Diagnostic caveats for difficult bacterial urinary tract infections

The objective of part one of this two-part series is to summarize diagnostic caveats derived from our experience with medical management of urinary tract infections (UTI) during the past 35 years.

This discussion is based on the premise that as veterinarians we should offer the quality of medical care that we would choose if we were the patients. When the diagnosis of the underlying causes of urinary tract infections becomes the rule rather than the exception, therapeutic failures will become the exception rather than the rule. Therapeutic caveats will follow in next month's Diagnote.

Why is it important to recognize that bacterial UTI is not a primary diagnostic entity?

Although the urinary tract communicates with an external environment loaded with bacteria and other potentially pathogenic agents, most of it is normally sterile, and all of it is normally resistant to infection. Resistance to urinary tract infection (UTI) is dependent on the interaction of several host defense mechanisms. The pathogenesis of UTIs is related to a balance between the virulence of uropathic infectious agents (analogous to seeds) and the functional status of host defense mechanisms (analogous to soil Table 1). Growth of bacteria (seeds) usually will not occur unless abnormalities of host defenses (suitable soil) is present. Therefore, in context of diagnosis, prognosis and therapy, a bacterial urinary tract infection (UTI) may be viewed as a secondary (or complicating) rather than a primary (or definitive) diagnostic entity.

Caveat: In addition to focusing on antimicrobial treatment of bacterial pathogens (which are usually secondary causes of urinary tract disease), it is also important to consider detection and treatment of abnormalities in host defenses that allow bacteria to colonize and invade tissues of the urinary tract (Tables 1 and 2). If UTIs are managed inappropriately, one or more sequela may occur (Table 3). Early detection followed by proper treatment and follow-up evaluation will minimize the occurrence and severity of these sequela.

Classifying it

What diagnostic classification will facilitate treatment of difficult UTIs?

Classification of UTIs based on the presence or absence of detectable abnormalities in host defense mechanisms allows differentiation of uncomplicated (or simple) urinary tract infections from complicated urinary tract infections (Tables 1 and 2).

Table 1 Natural and acquired urinary tract defenses against bacterial infection

An uncomplicated (or simple) UTI is defined as an infection in which an underlying structural, neurologic, immunologic or functional abnormality can not be identified. However, most bacteria survive and multiply only when host defenses are compromised. Many simple UTIs encompass transient and potentially reversible defects in the patient's innate defense mechanisms, even though the underlying cause may escape detection. Others occur when normal host defenses are overwhelmed by virulent uropathogens. For example, nosocomial UTI could occur as a result of improper transurethral catheterization in a hospital intensive care unit harboring resistant uropathogens. Uncomplicated UTIs are usually associated with a better prognosis for recovery.

Complicated UTIs occur as a result of bacterial invasion of the urinary system secondary to an identifiable disease that interferes with one or more defense mechanisms (Table 2). In general, the underlying cause must be removed or corrected if secondary bacterial infection is to be completely eradicated and prevented from recurring. Failure or inability to do so is a common cause of recurrent UTI (relapse or reinfection).

Table 2 Checklist of some predisposing causes of complicated urinary tract infections

Caveat: Differentiation of uncomplicated from complicated UTIs requires appropriate diagnostic evaluation, which may include transrectal palpation of the genitourinary tract, ultrasonography, survey and contrast radiography, cystoscopy, and aspiration, punch or surgical biopsy.

Preventing relapses

Why is it important to differentiate recurrent UTIs as relapses or re-infections?

Recurrent bacterial UTIs that occur following withdrawal of therapy may be classified as relapses or reinfections.

Table 3 Potential sequela to untreated or improperly treated bacterial urinary tract infections

Relapses are defined as recurrences of clinical signs caused by the same species of microbe. In this situation, remission of clinical signs and eradication of bacteria from the urine is not associated with eradication of pathogenic bacteria from tissues of the urinary tract. Relapses usually emerge within several days to a few weeks after remission of clinical manifestations of UTI; the bacteria may have become more resistant to antimicrobial agents than prior to therapy. The pathogenesis of relapsing UTI likely involves failure to completely eliminate pathogenic bacteria before antimicrobic therapy is withdrawn. Relapses represent antimicrobial treatment failures associated with one or more causes (Table 4). Relapses have the potential to cause significant morbidity if mismanaged (Table 3).

Table 4 Checklist of potential causes of recurrent UTIs due to relapses

Reinfections are defined as recurrent infections caused by a different pathogen(s). In this situation, bacteria have been eradicated from urine and surrounding tissue, but persistent dysfunction of one or more host defense mechanisms predisposes to infection with different uropathogens (Table 2 and 5). If superficial damage to tissues of the urinary tract induced by bacteria during the initial infection have time to heal, recurrence of clinical manifestations of reinfections often occur at a longer interval following cessation of therapy than relapses.

Table 5 Checklist of potential causes of recurrent UTIs due to reinfections

Caveat: The therapeutic plan for relapses often differs from the therapeutic plan for reinfections. Therefore it is important to compare results of bacterial culture of urine obtained prior to initiation of therapy to bacterial cultures of urine obtained during and/or after withdrawal of therapy.

Diagnostic and therapy vary

What is the gold standard of diagnosis of bacterial UTI?

Because UTI encompasses a spectrum of underlying abnormalities in host defense mechanisms in addition to bacterial pathogens, diagnostic and therapeutic requirements vary from case to case. There are no pathognomonic history, physical examination, radiographic or ultrasonographic findings associated with bacterial UTI.

