Diagnosing and managing recurrent urinary tract infections (Proceedings)

Recurrent urinary tract infections (UTI) are a common problem in dogs.1 There are 2 major types of UTI recurrence: relapse and reinfection. The implications of relapse versus reinfection are important for diagnosis and management of recurrent UTI. Relapses are defined as UTI recurrence of the same species and serologic strain of microorganisms within several weeks of withdrawal of therapy. Reinfections are recurrent infections caused microorganisms that are different than the prior UTI. In addition to recurrent infections, super-infections and persistent infections are also common issues. Super-infections are infections with resistant organisms that are acquired during treatment of an initial UTI. Persistent infections are when the same organism does not resolve during treatment of UTI.

Causes of recurrent UTI

Common causes of UTI relapse include inappropriate antibiotic use (incorrect dose or duration, poor owner compliance), failure to eliminate predisposing causes (uroliths, neoplasia), deep-seated infections that are inaccessible to the antibiotic (pyelonephritis, prostatitis), and emergence of drug-resistant pathogens. Common causes of apparent reinfection include failure to eliminate predisposing causes for UTI (e.g., perivulvar hooding and perivulvar dermatitis), systemic illness (e.g., diabetes mellitus and hyperadrenocorticism), presence of multiple pathogens in which only sensitive pathogens were eliminated by therapy, and spontaneous reinfection.

Most UTIs occur from ascending bacterial infection. There are normal host defenses that protect the urinary tract from infection. Normal voiding washes bacteria out of the urinary tract before they can establish an infection. Normal canine and feline urine is bactericidal from high osmolality and extremes in pH (< 6.0). Urothelium has also intrinsic antibacterial properties. Mechanical factors including the urethral high pressure zone, length of urethra, ureteral peristalsis, and ureterovesical "flap valves" act as mechanical barriers to ascending UTI.

Interference with normal host defenses may contribute to repeated ascending infections. Common contributing factors include incomplete voiding, urine stasis or reflux, disruption of or damage to the urothelium, alterations in immune competence, alterations of urine composition (dilute urine, glucosuria), or iatrogenic causes (perineal urethrostomy, indwelling urinary catheters). Young adult cats rarely have bacterial UTI unless prior procedures predispose them to acquired UTI, older cats are more commonly affected by UTI because of concurrent diseases that cause dilute urine and or impair immune competence.

Diagnostic approach for animals with recurrent UTI

The standard diagnostic evaluation for dogs with recurrent UTI should include CBC, serum biochemistry profile, urinalysis, urine culture, abdominal radiographs and ultrasound. The history should be reviewed for diseases or drugs that could contribute to immunosuppression. Physical examination should include careful examination of the vulva and peri-vulvar skin for evidence of recessed or "hooded" vulva with perivulvar dermatitis that may contribute to reinfection of the urinary tract. Subtle abnormalities of the perivulvar region is easily overlooked during routine physical examination and should be carefully evaluated in dogs with recurrent UTI. Rectal examination should also be included as a standard part of the physical examination to evaluate the urethra for masses or uroliths that could contribute to recurrent UTI.

Testing for hyperadrenocorticism should be performed if there is any data that might support the presence of hyperadrenocorticism. If available, cystoscopy is recommended for diagnostic evaluation for dogs with recurrent UTI if an underlying cause has not been identified during initial work-up. Cystoscopy helps rule out anatomic abnormalities, polyps, neoplasia or uroliths and permits mucosal biopsy for culture, cytology and histopathology.

Cultures of tissue or uroliths are more sensitive than routine urine culture for detecting chronic UTI especially in dogs previously treated with antibiotics. Bacteria were isolated from bladder mucosal cultures or urolith cultures in 18 to 24% of dogs despite concurrent negative urine cultures. While these studies utilized bladder mucosal samples from cystotomy, we have also been able to identify bacterial and mycoplasmal UTI from cultures of mucosal biopsies obtained via cystoscopy from dogs despite concurrent negative urine cultures.

Therapeutic approach for animals with recurrent UTI

Treatment of recurrent UTI should include attempts to obtain a specific diagnosis first followed by a systematic treatment approach. Treatment of recurrent UTI should be based on culture and sensitivity testing of urine samples obtained by cystocentesis or from culture of mucosal biopsies. A follow-up "therapeutic" urine culture should be obtained approximately 7 days after initiation of antibiotic therapy to prove in vivo efficacy of the drug selected on the basis of the initial in vitro susceptibility testing. Provided this "therapeutic" culture is negative, antibiotic therapy is continued at full doses for a total of 4 to 6 weeks depending on location and type of infection. Duration of antibiotics may need to be 6-8 weeks for suspected kidney or prostate infections. Follow-up urinalysis and urine culture should be repeated 1 week and 1 month after completion of antibiotic therapy to confirm resolution of the UTI.

