By Erika de Papp, DVM, DACVIM
Internal Medicine Service
Urinary tract infection (UTI) is defined as the multiplication and persistence of an infectious agent in the urogenital system. This is most often caused by an ascending infection involving normal bacteria present in the distal urogenital tract. Approximately 14% of dogs will experience a UTI during their lifetime, with an increased risk noted in spayed females. Although infectious agents other than bacteria can also colonize the urinary tract, bacterial infections are the most common.
UTI occurs when there is a breach in normal host defenses. These defenses include normal voiding ability, anatomic structures within the urinary tract, mucosal defense barriers, inherent antimicrobial properties of urine, and systemic immunocompetence.
Anatomic structures that protect the urinary tract include urethral high pressure zones, urethral and ureteral peristalsis, urethral length, urethral microplicae, ureterovesical flap valves, and prostatic secretions in males.
Cystoscopic image of proliferative lymphoid tissue in the vestibule of a dog with chronic UTI.
Mucosal defense barriers include the inherent antimicrobial properties of the uroepithelium, the glycosaminoglycan layer that lines the bladder, local antibody production, bacterial interference by commensal microbes present in the distal tract, and exfoliation of the uroepithelial cells.
The urine itself also has antimicrobial properties due to high osmolality and urea concentration, extremes of pH, presence of organic acids, and Tamm-Horsfall mucoproteins synthesized in the kidneys.
Finally, systemic immunocompetence of the host is important to prevent UTI. Dogs with underlying conditions such as diabetes, renal disease, and hyperadrenocorticism, as well as dogs being treated with immunosuppressive drugs, are at an increased risk of UTI development.
Clinical signs associated with the classic UTI include pollakiuria, stranguria, dysuria, hematuria, and inappropriate urination. These signs are typical of lower urinary tract disease. A dog with disease confined to the lower urinary tract should not show signs of systemic illness. If fever, inappetence, abdominal pain, or lethargy is present, this should prompt a more thorough investigation for underlying systemic disease causing a UTI, or involvement of the upper urinary tract. Additionally, it is important to remember that a certain percentage of dogs with UTI will present for a different reason, and may have no clinical signs related to urinary tract disease.
Diagnosis of UTI is dependent on a thorough history and physical exam as well as a urinalysis and urine culture. When obtaining the history it is important to differentiate pollakiuria from polyuria, and determine if polydipsia is present. The client should also be questioned as to whether the dog generates a normal urine stream and if a normal volume of urine is produced in a single attempt at voiding. Has the owner noted any signs of urinary incontinence? If blood is present in the urine, is it present throughout the urine stream or only at the end of urination, as differentiation may help localize the disease. A thorough medication history is also imperative.
A complete physical exam should include a rectal exam to palpate the urethra, and prostate if applicable. Bladder size and tone should be evaluated. It may be worthwhile to palpate the abdomen both before and after voiding if there is suspicion of inability to void completely. External genitalia should be closely observed, specifically noting vulvar conformation, evidence of perivulvar moisture or dermatitis, and any preputial lesions.
If the dog is showing only lower urinary tract signs and otherwise appears healthy with no chronic medical conditions, a urine sample is sufficient for the initial evaluation of UTI. If the dog has known predisposing conditions, a chronic history of UTI, or is showing signs of systemic illness, then a CBC and chemistry profile are indicated, and imaging should be considered.
Whenever possible the urine sample should be obtained via cystocentesis. Catheter samples are acceptable from male dogs. A voided sample is not considered adequate for evaluation of infection, unless the sediment is inactive and subsequent culture is negative.
Typical findings in the urine sediment include pyuria, hematuria, and bacteriuria. The leukocyte and nitrite markers on the urine dipsticks are not accurate for dogs (or cats), and should not be used to diagnose UTI. It is important to remember that lack of visible bacteriuria does not rule out a UTI. Greater than 10,000 bacteria/ml must be present to see bacterial rods in the urine sediment, and >100,000 bacteria/ml must be present to see cocci. For this reason, it is imperative to culture the urine.
