clinical Infectious Diseases. 2006; **42**(11):1544-1551

[187] Doyle B, Mawji Z, Horgan M, Stelliman P, et al. Decreasing nosocomial urinary tract infection in a large

academic community hospital. Lippincott's Case Management. 2001; **6**(3):127-136

[188] Cornia PB, Amory JK, Fraser S, Saint S, Lipsky BA. Computer-based order entry decreases duration of indwelling urinary catheterization in hospitalized patients. The American Journal of Medicine. 2003;**114**(5): 404-407

[189] Huang WC, Wann SR, Lin SL, Kunin CM, Kung MH, Lin CH, et al. Catheter-associated urinary tract infections in intensive care units can be reduced by prompting physicians to remove unnecessary catheters. Infection Control and Hospital Epidemiology. 2004;**25**(11):974-978

[190] Saint S, Kaufman SR, Thompson M, Rogers MA, Chenoweth CE. A reminder reduces urinary catheterization in hospitalized patients. Joint Commission Journal on Quality and Patient Safety. 2005;**31**(8):455-462

[191] Topal J, Conklin S, Camp K, Morris V, Balcezak T, Herbert P. Prevention of nosocomial catheterassociated urinary tract infections through computerized feedback to physicians and a nurse-directed protocol. American Journal of Medical Quality. 2005;**20**(3):121-126

[192] Meddings J, Rogers MA, Macy M, Saint S. Systematic review and metaanalysis: Reminder systems to reduce catheter-associated urinary tract infections and urinary catheter use in hospitalized patients. Clinical Infectious Diseases. 2010;**51**(5):550-560

[193] Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, et al. The surviving Sepsis campaign: Results of an international guideline-based

performance improvement program targeting severe sepsis. Intensive Care Medicine. 2010;**36**(2):222-231

[194] Mayumi T, Takada T, Hirata K, Yoshida M, Sekimoto M, Hirota M, et al. Pancreatitis bundles. Journal of Hepato-Biliary-Pancreatic Surgery. 2009;**2009**: 11

[195] Powers RJ, Wirtschafter DW. Decreasing central line associated bloodstream infection in neonatal intensive care. Clinics in Perinatology. 2010;**37**(1):247-272

[196] Rello J, Lode H, Cornaglia G, Masterton R. A European care bundle for prevention of ventilator-associated pneumonia. Intensive Care Medicine. 2010;**36**(5):773-780

[197] Venkatram S, Rachmale S, Kanna B. Study of device use adjusted rates in health care-associated infections after implementation of "bundles" in a closedmodel medical intensive care unit. Journal of Critical Care. 2010;**25**(1): 174-178

[198] Wazait HD, van der Meullen J, Patel HR, Brown CT, Gadgil S, Miller RA, et al. Antibiotics on urethral catheter withdrawal: A hit and miss affair. The Journal of Hospital Infection. 2004;**58**(4):297-302

[199] Niel-Weise BS, van den Broek PJ. Urinary catheter policies for long-term bladder drainage. Cochrane Database of Systematic Reviews. 2005;**1**:CD004201

[200] Olson ES, Cookson BD. Do antimicrobials have a role in preventing septicaemia following instrumentation of the urinary tract? The Journal of Hospital Infection. 2000;**45**(2):85-97

[201] Jewes LA, Gillespie WA, Leadbetter A, Myers B, Simpson RA,

#### *Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

Stower MJ, et al. Bacteriuria and bacteraemia in patients with long-term indwelling catheters–a domiciliary study. Journal of Medical Microbiology. 1988;**26**(1):61-65

[202] NICE Short Clinical Guidelines Technical Team. Prophylaxis against Infective Endocarditis: Antimicrobial Prophylaxis against Infective Endocarditis in Adults and Children Undergoing Interventional Procedures. London: National Institute for Health and Clinical Excellence; 2008

[203] Gould FK, Elliott TS, Foweraker J, Fulford M, Perry JD, Roberts GJ, et al. Guidelines for the prevention of endocarditis: Report of the working Party of the British Society for antimicrobial chemotherapy. The Journal of Antimicrobial Chemotherapy. 2006;**57**(6):1035-1042

[204] Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. Prevention of infective endocarditis: Guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007; **116**(15):1736-1754

[205] Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. American Journal of Infection Control. 1988;**16**(3):128-140

[206] Leblebicioglu H, Esen S. Hospitalacquired urinary tract infections in

Turkey: A nationwide multicentre point prevalence study. The Journal of Hospital Infection. 2003;**53**(3): 207-210

[207] Reilly J, Stewart S, Allardice GA, Noone A, Robertson C, Walker A, et al. Results from the Scottish national HAI prevalence survey. The Journal of Hospital Infection. 2008;**69**(1):62-68

[208] Lee MK, Chiu CS, Chow VC, Lam RK, Lai RW. Prevalence of hospital infection and antibiotic use at a university medical center in Hong Kong. The Journal of Hospital Infection. 2007; **65**(4):341-347

[209] Elpern EH, Killeen K, Ketchem A, Wiley A, Patel G, Lateef O. Reducing use of indwelling urinary catheters and associated urinary tract infections. American Journal of Critical Care. 2009; **18**(6):535-541

[210] Madani N, Rosenthal VD, Dendane T, Abidi K, Zeggwagh AA, Abouqal R. Health-care associated infections rates, length of stay, and bacterial resistance in an intensive care unit of Morocco: Findings of the International Nosocomial Infection Control consortium (INICC). International Archives of Medicine. 2009;**2**(1):29

[211] Rebmann T, Greene LR. Preventing catheter-associated urinary tract infections: An executive summary of the Association for Professionals in Infection Control and epidemiology, Inc, Elimination Guide. American Journal of Infectious Control. 2010;**38**(8): 644-646

[212] Rosenthal VD, Maki DG, Jamulitrat S, Medeiros EA, Todi SK, Gomez DY, et al. International Nosocomial Infection Control Consortium (INICC) report, data

summary for 2003-2008, issued June 2009. American Journal of Infectious Control. 2010;**38**(2): 95-104

[213] Weber DJ, Brown V, Huslage K, Sickbert-Bennett E, Rutala WA. Devicerelated infections in home health care and hospice: Infection rates, 1998-2008. Infection Control and Hospital Epidemiology. 2009;**30**(10):1022-1024