Male dogs with UTI should be assumed to have infection of the prostate; therefore, antibiotics selected for treatment of UTI in male dogs should achieve good prostate penetration. Examples of antibiotics with poor prostate penetration include penicillin, ampicillin, cephalosporins, and aminoglycosides. These antibiotics should be avoided in dogs with confirmed chronic prostatitis. Antibiotics that achieve good prostate concentration and are more likely to be effective for treatment of bacterial prostatitis in dogs include fluoroquinolones (enrofloxacin, marbofloxacin, and ciprofloxacin), erythromycin, clindamycin, trimethoprim-sulfa, carbenicillin, and chloramphenicol. Bactericidal antibiotics such as fluoroquinolones are generally preferred over bacteriostatic antibiotics for treatment of chronic prostatitis.

Episioplasty is often effective for resolving re-infections that occur secondary to perivulvar dermatitis. Resolution of relapsing UTI secondary to infected uroliths usually requires removal of the uroliths in order to achieve resolution of the UTI. The role of urinary incontinence as a cause of recurrent UTI is not definitively known. Effective treatment of urinary incontinence may reduce the risk of recurrent UTI in dogs. For dogs with persistent septal vaginal remnants, laser or surgical transaction of the remnant may be beneficial to preventing future ascending UTIs.

Preventative therapy for repeated reinfection (> 2 per 6 months) should only be utilized after an extensive search for any underlying cause. Preventative therapy consists of giving a single dose of an antibiotic immediately before bedtime after the dog has urinated. This approach will not resolve existing UTI and should only be used after effective treatment of any existing UTI. For dogs that have recurrent gram positive bacteria causing UTI, amoxicillin is recommend at a dose of 20 mg/kg given PO once daily at bedtime. For dogs with re-infections with gram negative organisms, preventative therapy should include either a first generation cephalosporin or nitrofurantoin (4 mg/kg PO once a day). Nitrofurantoin may rarely cause drug-induced hepatopathy and liver enzymes should be evaluated if any adverse effects are suspected. Preventative therapy will not be effective for relapses of the same organism due to a nidus within the urinary tract. Likewise pulse antibiotic therapy for 3-5 days every few weeks is not an effective strategy for management of recurrent UTI. These misuses of antibiotics are likely to induce multiple drug resistance in the organisms causing the UTI.

An alternative therapy for recurrent UTI is a rarely used urinary antiseptic methenamine mandelate. Methenamine is converted to formaldehyde in an acidic urine pH. Because bacteria cannot easily acquire resistance to formaldehyde, it may be efficacious in patients with resistant UTI and in patients with re-infections despite night time preventative doses of antibiotics. The recommended dose is 10-20 mg/kg PO q 8-12 h. If necessary, urine pH may need to be reduced by use of an acidifying diet or urinary acidifiers.

Difficult organisms causing recurrent UTI

Urinary tract infections with E. coli warrant some specific comments concerning treatment. Because of their ability to acquire antibiotic resistance through plasmid mediated resistance, E coli UTIs can become multi-resistant over time. Therefore, appropriate follow-up is especially important with this common uropathogen. Follow-up urine cultures are recommended for any dog or cat with recurrent UTI due to E. coli. For multiresistant E. coli, antibiotics to consider if testing suggests they are effective include amikacin, ceftiofur, imipenem or meropenem. Aminoglycosides are excreted in the urine and achieve very high urine concentrations but are also nephrotoxic. Therefore, aminoglycosides should only be used for shorter durations and with appropriate monitoring for nephrotoxicity. Monitoring for nephrotoxicity should include routine urinalysis and monitoring of urine GGT to creatinine ratios. Ceftiofur or cefoxitin are effective alternatives to aminoglycosides provided the E. coli isolated is sensitive in vitro. Imipenem or meropenem are highly effective against many strains of E. coli and may be required in animals with renal disease and recurrent gram negative UTI. However these antibiotics should be reserved for documented multi-resistant infections when other antibiotics have failed and renal disease prohibits the safe use of aminoglycosides.