In addition to bacterial infection, many diverse noninfectious disease processes, including neoplasia and urolithiasis, result in inflammatory lesions of the urinary tract characterized by exudation of RBC, WBC and protein into urine.

The resultant hematuria, pyuria and proteinuria suggest inflammatory urinary tract disease, but do not indicate its cause or location within the urinary tract. Diagnosis of bacterial UTI solely on the basis of urinalysis and detection of inflammatory cells in urine sediment will result in over-diagnosis. Therefore, it is essential to distinguish between inflammation and infection related to urinary tract disease. Although detection of bacteria in fresh urine sediment should prompt consideration of UTI, it should be verified by urine culture. Non-bacterial "look-alikes" in urine sediment are often confused with bacteria.

Quantitative urine culture is considered the gold standard for diagnosis of bacterial UTIs. In addition to facilitating differentiation of bacterial contaminants from bacterial pathogens, accurate identification of specific bacterial species aids in selection of antimicrobial drugs. Also recall that recurrent UTIs due to relapses can not be distinguished from recurrent UTIs due to reinfections without comparison of pretreatment bacterial culture results to follow-up culture results.

Caveat: Failure to perform bacterial urine cultures or failure to correctly interpret the results of urine cultures may lead to diagnostic errors and therapeutic failures. Although detection of bacteria in properly collected urine samples is highly indicative of bacterial UTI, further information is required to confirm and localize the site(s) of infection.

Quantitative urine culture

How should urine samples be collected for diagnostic culture?

We prefer to collect urine samples for bacterial culture by cystocentesis to eliminate problems of differentiating contaminants from pathogens. Detection of bacteria, even in low numbers, in urine aseptically collected by cystocentesis is indicative of UTI. However, false-positive results may occur if the needle penetrates a loop of intestine during cystocentesis, or if the sample is contaminated during transfer to culture media. For this reason, quantitative urine culture is routinely recommended, even for samples collected by cystocentesis. Urine culture results should be interpreted in context of other clinical findings (Table 6).

Table 6 Checklist of factors influencing interpretation of qualitative bacterial cultures of urine

Caveat: Catheter-induced UTIs (nosocomial infections) are common in patients with urinary tract diseases, and could even result in iatrogenic pyelonephritis, renal failure and septicemia. Therefore, transurethral catheterization of patients at increased risk for UTI should be evaluated in context of risks and benefits.

Collect before antibiotic administration

How should urine samples be preserved prior to culture?

If diagnostic bacterial cultures are to be performed, urine should be collected for culture before antibacterial therapy is initiated. If the patient is currently being treated with an antimicrobic, it should be discontinued for approximately three to five days prior to diagnostic urine culture in order to minimize inhibition of in vivo and in vitro bacterial growth.

Because urine may be a good culture medium at room temperature (bacterial counts may double every 20 minutes to 45 minutes), it should be cultured within 15 minutes to 30 minutes from the time of collection. Another indication for culture of fresh urine samples is that destruction of some fastidious bacteria may be detectable within an hour of collection. If for any reason culture of freshly collected urine samples is not possible, the samples should be kept in a sealed sterile container and immediately refrigerated following collection. Refrigerated samples may be stored for six hours to 12 hours without significant additional growth of bacteria. However, it is emphasized that fastidious organisms may be killed in the urine environment if refrigeration storage time is prolonged. Freezing urine samples may also destroy bacteria.

Caveat: Transport of urine specimens to a commercial microbiology laboratory results in increased time between urine collection and aerobic culture, and therefore adds a potential source of error, especially if the samples aren't properly preserved. In addition, 80 percent to 85 percent of bacterial UTIs are caused by a single species of bacteria, while only 15 percent to 20 percent are caused by more than one bacterial species. Therefore, detection of multiple species of bacteria suggests sample contamination, especially in urine samples collected by voiding or catheterization.

Putting it in practice

Why are quantitative bacterial urine cultures a standard of practice?

Bacteriuria, the presence of bacteria in urine, is not synonymous with UTI because urine may be contaminated with bacteria as it flows through the urethra, and after it is removed from the patient, but before it is cultured. Quantitative urine culture includes determination of the number of bacteria (colony-forming units) per milliliter of urine in addition to isolation and identification of bacteria. Because it facilitates differentiation of bacteria that have contaminated the urine sample from bacteria that are likely to be causing UTI, quantitative culture is the preferred method of diagnostic culture for urine samples obtained by any collection method.

The concept of significant bacteriuria was introduced to aid differentiation between harmless bacterial contaminants of urine and pathogenic organisms causing infectious disease of the urinary system. A high bacterial count in a properly collected and cultured urine sample indicates the high probability of UTI (Table 7). Small numbers of bacteria obtained from untreated patients usually indicate contamination.

Table 7 Interpretation-quantitative urine cultures in dogs and cats*

The lower limit of numbers of bacteria isolated from feline urine that indicate infection (so-called cutoff values) has not been precisely determined. However, it is usually less than those in dogs because feline urine appears to be less conducive to bacterial growth than urine of dogs (Table 7).

Caveat: When interpreting bacterial cultures, several variables should be considered (Table 6). In up to 20 percent of canine patients, bacterial UTI may be present with less than 10,000 colony-forming units per milliliter of urine. In this circumstance, samples collected by catheterization or during voiding might erroneously be interpreted as contaminants (Table 7). This observation emphasizes the importance of cystocentesis as the preferred method of collection for diagnostic urine culture.

Dr. Osborne, a diplomate of the American College of Veterinary Internal Medicine, is professor of medicine in the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota.