Infections of the Urogenital Tract

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133 Infections of the Urogenital Tract

Florian M.E. Wagenlehner, Kurt G. Naber

Infections in the intensive care unit (ICU) contribute significantly to patient morbidity. Depending on the type of ICU, nosocomial infections may account for 70% of infections.1 Nosocomial infections of the urogenital tract are frequent and sometimes underestimated in the ICU.2

image Definition

Urinary tract infection can be the primary cause for admission to the ICU or can be acquired after intensive care procedures. Because patients are frequently sedated in the ICU, clinical diagnosis of urinary tract infection (UTI) is often difficult. Nevertheless, UTI is an important cause of morbidity and antibiotic resistance in the ICU. Complicated UTI is a very heterogeneous entity, with a common pattern of the following factors3,4:

• Anatomic, structural, or functional alterations of the urinary tract which significantly impede urodynamic properties (e.g., stents, urine transport disturbances, instrumentation of the urinary tract, stones, tumors, neurologic disorders)
• Impaired renal function due to parenchymal diseases or prerenal, intrarenal, or postrenal nephropathies (e.g., acute and chronic renal insufficiencies, cardiac insufficiency)
• Accompanying diseases impairing the patient’s immune status (e.g., diabetes mellitus, liver insufficiency, use of immunosuppressive agents such as corticosteroids, AIDS, hypothermia)

image Etiology

Causative pathogens of UTI are almost exclusively bacteria and yeast. Viral pathogens are only found in patients with severe immunosuppression, such as after bone marrow transplantation. High antibiotic pressure and special circumstances in the ICU modulate the microbial spectrum. Escherichia coli is the most frequent pathogen but occurs less frequently than in uncomplicated community-acquired UTI. Other Enterobacteriaceae may also be uropathogens (e.g., Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, or Morganella species). Non-fermenters such as Pseudomonas aeruginosa, gram-positive cocci such as staphylococci and enterococci, and Candida species may also play an important role (Table 133-1). The microbial spectrum is likely to differ over time and from one institution to the next. To follow the spectrum and development of antibiotic resistance, each ICU has to update its own analyses.

TABLE 133-1 Bacterial Spectrum of Nosocomial Uropathogens (≥2%) from Distinct Surveillance Studies

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image Epidemiology

The Extended Prevalence of Infection in Intensive Care (EPIC II) study1 revealed that 51% of patients were infected on the study day, and 71% of all patients were receiving antibiotics. The total occurrence of the most frequent types of ICU-acquired infection were respiratory tract infections 63.5%, abdominal infections 19.6%, bloodstream infections 15.1%, and renal or urinary tract infections in 14.3%.1 The true incidence of UTI, however, may be even higher if meticulously looked for. In a prospective study specifically evaluating nosocomial UTI, nosocomial UTIs accounted for 28% of the nosocomial infections, lower respiratory tract infections for 21%, pneumonia for 12%, and bloodstream infections for 11%. The rates of urinary catheter–associated UTIs varied between 4.2% (symptomatic UTI) and 14.0% (asymptomatic UTI), which shows that asymptomatic bacteriuria is frequent in ICU patients, although symptoms of UTIs in intensive care patients are frequently difficult to assess.2 In the one-day point prevalence study in urological patients in Europe (PEP/PEAP study) asymptomatic bacteriuria accounted for 29% of nosocomial UTIs, followed by cystitis (26%), pyelonephritis (21%), and urosepsis (12%),5 showing that nosocomial UTI is present with high frequency in certain patient groups.

Urinary tract infections in the ICU are divided into two groups:

1 UTIs with nonurologic complicating causes: diabetes mellitus, renal insufficiency, immunodeficiency, infectious foci contiguous to the urogenital tract, or trauma patients
2 UTIs with urologic complicating causes: renal transplantation, neurogenic bladder dysfunction, procedures in the urogenital tract, urinary stones or foreign bodies in the urogenital tract

In UTI with primary nonurologic complicating causes, antimicrobial therapy is generally sufficient. However, in UTI with primary urologic causes, the complicating factors must be identified and treated. In such cases, antimicrobial therapy is only one component of the treatment.