[214] Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. American Journal of Infection Control. 2008;**36**(5):309-332

[215] Hospital in Europe Link for Infection Control through Surveillance. Surveillance of Nosocomial Infections in Intensive Care Units - Protocol. Version 6.1. 2004

[216] Kaye D. Urinary tract infections in the elderly. Bulletin of the New York Academy of Medicine. 1980;**56**(2): 209-220

[217] Babcock HM, Zack JE, Garrison T, Trovillion E, Jones M, Fraser VJ, et al. An educational intervention to reduce ventilator-associated pneumonia in an integrated health system: A comparison of effects. Chest. 2004;**125**(6):2224-2231

[218] Warren DK, Zack JE, Mayfield JL, Chen A, Prentice D, Fraser VJ, et al. The effect of an education program on the incidence of central venous catheterassociated bloodstream infection in a medical ICU. Chest. 2004 Nov;**126**(5): 1612-1618

[219] Prout S. Development of guidelines on obtaining catheter specimens of urine utilising a closed system with an incorporated safety gaurd mechanism for needle disposal. In: Proceedings of the 28th International Nursing and Midwifery Research Conference. Dublin; 2009

[220] McNulty CA, Bowen J, Foy C, Gunn K, Freeman E, Tompkins D, et al. Urinary catheterization in care homes for older people: Self-reported questionnaire audit of catheter management by care home staff. The Journal of Hospital Infection. 2006; **62**(1):29-36

[221] Fleming AA, Day J, Glanfield G. Registered nurse management of urinary catheters in a rehabilitation and long stay care hospital. International Journal of Nursing Practice. 2000;**6**(5):237-346

[222] Aldridge MD. Writing and designing readable patient education materials. Nephrology Nursing Journal. 2004;**31**(4):373-377

[223] Roy A, Abubakar I, Yates S, Chapman A, Lipman M, Monk P, et al. Evaluating knowledge gain from TB leaflets for prison and homeless sector staff: The National Knowledge Service TB pilot. European Journal of Public Health. 2008 Dec;**18**(6):600-603

[224] Saint S, Kowalski CP, Kaufman SR, Saint S, Kowalski CP, Kaufman SR, et al. Preventing hospital-acquired urinary tract infection in the United States: A national study. Clinical Infectious Diseases. 2008;**46**:243-250

[225] Nicolle LE, Bradley S, Colgan R, Nicolle LE, Bradley S, Colgan R, et al. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clinical Infectious Diseases. 2005;**40**:643-654

[226] Raz R, Schiller D, Nicolle LE. Chronic indwelling catheter replacement before antimicrobial therapy for

*Hospital-Acquired Urinary Tract Infections DOI: http://dx.doi.org/10.5772/intechopen.110532*

symptomatic urinary tract infection. The Journal of Urology. 2000;**164**:1254-1258

[227] Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual A, the Extended-Spectrum Beta-Lactamases– Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infeción Hospitalaria. 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 Diseases. 2012;**54**:167-174

[228] Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: Differences in therapy and mortality in a multicentre study. The Journal of Antimicrobial Chemotherapy. 2015; **70**(7):2133-2143

#### **Chapter 3**

## Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection

*Laura Cristina Nocua-Báez and Jorge Alberto Cortés*

#### **Abstract**

After clinical evaluation, suspicion of urinary tract infection might be modified by different tests that have the ability to augment (or diminish) the probability of a positive urinary culture and a confirmed diagnosis. In this review, we evaluate the possible role of different non microbiological test for the diagnosis of an urinary tract infection. Some of them might be easily available in the office or a busy emergency room, while others require more sophisticated infrastructure. Due to the high frequency of urinary tract infections, the diversity of symptoms, the difficulty of the diagnosis in some group of patients (e.g., older patients, those with dementia, etc.), and the lack of a gold standard, those non-microbiological tests might contribute to a correct diagnosis and a proper use of antibiotics in difficult cases.

**Keywords:** urinary tract infections, urine dipstick, biomarkers, renal gammagraphy, dipstick test

#### **1. Introduction**

Urinary tract infection (UTI) is an inflammation of the uroepithelial tissue, renal parenchyma or prostate resulting from pathological interaction with a microorganism. According to the anatomical location of the involvement, it might be divided into upper infection when it corresponds to pyelonephritis and lower, related to the renal pelvis or lower urinary tract, and refers almost exclusively to cystitis. Although this infectious disease is one of the most frequent reasons for consultation in all age groups, the most affected are women of reproductive age, with a peak between 14 and 24 years of age, due to the fact that sexual activity increases the probability of urovaginal colonization by Enterobacteriaceae present in the gastrointestinal tract. It is estimated that during their lifetime more than 60% of women may have at least one episode of urinary tract infection, and that it may recur 27% in the first 6 months, and more than once in 2.7% of patients [1].

The Enterobacterales group is the most frequent etiology of urinary tract infection, whose main pathogen is *Echerichia coli* in up to 90% of cases, followed by *Klebsiella spp, Proteus spp, Enterobacter spp, and Citrobacter spp*. Other microorganisms are *Enterococcus spp, Pseudomonas spp*, and *Staphylococcus saprophyticus*. UTI might be divided into complicated or uncomplicated, according to the presence of predisposing factors for failure of antimicrobial treatment such as anatomical or functional alterations of the urinary tract, pregnancy, and comorbidities such as diabetes mellitus [2]. The specific frequency of microorganisms for each group varies according to the clinical scenario, since in uncomplicated UTI, *E. coli* accounts for more than 90% of isolations, while in complicated UTI it is usually found in only 50 to 60% of patients.

