*Number, yearly percentages, and P values for temporal trend of non-susceptible cases of E. coli bacteraemia.*

 **2.**

**103**

(CSF) analysis.

*Management of* E. coli *Sepsis*

**6. Evaluation**

**7.2 Presentations**

*7.2.1 Pneumonia*

*7.2.2 Acute-bacterial meningitis*

and hemodynamic control are essential [68].

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

**7.1 History and physical examination**

The sepsis' diagnosis confirmation is done from the evaluation of the clinical status of the patient, analyzing some criteria. For adult patients, it is confirmed or a diagnosis of sepsis is made when two criteria are present: hyperthermia>38.3 °C or hypothermia <36°C, tachycardia>90 bpm, leukocytosis (>12,000 μL-1) or leukopenia (<4000 μL-1) or >10% bands, acutely altered mental status, tachypnea

Collect a careful history from patient, addressing information such as previous illnesses, surgeries, how long ago the symptoms started, if there are comorbidities, if it have traveled to a place recently and other details, added to a complete physical examination, which provides very relevant information and leads to a line of rationality, it is extremely important to start the development of a preliminary

All this information collected is recorded and saved in medical records, more recently, electronics, which are more organized, more readable and allows a better

Some of the most frequent reasons that lead patients to go to a medical consultation are dyspnea, cough with or without hemoptysis and chest pain, as these symptoms can be indications of serious illnesses, it shows the importance of asking

Ventilator-associated pneumonia (VAP) is the most common fatal hospital infection [59]. One of the bacteria most involved in the clinical picture in question is Enterobacteriaceae *Escherichia coli* [60, 61] and there is little awareness when it

in the pathogenicity of the lung compared to those present in urinary tract and bloodstream infections [62]. In addition, research on mice has also shown that these isolated strains are highly virulent extra-intestinal pathogens that express virulence factors, representing potential targets for new therapy. A French national study also demonstrated that, despite the genomic and phylogenetic characteristics of *E. coli* pneumonia isolates from critically ill patients, they belong to the same extra-intestinal pathogen as *E. coli*, they have specific distinct characteristics when lungs [63].

Studies show that these *E. coli* pathogenic islands (PAIs) are involved differently

*E. coli* meningitis is rare in adult forms of the disease [64–66], but it is a frequent pathogen in the pediatric field [67]. Despite its rarity, it has a serious clinical course [64–66]. It is usually diagnosed based on clinical signs and cerebrospinal fluid

Due to the severity of the disease, early diagnosis, adequate antibiotic treatment

> 20 bpm, hyperglycemia (>120 mg/dl) in the absence of diabetes [56].

**7. Clinical assessment and patient presentations**

differential diagnosis of the patient's complaints.

comparison, in relation to written records [57].

questions and exams in a way attentive and careful [58].

comes to the pathophysiology of *E. coli* pneumonia.

#### **6. Evaluation**

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

**102**

**Agent or phenotype** 

**1997** 

**1998** 

**1999** 

**2000** 

**2001** 

**2002** 

**2003** 

**2004** 

**2005 (January–**

**Total** 

*P*

*n* **= 663**

**June)** *n* **= 56**

*n* **= 58**

27 (46.6) 14 (24.1)

11 (22.4)

13 (25.0)

28 (33.7)

21 (24.4)

28 (40)

32 (36.8)

41 (33.6)

20 (35.7)

208 (31.4)

0.02

24 (49)

24 (46.2)

50 (60.2)

54 (62.8)

46 (65.7)

55 (63.2)

70 (57.9)

35 (62.5)

385 (58.2)

0.02

*n* **= 49**

*n* **= 52**

*n* **= 83**

*n* **= 86**

*n* **= 70**

*n* **= 87**

*n* **= 122**

**[n (%)]**

Ampicillin Trimethoprim/

sulfamethoxazole

Ciprofloxacin

Amoxicillin/

clavulanate

Gentamicin Piperacillin/

tazobactam

Cefotaxime ESBL production

MDR

**Table 2.**

0 4 (6.9)

4 (8.2) *Number, yearly percentages, and P values for temporal trend of non-susceptible cases of E. coli bacteraemia.*

5 (9.6)

9 (10.8)

9 (10.5)

12 (17.1)

15 (17.2)

17 (13.9)

12 (21.4)

87 (13.1)

0.006

0

0

2 (2.4)

3 (3.5)

3 (4.3)

2 (2.3)

9 (7.4)

3 (5.4)

22 (3.3)

0.002

11

2 (4.1)

0

2 (2.4)

3 (3.5)

5 (7.1)

3 (3.4)

12 (9.8)

4 (7.1)

31 (4.7)

0.001

4 (6.9) 1 (1.7)

4 (8.2)

1 (1.9)

8 (9.6)

6 (7.0)

4 (5.7)

5 (5.7)

2 (1.6)

2 (3.6)

33 (5)

0.4

6 (12.2)

5 (9.6)

5 (6.0)

8 (9.3)

6 (8.6)

7 (8.0)

8 (6.6)

8 (14.3)

57 (8.6)

0.8

9 (15.5) 9 (15.5)

4 (8.2)

9 (17.3)

16 (19.3)

8 (9.3)

7 (10)

11 (12.6)

15 (12.3)

20 (35.7)

99 (14.9)

0.1

7 (14.3)

10 (19.2)

7 (8.4)

14 (16.3)

16 (22.9)

22 (25.3)

27 (22.1)

13 (23.2)

125 (18.9)

0.02

The sepsis' diagnosis confirmation is done from the evaluation of the clinical status of the patient, analyzing some criteria. For adult patients, it is confirmed or a diagnosis of sepsis is made when two criteria are present: hyperthermia>38.3 °C or hypothermia <36°C, tachycardia>90 bpm, leukocytosis (>12,000 μL-1) or leukopenia (<4000 μL-1) or >10% bands, acutely altered mental status, tachypnea > 20 bpm, hyperglycemia (>120 mg/dl) in the absence of diabetes [56].

#### **7. Clinical assessment and patient presentations**

#### **7.1 History and physical examination**

Collect a careful history from patient, addressing information such as previous illnesses, surgeries, how long ago the symptoms started, if there are comorbidities, if it have traveled to a place recently and other details, added to a complete physical examination, which provides very relevant information and leads to a line of rationality, it is extremely important to start the development of a preliminary differential diagnosis of the patient's complaints.

All this information collected is recorded and saved in medical records, more recently, electronics, which are more organized, more readable and allows a better comparison, in relation to written records [57].

Some of the most frequent reasons that lead patients to go to a medical consultation are dyspnea, cough with or without hemoptysis and chest pain, as these symptoms can be indications of serious illnesses, it shows the importance of asking questions and exams in a way attentive and careful [58].

#### **7.2 Presentations**

#### *7.2.1 Pneumonia*

Ventilator-associated pneumonia (VAP) is the most common fatal hospital infection [59]. One of the bacteria most involved in the clinical picture in question is Enterobacteriaceae *Escherichia coli* [60, 61] and there is little awareness when it comes to the pathophysiology of *E. coli* pneumonia.

Studies show that these *E. coli* pathogenic islands (PAIs) are involved differently in the pathogenicity of the lung compared to those present in urinary tract and bloodstream infections [62]. In addition, research on mice has also shown that these isolated strains are highly virulent extra-intestinal pathogens that express virulence factors, representing potential targets for new therapy. A French national study also demonstrated that, despite the genomic and phylogenetic characteristics of *E. coli* pneumonia isolates from critically ill patients, they belong to the same extra-intestinal pathogen as *E. coli*, they have specific distinct characteristics when lungs [63].

#### *7.2.2 Acute-bacterial meningitis*

*E. coli* meningitis is rare in adult forms of the disease [64–66], but it is a frequent pathogen in the pediatric field [67]. Despite its rarity, it has a serious clinical course [64–66]. It is usually diagnosed based on clinical signs and cerebrospinal fluid (CSF) analysis.

Due to the severity of the disease, early diagnosis, adequate antibiotic treatment and hemodynamic control are essential [68].

*E. coli* meningitis follows a high degree of bacteraemia and invasion of the blood–brain barrier. With mortality rates ranging from 15 to 40%, Meningitis due to this bacterium leaves approximately 50% of survivors with some type of neurological sequelae [69–78].

Although the process is unknown, it is known that, for the onset of the disease, it is necessary to have an invasion of the blood–brain barrier by *E. coli*, which requires specific microbial and host factors such as specific signaling molecules for microbes and hosts. Thus, blocking these microbial and host factors that contribute to the invasion of the blood–brain barrier by *E. coli* is effective in preventing the penetration of *E. coli* into the brain.

With the complete discovery of this mechanism, it is likely that new targets for the prevention and therapy of *Escherichia coli* meningitis will be achieved [79].

Regarding treatment, it is currently known only that antimicrobial chemotherapy has limited efficacy [79–81].

#### *7.2.3 Intra-abdominal infections*

Intra-abdominal infections (IAI) are invasive and bacterial multiplications in the hollow organ walls and beyond. Usually, it is located in the abdominal cavity, in the retroperitoneum and in the abdominal organs, being a common complication in the post-surgical period [82]. In addition, they have a wide variety of pathological conditions, from appendicitis to fecal peritonitis, which makes IAI generally have a poor prognosis (especially in high-risk patients) and is an important cause of morbidity [83]. Mostly, the most common source of this infection is the appendix, followed by gastroduodenal perforations. The Gram-negative bacteria *E. coli* is the most common causative agent of IAI. Therefore, it is important to know that they have great sensitivity to imipenem, meropenem, mainly, and to amoxi-clavulanate, amikacin and piperacillin-tazobactam, next [84, 85]. However, amici-clavulanate is prescribed as a first-line drug in developing countries, due to cost factors [86].

#### *7.2.4 Enteric infections*

Although *E. coli* strains have been isolated as part of the normal beneficial flora of the intestine, some strains have developed pathogenic mechanisms to cause disease in humans and animals. One of these strains capable of causing diseases is enteric *Escherichia coli* (*E. coli*), comprising important pathogens, since they cause significant morbidity and mortality worldwide. Traditionally enteric *E. coli* was divided into 6 pathotypes, however two other divisions were proposed by several studies (as mentioned individually in topic 4) [87].