Urinary Tract Infections with Nonurologic Complicating Causes

Individuals with diabetes are at higher risk for urinary tract infection.6 Increased susceptibility in patients with diabetes is positively associated with increased duration and severity of diabetes as a result of impaired granulocyte function, decreased excretion of Tamm-Horsfall protein, low interleukin (IL)-6 and IL-8 levels in the urine that lead to lower “cidality” of the urine, and altered microflora in the genital region. In addition, diabetic cystopathy and nephropathy may be complicating factors in the urinary tract. In addition to antibiotics, treatment must address the metabolic situation. In pyelonephritis, usually a switch to insulin or to insulin-analogous therapy is necessary.

Immunosuppression is generally associated with increased risk of UTI. Patients with leukopenia (<1000/µL) show a higher rate of febrile UTIs and bacteremia due to UTI.4 Symptoms and findings in these patients frequently are not diagnostic. Febrile episodes, however, are due to infections in approximately 60% of cases.

Pathogens may be translocated into the urinary tract from contiguous infectious foci (e.g., appendicitis, sigmoid diverticulitis, translocation by ileus). Symptoms and localization of pain can be misleading and may delay diagnosis. Operations or trauma may cause hypothermia, tissue hypoxia, and hemodynamic alterations that produce kidney dysfunction and impaired mucosal perfusion. The use of latex catheters in these critical situations (e.g., operations with heart-lung machine) can also lead to urethral strictures. Silicone catheters or suprapubic catheters are recommended in these patients.7 Suprapubic catheters cannot prevent UTI. They can, however, lower the rate of UTI from 40% to 18%.8

Urinary Tract Infections with Urologic Complicating Causes

Patients show a high risk to develop bacteriuria after renal transplantation, threatening clinical outcomes for both the patient and transplant. Early infections (up to 3 months after transplantation) are differentiated from late infections (more than 3 months after transplantation). Early infections may present with no symptoms. In this phase, occult bacteremia (60% of bacteremias after renal transplantation originate from the urinary tract), allograft dysfunction, and recurrent UTI after antibiotic therapy are frequently seen.4 The newer immunosuppressive agents are associated with a lower incidence of rejection but a higher risk of late infection. In particular, mycophenolate mofetil is associated with an increasing incidence of UTI and with infections caused by cytomegalovirus.4 Infection can induce graft failure by the direct effect of cytokines and free radicals or reactivation of cytomegalovirus infection. It can be very difficult to distinguish rejection from infection.4 Patients must also be investigated for a surgical complication.

UTIs caused by Candida species are frequently asymptomatic. There is, however, a risk of obstructive fungal balls leading to candidemia or invasion of the anastomosis in renal transplant recipients. Asymptomatic candiduria should therefore be treated in these patients.4 Urine transport disturbances (e.g., from obstructive ureteral stone) require specific urologic therapy such as percutaneous nephrostomy or stenting. In the case of bladder obstruction, an indwelling urinary catheter (suprapubic or transurethral) will be the primary therapy in the ICU. Long-term indwelling catheters (more than 30 days) are associated with a selected microbial spectrum of difficult-to-treat uropathogens (e.g., Providencia spp., Proteus spp., Pseudomonas spp.).9 After initiation of antimicrobial therapy, the catheter should be exchanged to remove biofilm material.

image Pathophysiology

UTIs generally occur from organisms invading the urinary tract via the urethra. Pathogens originate from endogenous or exogenous nosocomial flora. Hematogenous spread to the urinary tract is rare.

In uncomplicated UTI, pathogens need to have very specific virulence factors enabling them to initiate an infection after invasion of the urinary tract. The medical conditions of an ICU patient may weaken physiologic barriers and defenses, thus facilitating entry of pathogens. In addition, the nosocomial environment in the ICU, including antibiotic pressure and decreased supply of oxygen or nutrients (e.g., iron) to tissues, can select pathogens with specific resistance patterns. A general adaptation strategy is the formation of hypermutator strains, which show 100- to 1000-fold increased mutation frequencies, enabling the pathogens to rapidly adapt to challenging environments and to thus develop effective mechanisms for antibiotic resistance.10,11