In the diagnosis of UTI, the analysis of symptoms is fundamental; patients may present a variety of clinical manifestations, the finding of which is not specific. In general, it is important to consider differential diagnoses at the abdominal level, urological pathologies such as urolithiasis, genital pathology in women, and sexually transmitted diseases. The clinical presentation of the disease varies depending on the location; in the case of cystitis, the most important manifestations are the irritative symptoms of dysuria, tenesmus, hematuria, tenesmus, polyuria, and pollakiuria, in the absence of vaginal symptoms such as irritation or leucorrhea. Upper tract infection is characterized by systemic inflammatory signs such as fever (temperature greater than 38.3°C), tachycardia, tachypnea, nausea, and chills, which are accompanied by laboratory alterations such as leukocytosis or leukopenia; severe lumbar or abdominal pain may also occur. Approximately 30% of cases of high UTI are accompanied by irritative urinary symptoms [3]. Because of the broad clinical presentation and the nonspecificity of symptoms, the most important criterion for the diagnosis of UTI is the identification of bacteriuria, usually with elevated colonyforming unit counts (greater than 100, 1000 or 100,000 depending on the clinical scenario). However, although urine culture is fundamental for establishing the picture, the differential diagnosis is broad, and the frequency of bacteriuria without symptoms of cystitis is relatively frequent in patients with complicated infection. Therefore, to improve diagnostic certainty in the presence of bacteriuria and to support the rational use of antimicrobials, non-microbiological laboratory tools can be used to support the diagnosis. The aim of this chapter is precisely to describe the usefulness of several non-microbiological diagnostic tests that can help support the diagnosis of a urinary tract infection.

#### **2. Limitations of bacteriuria identification**

Given the need to establish bacteriuria as a fundamental element in the diagnosis of UTI, it is important to understand the limitations of its identification. Often, the presence of bacteriuria alone, in relation to unclear clinical pictures or patients at risk of poor progression (e.g., patients with Alzheimer's disease) is used as an argument for the use of antibiotics. This brings problems such as diagnostic uncertainty, poor clinical results, risk of bacterial resistance, and adverse effects derived from their use. This is the reason why additional tests may be required, hopefully with rapid results, to clearly differentiate the sick patient from the colonized one. Here, we will briefly describe the problems of sample collection and bacteriuria.

#### **2.1 Collection and processing of the urine sample**

The proper collection of a urine sample is of vital importance in the study of a UTI, and the spontaneous midstream urine collection technique is preferable. Another strategy is the use of an urinary catheter. However, this may increase the risk

#### *Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

of development an infectious process, and it has been found that the use of catheter for the collection of the sample, even used only once, may favor the development of an infection in up to 1% of cases [4]. It is preferable to obtain the sample from the middle of the urinary stream in order to clean the urethra, which may be colonized by microorganisms not responsible for the clinical manifestations, at the beginning of urination. This strategy also favors the reduction of sample contamination that may be suspected with the finding of low epithelial cells and mucus in the urinary sediment. Some cleaning methods prior to sample collection have been used, such as washing the skin or periurethral mucous membranes, without finding consistent benefits for recommending it routinely [5]. In some cases, spontaneous sampling is difficult, especially in elderly patients or those with comorbidities involving compromised mobility, in which case the alternative is the use of catheterization. Suprapubic puncture is the method that best guarantees the absence of contamination of the sample, but it is uncomfortable, invasive, and impractical, so it is only used in very specific scenarios.

All samples should be processed as soon as possible and refrigerated, as bacteria can grow rapidly and their presence would be overestimated. Increases in the number of colony forming units (CFU) per ml greater than 105 CFU/mL have been documented 2–4 hours after collection, which increases the likelihood of false positives. The recommendation is to process the sample within 2 hours, otherwise refrigerate it or place it in a preservative. The processing of the sample for cultures corresponds to a microbiological test that is beyond the scope of this chapter. In general, it is considered the use of conventional media, semiquantitative methods, and an overnight incubation at 35–37°C in ambient air for a maximum of 48 hours or more in case of suspicion of fungal etiology [6, 7].

#### **2.2 Bacteriuria, risk factors, and frequency**

Traditionally it has been mentioned that urine is sterile in healthy individuals, without comorbidity. However, studies have identified bacteriuria in up to 5% of non-pregnant premenopausal women [8], and a complete microbiota related to urine has been recently identified [9]. Other classical risk factors for bacteriuria include urinary tract catheterization. Short-term use of bladder catheters may be associated with bacteriuria in relation to device care and duration of use. It is estimated that between 9 and 23% of patients may acquire bacteriuria as a result of device use [10]. Most patients resolve bacteriuria after device removal; however, a proportion may end up with a urinary tract infection that becomes clinically evident within 48 hours. Predictors of bacteriuria include ICU stay and a duration of the device for more than 10 days [11]. In fact, catheters of long duration, greater than 30 days, are considered to have a colonization frequency close to 100%, independent of other care measures. Intermittent catheterization in individuals who have spinal cord injury and require it for problems related to neurogenic bladder may have a frequency of bacteriuria ranging from 23 to 69%. Age, comorbidity, and site of care also have an effect on the frequency of bacteriuria: Postmenopausal women increase the frequency of bacteriuria in relation to decades of life and can reach 20% in those over 80 years of age. However, in the latter scenario, it is confounded by comorbidity and site of care [10]. Patients with diabetes may have a prevalence of bacteriuria that can reach 27%, while men or women residing in nursing homes or chronic care settings may have a frequency of up to 40 or 60%, respectively [10].

#### **3. Non-microbiologic urine tests for the diagnosis of urinary tract infection**

#### **3.1 Urinalysis**

Macroscopic and microscopic analysis of urine includes several parameters. Relevant information on each of them is presented below:

#### *3.1.1 Color, odor, and pH*

There are several initial characteristics to evaluate in a urine sample, such as color, odor, and pH. A change in odor does not suggest infection; finding it "strong" is usually due to a concentrated sample, although the presence of UTI may give a pungent odor. There are findings in urine color that may be nonspecifically related to infection, such as cloudy for pyuria, greenish or blue for *Pseudomonas spp,* purple for *Proteus spp, Morganella spp, Providencia spp*, and even *E. coli* (product of tryptophan metabolism to indoxyl sulfate) and red in relation to hematuria [12–14]. Normal urinary pH is slightly acidic between 4.5 and 5.5; alkalinization of urine may occur in the case of urolithiasis due to magnesium and ammonium phosphate crystals, due to infection related to microorganisms that interfere with urea metabolism, such as *Proteus spp* [12].