Enterococcus spp are also increasing in frequency as a cause of recurrent UTI, especially in dogs that have been treated with fluoroquinolones. There are several important features of this organism that contribute to frequent recurrence. During laboratory in vitro susceptibility testing, Enterococcus often appears to be susceptible to fluoroquinolones, although it is usually resistant to fluoroquinolones in vivo resulting in treatment failure. Enterococcus is able to overcome folic acid blockade in vivo and may be resistant to potentiated sulfas despite in vitro susceptible test results. Some animals with enterococcal UTI have no symptoms of their UTI for extended periods of time. There is a notable absence of pyuria in these animals with silent enterococcal UTI. In rare patients, enterococcal UTI may remain unresolved despite appropriate antibiotic therapy. In some dogs, treatment of any concurrent organisms may resolve the enterococcal UTI without specific treatment of the Enterococcus.

Recurrent UTI in cats

Cats less than 8 to 10 years of age uncommonly have bacterial UTI as a cause of lower urinary tract signs unless they have had perineal urethrostomy surgery or indwelling urinary catheters. The incidence of lower urinary tract disease in geriatric cats is very different than young adult cats. In one study, 46% of geriatric cats with lower urinary tract disease had UTI, 17% had UTI and uroliths, 10% had uroliths, 7% had urethral plugs, 7% were due to trauma, 5% had idiopathic cystitis, and 3% had neoplasia.3 Many geriatric cats with UTI have concurrent chronic kidney disease, diabetes mellitus or hyperthyroidism.

Conclusion

The key to successful management of recurrent UTI is to accurately diagnose the reason(s) for the recurrent nature of the problem in each case. Cystoscopy is an underutilized tool in the diagnosis of recurrent UTI. Appropriate follow-up cultures are required for successful management of recurrent UTI.

References

Seguin MA, Vaden SL, Altier C, et al. Persistent urinary tract infections and reinfections in 100 dogs (1989-1999). J Vet Intern Med 2003;17:622-631.

Westropp JL, Buffington CAT, Chew D. Feline lower urinary tract diseases, in Textbook of veterinary internal medicine: diseases of the dog and cat, ed. Ettinger SJ and Feldman EC, Elsevier Saunders, St. Louis, 2005, 1828-1850

Bartges JW, Barsanti JA. Bacterial urinary tract infections in cats, in Current Veterinary Therapy, ed. Bonagura JD, W.B. Saunders Co., Philadelphia, 2000, 880-883

Lightner BA, McLoughlin MA, Chew DJ, et al. Episioplasty for the treatment of perivulvar dermatitis or recurrent urinary tract infections in dogs with excessive perivulvar skin folds: 31 cases (1983-2000). J Am Vet Med Assoc 2001;219:1577-1581.

Forrester SD, Troy GC, Dalton MN, et al. Retrospective evaluation of urinary tract infection in 42 dogs with hyperadrenocorticism or diabetes mellitus or both. J Vet Intern Med 1999;13:557-560.

Hamaide AJ, Martinez SA, Hauptman J, et al. Prospective comparison of four sampling methods (cystocentesis, bladder mucosal swab, bladder mucosal biopsy, and urolith culture) to identify urinary tract infections in dogs with urolithiasis. J Am Anim Hosp Assoc 1998;34:423-430.

Gatoria IS. Comparison of three techniques for the diagnosis of urinary tract infections in dogs with urolithiasis. J Small Anim Pract 2006;47:727-732.

Adams LG, Syme HM. Canine lower urinary tract diseases, in Textbook of Veterinary Internal Medicine, ed. Ettinger SJ and Feldman BF, W.B.Saunders, Philadelphia, 2004,

Rivers BJ, Walter PA, O'Brien TD, et al. Evaluation of urine gamma-glutamyl transpeptidase-to-creatinine ratio as a diagnostic tool in an experimental model of aminoglycoside-induced acute renal failure in the dog. J Am Anim Hosp Assoc 1996;32:323-336.

Greene CE, Prescott JF. Enterococcal infections, in Infectious diseases of the dog and cat, ed. Greene CE, Saunders Elseiver, St. Louis, 2006, 309-310

Buffington CA, Chew DJ, Kendall MS, et al. Clinical evaluation of cats with nonobstructive urinary tract diseases. J Am Vet Med Assoc 1997;210:46-50.

Bailiff NL, Nelson RW, Feldman EC, et al. Frequency and risk factors for urinary tract infection in cats with diabetes mellitus. J Vet Intern Med 2006;20:850-855.