Although there are many etiological agents responsible for diarrhea, pathogenic *E. coli* is a major contributor. On the other hand, the onset and complications of enteric *E. coli* vary significantly, despite there are many common features in the pathogenic process of colonizing the intestinal mucosa and the onset of disease [88].

Outbreaks are common all over the world, with fatal consequences mainly in children under 5 years of age living in underdeveloped countries, where diarrheal diseases can lead to death more frequently [89].

The transmission of enteric *E. coli* is also a public health concern, related to the development of countries, since its transmission is through contaminated water and food. Thus, the seriousness in relation to the microorganism can be exemplified by national and international surveillance programs, created by developed countries that aim to constantly monitor outbreaks [90]. In developing countries ETEC,

**105**

*Management of* E. coli *Sepsis*

poisoning outbreaks [91, 92].

*7.2.5 UTI*

group of patients.

resistance [97].

**8. Workup**

**8.1 Urine culture**

culture) [100, 101].

**8.2 Blood culture**

needed to act against the pathogen [98].

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

EPEC and EAEC are considered to be the main causes of childhood diarrhea, and when left untreated, they have potentially fatal consequences. However. in developed countries, these infections are mild and self-limiting, with EHEC and, more recently, EAEC and STEAEC being the main *E. coli* pathotypes associated with food

Among the most common types of bacterial infections that occur both in the community and in hospitals, urinary tract infections (UTI) stand out. Urinary tract infections can be associated with the hospital (HAUTIs) and the community (CAUTIs). In the case of CAUTIs, it is known whether women are the predominant

Although the UTI is multifactorial, the main bacteria related to the diagnosis is

Co-trimoxazole (trimethoprim/sulfamethoxazole), nitrofurantoin, ciprofloxacin and ampicillin are the antibiotics commonly recommended for the treatment of UTIs. However, there is an overall increase in antibiotic resistance among pathogens

Since the evidence suggests a significant relationship between the extensive use of antibiotics and antimicrobial resistance, it is necessary to prescribe and use

For this reason, in order to guide the selection of empirical therapy, surveillance of antibiotic resistance is crucial for determining the pattern of antimicrobial

It aims to check the presence of fungi and bacteria in the urine, being carried out from a urine sample, which was placed in Petri dishes. The urine culture is placed in an incubator (1–2 days) and if there is any microorganism in the tested material, colonies grow and are visible on the plate. When the result is positive for some bacteria, a test antibiogram is performed, which determines the type of antibiotic

The culture of urine is important precisely because it allows the precise recogni-

As urine culture is most frequently requested when UTI is suspected, the most common bacteria found are *Escherichia coli* (between 47.5% and 56.4% of all urine

Blood culture is part of the routine assessment of patients with suspected bloodstream infection, and is crucial to guide therapeutic intervention. The ideal method for collecting blood culture is venepuncture, since it increases diagnostic yield, and

Since the timing of blood culture collection does not influence the detection of clinically relevant microorganisms, most authorities recommend collecting several sets simultaneously or for a short period of time, with the exception of patients with endovascular infection who need documented continuous bacteremia [103, 104].

tion of the bacteria and, consequently, the best antibiotic to be used [99].

has lower rates of contamination, according to some studies [102].

*E. coli*, predominant in both community and nosocomial UTIs [93].

in the urinary tract, which is a limitation on treatment options [94, 95].

antibiotics in order to reduce their complications and costs [96].

#### *Management of* E. coli *Sepsis DOI: http://dx.doi.org/10.5772/intechopen.93132*

EPEC and EAEC are considered to be the main causes of childhood diarrhea, and when left untreated, they have potentially fatal consequences. However. in developed countries, these infections are mild and self-limiting, with EHEC and, more recently, EAEC and STEAEC being the main *E. coli* pathotypes associated with food poisoning outbreaks [91, 92].

#### *7.2.5 UTI*

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

cal sequelae [69–78].

penetration of *E. coli* into the brain.

therapy has limited efficacy [79–81].

*7.2.3 Intra-abdominal infections*

cost factors [86].

*7.2.4 Enteric infections*

*E. coli* meningitis follows a high degree of bacteraemia and invasion of the blood–brain barrier. With mortality rates ranging from 15 to 40%, Meningitis due to this bacterium leaves approximately 50% of survivors with some type of neurologi-

it is necessary to have an invasion of the blood–brain barrier by *E. coli*, which requires specific microbial and host factors such as specific signaling molecules for microbes and hosts. Thus, blocking these microbial and host factors that contribute to the invasion of the blood–brain barrier by *E. coli* is effective in preventing the

the prevention and therapy of *Escherichia coli* meningitis will be achieved [79]. Regarding treatment, it is currently known only that antimicrobial chemo-

Although the process is unknown, it is known that, for the onset of the disease,

With the complete discovery of this mechanism, it is likely that new targets for

Intra-abdominal infections (IAI) are invasive and bacterial multiplications in the hollow organ walls and beyond. Usually, it is located in the abdominal cavity, in the retroperitoneum and in the abdominal organs, being a common complication in the post-surgical period [82]. In addition, they have a wide variety of pathological conditions, from appendicitis to fecal peritonitis, which makes IAI generally have a poor prognosis (especially in high-risk patients) and is an important cause of morbidity [83]. Mostly, the most common source of this infection is the appendix, followed by gastroduodenal perforations. The Gram-negative bacteria *E. coli* is the most common causative agent of IAI. Therefore, it is important to know that they have great sensitivity to imipenem, meropenem, mainly, and to amoxi-clavulanate, amikacin and piperacillin-tazobactam, next [84, 85]. However, amici-clavulanate is prescribed as a first-line drug in developing countries, due to

Although *E. coli* strains have been isolated as part of the normal beneficial flora

Although there are many etiological agents responsible for diarrhea, pathogenic *E. coli* is a major contributor. On the other hand, the onset and complications of enteric *E. coli* vary significantly, despite there are many common features in the pathogenic process of colonizing the intestinal mucosa and the onset of

Outbreaks are common all over the world, with fatal consequences mainly in children under 5 years of age living in underdeveloped countries, where diarrheal

The transmission of enteric *E. coli* is also a public health concern, related to the development of countries, since its transmission is through contaminated water and food. Thus, the seriousness in relation to the microorganism can be exemplified by national and international surveillance programs, created by developed countries that aim to constantly monitor outbreaks [90]. In developing countries ETEC,

of the intestine, some strains have developed pathogenic mechanisms to cause disease in humans and animals. One of these strains capable of causing diseases is enteric *Escherichia coli* (*E. coli*), comprising important pathogens, since they cause significant morbidity and mortality worldwide. Traditionally enteric *E. coli* was divided into 6 pathotypes, however two other divisions were proposed by several

studies (as mentioned individually in topic 4) [87].

diseases can lead to death more frequently [89].

**104**

disease [88].

Among the most common types of bacterial infections that occur both in the community and in hospitals, urinary tract infections (UTI) stand out. Urinary tract infections can be associated with the hospital (HAUTIs) and the community (CAUTIs). In the case of CAUTIs, it is known whether women are the predominant group of patients.

Although the UTI is multifactorial, the main bacteria related to the diagnosis is *E. coli*, predominant in both community and nosocomial UTIs [93].

Co-trimoxazole (trimethoprim/sulfamethoxazole), nitrofurantoin, ciprofloxacin and ampicillin are the antibiotics commonly recommended for the treatment of UTIs. However, there is an overall increase in antibiotic resistance among pathogens in the urinary tract, which is a limitation on treatment options [94, 95].

Since the evidence suggests a significant relationship between the extensive use of antibiotics and antimicrobial resistance, it is necessary to prescribe and use antibiotics in order to reduce their complications and costs [96].

For this reason, in order to guide the selection of empirical therapy, surveillance of antibiotic resistance is crucial for determining the pattern of antimicrobial resistance [97].

#### **8. Workup**

#### **8.1 Urine culture**

It aims to check the presence of fungi and bacteria in the urine, being carried out from a urine sample, which was placed in Petri dishes. The urine culture is placed in an incubator (1–2 days) and if there is any microorganism in the tested material, colonies grow and are visible on the plate. When the result is positive for some bacteria, a test antibiogram is performed, which determines the type of antibiotic needed to act against the pathogen [98].

The culture of urine is important precisely because it allows the precise recognition of the bacteria and, consequently, the best antibiotic to be used [99].

As urine culture is most frequently requested when UTI is suspected, the most common bacteria found are *Escherichia coli* (between 47.5% and 56.4% of all urine culture) [100, 101].

#### **8.2 Blood culture**

Blood culture is part of the routine assessment of patients with suspected bloodstream infection, and is crucial to guide therapeutic intervention. The ideal method for collecting blood culture is venepuncture, since it increases diagnostic yield, and has lower rates of contamination, according to some studies [102].

Since the timing of blood culture collection does not influence the detection of clinically relevant microorganisms, most authorities recommend collecting several sets simultaneously or for a short period of time, with the exception of patients with endovascular infection who need documented continuous bacteremia [103, 104].

Two to four sets of blood samples should be collected, whenever possible, at independent locations [103–106]. For adults, the volume required for the examination varies between 40 and 160 mL of blood, and for babies and children, the volume is age-based and does not exceed 1% of the patient's total blood volume [103, 107].

The importance of blood culture, as well as urine, is related to the determination of the bacteria and the antibiogram, which directs the treatment to the best antibiotic to be used [108].

#### **8.3 Localization of underlying abnormality**

In some cases, it is possible to suspect a complicated urinary tract infection/ urosepsis without being serious urological abnormalities. In such cases, there are some screening options that can be performed to assist in the management of the patient. Thus, simple abdominal radiography, intravenous urography, ultrasound, computed tomography and magnetic resonance imaging are cited [109].

#### **8.4 Imaging exams**

The anatomical identification of most areas of infection has become common with the development of high resolution cross-sectional images, which allow visualization of bacterial and viral metabolism, early diagnosis and treatment. Thus, the cross-sectional image was included as part of the routine investigation of unidentified infection sites and sources of sepsis. The trend is that the use of these images will become increasingly widespread and become part of standard clinical care in the near future [110].