#### *3.1.2 Pyuria by direct microscopy*

Pyuria supports the diagnosis of urinary tract inflammation, although it is not a specific element of infection because other pathologies can cause it, such as noninfectious prostatitis, urolithiasis, postoperative abdominal or pelvic procedures, use of urinary devices, sexually transmitted diseases, trauma, or sepsis. The absence of pyuria in patients decreases the likelihood of an infectious process in light of the relevant clinical elements; but it cannot be considered alone for the analysis of absence of disease. For the search of pyuria in the microscopic study of urine, the sample must be rapidly processed, in less than two hours, because of the accelerated deterioration of leukocytes. It is possible to directly observe leukocytes and leukocyte casts that can be counted in a centrifuged sample or with Gram stain. In general, counts greater than 2 leukocytes/mm3 are suggestive of inflammation, which, as noted, does not necessarily refer to infection. The most accurate test for the detection of pyuria is the measurement of the urinary leukocyte excretion rate, with a cut-off point for infection greater than 400. 000 leukocytes/hour, but this is not routinely used because of the impracticality of its realization; for this reason, it has been opted for the counting of cells with hemocytometers, where the correlation with the cut-off point of the leukocyte excretion rate and with significant Gram bacteriuria ≥105 CFU/ml is ⩾10 leukocytes/mm3; counts of 8–10 cells/mm3 have been correlated with values below <105 CFU/ml in samples without contamination by suprapubic aspiration in patients with dysuria [15, 16].

#### *3.1.3 Bacteriuria (without culture): direct microscopy and gram staining*

The finding of bacteria in the examination of a urine specimen is the main aid in the diagnosis of UTI. Bacteria can be observed directly in the sediment of an uncentrifuged specimen or with Gram staining, the later being the most relevant

#### *Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

method. Gram staining is simple and allows an early approach to the diagnosis of infection; it can even guide empirical antimicrobial treatment based on the characterization of infectious agents as Gram-positive or Gram-negative. The cutoff values of CFU/ml are not entirely standardized, and the main studies on their diagnostic performance are old. Significant bacteriuria without symptoms is defined as a repeated finding in women of ≥105 CFU/ml in a midstream urine specimen; in pregnant women, of more than ≥103 CFU/ml; and in men, of a specimen with ≥105 CFU/ml. For patients with symptoms, bacteriuria is significant with a finding on midstream urine collection in women ≥103 CFU/ml and in men ≥102 CFU/ml. For these cut-off points, different diagnostic yields have been reported with a sensitivity between 81 and 97% and specificity between 71 and 96%, [17–21].

#### **3.2 Dipstick test**

The dipstick allows the detection of enzyme activity in patients with suspected UTI such as nitrites from bacterial nitrate reductase activity, leukocyte elastase from leukocytes that are presumably active in the infected urinary tract, and the presence of red blood cells in relation to hematuria due to inflammation of the urinary tract. The dipstick has become a noninvasive, practical, and rapid tool that supports the diagnosis of an infection and can guide early decisions to initiate empirical antimicrobial treatment, but should always be interpreted in conjunction with the clinical picture of the patients.

#### *3.2.1 Nitrite test*

Urinary tract infection is often associated with the presence of nitrite in the urine as a result of bacterial nitrate reductase enzyme activity on nitrates [22]. The uropathogens that most cause UTI are nitrite producers; however, other microorganisms such as *Enterococcus spp, Pseudomonas spp, Streptococcus saprophyticus*, and other non-fermenting microorganisms do not produce it. One of the difficulties of this test is that it should ideally be performed after at least 4 hours without urination, because it requires the time necessary for the production of nitrites in the bladder by bacteria. The diagnostic performance of the nitrite test in correlation with significant bacteriuria in patients with UTI has been analyzed in several studies with variable findings, reaching sensitivity values of 70.5% and specificity of 58% [23]. However, sensitivity might be as low as 28.9% [24]. In a meta-analysis that included various population groups such as the elderly, children, pregnant women and the general population, a sensitivity of 40 to 60%, and a specificity of 85 to 98% were found, with the best performance in the elderly and the worst in pregnant women [25]. Therefore, its most important value is its positive predictive value.

#### *3.2.2 Leukocyte esterase test*

The leukocyte esterase test suggests pyuria in urine, its basis is the hydrolysis of ester substrates by the stereolytic activity of enzymes present in leukocytes that produce alcohols and acids, mainly in neutrophils, which have more than 10 proteins with this function. The positive result is evidenced by a change in the color of the test strip whose intensity is proportional to the amount of pyuria, due to the presence of resting or active leukocytes. The main false-positives of the test are the presence of bacteria in the vaginal discharge, parasites such as Trichomonas and eosinophils.

The most frequent false-negatives are high levels of protein or glucose, use of boric acid preservatives or large amounts of ascorbic or oxalic acid [6]. The diagnostic yield of leukocyte esterase is good in patients with suspected UTI in correlation with bacteriuria, with sensitivity varying from 72% to 97.5% and specificity from 74.5% to 84.7% [26, 27]. In association with UTI, a sensitivity of 64% and specificity of 73% has been documented. This performance varies according to the sampling setting; in primary care the sensitivity is 76%, while in tertiary care units it is 62%. Due to the fact that the reading of the test is observer dependent, if the physician is the one who performs it, the sensitivity is 86%; in the case of the test performed by nursing group, the sensitivity lowers to 67%, while if it is done by laboratory personnel, the resulting sensitivity is 59%. Therefore, the professional involved in the interpretation of the test strip must be well trained [28].

#### *3.2.3 Leukocyte esterase and nitrites*

The positive result of leukocyte esterase and nitrite simultaneously could further support the diagnosis; this has been evaluated in several studies where it has been found that the combination of these positive tests increases the sensitivity from 68–88%, with a variable performance in specificity. These findings appear to be more accurate in urology patients. However, it is not clear that finding these two positive tests together helps to clarify the diagnosis of UTI or asymptomatic bacteriuria [28–30]. The finding of a negative result of both tests helps to rule out infection, due to their high negative predictive value; however, the interpretation must be made taking into account the clinical scenario and the suspicion of differential diagnoses [25].

