By Juliette Bouillon, DVM, MVetSc, DACVIM (small animal internal medicine)

This article is the final installment of a series on bacterial urinary tract infection. To read part one, click here. 

When evaluating a patient with bacteriuria, it is important to classify and localize the urinary tract infection (UTI) so a decision can be made as to whether antimicrobial therapy is required. Over the past few decades, antimicrobial resistance (AMR) of urinary tract pathogens has been increasing, and careful as well as judicious use of antimicrobials should be pursued. This article is a comprehensive review of the current literature and guidelines for the diagnosis and management of bacterial UTI and subclinical bacteriuria (SB) in dogs and cats.

What is the goal of treating UTI?

Therapeutic goals differ based on the category of UTI identified. When treating sporadic cystitis, the clinician should aim for a clinical response within 48 hours of initiating treatment,³ with the ultimate goal of resolving clinical signs. Indeed, a microbiological cure is not explored, as urinalysis or urine culture is not recommended after treatment of sporadic cystitis when clinical signs have resolved.³ In a case of recurrent cystitis, the objectives are two-fold: clinical cure (i.e. resolution of clinical signs) and, ideally, microbiological cure (i.e. elimination of the organism).

Depending on treatment duration, urine culture can be considered after five to seven days of treatment and five to seven days after the end of antimicrobials, even if clinical cure is achieved.³ Positive culture documented during the treatment should raise concerns about treatment compliance, undiagnosed factors preventing bacterial elimination, and AMR.³ Posttreatment positive culture results should be viewed as a tool to allow diagnostic differentiation of relapse, reinfection and persistent infection, and point out the presence of elements allowing bacteriuria.³ They should not be used to decide whether treatment is necessary or not, especially when clinical cure is achieved, since these patients, henceforth, fall under the category of subclinical bacteriuria.³ In addition, although desired, microbiological cure may not be achievable in all cases. The short-term goal of pyelonephritis treatment is amelioration of clinical signs and clinicopathologic changes within 72 hours of treatment initiation.³ Clinical and microbiological cure can be assessed one to two weeks after the end of antimicrobial treatment. Lack of microbiological cure may represent subclinical bacteriuria, antimicrobial resistance, or presence of underlying complicating factors.³ Medium- to long-term goals include resolution of clinical signs, improvement or resolution of hematological changes and azotemia, and correction or control of identifiable underlying factors.³ Resolution of clinical signs and improvement of the size and architecture of the prostate, as well as semen quality, are treatment outcomes for patients with prostatitis.³

When to treat bacteriuria

Treatment of bacteriuria is indicated when a diagnosis of sporadic or recurrent cystitis is made (implying the presence of clinical signs) and when pyelonephritis or prostatitis is suspected based on diagnostic workup.³ With or without urinalysis abnormalities (pyuria, etc.) and in the absence of clinical signs, bacteriuria falls under the category of SB, for which treatment is rarely indicated and is discouraged as per the International Society for Companion Animal Infectious Diseases (ISCAID) guidelines for the diagnosis and management of bacterial UTI in dogs and cats.³ Exceptions include patients unable to display signs of lower urinary tract disease (LUTD) for which the decision of treatment needs to be made on a case-by-case basis according to clinical, clinicopathologic, and imaging results.³ Indication to treat these patients includes the presence of systemic signs, such as fever. Additional considerations for treatment of patients with SB include the presence of abnormalities on imaging testing (e.g. emphysematous cystitis), isolation of organisms that could lead to complications (e.g. Corynebacterium urealyticum and encrusting cystitis; urease-producing bacteria and struvite uroliths formation), the presence of a high risk of ascending or systemic infection, or that the bladder may be the origin of extra-urinary infection.³ The isolation of a multidrug-resistant (MDR) bacterial species should not influence the decision whether to treat SB.³

When should treatment be started?

Deciding when to start treatment depends on the category of UTI. In patients with sporadic and recurrent cystitis, withholding antimicrobial treatment pending urine culture and susceptibility results is appropriate.³ Analgesia can be provided while waiting for urine culture results to relieve the pain associated with urinary tract inflammation and improve clinical signs.³ One randomized controlled study conducted in 80 women with uncomplicated UTI showed 51.5 percent and 58.3 percent of women had resolution of clinical signs (dysuria, frequency and low abdominal pain) four days after starting ibuprofen or ciprofloxacin treatment respectively, demonstrating ibuprofen is equivalent to ciprofloxacin for treatment of clinical signs associated with uncomplicated UTI.⁵ Empirical antimicrobial treatment while waiting urine culture results can be considered in dogs with sporadic or recurrent cystitis or in patients with continued or worsening clinical signs three to four days after the start of anti-inflammatory treatment.³ Due to the low prevalence of bacterial UTIs in cats, it is reasonable to wait for urine culture results prior to initiation of antimicrobial treatment.³