An important mechanism contributing to UTI is the formation of biofilms, associated with the increased number of biomaterials used in medical practice. Biofilm infections develop not only around foreign bodies such as urinary catheters or stents but also in urinary stones, scar or necrotic tissue, obstructive uropathies, or even chronic bacterial prostatitis. Biofilm has been defined as an accumulation of microorganisms and their extracellular products, forming a structured community on a surface. The formation of biofilm generally consists of three steps:

1 Deposition of a host conditioning film
2 Attachment of microorganisms followed by microbial adhesion and anchorage to the surface by exopolymer production
3 Growth, multiplication, and dissemination of the organisms

The basic structural unit of a biofilm is a microcolony—that is, a discrete matrix-enclosed community consisting of bacteria of one or more species. The biofilm is usually built up of three layers12,13:

1 Linking film that attaches to the surface of a tissue or biomaterial
2 Base film of compact microorganisms
3 Surface film as an outer layer where planktonic organisms can be released to float freely and spread on the surface

Bacteria within the biofilms differ both in behavior and in phenotypic form from the planktonic, free-floating bacteria. The failure of antimicrobial agents to treat biofilms has been attributed to a variety of mechanisms:

• Organisms encapsulated in the biofilm grow more slowly than the planktonic ones, probably because the encapsulated bacteria have a decreased nutrient and oxygen supply, leading to a decreased metabolic rate and antimicrobial susceptibility. This may select a less susceptible genotype, forming a resistant population. Furthermore, antimicrobial binding proteins are poorly expressed in these slow-growing bacteria.
• The biofilm matrix itself delays or impedes the diffusion of antibiotic molecules into the deeper layer of the film (extrinsic resistance).
• Bacteria within the biofilm are phenotypically so different from their planktonic counterparts that antimicrobial agents fail to eradicate them. Bacteria within a biofilm activate many genes that alter the cell envelope and molecular targets by altering the susceptibility to antimicrobial agents (intrinsic resistance). These phenotypic changes are likely to play a more important role in the development of antimicrobial resistance than the external resistance (biofilm matrix, glycocalyx).
• Bacteria within a biofilm can sense the external environment, communicate with each other, and transfer genetic information and plasmids within biofilms.
• Bacteria in biofilms can usually survive antibacterial concentrations 100 to 150 times higher than needed to kill planktonic bacteria of the same species.14

Antimicrobial treatment can be effective only in “young” biofilms (<24 hours). At present, combination therapy with fluoroquinolones and macrolides or fosfomycin seems to be the most effective against biofilm infections. During an acute febrile phase of a biofilm infection, antimicrobial therapy is essential and can be effective because the planktonic bacteria are responsible for the febrile reactions and not the bacteria covered in the biofilm. However, to eradicate pathogens from biofilm, the biofilm itself has to be removed (e.g., catheter change, extraction of infectious stones).

image Diagnosis

Medical History and Physical Examination

Sedated intubated patients often are difficult to evaluate regarding their signs and symptoms of UTI. The patient or a family member should be asked about previous episodes of UTI as well as urologic diseases (e.g., stones, tumors) or operations.

The physical examination should include inspection and palpation of the costophrenic area, lower abdomen, pubic region, inguinal lymph nodes, genitals, and a digital transvaginal or transrectal examination. Ultrasound is an important diagnostic device, and its use should be frequently considered because of the close proximity of the urogenital organs to the intestine, spleen, liver, pancreas, gallbladder, ovary, or uterus.

Urinary Examinations

Urine specimens in ICU patients are almost exclusively collected from catheters. Because urine from catheters has to be collected into a closed system, the urine specimen should be taken from the puncture site at the catheter after disinfection, without opening the closed system. There are different complementary methods for laboratory examination of the urine specimen.

Dipstick Test

The dipstick test is done with undiluted urine and investigates the following infection-related parameters15:

• pH; an alkaline urine (pH >8.0) points to urease-producing organisms such as Proteus or Providencia and is associated with magnesium-ammonium-phosphate stones.
• Nitrate; most enterobacteria harbor a nitrate reductase that reduces nitrate to nitrite. Some common uropathogens such as Enterococcus and Staphylococcus lack nitrate reductase and will therefore not be detected using this parameter, whatever their urinary concentration. Positive detection of nitrate requires its inclusion in the patient’s diet.
• Leukocytes (positive leukocyte esterase); granulocytes are the most frequently detected leukocytes in the urine of UTI patients. Macrophages appear fairly often in patients with UTI, but their significance remains unknown.
• Erythrocytes (positive hemoglobin); hematuria remains a major sign of urinary tract and renal disease.
• Specific gravity/osmolality (degree of urine dilution)
• Protein; total protein in urine is a mixture of high- and low-molecular-weight plasma proteins from the kidney and urinary tract or bacteria.
• Glucose (metabolic condition of the patient)