#### **4. Acute phase reactants serum tests**

#### **4.1 C-reactive protein**

C-reactive protein (CRP) is a pentraxin that is released by the liver as part of the acute response to damage such as infection or inflammation, which has proven useful in the diagnosis of different infectious processes; in UTI it can support the anatomical location of the infection, the highest values have been correlated with acute pyelonephritis. Levels of 113.48 mg/L are associated with upper UTI versus 12.84 ± mg/L for those with lower tract infection. CRP has also been reported to be between 126.6 and 127.33 mg/L for upper UTI and between 4.7 and 14.5 mg/L for lower UTI. Attempts have been made to establish cut-off points for this biomarker in relation to upper UTI, finding that levels above 100 mg/L may be useful for this diagnosis [31, 32]. The performance of CRP with a cut-off point of 20 mg/L for acute pyelonephritis in adults has a sensitivity of 85.71% and specificity of 48%. However, in the search for the degree of renal damage related to the differentiation between tissue invasion by the microorganism vs. only cystitis, there is no clear usefulness of the role of this biomarker [33]. In children, a Cochrane meta-analysis found that a CRP value of 20 mg/L had a sensitivity of 94% and specificity of 39% for the diagnosis of acute pyelonephritis [34].

#### **4.2 Procalcitonin**

Procalcitonin (PCT) is a calcitonin precursor protein free of hormonal activity, used for the early diagnosis of bacterial infections and sepsis; it is also useful for the

#### *Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

correlation with the severity of disease and therefore corresponds to a prognostic predictor [35]. PCT is generally elevated in systemic involvement and not in localized infection such as cystitis. This biomarker is increased in acute pyelonephritis with a variable sensitivity and specificity ranging between 70 and 100% and between 70 and 95%, respectively [36, 37]. In a study performed with children where PCT was compared for the early diagnosis of UTI with CRP, erythrocyte sedimentation rate (ESR) and leukocyte count, with a cut-off value greater than 0.85 μg/L, it had a better performance with a sensitivity of 89%, a specificity of 97% and positive and negative predictive values of 96% and 91%, respectively [38]. Another benefit of the use of PCT in adults in this context is the prediction of secondary bacteremia that occurs in up to 23% of patients; a level higher than 0,25 μg/L has a sensitivity of 95% and a specificity of 50% for this clinical presentation, so PCT values could be helpful for early identification of complications of acute pyelonephritis that lead to longer hospital stay, mortality, and health care costs. A PCT level ≤ 0,25 μg/L reduces the use of blood cultures by up to 40%, with a loss in the detection of bacteremia of 3% [39]. It is worth remembering that PCT elevates its value in patients with renal failure (acute or chronic) and is not interpretable in patients with creatinine levels above 1.5 mg/dl. Currently, the available information on PCT in adults with pyelonephritis could not be used to generate a clear recommendation.

#### **4.3 Other biomarkers in urinary tract infection**

Due to the low specificity and intermediate sensitivity of non-microbiological tests for the diagnosis of UTI such as leukocyte esterase, nitrites, pyuria, PCT, and CRP, which even lead to overtreatment in up to 43% of patients and undertreatment in 13% [40], with consequences such as high recurrence, prolonged hospital stays, increased bacterial resistance and renal damage, in recent years there has been increased interest in the search for diagnostic tests that are reliable and easily performed.

One of the biomarkers is neutrophil gelatinase-associated lipocalin (NGAL), which is also an acute phase protein like CRP; it rises after 12 hours from the onset of a UTI, and its maximum peak occurs at 72 hours; it can be measured in serum or urine, and in the later, it is even a predictor of the resolution of the infection and at the same time of its duration [41]. One of the advantages of the use of NGAL is that it is not influenced by the glomerular filtration rate unlike CRP and PCT, but apparently it does not allow to establish the localization of the infectious process [42].

Another group of promising biomarkers are the cytokines present in all infectious and inflammatory processes, which could have a good sensitivity for UTI with an intermediate specificity. The most studied are interleukin 1-beta (IL-1ß) in urine and serum, and in children a value in urine greater than 150 pg./mL for the diagnosis of acute pyelonephritis has a sensitivity of 79% and a specificity of 88% [43]. Interleukin 6 (IL-6) in urine in elderly adult patients with a cut-off level of 30 pg./mL allows differentiation of acute pyelonephritis from asymptomatic bacteriuria with a sensitivity of 80% and a specificity of 82%, while its usefulness in defining UTI vs. asymptomatic bacteriuria has a sensitivity of 48% [44, 45]. Regarding interleukin-8 (IL-8) in urine, a value higher than 200 pg./mL in children indicates a UTI, with a sensitivity of 93% and a specificity of 90% [46].

Other tests have been studied such as heparin-binding protein product of neutrophil activation, matrix metalloprotease-9 (MMP-9) whose increase occurs simultaneously with NGAL, lactoferrin, and heat shock protein-70 which appear to be promising [47].

#### **5. Imaging tests**

Although diagnostic imaging has traditionally been considered in the context of suspected complicated pyelonephritis as a strategy for the identification of comorbidities that may explain the presence of the infection, in some complex scenarios its use may be considered to reach the diagnosis.

#### **5.1 Renal ultrasound**

Some authors recommend early imaging as a strategy for the timely detection of complications or confirmation of the suspicion of acute pyelonephritis, but it is considered that new and significant abnormal findings will be found in only 16% of patients; therefore, it is necessary to perform new studies that evaluate cost–benefit [48]. One of the most readily available imaging tests is ultrasonography (US), which allows an initial approach, with findings such as hydronephrosis, obstructive uropathy, papillary necrosis, renal abscess, local nephritis, inflammation of the perirenal fat, and emphysematous pyelonephritis. One study found a sensitivity of ultrasonography of only 33% compared to tomography for the diagnosis of acute pyelonephritis [49]. Now the use of contrast has been added to US, finding that compared to scintigraphy marked with dimercaptosuccinic acid and technetium 99 m (Tc-DMSA and 99mTc), the sensitivity of this test is 86.8%, and the specificity is 71.4% [50].

#### **5.2 Computerized axial tomography**

Another imaging technique for the diagnosis of high UTI is computed tomography (CT). The most frequently described findings for the diagnostic support of the infectious disease are the presence of localized hypodense lesions, product of renal ischemia due to infiltration of immune system cells such as neutrophils and lymphocytes, parenchymal edema, and perirenal fat and/or gas (suggestive of emphysematous pyelonephritis or abscesses). In a study with 24 patients with acute pyelonephritis, a correlation between CT and scintigraphy marked with DMSA and 99mTc was found in 11 cases, but 11 of the remaining 13 had an abnormal CT with normal scintigraphy, concluding that tomography has greater precision compared to scintigraphy [51]. CT vs. US has a sensitivity of 81% vs. 33% for the diagnosis of acute pyelonephritis [49]. In children the diagnosis of this infection is even more difficult, so imaging strategies have greater importance, one of the most used is the DMSA scan, which has been compared with CT, finding that the latter has the advantage of differentiating and determining the local inflammatory changes of the renal parenchyma that in the scan may go unnoticed [52].