#### *8.4.1 Ultrasonography*

When abdominal sepsis is suspected, ultrasound is a valuable tool. As it is a portable scanning technique, it is ideal for clinically unstable patients who cannot be transported to an examination room [110].

Ideal for the diagnosis of liver sepsis and gallbladder, ultrasound identifies and indicates the presence and location of intra-abdominal fluids (subphrenic space, in pericological calculations or pelvis) [110–113]. Intrahepatic fluids are also well visualized, and can even be drained percutaneously with ultrasound guidance [110].

The main obstacle for ultrasound responses is air interference, highlighted in loop regions of the intestine with intraluminal gas, since the USG image is darkened and makes it difficult to visualize interloop abscesses or peri-pancreatic collections. The intestine in patients with disease due to sepsis or recent intra-abdominal surgery is also capable of compromising the quality of the ultrasound [114].

#### *8.4.2 CT scanning*

The availability of CT scanners with multiple detectors allows rapid acquisition of images, making this method the most common in the diagnosis and detection of intra-abdominal abscesses [114, 115]. It is an interesting option especially for sick patients who have difficulty holding their breath, obese or with abdominal or chest bandages.

**107**

*Management of* E. coli *Sepsis*

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

CT even small infected collections [110].

and clinical applications, is still such an expensive tool.

investigation of infectious and inflammatory diseases [120].

**9. General management of sepsis and septic shock**

*8.4.3 Hybrid PET/MRI systems*

strategies.

tional costs).

pathogens.

disease [110].

**9.1 Hemodynamic support**

**8.5 Biologic scanning**

stones), in addition to being highly sensitive in the detection of chest pathologies (pneumonia, pleural effusion and localized collections) [113, 115–117]. For intra-abdominal fluids and abscesses, CT showed a sensitivity of 90–100%, while

Due to the contemporary contrast protocols available, it is possible to identify by

With the development of hybrid cameras, the combination of PET and magnetic resonance imaging was introduced, which despite having interesting advantages

The simultaneous acquisition of PET and magnetic resonance imaging can provide quantitative molecular functional information about the inflammatory lesion and precise location, in addition to anatomical changes with movement correction, improving the differential diagnosis and guiding anti-inflammatory treatment

Since MRI cannot visualize all parts of the body at once, the new hybrid technique may require collaboration between radiologists and nuclear medicine doctors to interpret the image and can be more expensive than PET/CT (capital and opera-

The functional image of inflammation and infection was mainly restricted to the flat image and SPECT, however, with the increasing development of PET radiopharmaceuticals, the detection and quantification of specific aspects of inflammatory processes became more sensitive. Precisely for this reason, there is an interesting potential in the application of hybrid whole body PET/MRI in the context of the

Imaging technique that uses biological radionuclides to track hidden infections and improve the specificity of the infection diagnosis that allows the detection of early pathophysiological changes even when there are no apparent anatomical changes. When compared to ex vivo techniques (blood culture), in vivo biological screening is preferred since it is accurate, does not require a sterile environment and does not expose the health team to the risk of contamination by blood-borne

This type of tool is used mainly in patients suspected of infection or abscess, but who have had negative results for the cross-sectional image. Thus, the use of marked leukocyte traffic allows a response to hidden sites, based on the recognition of white blood cells marked with radionuclides. The marked leukocytes travel to the infection sites and allow noninvasive images in areas of hidden infection, such as osteomyelitis, orthopedic prosthesis, endocarditis or inflammation and intestinal

Adequate organ perfusion must be ensured. Hypotension should be managed initially with intravenous fluid administration and the goal should be maintenance

ultrasound showed sensitivity between 80% and 85% [115, 118, 119].

In addition, CT is essential in the diagnosis of interloop and retroperitoneal pathologies (including retroperitoneal abscesses or pancreatitis or intra-biliary

#### *Management of* E. coli *Sepsis DOI: http://dx.doi.org/10.5772/intechopen.93132*

stones), in addition to being highly sensitive in the detection of chest pathologies (pneumonia, pleural effusion and localized collections) [113, 115–117]. For intra-abdominal fluids and abscesses, CT showed a sensitivity of 90–100%, while ultrasound showed sensitivity between 80% and 85% [115, 118, 119].

Due to the contemporary contrast protocols available, it is possible to identify by CT even small infected collections [110].

#### *8.4.3 Hybrid PET/MRI systems*

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

[103, 107].

otic to be used [108].

**8.4 Imaging exams**

care in the near future [110].

be transported to an examination room [110].

*8.4.1 Ultrasonography*

ultrasound [114].

*8.4.2 CT scanning*

**8.3 Localization of underlying abnormality**

Two to four sets of blood samples should be collected, whenever possible, at independent locations [103–106]. For adults, the volume required for the examination varies between 40 and 160 mL of blood, and for babies and children, the volume is age-based and does not exceed 1% of the patient's total blood volume

The importance of blood culture, as well as urine, is related to the determination of the bacteria and the antibiogram, which directs the treatment to the best antibi-

In some cases, it is possible to suspect a complicated urinary tract infection/ urosepsis without being serious urological abnormalities. In such cases, there are some screening options that can be performed to assist in the management of the patient. Thus, simple abdominal radiography, intravenous urography, ultrasound,

The anatomical identification of most areas of infection has become common with the development of high resolution cross-sectional images, which allow visualization of bacterial and viral metabolism, early diagnosis and treatment. Thus, the cross-sectional image was included as part of the routine investigation of unidentified infection sites and sources of sepsis. The trend is that the use of these images will become increasingly widespread and become part of standard clinical

When abdominal sepsis is suspected, ultrasound is a valuable tool. As it is a portable scanning technique, it is ideal for clinically unstable patients who cannot

Ideal for the diagnosis of liver sepsis and gallbladder, ultrasound identifies and indicates the presence and location of intra-abdominal fluids (subphrenic space, in pericological calculations or pelvis) [110–113]. Intrahepatic fluids are also well visualized, and can even be drained percutaneously with ultrasound guidance [110]. The main obstacle for ultrasound responses is air interference, highlighted in loop regions of the intestine with intraluminal gas, since the USG image is darkened and makes it difficult to visualize interloop abscesses or peri-pancreatic collections. The intestine in patients with disease due to sepsis or recent intra-abdominal surgery is also capable of compromising the quality of the

The availability of CT scanners with multiple detectors allows rapid acquisition of images, making this method the most common in the diagnosis and detection of intra-abdominal abscesses [114, 115]. It is an interesting option especially for sick patients who have difficulty holding their breath, obese or with abdominal or chest

In addition, CT is essential in the diagnosis of interloop and retroperitoneal pathologies (including retroperitoneal abscesses or pancreatitis or intra-biliary

computed tomography and magnetic resonance imaging are cited [109].

**106**

bandages.

With the development of hybrid cameras, the combination of PET and magnetic resonance imaging was introduced, which despite having interesting advantages and clinical applications, is still such an expensive tool.

The simultaneous acquisition of PET and magnetic resonance imaging can provide quantitative molecular functional information about the inflammatory lesion and precise location, in addition to anatomical changes with movement correction, improving the differential diagnosis and guiding anti-inflammatory treatment strategies.

Since MRI cannot visualize all parts of the body at once, the new hybrid technique may require collaboration between radiologists and nuclear medicine doctors to interpret the image and can be more expensive than PET/CT (capital and operational costs).

The functional image of inflammation and infection was mainly restricted to the flat image and SPECT, however, with the increasing development of PET radiopharmaceuticals, the detection and quantification of specific aspects of inflammatory processes became more sensitive. Precisely for this reason, there is an interesting potential in the application of hybrid whole body PET/MRI in the context of the investigation of infectious and inflammatory diseases [120].

#### **8.5 Biologic scanning**

Imaging technique that uses biological radionuclides to track hidden infections and improve the specificity of the infection diagnosis that allows the detection of early pathophysiological changes even when there are no apparent anatomical changes. When compared to ex vivo techniques (blood culture), in vivo biological screening is preferred since it is accurate, does not require a sterile environment and does not expose the health team to the risk of contamination by blood-borne pathogens.

This type of tool is used mainly in patients suspected of infection or abscess, but who have had negative results for the cross-sectional image. Thus, the use of marked leukocyte traffic allows a response to hidden sites, based on the recognition of white blood cells marked with radionuclides. The marked leukocytes travel to the infection sites and allow noninvasive images in areas of hidden infection, such as osteomyelitis, orthopedic prosthesis, endocarditis or inflammation and intestinal disease [110].

#### **9. General management of sepsis and septic shock**

#### **9.1 Hemodynamic support**

Adequate organ perfusion must be ensured. Hypotension should be managed initially with intravenous fluid administration and the goal should be maintenance of pulmonary capillary wedge pressure at 12–16 mm Hg or central venous pressure at 8–12 cm H2O. Urine output rate should be kept at greater than 0.5 mL/kg/hr. A mean arterial blood pressure of greater than 65 mmHg (systolic blood pressure greater than 90 mmHg) and a cardiac index of greater than or equal to 4 L/min/ m2 should be maintained. Vasopressor therapy should be initiated in the event of failure to achieve these goals with iv fluids alone. These include dopamine, dobutamine and norepinephrine [109].

#### **9.2 Respiratory support**

Ventilatory support should be provided for patients with progressive hypoxemia, hypercapnia, altered sensorium or respiratory muscle fatigue. A study of "early goal directed therapy" (EGDT) found that prompt resuscitation to maintain SvO2 > 70% was associated with improved survival in patients of severe sepsis [121]. In this study, failure to maintain saturation after fluids and vasopressors was followed by erythrocyte infusion to raise hematocrit to 30%. Patients requiring mechanical ventilation should be adequately sedated and stress ulcer prophylaxis should be administered.

#### **9.3 Metabolic support**

Blood glucose levels should be maintained at less than 150 mg/dL during initial few days of severe sepsis and normoglycemic range could be targeted later. Frequent blood glucose monitoring should be done to avoid hypoglycemia in patients on intensive insulin therapy. Multi-organ dysfunction, if any should be managed. Disseminated intravascular coagulation, if accompanied by major bleeding, should be treated with fresh-frozen plasma and platelet transfusion. Hypercatabolic individuals with acute renal failure benefit substantially from hemodialysis or hemofiltration. Prophylaxis for deep vein thrombosis and nutritional supplementation should be undertaken [109].