Microscopy

There are two possibilities of microscopic evaluation15:

1 Chamber counting of uncentrifuged urine (standard values for urine shown in Table 133-2)
2 Urinary sediment findings; at least 10 fields of vision at 400× magnification are counted, and the mean value of particles is registered. However, centrifugation methods are never quantitative in counting erythrocytes and leukocytes because of variable loss during centrifugation.

TABLE 133-2 Standard Values for Urine in Counting Chamber and Field of Vision

  Erythrocytes Leukocytes
Uncentrifuged urine (chamber counting) <10/mL <10/mL

Data from European Urinalysis Guidelines, 2000.

Microbiology

To differentiate contamination in urine from significant bacteriuria, quantitative microbiology is needed. The microbial count has to be interpreted in relation to the urinary dilution.

Clinical Diagnosis

To survey and compare infection rates in different institutions, UTIs should be classified according to widely accepted definitions, such as the definitions of the U.S. Centers for Disease Control and Prevention (CDC). The CDC/National Healthcare Safety Network (NHSN) definitions16 stratify health care associated UTIs into symptomatic, asymptomatic, and other infections of the urinary tract. To be of value in determining a nosocomial infection, the urine specimens must be obtained aseptically using an appropriate technique such as clean catch collection, bladder catheterization, or suprapubic aspiration.

image Therapy

General Principles

Not all bacteriuric patients in the ICU need to be treated. Asymptomatic bacteriuria in general does not have to be treated.17 Therapy should only be started in patients with significant symptoms and morbidity and in whom asymptomatic bacteriuria may be deleterious (e.g., before traumatizing intervention of the urinary tract and in pregnant women). In the ICU, indications for treatment of asymptomatic UTI might include some other circumstances such as renal transplant, severe diabetes mellitus, or severe immunosuppression. In complicated UTI, antibiotic therapy can only be successful when the complicating factors can be eliminated or urodynamic functions restored. Treatment of complicated UTI therefore comprises adequate antibiotic treatment and successful urologic intervention.

Antibiotic Therapy

For therapy of complicated UTI, antibiotics must possess appropriate pharmacodynamic and pharmacokinetic prerequisites: high renal unmetabolized clearance with good antibacterial activity, both in acidic and alkaline urine. Moreover, microbial resistance patterns must be considered in the choice of antibiotics. Increasing antibiotic resistance, especially amongst enterobacteria, makes prudent antibiotic treatment more and more difficult. The increasing appearance of quinolone-resistant and extended-spectrum β-lactamase (ESBL)-forming enterobacteria will inevitably lead to increased use of carbapenems in the empirical treatment, thus increasing the antibiotic pressure on these highly potent antibiotics. To diminish the selection pressure for resistant pathogens, antibiotics from different classes should be used.

Multiple antimicrobial agents are available for therapy for complicated UTI (Table 133-3): second- or third-generation cephalosporins, broad-spectrum penicillins with β-lactamase inhibitors, monobactams, and carbapenems. For empirical therapy for severe UTI, broad-spectrum antibiotics should be used (e.g., broad-spectrum penicillins with β-lactamase inhibitors, third-generation cephalosporins, fluoroquinolones, or carbapenems). Synergism with aminoglycosides, which inhibit protein synthesis and thus block the forming of toxins or virulence factors, might be useful for initial therapy, but side effects have to be considered.

TABLE 133-3 Division and Dosage of Distinct Antibiotics Recommended for Treatment of Urinary Tract Infections

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Candiduria is a common problem in ICUs. It may represent harmless colonization, but it can also be an early sign of systemic candidosis.18 A second urine culture after exchanging the urethral catheter can rule out contamination. In the critically ill patient, systemic therapy for Candida species should be started according to susceptibility testing or species differentiation (see Table 133-3). Complicating factors such as diabetes mellitus or urologic abnormalities should be treated concomitantly. Systemic antimycotic therapy is preferred to local instillation therapy because of the potentially systemic nature of candiduria in ICU patients.