Patients with suspected pyelonephritis should be treated immediately while waiting urine culture results.³ In patients with prostatitis, empirical antimicrobial treatment can be started while waiting for urine culture results unless there is a prostatic abscess, in which case, it is advised to wait for culture results to provide adequate antimicrobial therapy at the time of abscess drainage.^3,6 In patients with infection-associated uroliths (i.e. struvite uroliths) and with or without evidence of bacterial cystitis, treatment should be based ideally on urine culture and susceptibility results and therefore withheld until then.³ If culture results are not available in individuals with infection-associated uroliths and evidence of bacterial cystitis, the patient can be managed similarly to those with sporadic bacterial cystitis.³ In patients with non-infection-associated uroliths, antimicrobial treatment is only indicated when concurrent bacterial cystitis is present.³

Which antimicrobial should be used in the case of empirical treatment?

Antimicrobials used for treatment of UTIs should be selected based on their antimicrobial activity and their capability to attain high concentration in urine, along with renal or prostatic tissue.^7,8 The majority of antimicrobials are predominantly eliminated through renal excretion, allowing them to achieve high urine concentration that exceeds 10 to 100 times serum concentration.^7,9 Ideally, these antimicrobials should be associated with minimal side effects, are easy to administer, and are affordable. Antimicrobials used to treat prostatitis should be able to cross the blood-prostate barrier, implying they should have inherent properties such as lipid solubility, low-protein binding, and the ability to ionize at the acidic prostatic pH (i.e. be a weak base).^8,10

First-line antimicrobials to treat sporadic or recurrent cystitis are amoxicillin, amoxicillin with clavulanic acid if amoxicillin alone is not available, and trimethoprim-sulfonamides (TMS).³ However, empirical choice should be guided by regional or ideally on-site antimicrobial susceptibility and resistance pattern, as resistance rates vary in different geographical areas.^3,11,12 For example, one study demonstrated 67.2 percent of Staphylococci isolates were resistant to trimethoprim-sulfamethoxazole, making TMS a poor empirical choice for UTI in dogs in Brazil.¹³ Contrastingly, another study showed E. coli had a good susceptibility pattern to TMS, suggesting TMS as an effective empirical treatment in dogs and cats suffering from UTI in the U.S.¹² Studies reporting antimicrobial susceptibility patterns in dogs and cats should be interpreted cautiously, particularly regarding the selected population, as AMR has been shown to be higher in complicated than uncomplicated UTI.¹⁴ Additionally, the use of laboratory data may induce a bias toward resistance, since clinicians are more likely to perform urine cultures in complicated cases of UTI.¹¹ Therefore, the development of clinic-level antimicrobial susceptibility patterns is encouraged.³

First-line antimicrobials to treat cases of pyelonephritis and prostatitis should be based on local antimicrobial susceptibility patterns of Enterobacteriaceae, with fluoroquinolone or third-generation cephalosporin (cefpodoxime, cefotaxime, or ceftazidime) being adequate choices for pyelonephritis, and fluoroquinolone or TMS for prostatitis.³

Interpreting susceptibility results

Agar disk diffusion (i.e. Kirby Bauer method) and microdilution technique to determine minimal inhibitory concentration (MIC) are the main susceptibility tests, the latter becoming more common in laboratories.¹⁵ Culture and susceptibility reports indicate the organism(s) isolated, providing also a list of antimicrobials marked as resistant (R), intermediate (I), or susceptible (S).^4,15 These categories reflect the likelihood of treatment success, with susceptible bacterial isolates being more likely to be treated successfully compared to resistant bacterial isolates.¹⁵ Susceptibility or resistance is determined by comparing a drug's clinical breakpoints to the pathogen's MIC,¹⁵ which is defined by the lowest concentration of antibiotic that inhibits bacterial growth. Susceptible and resistance breakpoints are established by the Clinical Laboratory Standards Institute (CLSI) and refer to the specific concentrations of an antimicrobial above and below which there is susceptibility and resistance, respectively. These breakpoints are species-specific and based on the target pathogen, in vitro microbiological data, and animal and human pharmacologic and pharmacodynamic data, as well as clinical and bacteriological outcome data from prospective clinical studies.¹⁶ However, therapeutic decision is not as easy as selecting an antimicrobial with an "S" on the susceptibility results.