## **10. Treatment of carbapenem-resistant Enterobacteriaceae**

#### **10.1 Monotherapy vs. combination therapy for treatment**

Considering the limited knowledge about the combination of antibiotics, the susceptibility of these pathogens to drugs and the lack of evidence to support the routine use of combined antimicrobial therapy, the decision regarding the ideal therapy is the responsibility of medical professionals [122]. Regarding the most appropriate approach, it is prioritized in the literature that the optimization of antimicrobial therapy includes adaptation of the appropriate antibiotics in terms of class, dose, frequency, route and duration [123].

The combination of different antibiotics has been widely used by large centers when it comes to invasive infections by multi-resistant Gram-negative bacteria [122].

#### *10.1.1 Positive and negative aspects of combination therapy for treatment*

The various positive and negative aspects of combination therapy are depicted in **Table 3**.

**109**

*Management of* E. coli *Sepsis*

**treatment**

support its use

**10.2 Colistin**

**Table 3.**

antibiotics [124]

**10.3 Carbapenems**

mediated by plasmids.

and NDM of b-lactamase [131].

**10.4 Tigecycline and other tetracyclines**

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

**Positive aspects of combination therapy for** 

1. Greater probability of choosing an effective agent and well-founded theoretical reasons to

2. Considering the increase in mortality related to the delay in the establishment of treatment and delays in appropriate and effective antimicrobial treatment, it is prudent to initiate empirical broad-spectrum antimicrobial treatment in the first suspected infection in critically ill patients 3. Indicated for patients with compromised immune systems, previous ICU admissions or who have recently received broad-spectrum

*Comparison of positive and negative aspects of combination therapy.*

Antibiotics such as colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB), and when the pathogen does not respond to colistin, therapeutic options are severely restricted. Thus, it becomes

The combination of colistin + salicylate + potent efflux pump inhibitor (BC1) has been documented with highly positive results, providing a connection between colistin and the efflux pump inhibitor (BC1), which prevents extrusion of colistin [126]. The reduction in affinity between the drug and Gram-negative bacteria is due to the modification of lipid A, linked to the appearance of the gene that confers resistance to bacteria, which is present in animals that receive colistin and are part of human food. Despite this, there is still no complete explanation of the mutation and resistance of Gram-negative bacteria (especially Enterobacteriaceae) in patients

**Negative aspects of combination therapy for** 

1. Increased toxicity in treatment by combining antibiotics (nephrotoxicity and ototoxicity). In such cases, it is suggested to discontinue the old therapy and introduce a new one, based on the clinical evolution of the patient and the results of the culture and

2. This type of therapy has not been shown to be effective by clinical data (meta-analyses performed with the evaluation of randomized clinical trials demonstrate that there was no difference in clinical results between the two strategies for definitive treatment of Gram-negative bacteria infections) [124]

**treatment**

susceptibility profile

Due to the increased resistance of bacteria to cephalosporin (and aminopenicillins), the use of narrow-spectrum β-lactamases, especially carbapenems, has increased considerably, being the only β-lactamase antibiotics with proven effec-

With the discovery of *E. coli* isolates capable of producing new b-lactamases, a new strain of *E. coli* was found capable of resisting the action of carbapenems,

These enzymes are able to confer resistance to drugs of the class b-lactamases, and in relation to *E. coli* specifically, the main types of enzymes are CMY, CTX-M

Tigecycline is a new expanded-spectrum antimicrobial agent in the glycylcycline

class. Developed with the objective of overcoming the most common processes of bacterial resistance, the drug has emerged as a great therapeutic option in the

tiveness in serious infections due to ESBL-producing bacteria [128–130].

necessary to restore the sensitivity of the pathogen to the drug [125].

who received administered colistin [127].


#### **Table 3.**

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

of pulmonary capillary wedge pressure at 12–16 mm Hg or central venous pressure at 8–12 cm H2O. Urine output rate should be kept at greater than 0.5 mL/kg/hr. A mean arterial blood pressure of greater than 65 mmHg (systolic blood pressure greater than 90 mmHg) and a cardiac index of greater than or equal to 4 L/min/

 should be maintained. Vasopressor therapy should be initiated in the event of failure to achieve these goals with iv fluids alone. These include dopamine, dobuta-

Ventilatory support should be provided for patients with progressive hypoxemia, hypercapnia, altered sensorium or respiratory muscle fatigue. A study of "early goal directed therapy" (EGDT) found that prompt resuscitation to maintain SvO2 > 70% was associated with improved survival in patients of severe sepsis [121]. In this study, failure to maintain saturation after fluids and vasopressors was followed by erythrocyte infusion to raise hematocrit to 30%. Patients requiring mechanical ventilation should be adequately sedated and stress ulcer prophylaxis

Blood glucose levels should be maintained at less than 150 mg/dL during initial few days of severe sepsis and normoglycemic range could be targeted later. Frequent blood glucose monitoring should be done to avoid hypoglycemia in patients on intensive insulin therapy. Multi-organ dysfunction, if any should be managed. Disseminated intravascular coagulation, if accompanied by major bleeding, should be treated with fresh-frozen plasma and platelet transfusion. Hypercatabolic individuals with acute renal failure benefit substantially from hemodialysis or hemofiltration. Prophylaxis for deep vein thrombosis and nutritional supplementa-

Considering the limited knowledge about the combination of antibiotics, the susceptibility of these pathogens to drugs and the lack of evidence to support the routine use of combined antimicrobial therapy, the decision regarding the ideal therapy is the responsibility of medical professionals [122]. Regarding the most appropriate approach, it is prioritized in the literature that the optimization of antimicrobial therapy includes adaptation of the appropriate antibiotics in terms of

The combination of different antibiotics has been widely used by large centers when it comes to invasive infections by multi-resistant Gram-negative

The various positive and negative aspects of combination therapy are depicted

*10.1.1 Positive and negative aspects of combination therapy for treatment*

**10. Treatment of carbapenem-resistant Enterobacteriaceae**

**10.1 Monotherapy vs. combination therapy for treatment**

class, dose, frequency, route and duration [123].

**108**

bacteria [122].

in **Table 3**.

m2

mine and norepinephrine [109].

**9.2 Respiratory support**

should be administered.

**9.3 Metabolic support**

tion should be undertaken [109].

*Comparison of positive and negative aspects of combination therapy.*

#### **10.2 Colistin**

Antibiotics such as colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB), and when the pathogen does not respond to colistin, therapeutic options are severely restricted. Thus, it becomes necessary to restore the sensitivity of the pathogen to the drug [125].

The combination of colistin + salicylate + potent efflux pump inhibitor (BC1) has been documented with highly positive results, providing a connection between colistin and the efflux pump inhibitor (BC1), which prevents extrusion of colistin [126].

The reduction in affinity between the drug and Gram-negative bacteria is due to the modification of lipid A, linked to the appearance of the gene that confers resistance to bacteria, which is present in animals that receive colistin and are part of human food. Despite this, there is still no complete explanation of the mutation and resistance of Gram-negative bacteria (especially Enterobacteriaceae) in patients who received administered colistin [127].

#### **10.3 Carbapenems**

Due to the increased resistance of bacteria to cephalosporin (and aminopenicillins), the use of narrow-spectrum β-lactamases, especially carbapenems, has increased considerably, being the only β-lactamase antibiotics with proven effectiveness in serious infections due to ESBL-producing bacteria [128–130].

With the discovery of *E. coli* isolates capable of producing new b-lactamases, a new strain of *E. coli* was found capable of resisting the action of carbapenems, mediated by plasmids.

These enzymes are able to confer resistance to drugs of the class b-lactamases, and in relation to *E. coli* specifically, the main types of enzymes are CMY, CTX-M and NDM of b-lactamase [131].

#### **10.4 Tigecycline and other tetracyclines**

Tigecycline is a new expanded-spectrum antimicrobial agent in the glycylcycline class. Developed with the objective of overcoming the most common processes of bacterial resistance, the drug has emerged as a great therapeutic option in the

treatment of serious infections, which endanger the patient's life, and which no longer respond to traditional antibiotics. The use of tigecycline is mainly interesting for the initial therapy of major infections, and is largely effective in the action against multi-resistant Gram-negative bacteria [132].

#### **10.5 Aminoglycosides**

Aminoglycosides are natural or semi-synthetic drugs obtained from actinomycetes, used as an antibiotic since the beginning of bacterial treatment. As it was replaced in the 1980s by cephalosporins, carbapenems and fluoroquinolones, aminoglycosides had little use.

With the increase in the number of cases of multidrug-resistant bacteria, aminoglycosides were again considered for their ability to synergize with a variety of other classes of antibacterials, improving the safety and effectiveness of the class through optimized dosing regimens, being broad-spectrum and quickly bactericidal.

Enzymatic modification by acetylation of an amino group, impaired uptake and phosphorylation of aminoglycosides are the most commonly reported processes that confer resistance to bacteria in relation to aminoglycosides [133].

#### **10.6 Fosfomycin**

Fosfomycin is an antibiotic from the 1969s, prescribed mainly in its oral form for the treatment of uncomplicated urinary tract infections (UTI), and considered as an option in the treatment of bacteria with advanced resistance, causing serious infections [134].

For *E. coli* NDM-producing strains, fosfomycin, colistin and tigecycline are more effective than other antibiotics [135].

The best pharmacological approach to *E. coli* infections resistant to carbapenems is still an obstacle to be overcome, since patients infected with this type of bacteria have more limited clinical results and when compared to patients infected with bacteria susceptible to drugs [136].

#### **10.7 Duration of therapy**

The duration of treatment for infection caused by *Escherichia coli* varies in the literature, but most patients require treatment for about 14–21 days [109]. For *E. coli* perinephric abscesses or prostatitis, it is recommended that the minimum antibiotic use time should be 6 weeks, intra-abdominal infections 14–21 days, and pneumonia 14 days (**Table 4**) [137].