Urologic Therapy

Urologic operative therapy of complicated UTI is divided into acute therapy and delayed drainage therapy. The primary aim of acute therapy is improved urinary flow, with minimal patient contamination by infected urine. In primary therapy, catheters, stents, or drains are frequently used. Delayed drainage therapy of the urinary tract (e.g., lithotomy, prostatic resection, ureter reimplantation) is frequently performed after days or weeks of stabilization.

Prophylaxis of Catheter-Associated Urinary Tract Infections

Some 80% to 90% of nosocomial UTIs are associated with urinary catheters or instrumentation of the urinary tract. The best prophylaxis is to avoid a catheter or, if catheterization is necessary, to minimize catheter duration. Various techniques have been used to avoid catheter-related infections.

Silver coating of catheters may exert a bactericidal effect, but the concentration of free silver ions must be high, whereas the exposure to albumin and chloride ions has to be low, because silver-chloride complexes can precipitate.19 Heparin-coated catheters also demonstrate promising results. Suprapubic catheterization can initially decrease the rate of UTI from 40% to 18%, because the proximity to the anal region as well as the irritation of the urethral mucosa with ensuing mucopurulent discharge are avoided.8 Urinary drainage should be performed with a closed system that should not be opened either for emptying or for urinary sampling. The sites used for urinary sampling must be adequately sterilized. A rigid vertical, ventilated, drop chamber should be available to prevent encrustation.20 General hygienic procedures such as aseptic catheter insertion, wearing of disposable gloves, and hygienic hand disinfection to prevent cross-contamination or cross-infection are mandatory. International consensus recommendations for the use of urinary catheters to prevent healthcare-associated infections have been recently described.21

Recommended Evidence-Based Measurements For Preventing Catheter-Associated Urinary Tract Infections

The primary methodologies for preventing catheter-associated UTIs21 include:

• Limiting unnecessary catheterization and discontinuation of the catheter as early as possible
• Policies and procedures for recommended catheter insertion indications, insertion and maintenance techniques, discontinuation strategies, and replacement indications should be developed and closely followed.
• Alternatives to indwelling urethral catheterization should be considered, such as condom catheterization, intermittent catheterization, or suprapubic catheterization, although data are insufficient to recommend one over the other.
• Closed catheter drainage systems should be used.
• Most other measures for prevention of catheter-associated UTI, such as prophylaxis with systemic antimicrobials, methenamine salts, cranberry products, enhanced meatal care, and catheter irrigation with either antimicrobials or saline, are not recommended.21
• It is also unclear whether routine catheter changes reduce the risk for catheter-associated bacteriuria or UTI.

image Special Clinical Issues

Infections of the Upper Urinary Tract and Contiguous Organs

Pyelonephritis

The high osmolality of the renal medulla has a negative effect on leukocyte function. For that reason, the interstitium of the renal medulla is much more affected in pyelonephritis than the cortex is. Clinical symptoms are unilateral or bilateral flank pain, painful micturition, dysuria, and fever (>38°C). Focal nephritis is limited to one or more renal lobules, comparable to lobular pneumonia. Ultrasonographic findings are of a circumscribed lesion with interrupted echoes that break through the normal cortex/medulla organization. Computed tomography (CT) scan shows typical wedge-shaped, poorly limited areas of diminished sonographic density. As differential diagnoses, renal abscess, tumor, and renal infarction must be taken into account. Emphysematous pyelonephritis characteristically shows gas formation in the renal parenchyma and perirenal space. Diabetes mellitus or obstructive renal disease are predisposing factors. The most frequently isolated organisms are E. coli, Klebsiella pneumoniae, and Enterobacter cloacae. Fermentation of glucose in Enterobacteriaceae occurs via two different metabolic pathways: mixed acid fermentation and the butylene glycol pathway. Organisms of the Klebsiella-Enterobacter-Hafnia-Serratia group, and to a lesser extent E. coli, use the butylene glycol pathway and produce copious amounts of CO2, which appears clinically as gas formation.22 Aggravated by diminished tissue perfusion, the contralateral side is often affected as well.