When interpreting culture and susceptibility results and choosing an antimicrobial, the clinician should consider the following:

• the bacterial species isolated and its susceptibility pattern;
• whether the infection is mono or polymicrobial;
• the pharmacokinetic and pharmacodynamic of the antimicrobial;
• host factors (e.g. renal or hepatic dysfunction, sepsis, etc.);
• the use of human/veterinary or serum/plasma breakpoints by the laboratory;
• local susceptibility patterns;
• potential adverse effects; and
• problems regarding critically important antimicrobials for humans.^3,4,15

Isolation of common uropathogen is consistent with urinary tract infections. Polymicrobial infections may reflect contamination.¹⁷ As such, relevance of each isolate should be evaluated in terms of bacterial species and level of growth.⁴ Some bacteria may be contaminants not warranting treatment.⁴ However, if both organisms are deemed to be clinically significant, treatment should ideally target both pathogens.⁴

In vitro susceptibility results should be interpreted in the context of the patient, as health status may interfere with treatment use, dosing, and success. For example, the use of aminoglycosides may be limited in patients with renal disease due to their potential nephrotoxicity.¹⁸ Additional consideration include patient, bacteria, and drug interactions. For example, some drug interactions decrease antimicrobial absorption.

Serum breakpoints interpretive criteria are commonly used to determine susceptibility patterns of organisms.^4,14 These breakpoints should be used to make treatment decisions in cases of pyelonephritis and prostatitis, as antimicrobials need to achieve good renal and prostatic tissue concentration.^3,15 However, drug concentration differs in various tissues; urine breakpoints may reveal higher susceptibility of isolates, particularly in cases of cystitis, as most antimicrobials reach high concentration in urine.¹⁴ Therefore, some bacteria apparently resistant in vitro may be susceptible in vivo due to the high antimicrobial urinary concentrations achieved in vivo.^15,19,20 This is particularly the case for bacteria reported to be intermediate/resistant to amoxicillin and amoxicillin-clavulanate, where effective treatment is still possible in patients with sporadic cystitis and where local prevalence of resistance is inferior to 10 percent.^4,15,21

Some organisms are intrinsically resistant to various antimicrobials. However, when evaluated in vitro, such organisms may be reported as susceptible to these same antimicrobials. Therefore, when interpreting culture and susceptibility results, the clinician should be aware of inherent in vivo resistance of organisms and antimicrobial inefficacy to avoid unnecessary use of antimicrobials that are inactive against the isolated organism. For example, Enterococci should be considered resistant to cephalosporins, clindamycin, aminoglycosides, and TMS, as these antimicrobials are ineffective in vivo, despite apparent in vitro susceptibility.²² Similarly, methicillin-resistant Staphylococci may be incorrectly reported as susceptible to penicillins and cephalosporins in vitro.²³ Detailed intrinsic resistance and unusual phenotypes that should be recognized when interpreting a susceptibility report are available on European Committee on Antimicrobial Susceptibility Testing's (EUCAST's) website (bit.ly/3cdYF3a).

If more information is needed or unusual phenotypes are detected, the clinician should contact the laboratory and consult a microbiologist.

Antimicrobial resistance and antimicrobial stewardship

Antimicrobial resistance has increased over the past decade.^{11,14,24–27} For example, one study from Brazil showed 67.2 percent of Staphylococci isolated between 2006 and 2007 from adult dogs with a presumptive diagnosis of UTI were resistant to TMS, while resistance was reported to be only two percent 25 years before.¹³ Antimicrobial resistance was found to increase with prior antimicrobial treatment and complicated versus uncomplicated infections.^14,21,28 Additional reported risk factors include severe underlying illness, hospitalization for ≥ three days, and surgical interventions.^21,29 With AMR, multidrug-resistant bacteria have become more common.^8,26 MDR bacteria are resistant to ≥ three categories of antimicrobials. These are different than antimicrobial classes—they are more therapeutically relevant and are defined for each of the organisms or organism groups.³⁰ One study found the urinary tract to be the most common extraintestinal source of MDR E. coli and Enterobacter spp. in dogs.²¹ Methicillin-resistant Staphylococci are bacteria-resistant to semi-synthetic penicillin (e.g. methicillin, oxacillin, or cloxacillin), which have β-lactam rings that are not hydrolyzed by β-lactamases.³¹ Methicillin-resistant Staphylococci are always considered MDR bacteria, even if they are only resistant to one category of antimicrobials.³⁰ Oxacillin resistance reported on culture and susceptibility results is frequently used to identify methicillin-resistant Staphylococcus pseudintermedius, while either cefoxitin or oxacillin resistance identifies Staphylococcus aureus.¹³