#### **5.3 Nuclear magnetic resonance imaging (NMR)**

Magnetic resonance imaging is an imaging test that has the advantage of not using radiation, but may not be readily available in all clinical settings. Alterations in patients with acute pyelonephritis include areas of hyperintensity or hypointensity, decrease or loss of normal corticomedullary differentiation, scarring, complications such as perirenal fluid, collections or abscesses and gas. This diagnostic tool can also differentiate acute lesions from scarring, which cannot be determined with conventional nuclear medicine techniques. The diagnostic performance of this test in patients with acute pyelonephritis has shown a sensitivity of 96% and a specificity of

86% [53]. Another study showed a sensitivity of 89,5% and specificity of 87,5% for NMR and a S of 86,8% and E of 87,5% for computed tomography [49].

#### **5.4 Nuclear medicine: radioactive isotope scintigraphy**

Scintigraphy labeled with radioactive isotopes such as DMSA and 99mTc is a test that has been used mainly in pediatric patients in order to identify renal involvement and to define prognosis. Its use in adults has been limited. This diagnostic tool is useful to determine the functional renal tubular mass, so its great advantage is to detect regional damage, specially cortical involvement. There is consensus on its use in the search for renal scarring, for example, after acute pyelonephritis, but its diagnostic capacity for acute events is controversial. Single photon emission computed tomography (SPECT) is another scintigraphy technique, which is also more popular in the pediatric setting. In animal models when comparing SPECT vs. CT vs. MRI for the diagnosis of acute pyelonephritis, SPECT has a sensitivity of 92.1% and a specificity of 93.8%, MR of 89,5% and 87,5%, CT of 88,2% and 93,5%, and US of 56,6% and 81,4%, respectively [54]. For the detection of acute pyelonephritis, in the comparison of the use of planar or standard DMSA vs. SPECT, the latter technique has a sensitivity of 97% and specificity of 66%, vs. 82% and 97%, respectively, for standard DMSA [55].

In **Table 1**, the diagnostic performance of the different non-microbiological tests for urinary tract infection is summarized. Cut-off points and specific test findings are given in the text.



#### **Table 1.**

*Diagnostic yield of non-microbiological tests for urinary tract infection.*

#### **6. Conclusions**

Urinary tract infection is a common disease in all age ranges, which requires early diagnosis for timely treatment to reduce patient complications. There are several non-microbiological tests available that support the diagnosis of this infection and decision making for the start of empirical antimicrobial treatment; the most commonly used are direct microscopy of the urine sample, Gram stain and dipstick, all of which should always be interpreted with the clinical manifestations of the patients. The most important finding is the presence of bacteria in the urine sample. There are several biomarkers that can aid in UTI diagnosis, localization and prognosis of patients, such as CRP; promising new biomarkers that may contribute to diagnosis are being studied, such as NGAL, IL-1ß, IL-6, and IL-8. Imaging techniques are also tools for the diagnosis of UTI, with greater importance in the search for complications or associated structural or functional alterations, and limited information for their routine use in clinical settings.

*Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

#### **Author details**

Laura Cristina Nocua-Báez1 and Jorge Alberto Cortés1,2\*

1 Facultad de Medicina, Department of Internal Medicine, Universidad Nacional de Colombia, Sede Bogotá, Bogotá, Colombia

2 Infectious Diseases Unit, Hospital Universitario Nacional, Bogotá, Colombia

\*Address all correspondence to: jacortesl@unal.edu.co

© 2023 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.

### **References**

[1] Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections. Therapeutic Advances in Urology. 2019;**11**:1756287219832172. DOI: 10.1177/1756287219832172

[2] Klein RD, Hultgren SJ. Urinary tract infections: Microbial pathogenesis, host pathogen interactions and new treatment strategies. Nature Reviews. Microbiology. 2020;**18**(4):211-226. DOI: 10.1038/ s41579-020-0324-0

[3] Johnson JR, Russo TA. Acute pyelonephritis in adults. The New England Journal of Medicine. 2018;**378**(1):48-59. DOI: 10.1056/nejmcp1702758

[4] Cuervo Maldonado Sonia Isabel, Alberto Cortés Luna Jorge Alberto. Nosocomial Urinary Tract Infections [Internet]. 2010. Available from: www. intechopen.com

[5] Lifshitz E, Kramer L. Outpatient urine culture: does collection technique matter? Archives of Internal Medicine. 2000;**160**(16):2537-2540. DOI: 10.1001/ archinte.160.16.2537

[6] Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clinical Infectious Diseases. 2004;**38**(8):1150-1158. DOI: 10.1086/383029

[7] Silver SA, Baillie L, Simor AE. Positive urine cultures: A major cause of inappropriate antimicrobial use in hospitals? Canadian Journal of Infectious Diseases and Medical Microbiology. 2009;**20**(4):107-111. DOI: 10.1155/2009/702545

[8] Hooton TM, Roberts PL, Stapleton AE. Asymptomatic bacteriuria and pyuria in premenopausal women. Clinical Infectious Diseases. 2021;**72**(8):1332-1338. DOI: 10.1093/cid/ ciaa274

[9] Perez-Carrasco V, Soriano-Lerma A, Soriano M, Gutiérrez-Fernández J, Garcia-Salcedo JA. Urinary microbiome: Yin and Yang of the urinary tract. Frontiers in Cellular and Infection Microbiology. 2021;**18**(11):617002. DOI: 10.3389/fcimb.2021.617002

[10] Colgan R, Nicolle LE, Mcglone A, Hooton TM. Asymptomatic Bacteriuria in Adults. American Family Physician. 2006;**74**(6):985-990

[11] Ortiz-Ramirez L et al. Factores asociados: características clínicas, microbiológicas y perfiles de resistencia en infecciones urinarias asociadas a catéter en dos hospitales de alta complejidad. Infection. 2022;**26**(2):161- 167. DOI: 10.22354/inv26i2.1016