**Table 4.**

*Recommended duration of antibiotic therapy depending upon the type of infection.*

#### **11. Special considerations**

#### **11.1 Urinary infections in diabetes mellitus**

In general, infectious diseases occur more frequently and cause greater concern when dealing with diabetic patients. This occurs because the environment offered

**111**

*Management of* E. coli *Sepsis*

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

commonly found uropathogens [140, 141].

treatment for this portion of patients [142].

most common etiological agent [144, 145].

antimicrobial regimen [148, 149].

less in the community [153].

with the condition) [156].

diabetes mellitus [157, 158].

ment was successful or not [155].

**11.3 Emphysematous pyelonephritis**

than 100,000 eventually requiring hospitalization [146].

**11.2 Acute pyelonephritis**

by the organism is rich in glucose, which favors immune dysfunction, including

Moreover, when comparing *E. coli* isolated in the urine of diabetics and nondiabetics, the same virulence factors and the same resistance to antimicrobials are found, inferring that there is no difference in the causative bacteria. This way, what makes the prevalence of urinary infections to be higher in diabetic patients is the greater adhesion of *E. coli* bacteria to diabetic uroepithelial cells, the reduction of

Hence, to treat the disease, the most commonly prescribed antimicrobials are used—amoxicillin, nitrofurantoin, trimethoprim/sulfamethoxazole (TMP/SMX) and ciprofloxacin. It is understood that the same treatment choice used by nondiabetic patients can be made, depending only on the local resistance patterns of the

Generally, most uropathogens have a high resistance to TMP/SMX, in addition, this antimicrobial can cause hypoglycemia, which makes it not a good first choice of

As for the treatment, it is recommended to consider the urinary tract infection complicated, it is advisable to keep the treatment for a period of 7 to 14 days [143].

Acute pyelonephritis is an infection located in the upper urinary tract, which accommodates either parenchyma and renal pelvis, with *Escherichia coli* being the

Approximately 250,000 cases of this disease are reported each year, with more

In order to confirm the diagnosis of the disease, the patient's urine culture is performed before the start of antibiotic therapy [147]. In addition, it is recommended to perform a microbial susceptibility test in order to select the most appropriate

If the diagnosis is uncertain or the patient is immunocompromised and suspected

On the other hand, in cases of complicated infections, sepsis or failed outpatient treatment, hospital treatment is best indicated [154]. After antibiotic therapy, urine culture should be performed again after 1–2 weeks to conclude whether the treat-

Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the renal parenchyma and its surrounding tissues—resulting in the presence of gas in the renal parenchyma, collecting system or perinephric tissue—and is caused in 70% of cases by *Escherichia coli* (isolated in cultures of urine or pus from patients

The clinical evolution of EPN when not recognized and treated immediately can be serious and pose a risk to the patient's life. Another fact that should be mentioned is that up to 95% of the cases of EPN are underlyingly associated with uncontrolled

of having a hematogenic infection, blood culture analysis is requested [150, 151]. In the last few decades, there has been an increasing rate of resistance of *E. coli* bacteria to beta-lactam antibiotics of extended spectrum [152]. Thus, for patients with mild and uncomplicated acute pyelonephritis, fluoroquinolone is a good choice for initial outpatient antibiotic therapy, if the drug resistance rate is 10% or

decreasing the antibacterial activity of the urine and its motility [138].

urinary cytokine secretion and the number of leukocytes [139].

#### *Management of* E. coli *Sepsis DOI: http://dx.doi.org/10.5772/intechopen.93132*

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

against multi-resistant Gram-negative bacteria [132].

**10.5 Aminoglycosides**

**10.6 Fosfomycin**

aminoglycosides had little use.

effective than other antibiotics [135].

bacteria susceptible to drugs [136].

**10.7 Duration of therapy**

14 days (**Table 4**) [137].

**11. Special considerations**

**11.1 Urinary infections in diabetes mellitus**

**Condition General Perinephric** 

**abscesses**

*Recommended duration of antibiotic therapy depending upon the type of infection.*

treatment of serious infections, which endanger the patient's life, and which no longer respond to traditional antibiotics. The use of tigecycline is mainly interesting for the initial therapy of major infections, and is largely effective in the action

Aminoglycosides are natural or semi-synthetic drugs obtained from actinomycetes, used as an antibiotic since the beginning of bacterial treatment. As it was replaced in the 1980s by cephalosporins, carbapenems and fluoroquinolones,

optimized dosing regimens, being broad-spectrum and quickly bactericidal.

that confer resistance to bacteria in relation to aminoglycosides [133].

With the increase in the number of cases of multidrug-resistant bacteria, aminoglycosides were again considered for their ability to synergize with a variety of other classes of antibacterials, improving the safety and effectiveness of the class through

Enzymatic modification by acetylation of an amino group, impaired uptake and phosphorylation of aminoglycosides are the most commonly reported processes

Fosfomycin is an antibiotic from the 1969s, prescribed mainly in its oral form for the treatment of uncomplicated urinary tract infections (UTI), and considered as an option in the treatment of bacteria with advanced resistance, causing serious infections [134]. For *E. coli* NDM-producing strains, fosfomycin, colistin and tigecycline are more

The best pharmacological approach to *E. coli* infections resistant to carbapenems is still an obstacle to be overcome, since patients infected with this type of bacteria have more limited clinical results and when compared to patients infected with

The duration of treatment for infection caused by *Escherichia coli* varies in the literature, but most patients require treatment for about 14–21 days [109]. For *E. coli* perinephric abscesses or prostatitis, it is recommended that the minimum antibiotic use time should be 6 weeks, intra-abdominal infections 14–21 days, and pneumonia

Duration 14–21 days 42 days 42 days 14–21 days 14 days

**Prostatitis Intra-abdominal infections**

**Pneumonia**

In general, infectious diseases occur more frequently and cause greater concern when dealing with diabetic patients. This occurs because the environment offered

**110**

**Table 4.**

by the organism is rich in glucose, which favors immune dysfunction, including decreasing the antibacterial activity of the urine and its motility [138].

Moreover, when comparing *E. coli* isolated in the urine of diabetics and nondiabetics, the same virulence factors and the same resistance to antimicrobials are found, inferring that there is no difference in the causative bacteria. This way, what makes the prevalence of urinary infections to be higher in diabetic patients is the greater adhesion of *E. coli* bacteria to diabetic uroepithelial cells, the reduction of urinary cytokine secretion and the number of leukocytes [139].

Hence, to treat the disease, the most commonly prescribed antimicrobials are used—amoxicillin, nitrofurantoin, trimethoprim/sulfamethoxazole (TMP/SMX) and ciprofloxacin. It is understood that the same treatment choice used by nondiabetic patients can be made, depending only on the local resistance patterns of the commonly found uropathogens [140, 141].

Generally, most uropathogens have a high resistance to TMP/SMX, in addition, this antimicrobial can cause hypoglycemia, which makes it not a good first choice of treatment for this portion of patients [142].

As for the treatment, it is recommended to consider the urinary tract infection complicated, it is advisable to keep the treatment for a period of 7 to 14 days [143].

#### **11.2 Acute pyelonephritis**

Acute pyelonephritis is an infection located in the upper urinary tract, which accommodates either parenchyma and renal pelvis, with *Escherichia coli* being the most common etiological agent [144, 145].

Approximately 250,000 cases of this disease are reported each year, with more than 100,000 eventually requiring hospitalization [146].

In order to confirm the diagnosis of the disease, the patient's urine culture is performed before the start of antibiotic therapy [147]. In addition, it is recommended to perform a microbial susceptibility test in order to select the most appropriate antimicrobial regimen [148, 149].

If the diagnosis is uncertain or the patient is immunocompromised and suspected of having a hematogenic infection, blood culture analysis is requested [150, 151].

In the last few decades, there has been an increasing rate of resistance of *E. coli* bacteria to beta-lactam antibiotics of extended spectrum [152]. Thus, for patients with mild and uncomplicated acute pyelonephritis, fluoroquinolone is a good choice for initial outpatient antibiotic therapy, if the drug resistance rate is 10% or less in the community [153].

On the other hand, in cases of complicated infections, sepsis or failed outpatient treatment, hospital treatment is best indicated [154]. After antibiotic therapy, urine culture should be performed again after 1–2 weeks to conclude whether the treatment was successful or not [155].

#### **11.3 Emphysematous pyelonephritis**

Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the renal parenchyma and its surrounding tissues—resulting in the presence of gas in the renal parenchyma, collecting system or perinephric tissue—and is caused in 70% of cases by *Escherichia coli* (isolated in cultures of urine or pus from patients with the condition) [156].

The clinical evolution of EPN when not recognized and treated immediately can be serious and pose a risk to the patient's life. Another fact that should be mentioned is that up to 95% of the cases of EPN are underlyingly associated with uncontrolled diabetes mellitus [157, 158].

In addition to the risk of developing EPN primarily, the risk of developing secondary to an obstruction of the urinary tract is considerably relevant, about 25–40% can be considered as positive findings in EPN [159, 160].

The combination of percutaneous drainage (PCD) and medical management (MM) revealed a significant reduction in mortality rates [161, 162]. Thus, it is recommended that PCD be performed in patients with localized areas of gas and the presence of functional renal tissue. Another approach that can be used in association with treatment is emergency nephrectomy, classified as simple, radical or laparoscopic [163].

#### **11.4 Renal abscess**

Being caused by kidney stones, structural abnormality, history of urological surgery, trauma or any other cause of obstruction, renal abscess can also be related to pathogens [164]. The predominant organisms causing renal abscesses are Gramnegative organisms, and the most common is *Escherichia coli* [165–167].

Among the various intra-abdominal abscesses, renal abscess is a rare entity, especially in children and accounts for a number of cases of "missed diagnoses" [166, 168]*.*

With regard to the symptoms of pediatric patients, the presentation of fever, flank pain, with or without a palpable mass, has been established in the literature; increased leukocyte count and increased erythrocyte sedimentation rate [169].

Early diagnosis is a key factor in the management of these patients, which can be aided by Ultrasound (USG). Drainage of pus and appropriate antibiotic therapy is the gold standard for treatment, being able to treat a great amount of cases. Thereby, the most successful combination of antibiotics was ceftriaxone, being associated with amikacin. Cases that cannot be resolved by the conventional approach can be treated with surgery, such as nephrectomy. Thus, complications such as extension of the peritoneal cavity, skin or chest can be avoided [166, 167].