Renal and Perirenal Abscess

Clinical symptoms are rigors, fever, back or abdominal pain, flank tenderness, mass lesion and redness of the flank, and protection of upper lumbar and paraspinal muscles. Respiratory insufficiency, hemodynamic instability, or reflectory paralytic ileus occurs frequently. Frequent signs of renal abscess formation are fever and leukocytosis for more than 72 hours, despite antibiotic therapy. Urinary culture may be negative in 14% to 20%.23 Frequently isolated organisms are E. coli, K. pneumoniae, Proteus spp., and Staphylococcus aureus from hematogenous spread. Caudad, the fascial limitations are open, and the perirenal fat is in close contact with the pelvic fat tissue. A perinephritic abscess may therefore point to groin or perivesical tissue or to the contralateral side, thus penetrating the peritoneum. Inflammation of flank, thigh, back, buttocks, and lower abdomen may occur. Because of late diagnosis, the mortality can be as high as 57%. Blood cultures are positive in 10% to 40%, and urinary cultures are positive in 50% to 80%.24

Infections of the Lower Urinary Tract and Contiguous Organs

Cystitis

Cystitis is frequently limited to the bladder mucosa and hence shows no systemic signs or symptoms. An ascending infection can, however, clinically result. Cystitis in the ICU is almost exclusively catheter associated and can cause hematuria. Spontaneous elimination is frequently found after removal of the indwelling catheter, but less frequently in elderly patients.4

Epididymitis/Orchitis

Epididymitis in the ICU usually is an ascending infection and can also involve the testis as well. Possible causes are subvesical obstruction, transurethral resection of the prostate, or an indwelling transurethral urinary catheter, in which case the pathogens are identical with the pathogens in the urine. Of note, epididymitis is frequently involved in urogenital tuberculosis. Orchitis with the formation of a sterile hydrocele can appear in the course of polyserositis or cardiac failure and may point to a generalized systemic disease.

Cavernitis

Cavernitis of the penis is a rare phlegmonous infection of the cavernous bodies. Possible causes are indwelling transurethral urinary catheters, penile operations, autoinjection for erectile dysfunction, pelvic operations, or trauma. Pathogens may represent skin flora or uropathogens. Treatment consists of suprapubic catheterization, broad-spectrum antibiotic therapy and, if needed, operative débridement.

Acute Prostatitis and Prostatic Abscess

Acute prostatitis and prostatic abscess are bacterial infections of the prostate gland. The bacterial spectrum consists of 53% to 80% E. coli and other enterobacteria, 19% gram-positive bacteria, and 17% anaerobic bacteria.25 In regions with a high incidence of Neisseria gonorrhoeae, the prostate may be involved. Symptoms are high fever, rigors, dysuria, urinary retention, and perineal pain. Rectal palpation reveals an enlarged, tender prostate. Prostate massage is contraindicated. In acute prostatitis, the pathogens are usually detected in urine. However, the urine may be sterile in prostatic abscess formation. Therapy consists of a combination of antibiotic therapy with broad-spectrum antibiotics, as well as insertion of a suprapubic catheter. In the case of a prostatic abscess, urologic drainage is necessary.25

Fournier’s Gangrene

Fournier’s gangrene is a necrotizing fasciitis of the dartos and Colles fascias. It is mainly seen in men in the fourth to seventh decade but also occurs in women or the newborn. Causes are operations or trauma in the genital or perineal region, including microlesions, or infectious processes from the rectal or urethral areas. Important predisposing factors are diabetes mellitus, liver insufficiency, chronic alcoholism, hematologic diseases, or malnutrition. Patient-related predictors of mortality are increasing age, increased Charlson comorbidity index, preexisting conditions such as congestive heart failure, renal failure or coagulopathy, and hospital admission via transfer.26 Fatality rates nowadays were 7.5% in one large study.27 The infectious process follows anatomically preformed spaces. The superficial perineal fascia is fixed dorsally at the transverse deep perineal muscle and laterally at the iliac bone and merges ventrally in the superficial abdominal fascia. Hence, a ventrally open and craniodorsally and laterally closed space is formed (Colles space) that facilitates the spread of infection. In contrast to gas gangrene, the fascial borders are respected in Fournier’s gangrene. A mixed bacterial flora is seen, consisting of gram-positive cocci, enterobacteria, and anaerobic bacteria. The released toxins facilitate platelet aggregation and activation of complement, which in conjunction with the release of heparinase by anaerobic bacteria, leads to small vessel thrombosis and tissue necrosis. The destruction of tissue enhances the potential of acute renal failure. Fournier’s gangrene is a rapidly progressing infection leading to septic shock if not treated in time.