[12] Simerville JA, Maxted WC, Pahira JJ. Urinalysis: A comprehensive review. American Family Physician. 2005;**71**(6):1153-1162

[13] Raymond JR, Yarger WE. Abnormal urine color: differential diagnosis. Southern Medical Journal. 1988;**81**(7): 837-841. DOI: 10.1097/00007611- 198807000-00008

[14] Aycock RD, Kass DA. Abnormal urine color. Southern Medical Journal. 2012;**105**(1):43-47. DOI: 10.1097/ SMJ.0b013e31823c413e

[15] Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK. Diagnosis of coliform infection in acutely dysuric women. The New England Journal of Medicine. *Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

1982;**307**(8):463-468. DOI: 10.1056/ NEJM198208193070802

[16] Pappas PG. Laboratory in the diagnosis and management of urinary tract infections. The Medical Clinics of North America. 1991;**75**(2):313-325. DOI: 10.1016/s0025-7125(16)30456-4

[17] Tilton RE, Tilton RC. Automated direct antimicrobial susceptibility testing of microscopically screened urine cultures. Journal of Clinical Microbiology. 1980;**11**(2):157-161. DOI: 10.1128/jcm.11.2.157-161.1980

[18] Winquist AG, Orrico MA, Peterson LR. Evaluation of the cytocentrifuge gram stain as a screening test for bacteriuria in specimens from specific patient populations. American Journal of Clinical Pathology. 1997;**108**(5):515-524. DOI: 10.1093/ ajcp/108.5.515

[19] Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America; American Society of Nephrology; American geriatric society. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clinical Infectious Diseases. 2005;**40**(5):643-654. DOI: 10.1086/427507

[20] Cardoso CL, Muraro CB, Siqueira VL, Guilhermetti M. Simplified technique for detection of significant bacteriuria by microscopic examination of urine. Journal of Clinical Microbiology. 1998;**36**(3):820-823. DOI: 10.1128/JCM.36.3.820-823.1998

[21] McNair RD, MacDonald SR, Dooley SL, Peterson LR. Evaluation of the centrifuged and gram-stained smear, urinalysis, and reagent strip testing to detect asymptomatic bacteriuria

in obstetric patients. American Journal of Obstetrics and Gynecology. 2000;**182**(5):1076-1079. DOI: 10.1067/ mob.2000.105440

[22] Lundberg JO, Carlsson S, Engstrand L, Morcos E, Wiklund NP, Weitzberg E. Urinary nitrite: More than a marker of infection. Urology. 1997;**50**(2):189-191. DOI: 10.1016/ S0090-4295(97)00257-4

[23] Bafna P, Deepanjali S, Mandal J, Balamurugan N, Swaminathan RP, Kadhiravan T. Reevaluating the true diagnostic accuracy of dipstick tests to diagnose urinary tract infection using Bayesian latent class analysis. PLoS One. 2020;**15**(12):e0244870. DOI: 10.1371/ journal.pone.0244870

[24] Coulthard MG. Using urine nitrite sticks to test for urinary tract infection in children aged <2 years: A meta-analysis. Pediatric Nephrology. 2019;**34**(7):1283-1288. DOI: 10.1007/ s00467-019-04226-6

[25] Bellazreg F, Abid M, Lasfar NB, Hattab Z, Hachfi W, Letaief A. Diagnostic value of dipstick test in adult symptomatic urinary tract infections: Results of a cross-sectional Tunisian study. The Pan African Medical Journal. 2019;**21**(33):131. DOI: 10.11604/ pamj.2019.33.131.17190

[26] Nava MO, Mirzaei N, Ebrahimian V, Molaei M, Tohidnia F, Pursafar M. Diagnostic value of leukocyte esterase and nitrite tests for the detection of urinary tract infection. Biomedical and Pharmacology Journal. 2012;**5**(2):1-4

[27] Oneson R, Gröschel DH. Leukocyte esterase activity and nitrite test as a rapid screen for significant bacteriuria. American Journal of Clinical Pathology. 1985;**83**(1):84-87. DOI: 10.1093/ ajcp/83.1.84

[28] Devillé WL, Yzermans JC, van Duijn NP, Bezemer PD, van der Windt DA, Bouter LM. The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy. BMC Urology. 2004;**4**:4. DOI: 10.1186/1471-2490-4-4

[29] Semeniuk H, Church D. Evaluation of the leukocyte esterase and nitrite urine dipstick screening tests for detection of bacteriuria in women with suspected uncomplicated urinary tract infections. Journal of Clinical Microbiology. 1999;**37**(9):3051-3052. DOI: 10.1128/ JCM.37.9.3051-3052.1999

[30] Mambatta AK, Jayarajan J, Rashme VL, Harini S, Menon S, Kuppusamy J. Reliability of dipstick assay in predicting urinary tract infection. Journalof Family Medicine and Primary Care. 2015;**4**(2):265-268. DOI: 10.4103/2249-4863.154672

[31] Agrawal P, Pandey A, Sompura S, Pursnani ML. Role of blood C - reactive protein levels in upper urinary tract infection and lower urinary tract infection in adult patients (>16 years). The Journal of the Association of Physicians of India. 2013;**61**(7): 462-463

[32] Narayan Swamy SN, Jakanur RK, Sangeetha SR. Significance of C-reactive protein levels in categorizing upper and lower urinary tract infection in adult patients. Cureus. 2022;**14**(6):e26432. DOI: 10.7759/cureus.26432

[33] Xu RY, Liu HW, Liu JL, Dong JH. Procalcitonin and C-reactive protein in urinary tract infection diagnosis. BMC Urology. 2014;**14**:45. DOI: 10.1186/1471-2490-14-45

[34] Shaikh N, Borrell JL, Evron J, Leeflang MM. Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children. Cochrane Database of Systematic Reviews 2015;1(1):CD009185. DOI: 10.1002/14651858.CD009185.pub2

[35] Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. American Journal of Respiratory and Critical Care Medicine. 2001;**164**(3):396- 402. DOI: 10.1164/ajrccm.164.3.2009052

[36] Kotoula A, Gardikis S, Tsalkidis A, Mantadakis E, Zissimopoulos A, Kambouri K, et al. Procalcitonin for the early prediction of renal parenchymal involvement in children with UTI: Preliminary results. International Urology and Nephrology. 2009;**41**(2):393-399. DOI: 10.1007/ s11255-008-9472-2