#### **11.5 Perinephric abscess**

Perinephric abscess results from perirenal fatty necrosis, usually a complication of urological infection (more than 75%) [170]. Most of these abscesses have *Escherichia coli* as the main responsible, about 51.4% [171]. Perinephric abscess, when more diffuse, is capable of affecting the renal capsule and also Gerota's fascia [170]. Since the condition has an insidious onset of nonspecific protein symptoms, it is necessary for a clinical physician to maintain a high level of attention to avoid possible delay in diagnosis, since perinephric abscesses are associated with significant morbidity and mortality [172].

#### **11.6 Renal papillary necrosis**

Renal papillary necrosis (NPN) is a condition defined as ischemic necrobiosis of the papilla in the kidney medulla. Among several etiological factors important for the involvement of papillary necrosis, pyelonephritis due to bacterial uropathogens such as *E. coli* is one of those mentioned in the literature [173].

In order to improve the prognosis of the disease and reduce morbidity, the ideal is that the diagnosis of the disease is as early as possible. In this sense, it is clear that the radiological image is able to offer an early diagnosis and guidance in relation to the immediate treatment of papillary necrosis, thus minimizing the decline in renal function [174].

**113**

*Management of* E. coli *Sepsis*

**11.7 Prostatic abscess**

related to the clinical picture.

additional therapies [176].

metabolism to avoid complications.

**12. Prevention**

**13. Conclusion**

*DOI: http://dx.doi.org/10.5772/intechopen.93132*

complications, such as prostate abscess or fistula [175].

Failure to respond to standard therapy for acute bacterial prostatitis can lead to

Acute bacterial prostatitis is a common and clinically important genitourinary disorder that has a higher incidence in patients with diabetes, cirrhosis and suppressed immune system. Usually caused by an ascending infection, it can also be triggered by organisms that cause other common genitourinary infections that may also be responsible for acute bacterial prostatitis. Being introduced during transrectal prostate biopsy, the clinical presentation ranges from mild symptoms of the lower urinary tract to total sepsis, and *Escherichia coli* is one of the main bacteria

Regarding the therapeutic approach, oral or intravenous antibiotics are most effective in curing the infection. In this sense, the progression to chronic bacterial prostatitis is uncommon. It should be noted that special attention is needed in relation to immunosuppressed patients, whereas bacterial prostatitis in these patients may be caused by atypical infecting organisms and, therefore, may require

It is already known that iron is an essential micronutrient for most bacteria and hosts, in this thought line, it is also known that there are relatively rare classical siderophilic pathogens that cause an increase in hepcidin in the body, responsible for the sequestration of iron for macrophages and enterocytes and, consequently hypoferremia [177–180]. So, current studies investigate if this mechanism used by the body against rare siderophilic bacteria, it also works for a wider set of bacteria. Results of these studies are shown to be positive, by demonstrating that excess iron allows rapid bacterial replication and spread, which means a susceptibility to infection caused by *E. coli* and that hepcidin is essential to protect against infections caused by *Escherichia coli.* [181, 182]*.* Thus, the use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron

With regard to urinary tract infection, an effective preventive measure is the characterization and correction of the underlying genitourinary abnormalities that promote the infection. Another alternative mentioned in the literature is the future

Early symptom recognition, followed by appropriate investigations, accurate diagnosis and early goal-directed therapy, is essential to improve results. Patient management includes an interprofessional team approach, with microbiologists,

development of catheters whose material limits the growth of biofilm [109].

radiologists, surgeons and intensive care physicians [109].

#### **11.7 Prostatic abscess**

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

25–40% can be considered as positive findings in EPN [159, 160].

or laparoscopic [163].

**11.4 Renal abscess**

[166, 168]*.*

**11.5 Perinephric abscess**

cant morbidity and mortality [172].

**11.6 Renal papillary necrosis**

In addition to the risk of developing EPN primarily, the risk of developing secondary to an obstruction of the urinary tract is considerably relevant, about

The combination of percutaneous drainage (PCD) and medical management (MM) revealed a significant reduction in mortality rates [161, 162]. Thus, it is recommended that PCD be performed in patients with localized areas of gas and the presence of functional renal tissue. Another approach that can be used in association with treatment is emergency nephrectomy, classified as simple, radical

Being caused by kidney stones, structural abnormality, history of urological surgery, trauma or any other cause of obstruction, renal abscess can also be related to pathogens [164]. The predominant organisms causing renal abscesses are Gram-

Among the various intra-abdominal abscesses, renal abscess is a rare entity, especially in children and accounts for a number of cases of "missed diagnoses"

With regard to the symptoms of pediatric patients, the presentation of fever, flank pain, with or without a palpable mass, has been established in the literature; increased leukocyte count and increased erythrocyte sedimentation rate [169]. Early diagnosis is a key factor in the management of these patients, which can be aided by Ultrasound (USG). Drainage of pus and appropriate antibiotic therapy is the gold standard for treatment, being able to treat a great amount of cases. Thereby, the most successful combination of antibiotics was ceftriaxone, being associated with amikacin. Cases that cannot be resolved by the conventional approach can be treated with surgery, such as nephrectomy. Thus, complications such as extension of the peritoneal cavity, skin or chest can be avoided [166, 167].

Perinephric abscess results from perirenal fatty necrosis, usually a complication of urological infection (more than 75%) [170]. Most of these abscesses have *Escherichia coli* as the main responsible, about 51.4% [171]. Perinephric abscess, when more diffuse, is capable of affecting the renal capsule and also Gerota's fascia [170]. Since the condition has an insidious onset of nonspecific protein symptoms, it is necessary for a clinical physician to maintain a high level of attention to avoid possible delay in diagnosis, since perinephric abscesses are associated with signifi-

Renal papillary necrosis (NPN) is a condition defined as ischemic necrobiosis of the papilla in the kidney medulla. Among several etiological factors important for the involvement of papillary necrosis, pyelonephritis due to bacterial uropathogens

In order to improve the prognosis of the disease and reduce morbidity, the ideal is that the diagnosis of the disease is as early as possible. In this sense, it is clear that the radiological image is able to offer an early diagnosis and guidance in relation to the immediate treatment of papillary necrosis, thus minimizing the decline in renal

such as *E. coli* is one of those mentioned in the literature [173].

negative organisms, and the most common is *Escherichia coli* [165–167].

**112**

function [174].

Failure to respond to standard therapy for acute bacterial prostatitis can lead to complications, such as prostate abscess or fistula [175].

Acute bacterial prostatitis is a common and clinically important genitourinary disorder that has a higher incidence in patients with diabetes, cirrhosis and suppressed immune system. Usually caused by an ascending infection, it can also be triggered by organisms that cause other common genitourinary infections that may also be responsible for acute bacterial prostatitis. Being introduced during transrectal prostate biopsy, the clinical presentation ranges from mild symptoms of the lower urinary tract to total sepsis, and *Escherichia coli* is one of the main bacteria related to the clinical picture.

Regarding the therapeutic approach, oral or intravenous antibiotics are most effective in curing the infection. In this sense, the progression to chronic bacterial prostatitis is uncommon. It should be noted that special attention is needed in relation to immunosuppressed patients, whereas bacterial prostatitis in these patients may be caused by atypical infecting organisms and, therefore, may require additional therapies [176].

#### **12. Prevention**

It is already known that iron is an essential micronutrient for most bacteria and hosts, in this thought line, it is also known that there are relatively rare classical siderophilic pathogens that cause an increase in hepcidin in the body, responsible for the sequestration of iron for macrophages and enterocytes and, consequently hypoferremia [177–180]. So, current studies investigate if this mechanism used by the body against rare siderophilic bacteria, it also works for a wider set of bacteria. Results of these studies are shown to be positive, by demonstrating that excess iron allows rapid bacterial replication and spread, which means a susceptibility to infection caused by *E. coli* and that hepcidin is essential to protect against infections caused by *Escherichia coli.* [181, 182]*.* Thus, the use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism to avoid complications.

With regard to urinary tract infection, an effective preventive measure is the characterization and correction of the underlying genitourinary abnormalities that promote the infection. Another alternative mentioned in the literature is the future development of catheters whose material limits the growth of biofilm [109].

#### **13. Conclusion**

Early symptom recognition, followed by appropriate investigations, accurate diagnosis and early goal-directed therapy, is essential to improve results. Patient management includes an interprofessional team approach, with microbiologists, radiologists, surgeons and intensive care physicians [109].

#### **Author details**

Akshay Kumar1 \*, Ana Francesca Vommaro Leite2 , Lais Sanches Maekawa<sup>2</sup> , Roopvir Kaur3 , Silas Jose Braz Filo2 , Purnadeo Persaud4 , Juber Dastagir Shaikh<sup>5</sup> , Asim Kichloo6 and Nimisha Shiwalkar7

1 Medanta Hospital, Gurugram, India

2 University of Minas Gerais, Brazil

3 Government Medical College, Amritsar, India


\*Address all correspondence to: drakshay82@gmail.com

© 2020 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.

**115**

*Management of* E. coli *Sepsis*

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[8] Donnenberg MS. Capítulo 220: Enterobacteriaceae. In: Mandell GL, Bennett JE, Dolin R, Blase MJ, editors. Mandell, Douglas y Bennett. Enfermedades Infecciosas. Principios y Práctica. 8va Edición ed. España: Elsevier; 2016. pp. 2640-2655

[9] Artico MJ, Rocchi M, Gasparotto A,

Mollo V, et al. Bacteriemias de origen comunitario en pacientes adultos que acuden al servicio de urgencias de un

Ocaña Carrizo V, Navarro M,

2019;**26**(4):532-537

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*DOI: http://dx.doi.org/10.5772/intechopen.93132*

hospital universitario. Revista Argentina de Microbiología. 2012;**44**(1):10-15

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[13] Biran D, Ron EZ. Extraintestinal pathogenic *Escherichia coli*. Current

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[15] Peralta G, Sanchez MB, Garrido JC, et al. Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with *Escherichia coli* bacteraemia. The Journal of Antimicrobial Chemotherapy.