Therapy for Fournier’s gangrene consists of immediate operative débridement followed by subsequent operations until the infectious process has been controlled. A suprapubic catheter is advisable, and a colostomy may have to be performed in cases in which fecal contamination of the wound is inevitable. Combination of antibiotic therapy with broad-spectrum β-lactam antibiotics, fluoroquinolones, and clindamycin is recommended.

Urosepsis

In 20% to 30% of all septic patients, the initial infectious focus is in the urogenital tract. The most frequent causes for urosepsis are obstructive diseases of the urinary tract such as ureteral stones, anomalies, stenosis, or tumor. Effective treatment eliminates the infectious focus and improves organ perfusion.

Immediately after microbiological sampling of urine and blood, empirical broad-spectrum antibiotic therapy should be started parenterally. Adequate initial (e.g., in the first hour) antibiotic therapy ensures improved outcome in septic shock.28,29 Inappropriate antimicrobial therapy in severe UTI is linked to a higher mortality rate,30 as it has been shown with other infections as well.31,32 Empirical antibiotic therapy therefore needs to follow rules33 which are based upon the expected bacterial spectrum, institutional-specific resistance rates, specific pharmacokinetic and pharmacodynamic factors in UTI, and individual patient characteristics.

The bacterial spectrum in urosepsis predominantly consists of enterobacteria such as E. coli, Proteus spp., Enterobacter and Klebsiella spp., non-fermenting organisms such as P. aeruginosa, and also gram-positive organisms.34–36 Candida spp. and Pseudomonas spp. occur as causative agents in urosepsis mainly if host defense is impaired.37 Patients with candiduria also show frequently invasive candidiasis and candidemia.38,39 Candiduria at any time in an ICU is associated with higher mortality rates (OR, 2.86).39 Viruses are not common causes of urosepsis.

Although urosepsis is a systemic disease, the activity of an antibiotic at the site of the infection is critical. A variety of studies show that inflammatory mediators such as IL-6, CXC chemokines, endotoxin, or HMGB1 are produced and released in the urinary tract.40–43 Therefore predominantly antimicrobial substances with a high activity in the urogenital tract are recommended.44,45

The increasing antibiotic resistance rates of pathogens causing urosepsis significantly diminish the choice of antibiotics available for adequate empirical initial treatment in urosepsis. In particular, the increasing rates of Enterobacteriaceae producing ESBL pose clinically relevant problems.46–48 Other recent developments of concern include increased rates of fluoroquinolone-resistant enterobacteria and vancomycin-resistant enterococci.49,50 There are no specific pharmacokinetic/pharmacodynamic parameters yet available for the treatment of uroseptic patients.

Correct dosing in urosepsis has to consider the altered systemic and especially renal pathophysiology that exists in patients with urosepsis. Sepsis and the treatment thereof result in higher clearances of antibacterial drugs.51 The increased volume of distribution as a result of peripheral edema in sepsis will lead to underexposure, especially of hydrophilic antimicrobials such as β-lactams and aminoglycosides, which exhibit a volume of distribution mainly restricted to the extracellular space.52 Urosepsis may also cause multiple organ dysfunction such as hepatic or renal dysfunction, resulting in decreased clearance of antibacterial drugs. Increased dosing is therefore necessary. As β-lactams are time-dependent antibacterials, optimal administration would be by continuous infusion. In one study, an area under the antibiotic concentration time curve (AUIC) ≥ 250 and time over the minimal inhibitory concentration (T > MIC) = 100% has been associated with treatment success.53 Fluoroquinolones, on the other hand, display largely concentration-dependent activity. The volume of distribution of fluoroquinolones in sepsis is not greatly influenced by fluid shifts, and therefore no alterations of standard doses are necessary unless renal dysfunction occurs.51