Samples for culture should be submitted to the lab immediately and plated as soon as possible. Ideally the sample should be plated within 30 minutes. If this is not possible, the sample should be refrigerated and plated up to a maximum of 24 hours later. When interpreting culture results, quantitative culture is most useful. If samples are obtained via cystocentesis, ≥1,000 cfu/ml is considered significant. If samples are obtained via catheter, ≥10,000 cfu/ml is significant.
The most common microbial isolates from the urinary tract include E. coli, Staphylococcus spp., Enterococcus spp., Streptococcus spp., Proteus spp., Klebsiella spp., and Pseudomonas spp., with E. coli being the most prevalent by far.14
Sensitivity testing will allow appropriate antimicrobial choices. Although empiric use of antibiotics based on the most likely pathogen is frequently employed, this is not recommended. Minimum inhibitory concentrations (MIC) are used to determine antibiotic efficacy. The MIC is the minimum concentration of antibiotic necessary to completely inhibit bacterial growth. Efficacy for treating a UTI is expected if the urine concentration of the drug is at least four times greater than the MIC. If the culture results indicate that the bacteria are sensitive in vitro, good in vivo efficacy is expected. However, bacteria that show only intermediate sensitivity may also be effectively eradicated if the drug reaches high urine concentrations. Urine concentrations of drugs are often 10-100 times higher than plasma concentrations, therefore culture results may underestimate drug efficacy.24
Therapy of the uncomplicated UTI is typically achieved with 7-14 days of treatment. The duration of therapy necessary is based on convention rather than research. The uncomplicated UTI is a first time or rare infection involving only the lower urinary tract, in an otherwise healthy animal. An empiric antibiotic may be chosen while awaiting culture results, and then adjusted as needed. The International Society for Companion Animal Infectious Diseases (ISCAID) recommends treating an uncomplicated UTI for 7 days. They further recommend Amoxicillin at 11-15 mg/kg PO TID or Trimethoprim-sulfonamide at 15 mg/kg PO BID while awaiting culture results.22 Further studies are needed to determine the appropriate length of treatment for the uncomplicated UTI but two recent studies showed no difference between short duration treatment (3 days) and treatments varying from 10-14 days.4,25
An uncomplicated UTI is relatively easy to treat. Things become more challenging in the face of recurrent UTI. Recurrent UTI is a common cause for referral in veterinary medicine. Recurrences come in several forms; relapse, reinfection, persistent infection, and superinfection. A relapse is defined as a recurrence caused by the same species and strain of bacteria, typically within days to weeks of completion of antibiotics. A reinfection is defined as a recurrence caused by a different organism, typically with a longer disease free interval than a relapsing infection. A persistent infection is one in which the causative organism is not eliminated in spite of therapy, which would be documented by a positive culture during antibiotic therapy. And finally, a superinfection is the development of infection with a different pathogen, while being treated for the original pathogen. Thankfully superinfections are rare, and typically associated with indwelling urinary catheters or cystostomy tubes.
A relapse is usually associated with antimicrobial failure. Failure can be due to a number of causes. These include; incorrect dose, frequency, or duration of drug, poor client or patient compliance, poor drug absorption or bioavailability, the emergence of drug resistance, deep seated infections, or a persistent nidus of infection.
Reinfection is typically associated with either a failure to identify or eliminate an underlying cause of disease. It may also be associated with previous infection with multiple pathogens and eradication of only one of the pathogens. Finally, it can also be iatrogenic, following procedures such as cystoscopy or catheterization. If reinfection is documented more than 3 times per year, a complete work-up to identify an underlying cause for the UTI should be pursued. If reinfection occurs rarely, then each UTI can be treated as a single event.
When approaching the recurrent UTI, it is important to verify client compliance prior to pursuing an exhaustive work-up. Is the client giving the correct dose of antibiotic, and at the correct frequency, and is the client sure that the dog is ingesting all of the medication? Additionally, clients may have the tendency to stop medication once the clinical signs resolve, resulting in shortened duration of therapy.
Once it has been established that the dog has been medicated appropriately, the search for an underlying cause of disease should commence. Additionally, longer duration of therapy is appropriate for recurrent infections and additional use of cultures is important for monitoring response.
The diagnostic work-up should include a CBC, chemistry profile, survey abdominal radiographs and/or abdominal ultrasound (US). Cystoscopy is a useful additional tool if initial diagnostics are negative, or more information is needed. If lab work indicates a leukocytosis, pyelonephritis or prostatitis should be considered, as well as other non-urinary tract diseases. A UTI confined to the bladder should not result in a leukocytosis. The chemistry profile will allow the practitioner to rule out diabetes mellitus and azotemia, and will increase the index of suspicion for diseases such as hyperadrenocorticism. Confirmatory tests for hyperadrenocorticism should be pursued as indicated.
Radiographs are useful for diagnosing radiopaque uroliths as well as evaluating renal size, and bladder position. Bladder masses and polyps may be visible but are likely to be missed unless quite large. Sublumbar lymphadenopathy may also be noted with metastatic bladder neoplasia.
Abdominal US is an excellent imaging modality to evaluate the bladder more thoroughly and evaluate bladder wall thickness (although this will vary with bladder volume), mucosal irregularity, and both radiopaque and non-radiopaque uroliths. Small bladder masses will be visible on US when not visible on radiographs. Additional advantages over radiographs include the ability to evaluate renal pelvic size and ureteral size, and identify anatomic abnormalities such as urachal diverticuli. Contrast radiography may also be used to further evaluate the urinary tract but this is more labor intensive and has become much less common since the advent of US.
One of the disadvantages of US is that evaluation of the urethra is only possible at its most proximal point, as it joins the bladder. Contrast radiography can evaluate the urethra, but cystoscopy is a more sensitive means of urethral mucosal evaluation. Cystoscopy is also useful for evaluating vestibulovaginal anatomy and bladder mucosa. The added advantage is that samples can be obtained for cytology, histopathology, and culture. Uroliths can also be removed depending on size. Due to the limited urethral diameter of the male dog, uroliths should be <3mm. In female dogs the urolith should be no more than twice the diameter of the cystoscope.(Cystoscopes typically range from 1.9mm up to 4mm in diameter.)17
Therapy of the recurrent UTI requires a longer duration of antibiotics, typically 4 weeks. If pyelonephritis is suspected then therapy should be extended to 6 weeks. If an underlying cause can be identified and eliminated, therapy should continue at least 2-3 weeks beyond resolution of the problem. Other approaches to proper therapy include the use of therapeutic cultures. This is a culture that is performed 5-7 days after starting antibiotics, in order to demonstrate antibiotic efficacy during treatment. Cultures should always be performed again 5-7 days after completion of treatment. With chronic, recurrent UTI, a culture should also be considered just prior to completion of treatment. Finally, a follow-up culture should be repeated one month after completing the antibiotic treatment.
Management of underlying disease is very important. It has been reported that approximately 42% of dogs with diabetes mellitus, hyperadrenocorticism, or both diseases have a concurrent UTI. Less than 5% of these dogs had signs of lower urinary tract disease.7 Iatrogenic disease, caused by chronic administration of glucocorticoids has also been reported to increase the incidence of UTI, and none of the affected dogs had clinical signs consistent with UTI.20 Routine use of urine cultures is recommended as a screening measure for UTI in dogs with diabetes mellitus, hyperadrenocorticism, and those receiving long-term steroid therapy. The same recommendation holds for dogs receiving chronic chemotherapy.