[16] Melzer M, Petersen I. Mortality following bacteraemic infection caused by extended spectrum beta-lactamase (ESBL) producing E. coli compared to non-ESBL producing *E. coli*. The Journal

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[12] Mora-Rillo M, Fernández-

[1] Foxman B. The epidemiology of urinary tract infection. Nature Reviews.

[2] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews. Microbiology. 2004;**2**:123-140

[3] Kim KS. Current concepts on the pathogenesis of *Escherichia coli* meningitis: Implications for therapy and prevention. Current Opinion in Infectious Diseases. 2012;**25**:273-278

[4] Leimbach A, Hacker J, Dobrindt U. *E. coli* as an all-rounder: The thin line between commensalism and pathogenicity. Current Topics in Microbiology and Immunology.

gastrointestinal microflora. Trends in

#### **References**

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

\*, Ana Francesca Vommaro Leite2

, Purnadeo Persaud4

6 Department of Internal Medicine, Central Michigan University, United States

7 University of Texas Southwestern Medical Center, Dallas, Texas, United States

© 2020 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,

, Silas Jose Braz Filo2

3 Government Medical College, Amritsar, India

4 Kansas City University, Kansas City, United States

\*Address all correspondence to: drakshay82@gmail.com

1 Medanta Hospital, Gurugram, India

2 University of Minas Gerais, Brazil

5 MGM Hospital, Navi Mumbai, India

provided the original work is properly cited.

and Nimisha Shiwalkar7

, Lais Sanches Maekawa<sup>2</sup>

, Juber Dastagir Shaikh<sup>5</sup>

,

,

**114**

**Author details**

Akshay Kumar1

Roopvir Kaur3

Asim Kichloo6

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[2] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews. Microbiology. 2004;**2**:123-140

[3] Kim KS. Current concepts on the pathogenesis of *Escherichia coli* meningitis: Implications for therapy and prevention. Current Opinion in Infectious Diseases. 2012;**25**:273-278

[4] Leimbach A, Hacker J, Dobrindt U. *E. coli* as an all-rounder: The thin line between commensalism and pathogenicity. Current Topics in Microbiology and Immunology. 2013;**358**:3-32

[5] Berg RD. The indigenous gastrointestinal microflora. Trends in Microbiology. 1996;**4**:430-435

[6] Gordon DM, Cowling A. The distribution and genetic structure of *Escherichia coli* in Australian vertebrates: Host and geographic effects. Microbiology. 2003;**149**:3575-3586

[7] Wasiński B. Extra-intestinal pathogenic *Escherichia coli*-threat connected with food-borne infections. Annals of Agricultural and Environmental Medicine. 2019;**26**(4):532-537

[8] Donnenberg MS. Capítulo 220: Enterobacteriaceae. In: Mandell GL, Bennett JE, Dolin R, Blase MJ, editors. Mandell, Douglas y Bennett. Enfermedades Infecciosas. Principios y Práctica. 8va Edición ed. España: Elsevier; 2016. pp. 2640-2655

[9] Artico MJ, Rocchi M, Gasparotto A, Ocaña Carrizo V, Navarro M, Mollo V, et al. Bacteriemias de origen comunitario en pacientes adultos que acuden al servicio de urgencias de un

hospital universitario. Revista Argentina de Microbiología. 2012;**44**(1):10-15

[10] Salyers AA, Whitt DD. Bacterial Pathogenesis: A Molecular Approach. Washington, DC: ASM Press; 2002

[11] Bertani B, Ruiz N. Function and biogenesis of lipopolysaccharides. EcoSal Plus. 2018;**8**(1)

[12] Mora-Rillo M, Fernández-Romero N, Navarro-San Francisco C, Díez-Sebastián J, Romero-Gómez MP, Fernández FA, et al. Impact of virulence genes on sepsis severity and survival in *Escherichia coli* bacteremia. Virulence. 2015;**6**(1):93-100

[13] Biran D, Ron EZ. Extraintestinal pathogenic *Escherichia coli*. Current Topics in Microbiology and Immunology. 2018;**416**:149-161

[14] Mendoza-Palomar N, Balasch-Carulla M, González-Di Lauro S, et al. *Escherichia coli* early-onset sepsis: Trends over two decades. European Journal of Pediatrics. 2017;**176**(9):1227-1234

[15] Peralta G, Sanchez MB, Garrido JC, et al. Impact of antibiotic resistance and of adequate empirical antibiotic treatment in the prognosis of patients with *Escherichia coli* bacteraemia. The Journal of Antimicrobial Chemotherapy. 2007;**60**:855-863

[16] Melzer M, Petersen I. Mortality following bacteraemic infection caused by extended spectrum beta-lactamase (ESBL) producing E. coli compared to non-ESBL producing *E. coli*. The Journal of Infection. 2007;**55**:254-259

[17] Gransden WR, Eykyn SJ, Phillips I, Rowe B. Bacteremia due to *Escherichia coli*: A study of 861 episodes. Reviews of Infectious Diseases. 1990;**12**:1008-1018

[18] Laupland KB, Gregson DB, Church DL, Ross T, Pitout JD.

Incidence, risk factors and outcomes of *Escherichia coli* bloodstream infections in a large Canadian region. Clinical Microbiology and Infection. 2008;**14**(11):1041-1047

[19] Jackson LA, Benson P, Neuzil KM, Grandjean M, Marino JL. Burden of community-onset *Escherichia coli* bacteremia in seniors. The Journal of Infectious Diseases. 2005;**191**:1523-1529

[20] Katouli M. Population structure of gut *Escherichia coli* and its role in development of extra-intestinal infections. Iranian Journal of Microbiology. 2010;**2**(2):59

[21] Thursby E, Juge N. Introduction to the human gut microbiota. Biochemical Journal. 2017;**474**(11):1823-1836

[22] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews. Microbiology. 2004;**2**:123-140

[23] Croxen MA, Finlay BB. Molecular mechanisms of *Escherichia coli* pathogenicity. Nature Reviews. Microbiology. 2010;**8**:26-38

[24] Trabulsi LR, Keller R, Tardelli Gomes TA. Typical and atypical enteropathogenic *Escherichia coli*. Emerging Infectious Diseases. 2002;**8**:508-513

[25] Bieber D, Ramer SW, Wu CY, Murray WJ, Tobe T, Fernandez R, et al. Type IV pili, transient bacterial aggregates, and virulence of enteropathogenic *Escherichia coli*. Science. 1998;**280**:2114-2118

[26] Frankel G, Phillips AD, Rosenshine I, Dougan G, Kaper JB, Knutton S. Enteropathogenic and enterohaemorrhagic *Escherichia coli*: More subversive elements. Molecular Microbiology. 1998;**30**:911-921

[27] Gomez-Duarte OG, Kaper JB. A plasmid-encoded regulatory

region activates chromosomal eaeA expression in enteropathogenic *Escherichia coli*. Infection and Immunity. 1995;**63**:1767-1776

[28] Hu J, Torres AG. Enteropathogenic *Escherichia coli*: Foe or innocent bystander? Clinical Microbiology and Infection. 2015;**21**(8):729-734

[29] Gomes TAT, Elias WP, Scaletsky ICA, Guth BEC, Rodrigues JF, Piazza RMF, et al. Diarrheagenic *Escherichia coli*. Brazilian Journal of Microbiology. 2016;**47**(Suppl. 1):3-30

[30] Diepold A, Armitage JP. Type III secretion systems: The bacterial flagellum and the injectisome. Philosophical Transactions of the Royal Society, B: Biological Sciences. 2015;**370**(1679):20150020

[31] Berkes J, Viswanathan VK, Savkovic SD, Hecht G. Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut. 2003;**52**(3): 439-451

[32] Madhavan TP, Sakellaris H. Colonization factors of enterotoxigenic *Escherichia coli*. Advances in Applied Microbiology. 2015;**90**:155-197. DOI: 10.1016/bs.aambs.2014.09.003

[33] Loos M, Geens M, Schauvliege S, Gasthuys F, van der Meulen J, Dubreuil JD, et al. Role of heat-stable enterotoxins in the induction of early immune responses in piglets after infection with enterotoxigenic *Escherichia coli*. PLoS One. 2012;**7**:e41041

[34] Beltran AR, Carraro-Lacroix LR, Bezerra CN, Cornejo M, et al. *Escherichia coli* heat-stable enterotoxin mediates Na+ /H+ exchanger 4 inhibition involving cAMP in T84 human intestinal epithelial cells. PLoS One. 2015;**10**:e0146042

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two different populations. BMC Microbiology. 2013;**13**(1):22

[44] Sarowska J, Futoma-Koloch B, Jama-Kmiecik A, Frej-Madrzak M, Ksiazczyk, et al. Virulence factors, prevalence and potential transmission

Escherichia coli isolated from different sources: Recent reports. Gut Pathogens.

of extraintestinal pathogenic

[45] Smith JL, Fratamico PM, Gunther NW. Extraintestinal pathogenic *Escherichia coli*.

Foodborne Pathogens and Disease.

[46] Areda MA, Bailey CR, O'Mara D, Weiss CR. Transplant uretero-inguinal hernia resulting in urosepsis. Radiology

Case Reports. 2019;**14**(1):14-17

[47] Thornton HV, Hammond A, Hay AD. Urosepsis: A growing and preventable problem? The British Journal of General Practice.

[48] Fadel MG, Louis C, Tay A, Bolgeri M. Obstructive urosepsis secondary to ureteric herniation into the sciatic foramen. BML Case Reports.

in Urology. 2018;**10**:43-49

[50] Heppner HJ, Yapan F, Wiedemann A. Urosepsis in

2016;**47**(1):54-59

[49] Scotland KB, Lange D. Prevention and management of urosepsis triggered by ureteroscopy. Research and Reports

geriatric patients. Aktuelle Urologie.

[51] Goveas B. Urosepsis: A simple infection turns toxic. The Nurse Practitioner. 2017;**42**(7):53-54

[52] Porat A, Kesler S. Urosepsis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020

2018;**68**(675):493-494

2018 27;2018

2019;**11**(1):10

2007;**4**(2):134-163

enterotoxigenic *Escherichia coli*. Cellular Microbiology. 2006;**8**(9):1516-1527

[37] Ceponis PJ, Riff JD, Sherman PM. Epithelial cell signaling responses to enterohemorrhagic *Escherichia coli* infection. Memórias do Instituto Oswaldo Cruz. 2005;**100**:199-203

[38] Boyer O, Niaudet P. Hemolytic uremic syndrome: New developments in pathogenesis and treatment. International Journal of Nephrology.

[39] Polito MG, Kirsztajn GM. Microangiopatias trombóticas:

2010;**32**(3):303-315

púrpura trombocitopênica trombótica e síndrome hemolítico-urêmica. Brazilian Journal of Nephrology.

[40] Ud-Din A, Wahid S. Relationship among *Shigella* spp. and enteroinvasive *Escherichia coli* (EIEC) and their differentiation. Brazilian Journal of Microbiology. 2014;**45**(4):1131-1138

[41] Tulloch EF, Ryan KJ, Formal SB, Franklin FA. Invasive enteropathic *Escherichia coli* dysentery: An outbreak

[42] Jafari A, Aslani MM, Bouzari S. *Escherichia coli*: A brief review of diarrheagenic pathotypes and their role in diarrheal diseases in Iran. Iranian Journal of Microbiology. 2012;**4**(3):102

[43] Mansan-Almeida R, Pereira AL, Giugliano LG. Diffusely adherent *Escherichia coli* strains isolated from children and adults constitute

in 28 adults. Annals of Internal Medicine. 1973;**79**(1):13-17

Fleckenstein JM. Directed delivery of heat-labile enterotoxin by

[36] Sears CL, Kaper JB. Enteric bacterial toxins: Mechanisms of action and linkage to intestinal secretion. Microbiological Reviews.

1996;**60**(1):167

2011

*Management of* E. coli *Sepsis DOI: http://dx.doi.org/10.5772/intechopen.93132*

E. Coli *Infections - Importance of Early Diagnosis and Efficient Treatment*

region activates chromosomal eaeA expression in enteropathogenic

1995;**63**:1767-1776

*Escherichia coli*. Infection and Immunity.

[28] Hu J, Torres AG. Enteropathogenic *Escherichia coli*: Foe or innocent bystander? Clinical Microbiology and

Scaletsky ICA, Guth BEC, Rodrigues JF, Piazza RMF, et al. Diarrheagenic *Escherichia coli*. Brazilian Journal of Microbiology. 2016;**47**(Suppl. 1):3-30

[30] Diepold A, Armitage JP. Type III secretion systems: The bacterial flagellum and the injectisome. Philosophical Transactions of the Royal Society, B: Biological Sciences.

Infection. 2015;**21**(8):729-734

[29] Gomes TAT, Elias WP,

2015;**370**(1679):20150020

439-451

[31] Berkes J, Viswanathan VK, Savkovic SD, Hecht G. Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut. 2003;**52**(3):

[32] Madhavan TP, Sakellaris H.

Colonization factors of enterotoxigenic *Escherichia coli*. Advances in Applied Microbiology. 2015;**90**:155-197. DOI: 10.1016/bs.aambs.2014.09.003

[33] Loos M, Geens M, Schauvliege S, Gasthuys F, van der Meulen J,

Dubreuil JD, et al. Role of heat-stable enterotoxins in the induction of early immune responses in piglets after infection with enterotoxigenic

[34] Beltran AR, Carraro-Lacroix LR, Bezerra CN, Cornejo M, et al.

*Escherichia coli* heat-stable enterotoxin

exchanger 4 inhibition

*Escherichia coli*. PLoS One.

/H+

involving cAMP in T84 human intestinal epithelial cells. PLoS One.

2012;**7**:e41041

mediates Na+

2015;**10**:e0146042

Incidence, risk factors and outcomes of *Escherichia coli* bloodstream infections in a large Canadian region. Clinical Microbiology and Infection.

[19] Jackson LA, Benson P, Neuzil KM, Grandjean M, Marino JL. Burden of community-onset *Escherichia coli* bacteremia in seniors. The Journal of Infectious Diseases. 2005;**191**:1523-1529

[20] Katouli M. Population structure of gut *Escherichia coli* and its role in development of extra-intestinal infections. Iranian Journal of Microbiology. 2010;**2**(2):59

[21] Thursby E, Juge N. Introduction to the human gut microbiota. Biochemical

[22] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews. Microbiology. 2004;**2**:123-140

[23] Croxen MA, Finlay BB. Molecular

mechanisms of *Escherichia coli* pathogenicity. Nature Reviews. Microbiology. 2010;**8**:26-38

[24] Trabulsi LR, Keller R, Tardelli Gomes TA. Typical and atypical enteropathogenic *Escherichia coli*. Emerging Infectious Diseases.

[25] Bieber D, Ramer SW, Wu CY, Murray WJ, Tobe T, Fernandez R, et al. Type IV pili, transient bacterial

aggregates, and virulence of enteropathogenic *Escherichia coli*. Science. 1998;**280**:2114-2118

[26] Frankel G, Phillips AD,

Rosenshine I, Dougan G, Kaper JB, Knutton S. Enteropathogenic and enterohaemorrhagic *Escherichia coli*: More subversive elements. Molecular Microbiology. 1998;**30**:911-921

[27] Gomez-Duarte OG, Kaper JB. A plasmid-encoded regulatory

2002;**8**:508-513

Journal. 2017;**474**(11):1823-1836

2008;**14**(11):1041-1047

**116**

[35] Dorsey FC, Fischer JF, Fleckenstein JM. Directed delivery of heat-labile enterotoxin by enterotoxigenic *Escherichia coli*. Cellular Microbiology. 2006;**8**(9):1516-1527

[36] Sears CL, Kaper JB. Enteric bacterial toxins: Mechanisms of action and linkage to intestinal secretion. Microbiological Reviews. 1996;**60**(1):167

[37] Ceponis PJ, Riff JD, Sherman PM. Epithelial cell signaling responses to enterohemorrhagic *Escherichia coli* infection. Memórias do Instituto Oswaldo Cruz. 2005;**100**:199-203

[38] Boyer O, Niaudet P. Hemolytic uremic syndrome: New developments in pathogenesis and treatment. International Journal of Nephrology. 2011

[39] Polito MG, Kirsztajn GM. Microangiopatias trombóticas: púrpura trombocitopênica trombótica e síndrome hemolítico-urêmica. Brazilian Journal of Nephrology. 2010;**32**(3):303-315

[40] Ud-Din A, Wahid S. Relationship among *Shigella* spp. and enteroinvasive *Escherichia coli* (EIEC) and their differentiation. Brazilian Journal of Microbiology. 2014;**45**(4):1131-1138

[41] Tulloch EF, Ryan KJ, Formal SB, Franklin FA. Invasive enteropathic *Escherichia coli* dysentery: An outbreak in 28 adults. Annals of Internal Medicine. 1973;**79**(1):13-17

[42] Jafari A, Aslani MM, Bouzari S. *Escherichia coli*: A brief review of diarrheagenic pathotypes and their role in diarrheal diseases in Iran. Iranian Journal of Microbiology. 2012;**4**(3):102

[43] Mansan-Almeida R, Pereira AL, Giugliano LG. Diffusely adherent *Escherichia coli* strains isolated from children and adults constitute

two different populations. BMC Microbiology. 2013;**13**(1):22

[44] Sarowska J, Futoma-Koloch B, Jama-Kmiecik A, Frej-Madrzak M, Ksiazczyk, et al. Virulence factors, prevalence and potential transmission of extraintestinal pathogenic Escherichia coli isolated from different sources: Recent reports. Gut Pathogens. 2019;**11**(1):10

[45] Smith JL, Fratamico PM, Gunther NW. Extraintestinal pathogenic *Escherichia coli*. Foodborne Pathogens and Disease. 2007;**4**(2):134-163

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[47] Thornton HV, Hammond A, Hay AD. Urosepsis: A growing and preventable problem? The British Journal of General Practice. 2018;**68**(675):493-494

[48] Fadel MG, Louis C, Tay A, Bolgeri M. Obstructive urosepsis secondary to ureteric herniation into the sciatic foramen. BML Case Reports. 2018 27;2018

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[50] Heppner HJ, Yapan F, Wiedemann A. Urosepsis in geriatric patients. Aktuelle Urologie. 2016;**47**(1):54-59

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FL: StatPearls Publishing; 2020

2011;**8**(4):207-212

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Reports. 2013;**3**(4):69-71

Publishing; 2020

2007;**63**(3):223-225

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[161] Khaira A, Gupta A, Rana DS, Gupta A, Bhalla A, Khullar D. Retrospective analysis of clinical

of 19 patients of emphysematous pyelonephritis. International Urology and Nephrology. 2009;**41**:959-966

profile, prognostic factors and outcomes

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1980;**124**:119-121

2004;**59**:192-197

**124**

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**Chapter 7**

Diseases

**Abstract**

**127**

*and Ashok Palaniappan*

Computational Studies of Drug

Multidrug-Resistance Phenotypes

Mammalian ABCB1 P-glycoprotein is an ATP- dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely (1) Protozoa:

*Leishmania major,Trypanosoma cruzi*; (2) Helminths: *Onchocerca volvulus, Schistosoma mansoni*. Based on structural modelling of the organismal P-gp homologues, potential antibiotics targeting these structures were identified based on similarity and repurposing of existing drugs. Docking studies of the Pgp receptor—antibiotic ligand complexes were carried out and the most tenable target-ligand conformations assessed. The interacting residues were identified, and binding pockets studied. The in silico studies yielded measurements of the relative efficacy of the new drugs, which need experimental validation. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases. The potential mechanisms of multidrug

**Keywords:** P-glycoprotein, neglected tropical diseases, multidrug resistance, homology modeling, receptor-ligand docking, differential ligand affinity,

synergistic effects, leishmaniasis, trypanosomiasis, onchocerciasis, schistosomiasis

resistance emergence in *E. coli* were examined.

in Agents of Neglected Tropical

Repurposing Targeting

P-Glycoprotein-Mediated

*Nivedita Jaishankar, Sangeetha Muthamilselvan*

## **Chapter 7**
