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

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