Bacterial resistance creates therapeutic challenges for UTIs in dogs and cats. In addition, dogs and cats with MDR high-risk clonal lineage UTI may contribute to the spread of resistant bacteria in the environment, as well as transmission to humans.^26,32,33 Conversely, increased resistance in fecal and environmental bacteria can be viewed as a potential source of refractory UTIs in veterinary patients.^27,34 Live product organisms (LPOs) have recently been studied as an alternative approach to treat UTIs. One study in mice with induced cystitis demonstrated similar anti-infective activities between the LPO tested and ciprofloxacin.³⁵ Two studies confirmed the safety of LPO in healthy dogs and dogs with recurrent UTIs.^36,37 Data from the dogs with recurrent UTIs were promising and future studies are required to investigate the clinical potential of LPO.

How long should you prescribe antimicrobials?

Although evidence of efficacy of short-course antimicrobial treatment of canine and feline UTIs is lacking, it is more and more believed that short-duration treatments are effective in regard to UTIs.³ To date, there are no clinical studies investigating the effect of duration of the same antimicrobial.³⁸ Two prospective, controlled, randomized, blinded clinical trials evaluated the efficacy of short-duration trimethoprim-sulfamethoxazole and high-dose, short duration of enrofloxacin in dogs with uncomplicated cystitis.^39,40 Efficacy was similar between three-day trimethoprim-sulfamethoxazole and 10-day cephalexin treatment. Similarly, three-day enrofloxacin treatment was not inferior to 14-day amoxicillin-clavulanate treatment.^39,40 Another prospective controlled trial in eight healthy dogs with induced cystitis evaluated the efficacy of one-day and three-day treatment of gentamycin and TMS.⁴¹ Single-dose treatments were not successful at treating the UTI, independent of the drug administered. Three-day treatment regimens were ineffective except for TMS, which allowed microbiological cure in four out of four female dogs. ISCAID guidelines for the diagnosis and management of bacterial UTI in dogs and cats recommend duration therapy of three to five days for sporadic and recurrent cystitis.³ In persistent and relapsing infections suspected to be secondary to factors inhibiting the antimicrobial response (e.g. bladder wall invasion), seven- to 14-day treatment may be considered.³ Pyelonephritis should be treated during 10 to 14 days, while prostatitis should be treated for four to six weeks.^3,10

Are additional treatments necessary?

In case of sporadic and recurrent cystitis, systemic analgesics (e.g. NSAIDs) are the only additional treatment to be considered with the purpose of improving clinical signs.³ Bladder instillation with various drugs is not advised, as efficacy is unproven and infection, injury, or inflammation could result from repeated urinary catheterization.³ Other adjunctive treatments, such as cranberry extract, have not proven to be helpful for treatment of sporadic or recurrent cystitis.³ Patients with pyelonephritis should be treated for renal failure when present (Figure 1).⁴² Surgical or chemical castration is an integral part of the treatment of prostatitis in dogs.^3,10 When prostatitis is associated with a prostatic abscess larger than 1 cm in diameter, drainage of the abscess should be performed,^3,10 and this is only once the patient is receiving targeted antimicrobials based on culture and susceptibility results.³

When to recheck the patient and how

In patients with sporadic and recurrent cystitis, patient reevaluation after cessation of treatment is indicated to document resolution of clinical signs. Urinalysis or urine culture is not necessary for sporadic cystitis when clinical signs have resolved.³ Consideration can be given for intra- and posttreatment urine culture in patients with recurrent cystitis who receive longer duration treatment.³ Patients with pyelonephritis and prostatitis should be rechecked at the end of the treatment to confirm eradication of the infection.^3,10 Physical examination, serum creatinine concentrations, imaging testing, urinalysis, and aerobic bacterial urine culture can be performed as directed by the case.^3,10

What are preventive treatment options?

