Managing complicated urinary tract infections (Proceedings)

Most bacterial infections of the lower urinary tract respond quickly to antimicrobial treatment; however, urinary tract infections (UTI) associated with defects in the host immune system (complicated UTI) often fail to respond or recur after antibiotic withdrawal and can be a therapeutic challenge.

Etiology

The most common bacterial pathogens associated with UTI in the dog include Escherichia coli, Klebsiella, Staphylococcus, Enterococcus, Proteus, Pseudomonas, Enterobacter, and Streptococcus. These are dermal or intestinal floras that ascend the urethra and then adhere to the mucosa of the bladder and multiply. Although many enteric organisms are anaerobes, the oxygen tension in urine probably inhibits growth of strict anaerobic bacteria and therefore, anaerobic UTI is rare. A recent study of recurrent and persistent UTI in dogs showed that 25% of culture positive urine specimens had two or more bacterial species isolated. Mycoplasmal infections are relatively rare but have been associated with recurrent or persistent UTI in dogs. Mycoplasma should be considered in dogs with persistent pyuria and negative urine culture, dogs with persistently alkaline urine and negative urine cultures, and dogs with persistent or recurrent UTI that don't respond to appropriate conventional antibiotic treatment.

Normal Host Defense Mechanisms

The status of host defense mechanisms appears to be the most important factor influencing the pathogenesis of UTI. Normal voiding is an efficient natural defense mechanism against UTI. Mechanical washout as a result of complete voiding is responsible for removing greater than 95% of non-adherent bacteria that gain entrance into the urinary bladder. Increased urine production and frequency of voiding enhance washout of bacteria. Disorders that decrease the frequency and/or volume of voided urine, or that result in an increased urine residual volume may predispose animals to UTI. Normal urine residual volume for dogs is less than 0.2 to 0.4 ml/kg body weight.

Bacteria are normally present in increasing numbers from the mid to distal urethra, but seldom do these organisms cause UTI in normal dogs. The high-pressure zone in the mid urethra and spontaneous urethral contractions help prevent ascension of bacteria. Differences in epithelial morphology (decreased epithelial receptor sites) also help decrease bacterial colonization in the proximal and mid urethra. The length of the urethra and bactericidal prostatic secretions in male dogs are thought to decrease the incidence of UTI compared with female dogs, however, nearly equal gender distribution in recurrent/persistent UTI has recently been reported. In both sexes, the valve-like nature of the vesicoureteral junction helps protect against bacterial ascension to the upper urinary tract.

Colonization of vulval and preputial luminal mucous membranes by nonpathogenic flora serves to decrease colonization by uropathogens. Normal flora occupy most of the epithelial receptor sites, produce bacteriocins that interfere with uropathogen metabolism, and have a high affinity but low requirement for essential nutrients required by uropathogens. Mucosal secretions also help prevent adherence of uropathogens to epithelium; immunoglobulins coat pathogenic bacteria and glycosaminoglycans form a protective barrier over the mucosal surface.

The antibacterial property of urine is an additional important host defense mechanism against UTI. Urine is frequently bacteriostatic and sometimes can be bactericidal depending on its composition. Low pH and high concentrations of urea and weak organic acids in concentrated urine inhibit bacterial growth. Although polyuric disorders may increase washout of non-adhered bacteria from the bladder, UTI may occur due to decreased antibacterial properties of urine.

Complicated vs. Uncomplicated Urinary tract Infections

Uncomplicated UTI are infections without detectable underlying structural or functional abnormalities in the host's defense mechanisms. This form of infection is easiest to treat and is usually cleared soon after appropriate antibiotic treatment is initiated. Complicated UTI are associated with a defect in the host's defense mechanisms; i.e., interference with normal micturition, anatomic defects, damage to mucosal barriers, alterations in urine volume or composition, or systemic immunocompromise. In almost all cases, the underlying defect must be corrected in order to eliminate the UTI.

Abnormal micturition often results in incomplete voiding and retention of urine, which allows for multiplication of bacteria within the urinary tract. Damage to mucosal barriers may result in UTI, depending on the extent of the lesion and concurrent introduction of uropathogens. It is interesting to note that pathogenic bacterial inoculation of the urinary bladder in experimental animals usually fails to establish a UTI unless the uroepithelium is first damaged by a chemical or mechanical insult. Any time the urinary bladder is catheterized; bacteria are carried up the urethra to the bladder. If the catheter is inserted too far and damages the bladder mucosa, the chance of infection increases. Anatomic defects may allow ascending migration of bacteria (e.g., indwelling urinary catheters or an ectopic ureter) or may damage mucosal barriers (e.g., urolithiasis, neoplasia, urachal remnant, thickened bladder wall due to chronic inflammation). Altered urine composition (glucosuria or excretion of irritating drugs like cyclophosphamide) can enhance the environment for bacterial growth. In addition to the above local factors, systemic disorders such as renal failure, hyperadrenocorticism, prolonged steroid administration, neoplasia, and diabetes mellitus can result in complicated UTI. In a recent retrospective study, aerobic urine cultures from 159 dogs with diabetes mellitus yielded bacterial growth in 34 cases (21%).

Elimination of clinical and laboratory signs of complicated UTI with antibiotic treatment is usually not possible; signs either persist during antibiotic treatment or recur shortly after antibiotic withdrawal. Although antibiotic treatment is the cornerstone of management, the status of host defense mechanisms is thought to be the single most important determinant of the outcome of UTI treatment. In complicated UTI, antibiotic treatment should control the pathogenic bacterial growth for a period sufficient to allow host defense mechanisms to prevent colonization of the urinary tract without further antibiotic administration.

