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Chronic Urinary Tract Infections in Companion Animals

Recurrent urinary tract infections (UTI) are common in dogs compared to cats. Recurrent UTIs are classified as relapse or reinfection and these classifications have clinical implications for diagnosis and management. Relapses are defined as UTI recurrence of the same species and strain of microorganisms within several weeks of withdrawal of therapy. Reinfections are recurrent infections caused by microorganisms that are different than the prior UTI. In addition to recurrent infections, dogs with a positive urine culture despite antibiotic treatment have either a super-infection or a persistent infection. Super-infections are infections with resistant bacteria acquired during treatment of an initial UTI. Persistent infections occur when the original organism persists despite treatment.


Causes of Recurrent UTI


Common causes of a UTI relapse include inappropriate antibiotic use, persistence of the UTI within a urinary tract nidus (uroliths, neoplasia, pyelonephritis, prostatitis), and emergence of drug-resistant pathogens. Common causes of reinfection include failure to eliminate predisposing causes (perivulvar hooding with perivulvar dermatitis, morbid obesity), systemic illness (CKD, diabetes mellitus, hyperadrenocorticism), and spontaneous reinfection.


Most UTIs occur from ascending bacterial infections rather than hematogenous spread. 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. The urothelium has also intrinsic antibacterial properties. Mechanical factors including high urethral pressures, urethral length, ureteral peristalsis, and the ureterovesical "flap valve" effect act as mechanical barriers to ascending UTI.


Interference with normal host defenses may contribute to recurrent ascending infections. Common contributing factors include incomplete voiding, urine stasis or reflux, urothelial disruption, alterations in immune competence, alterations of urine composition (dilute urine, glucosuria), or iatrogenic causes (perineal urethrostomy, indwelling urinary catheters). While 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 immunosuppression.


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 perivulvar skin for evidence of a recessed or "hooded" vulva with perivulvar dermatitis that may contribute to reinfections. 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 support for hyperadrenocorticism. If available, cystoscopy is recommended for diagnostic evaluation for dogs with recurrent UTI unless an underlying cause has been identified. Cystoscopy helps to 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. Cultures of mucosal biopsies are readily obtained during cystoscopy. Cytology and histopathology of cystoscopic biopsies are required to differentiate benign polyps and polypoid cystitis from neoplasia (TCC).


Therapeutic Approach For Animals with Resistant UTI


Treatment of recurrent or resistant UTI should include attempts to obtain a specific diagnosis first, followed by a systematic treatment approach. Treatment of a recurrent UTI should be based on a urine culture and sensitivity testing obtained by cystocentesis or from a 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 antibiotics selected. This "therapeutic" culture will be positive in dogs that have persistent infections when treatment fails to resolve the resistant infection. Positive "therapeutic" cultures necessitate change in antibiotic treatment. If 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 should be 6 to 8 weeks for suspected kidney or prostate infections. Follow-up urinalysis and urine culture should be repeated 1 week and 1 month after antibiotic completion.


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


Episioplasty (surgical repair of a defect of the vulva) is often effective for resolving reinfections that occur secondary to perivulvar dermatitis. Weight loss and control of an active UTI are also recommended prior to episioplasty. 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 vaginal septal remnants, laser or surgical transaction of the remnant may be beneficial to preventing future ascending UTIs.


Preventative therapy for recurrent UTIs should be used for patients with reinfection with a goal of preventing establishment of a new infection. Preventative therapy will not be effective for relapses of the same organism due to a nidus within the urinary tract. Administration of cranberry juice or cranberry extract is suggested to reduce recurrence of UTIs in humans, although not all studies support efficacy of these products in humans. Cranberry extracts containing proanthocyanidins (PACs) inhibit the attachment of the P-fimbriated E. coli to uroepithelial cells in vitro. A recent study confirmed that cranberry extract administered to normal dogs resulted in excretion of PACs in their urine, which inhibited attachment of UPEC to canine uroepithelial cells in vitro. There are no placebo-controlled clinical trials evaluating efficacy of cranberry extracts containing PACs for prevention of recurrent UTIs in dogs. The main application of cranberry extracts would be for prevention of reinfection of UTI in dogs with a history of UTI with gram-negative organisms. Cranberry extracts would not be effective for elimination of established resistant infections nor would they be effective for UTI relapse in cases where the UTI has a nidus within the urinary tract, such as an infected urolith.


An alternative therapy for prevention of recurrent UTI is the urinary antiseptic methenamine hippurate. 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 reinfections. Urine pH should be maintained ≤ 6.0 by an acidifying diet or urinary acidifiers.


Night-time dosing of antibiotics may be utilized for prevention for repeated reinfection (> 2 per 6 months) despite other means of prevention, but this should only be utilized after an extensive search for any underlying cause and correction of anatomic abnormalities, such as perivulvar hooding. Preventative antibiotic therapy consists of giving a dose of an antibiotic immediately before bedtime after the dog has urinated. This approach will not resolve existing UTIs 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 given once daily at bedtime. For dogs with reinfections with gram-negative organisms, preventative therapy may include either a first-generation cephalosporin or nitrofurantoin. Nitrofurantoin may rarely cause drug-induced hepatopathy and liver enzymes should be evaluated if any adverse effects are suspected.


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.

 





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