With the advent of AMR, there is a developing interest for non-antimicrobial preventative treatment of UTIs. Topical vaginal estrogen, oral or intravaginal probiotic Lactobacillus spp., and cranberry prophylaxis have been shown effective for decreasing UTI recurrence in women.^43,44 Evidence of efficacy of various non-antimicrobial prophylactic treatments of UTIs is lacking in veterinary medicine.³ Cranberry products contain proanthocyanidins, which are molecules preventing UTIs by inhibiting bacterial adhesion to uroepithelial cells, particularly P-fimbriated E. coli.⁴⁵ A randomized, placebo-controlled, blinded, prospective clinical trial failed to prove the efficacy of cranberry extracts to reduce bacteriuria in dogs with acute thoracolumbar intervertebral disk herniation.⁴⁶ Lack of study power, inappropriate dose rate, and poor bioavailability of the cranberry extract were suggested as potential causes of failure to demonstrate efficacy. Two recent studies confirmed the preventive effects of cranberry extracts on the in vitro bacterial attachment to canine and feline uroepithelial cells, as well as the in vivo development of UTI in dogs.^47,48 D-mannose inhibits bacterial adhesion by preventing interaction between E. coli lectin fimbriae H (FimH) and the uroepithelial glycoprotein uroplakin Ia.⁴⁹ There is no study evaluating the efficacy of D-mannose to prevent UTI in dogs and cats.⁴⁹ Recently, the use of probiotics has become popular in human and veterinary medicine.^50,51 Probiotics are live microorganisms that, when consumed in adequate amounts, have the potential to confer a beneficial health effect.⁵⁰ In the human literature, probiotics are hypothesized to prevent bacterial UTI by modulating host immunity, preventing adherence of pathogenic bacteria to the urogenital epithelium, and modulating bacterial growth and/or colonization.⁵¹ Two studies assessed the normal vaginal microbiota in dogs: Hutchins et al. evaluated 21 healthy spayed female dogs and 23 female dogs with recurrent UTIs, while Delucchi et al. selected 42 healthy and ill bitches.^52,53 In the later study, lactic acid-producing bacteria (LAB), such as Lactobacillus murinus, Lactobacillus plantarum, and Enterococcus canintestini, were detected in 41 out of 42 dogs. Eight selected isolates were tested and showed antimicrobial activity against P. mirabilis, S. aureus, and E. coli, emphasizing the potential probiotic properties of the vaginal organisms.⁵³ Interestingly, in the study from Hutchins et al., LAB were uncommonly isolated.⁵² Enterococcus canintestini was the LAB identified most frequently.⁵² This study failed to identify a difference in vaginal microbiota between healthy dogs and those with recurrent UTIs. Another study from Hutchins et al. evaluating the effect of an oral probiotic on the vaginal microbiota in healthy spayed female dogs found again low prevalence of LAB bacteria.⁵⁴ Sampling methods were suspected to explain the difference in results compared to the study of Delucchi et al. Nevertheless, Hutchin's study failed to show increased prevalence of vaginal LAB in dogs after administration of the oral probiotic supplement.⁵⁴ Lack of probiotic survival in the gastrointestinal tract environment and inappropriate LAB bacteria species constituting the probiotics were suggested as potential factors to explain these findings. Additional studies are necessary to further evaluate the clinical utility of probiotics to prevent UTIs in dogs and cats.

When is preventive treatment indicated?

The paucity of veterinary literature regarding preventive measures of UTIs in dogs and cats inhibit the recommendation of non-antimicrobial treatments for prevention of SB, sporadic, recurrent, and catheter-associated cystitis.³

Bacteriuria can be a common finding in some categories of veterinary patients. The clinician should be able to classify the UTI to make appropriate treatment decisions. In addition, the clinician should be familiar with ISCAID guidelines for the diagnosis and management of bacterial urinary tract infections in dogs and cats. Knowledge of pharmacological properties of antibiotics and potential pitfalls of urine culture and susceptibility reports are essential for guiding therapeutic decisions.

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Juliette Bouillon, DMV, MVetSc, DACVIM (small animal internal medicine), is assistant professor of small animal internal medicine at Ross University School of Veterinary Medicine (RUSVM). Originally from Paris, France, Dr. Bouillon completed her veterinary studies in Liège, Belgium, and graduated in 2011. After one year in a general small animal practice in Paris, she performed a rotating internship at the veterinary school in Nantes, France, followed by a specialized internship in private practice in Bordeaux, France. Following this, Bouillon spent a year in French Guiana in South America working as a small animal general practitioner before starting the residency and graduate program at the Western College of Veterinary Medicine (WCVM) in Saskatoon, Canada, where she completed a master of veterinary science degree for which she studied the effects of dexmedetomidine on glucose homeostasis in healthy cats. She completed her residency and became board certified as a Diplomate to the American College of Veterinary Internal Medicine (small animal internal medicine) in September 2019. Beyond veterinary medicine, Bouillon enjoys spending time with her family and practicing activities such as running, yoga, and snorkeling.