[37] Bharath MS et al. Role of procalcitonin and C-reactive protein in urinary tract infection diagnosis in adults. International Journal of Advances in Medicine. 2017;**4**(2):417-419. DOI: 10.18203/2349-3933.ijam20171001

[38] Kotoula A, Gardikis S, Tsalkidis A, Mantadakis E, Zissimopoulos A, Deftereos S, et al. Comparative efficacies of procalcitonin and conventional inflammatory markers for prediction of renal parenchymal inflammation in pediatric first urinary tract infection. Urology. 2009;**73**(4):782-786. DOI: 10.1016/j.urology.2008.10.042

[39] van Nieuwkoop C, Bonten TN, Van't Wout JW, Kuijper EJ, Groeneveld GH, Becker MJ, et al. Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: A prospective observational study. Critical Care. 2010;**14**(6):R206. DOI: 10.1186/cc9328

*Non-Microbiological Tests for the Diagnosis of Urinary Tract Infection DOI: http://dx.doi.org/10.5772/intechopen.110279*

[40] Hannula A, Perhomaa M, Venhola M, Pokka T, Renko M, Uhari M. Long-term follow-up of patients after childhood urinary tract infection. Archives of Pediatrics & Adolescent Medicine. 2012;**166**(12):1117-1122. DOI: 10.1001/archpediatrics.2012.1383

[41] Jung N, Byun HJ, Park JH, Kim JS, Kim HW, Ha JY. Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection. Korean Journal of Pediatrics. 2018;**61**(1):24-29. DOI: 10.3345/ kjp.2018.61.1.24

[42] Urbschat A, Obermüller N, Paulus P, Reissig M, Hadji P, Hofmann R, et al. Upper and lower urinary tract infections can be detected early but not be discriminated by urinary NGAL in adults. International Urology and Nephrology. 2014;**46**(12):2243-2249. DOI: 10.1007/s11255-014-0831-x

[43] Sheu JN, Chen MC, Cheng SL, Lee IC, Chen SM, Tsay GJ. Urine interleukin-1beta in children with acute pyelonephritis and renal scarring. Nephrology (Carlton, Vic.). 2007;**12**(5):487-493. DOI: 10.1111/j.1440-1797.2007.00819.x

[44] Kjölvmark C, Tschernij E, Öberg J, Påhlman LI, Linder A, Åkesson P. Distinguishing asymptomatic bacteriuria from urinary tract infection in the elderly - the use of urine levels of heparin-binding protein and interleukin-6. Diagnostic Microbiology and Infectious Disease. 2016;**85**(2):243-248. DOI: 10.1016/j. diagmicrobio.2016.03.005

[45] Sundén F, Wullt B. Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population. International Journal of Urology. 2016;**23**(2):168-174. DOI: 10.1111/iju.13002

[46] Rao WH, Evans GS, Finn A. The significance of interleukin 8 in urine. Archives of Disease in Childhood. 2001;**85**(3):256-262. DOI: 10.1136/ adc.85.3.256

[47] Horváth J, Wullt B, Naber KG, Köves B. Biomarkers in urinary tract infections - which ones are suitable for diagnostics and follow-up? GMS Infectious Diseases. 2020;**26**(8):Doc24. DOI: 10.3205/id000068

[48] Shen Y, Brown MA. Renal imaging in pyelonephritis. Nephrology (Carlton, Vic.). 2004;**9**(1):22-25. DOI: 10.1111/j.1440-1797.2003.00226.x

[49] Yoo JM, Koh JS, Han CH, Lee SL, Ha US, Kang SH, et al. Diagnosing acute pyelonephritis with CT, Tc-DMSA SPECT, and Doppler ultrasound: A comparative study. Korean Journal of Urology. 2010;**51**(4):260-265. DOI: 10.4111/kju.2010.51.4.260

[50] Jung HJ, Choi MH, Pai KS, Kim HG. Diagnostic performance of contrast-enhanced ultrasound for acute pyelonephritis in children. Scientific Reports. 2020;**10**(1):10715. DOI: 10.1038/ s41598-020-67713-z

[51] Sattari A, Kampouridis S, Damry N, Hainaux B, Ham HR, Vandewalle JC, et al. CT and 99mTc-DMSA scintigraphy in adult acute pyelonephritis: A comparative study. Journal of Computer Assisted Tomography. 2000;**24**(4):600- 604. DOI: 10.1097/00004728- 200007000-00016

[52] Lee J, Kwon DG, Park SJ, Pai KS. Discordant findings on dimercaptosuccinic acid scintigraphy in children with multi-detector row computed tomography-proven acute pyelonephritis. Korean Journal of Pediatrics. 2011;**54**(5):212-218. DOI: 10.3345/kjp.2011.54.5.212

[53] Sriman R, Venkatesh K, Mathew C, Pankaj M, Shankar R. Validity of diffusion-weighted magnetic resonance imaging in the evaluation of acute pyelonephritis in comparison with contrast-enhanced computed tomography. Polish Journal of Radiology. 2020;**85**:e137-e143. DOI: 10.5114/ pjr.2020.93669

[54] Majd M, Nussbaum Blask AR, Markle BM, Shalaby-Rana E, Pohl HG, Park JS, et al. Acute pyelonephritis: Comparison of diagnosis with 99mTc-DMSA, SPECT, spiral CT, MR imaging, and power Doppler US in an experimental pig model. Radiology. 2001;**218**(1):101-108. DOI: 10.1148/ radiology.218.1.r01ja37101

[55] Craig JC, Wheeler DM, Irwig L, Howman-Giles RB. How accurate is dimercaptosuccinic acid scintigraphy for the diagnosis of acute pyelonephritis? A meta-analysis of experimental studies. Journal of Nuclear Medicine. 2000;**41**(6):986-993

[56] Kuil SD, Hidad S, Fischer JC, Harting J, Hertogh CMPM, Prins JM, et al. Sensitivity of C-reactive protein and Procalcitonin measured by pointof-care tests to diagnose urinary tract infections in nursing home residents: A cross-sectional study. Clinical Infectious Diseases. 2021;**73**(11):e3867-e3875. DOI: 10.1093/cid/ciaa1709

Section 2