Depending on local susceptibility patterns, a third-generation cephalosporin such as piperacillin in combination with a β-lactamase inhibitor (BLI) or carbapenem may be appropriate for empirical treatment.4,53–57 In areas with a high (>10%) rate of Enterobacteriaceae producing ESBL, initial treatment with a carbapenem might be advisable.54–58 Aminoglycosides as monotherapy might be an alternative; however, the data supporting monotherapy in uroseptic patients are not sufficient.59 In case of candiduria with signs of sepsis, antifungal treatment is recommended.38,39

Key Points

1 Complicated urinary tract infection (UTI) is a very heterogeneous entity with a common pattern of complicating factors.
2 The bacterial spectrum of complicated UTI is much broader than in uncomplicated UTI, comprising a variety of gram-negative and gram-positive pathogens and among these, frequently multiresistant pathogens.
3 UTIs are frequent in ICUs. It would be pragmatic to stratify UTIs into those with nonurologic complicating causes, in which antimicrobial therapy is the primary therapy, and those with urologic complicating causes, in which the complicating urologic anomaly has to be effectively treated.
4 Pathogens of nosocomial complicated UTIs may be characterized by certain properties such as adaptation strategies to changing environments (i.e., hypermutator strains) or propensity to biofilm formation.
5 The diagnosis of UTI is based on medical history and thorough physical examination, including bedside ultrasound as well as investigations of urine (dipstick test, microscopy, and microbiology). For clinical diagnosis, general accepted criteria should be employed. Symptomatic UTIs in ICU patients are especially difficult to evaluate.
6 Not all bacteriuric patients in ICUs need to be treated. Therapy should, however, be started in those with significant symptoms and morbidity, and in those, even asymptomatic bacteriuria may be deleterious. Management of complicated UTI comprises adequate antibiotic therapy and successful treatment of complicating factors.
7 Prophylaxis of UTI is important. However, the percentage of infections that can be prevented is not known. Important points in prophylaxis encompass training of staff, hygiene measures, type of catheter and drainage, and patient care.
8 Special clinical pictures of UTI and infections of contiguous organs are seen in the ICU. UTIs of the upper urinary tract are distinguished from those of the lower urinary tract and infections of the male adnexal glands and fasciitis of the perineum and scrotum. All these pictures can potentially merge into urosepsis if the UTI is not treated adequately. The urogenital tract is the source for sepsis in 20% to 30% of cases.

Annotated References

Goto T, Nakame Y, Nishida M, Ohi Y. Bacterial biofilms and catheters in experimental urinary tract infection. Int J Antimicrob Agents. 1999;11:227-231.

An experimental setup to study the antibiotic susceptibility of pathogens in biofilm. Fluoroquinolones, and perhaps macrolides, have advantageous effects in the treatment of biofilm infections.

Grabe M, Bishop MC, Bjerklund-Johansen TE, Botto H, Cek M, Lobel B, et al. Guidelines on urological infections. In: European Association of Urology guidelines. Arnhem, The Netherlands: European Association of Urology; 2009:1-110.

This is the extensive version of the UTI Guidelines elaborated by the Urinary Tract Infection Working Group of the Health Care Office of the European Association of Urology (ESIU). The topics include classification, diagnosis, treatment, and follow-up of uncomplicated UTI, UTI in children, UTI in diabetes mellitus, renal insufficiency, renal transplant recipients and immunosuppression, complicated UTI due to urological disorders, sepsis syndrome, urosepsis, urethritis, prostatitis, epididymitis, orchitis, and principles of perioperative prophylaxis in urology.

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. Clin Infect Dis. 2010;50:625-663.

These international guidelines deal with diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults, the most frequent cause for UTI in the intensive care units.

Oliver A, Cantón R, Campo P, et al. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science. 2000;288:1251-1253.

This study elucidates an excellent model for the special propensities of nosocomial pathogens. There were 36.7% of patients with cystic fibrosis who harbored P. aeruginosa isolates with 100- to 1000-fold increased mutation rates, thus enabling them to rapidly adapt to changing environmental needs.

Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323-2329.

This multicenter 1-day prevalence study on 1265 ICUs in 75 countries investigated 14,414 patients; 51% were infected on the study day. The ICU mortality rate of infected patients was more than twice that of noninfected patients. Therefore, infection control in critically ill patients is important.

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