Recurrent Urinary Tract Infections

Recurrence of clinical and laboratory signs of UTI can be classified into two groups: relapses and reinfections. Relapses are infections caused by the same species of bacteria usually within several days of cessation of treatment. In this case the previous antimicrobial treatment failed to eliminate the infection. Relapses may be due to use of improper antibiotic or dose, emergence of drug-resistant pathogens, or failure to eliminate predisposing causes that alter normal host defense mechanisms and allow the persistence of the bacteria. Urinary tract infections that relapse are frequently associated with a higher degree of antimicrobial resistance compared to the original infection. Relapses in male dogs may be caused by chronic prostatic infections.

On the other hand, recurrent UTI may be reinfections. In this case, the previous antibacterial treatment cleared the first infection and the urinary tract has subsequently become infected with another bacteria. In most cases the time between reinfections is greater than the time between relapses. Reinfections often indicate failure to eliminate predisposing causes that alter normal host defense mechanisms. Alternatively, reinfections may be iatrogenic (follow-up catheterization) or spontaneous. Reinfections with less invasive bacteria (e.g., Pseudomonas aeruginosa) generally suggest the host's immune system is compromised.

Superinfections occur when additional bacteria colonize the urinary tract during the course of treatment. Superinfections are often associated with urine diversion techniques (e.g., cystostomy, urethrostomy, and indwelling urinary catheters) and can appear to be persistent or recurrent UTI.

Treatment

It is important to try to identify those patients with immune system defects; therefore a complete physical examination should be performed on all animals that present with signs of UTI. If a simple UTI is suspected, bacterial sensitivity results are not available, antibiotic treatment choice should be based on bacterial identification or the gram-staining characteristics of the bacteria. Clinical experience at several different veterinary teaching hospitals indicates that intelligent choices may be made about bacterial susceptibility to antibiotics. Without benefit of bacterial sensitivity testing, the following are the drugs of choice for the bacteria listed: E. coli - enrofloxacin; Proteus - amoxicillin-clavulanic acid; Staph - amoxicillin-clavulanic acid; Strep - amoxicillin-clavulanic acid; Enterobacter - tetracyclines; Klebsiella - enrofloxacin; Pseudomonas - tetracycline. If bacterial identification is unknown, treatment is best based on the gram-staining characteristics, i.e., ampicillin/amoxicillin or amoxicillin-clavulanic acid for gram-positive bacteria and trimethoprim-sulfa or enrofloxacin for gram-negative bacteria. In cases of suspected or known complicated UTI or in cases of recurrent UTI, bacterial culture and sensitivity of the urine is necessary.

Cystocentesis is the preferred method of collection for urine culture and sensitivity. The urine sample should be submitted in a sealed container for culture as quickly as possible. Refrigeration is recommended if a delay in culturing is anticipated. Many practices inoculate a blood agar plate with urine and then submit the plate for identification and sensitivity if there is bacterial growth after incubation. Minimum inhibitory concentrations (MIC) and Kirby-Bauer agar diffusion tests can be used to determine bacterial sensitivity. The Kirby-Bauer method is acceptable for most UTI; however the MIC technique is often advantageous with apparently resistant UTI.

Steps to follow for management of a UTI are given in Table 1. The duration of therapy of lower UTI must be individualized and should be based on the cessation of clinical signs and elimination of abnormal urine sediment as well as a negative urine culture. In general uncomplicated lower UTI should be treated for 2 to 3 weeks, while complicated UTI should be treated for a minimum of 4 weeks. Verification of proper selection of antibiotic therapy can be made after three to five days of therapy, by assuring that the urine is sterile. The urine sediment, however, may be still abnormal at this time.

TABLE 1. Steps to follow for management of urinary tract infections

Reasons for poor therapeutic response are listed in Table 2. Recurrent UTI should always be evaluated by urine culture and sensitivity. Additionally, attempts should be intensified to identify defects in the host immune system. Double contrast cystography and ultrasonography may be used to rule out anatomic abnormalities and mucosal lesions of the bladder. In male dogs, semen and prostatic wash cytology and culture as well as ultrasonographic examination should be employed to rule out bacterial prostatitis. Excretory urography, ultrasonography, and renal biopsy may confirm the presence of pyelonephritis; however these parameters may be normal in chronic pyelonephritis. Finally, consideration should be given to the possibility of otherwise asymptomatic hyperadrenocorticism causing recurrent UTI, especially infections associated with low numbers of WBCs and RBCs in the urine sediment.

TABLE 2. Reasons for poor therapeutic response when treating urinary tract infections

The prognosis for complicated UTI is always guarded in comparison to uncomplicated UTI. The single most important treatment for a complicated UTI is correction of the underlying defect in the host defense mechanisms. If predisposing factors cannot be identified or corrected, relapses and reinfections are common. For animals with frequent infections, which cannot be cured, low dose (1/3 to 1/2 of the conventional daily dose) antimicrobial administration at bedtime may be recommended after the urinary tract has been sterilized with standard dose antibiotic treatment. This allows the drug to be present in the bladder overnight supplementing the animal's defense mechanisms. Low (sub therapeutic) dosages of antibiotic may reduce infections by interfering with bacterial fimbria production and therefore uroepithelial attachment. For recurrences due to gram-positive bacteria, penicillins are recommended; while for recurrences caused by gram-negative bacteria, trimethoprim-sulfa or enrofloxacin is recommended. It should be noted however, that long-term, sub therapeutic antibiotic treatment could predispose the animal to a resistant UTI. Any "break-through" UTI should be treated with therapeutic antibiotic dosages on the basis of bacterial culture and sensitivity.