Removal of uroliths and urinary tract masses is also indicated. The latter is not always possible given the frequent trigonal location of common neoplastic masses such as transitional cell carcinoma. Uroliths can be removed via dissolution (struvite, urate, cystine), urohydropropulsion (if <3mm), cystoscopy, cystotomy, and laser lithotripsy (limited availability). Culture of the urolith and bladder mucosa is recommended if the urine culture is negative. Bacteria were isolated from uroliths or mucosa in 23.8% of dogs with negative urine cultures in one study.8
Vulvar conformation should be carefully evaluated in dogs with recurrent UTI. A recessed, hooded, or juvenile vulva may predispose to UTI. Many of the affected dogs also have perivulvar dermatitis. It is important to perform an exhaustive diagnostic work-up in these cases, as poor vulvar conformation is fairly common, and may or may not be the underlying problem. However, episioplasty has been shown to be a very effective means of correcting the problem and reducing the incidence of UTI in dogs.13
Periodically practitioners face the problem of negative urine culture results despite clinical signs of lower urinary tract disease, pyuria, alkaline urine, and struvite crystals. In these cases, uncommon, fastidious, urease producing bacteria such as Ureaplasma and Corynebacterium should be considered. These microbes can grow very slowly, so cultures should be evaluated for 5 days before being called negative. It may be worthwhile consulting the diagnostic laboratory if these bacteria are suspected, as special growth media may be required.
Another problem that can occur is lack of in vivo response to antibiotics despite in vitro sensitivity reported on the urine culture. As previously noted, because most antibiotics reach very high concentrations in the urine, the sensitivity testing may actually underestimate drug efficacy. However, for particularly virulent uropathogens such as uropathogenic E. coli, the bacteria may persist within bladder tissue and evade the antibiotics.5 For these more difficult infections, aggressive antibiotic strategies may be necessary. When treating with concentration dependent antibiotics (fluoroquinolones, aminoglycosides), activity is based on peak serum concentrations, and once daily dosing is indicated. With tough infections, a higher dose may provide greater efficacy. On the other hand, if time dependent antibiotics (β-lactams) are being used, then frequency of dosing is the most important factor determining efficacy. If using a drug with a short half life, it may be more effective to give the drug three times a day rather than twice a day, in order to keep the drug concentration above the MIC for an adequate period of time. It is important to aim to keep drug concentrations above MIC for at least 50% of the dosing interval when treating with a time dependent antibiotic. Finally, drug choice should be based on more than just the sensitivity results. Using the MIC to determine which drug is most active against the bacteria may result in better drug choices.
Ultimately one of the most daunting infections practitioners face is the multi-drug resistant (MDR) UTI. Hopefully with proper use of cultures and proper diagnostic work-ups, most resistant infections can be avoided. However, this is an ever emerging problem in both human and veterinary medicine. Currently, resistance to the carbapenem class of antibiotics is rare.16 The major disadvantage of these antibiotics is expense. Imipenem is typically given IV and requires large fluid volumes, so is not practical for home use. Meropenem can be given subcutaneously and therefore can be given at home. We have successfully managed a variety of resistant infections with meropenem but this is cost prohibitive for some clients. Aminoglycosides are another class of drug to which resistance is fairly low, but nephrotoxicity is a significant concern and prolonged use is therefore discouraged. If used, careful monitoring of renal function is necessary. Therapeutic drug monitoring may allow lower doses to be used but this is not practical for most laboratories or practitioners. The third generation fluoroquinolones are a new class of drugs with broader spectrum of activity than the existing fluoroquinolones, but these are not widely available or have only limited licensure in the US at this time. Fosfomycin is a natural antibiotic that has shown in vitro efficacy against some MDR strains of fecal E. coli but clinical studies are needed (Boothe, ACVIM 2104).
When an underlying cause of UTI either cannot be identified or cannot be eliminated, additional strategies need to be employed to combat recurrent UTI. Preventative therapy is one option. This consists of long term, low dose (1/3 to1/2 the normal daily dose) antibiotic therapy typically given at night after the patient voids for the last time. It is imperative that this type of therapy only be given after an existing UTI has been cleared with a full course of antibiotics at the full dose. ISCAID does not recommend this type of therapy for relapsing infections, as this may promote bacterial resistance.22 However, a retrospective study of recurrent UTI in dogs reported that preventative therapy seemed to be the most effective strategy for dealing with recurrent UTI whether they were relapses or reinfections.18 Treatment is typically continued for a period of six months, with intermittent use of therapeutic cultures to ensure that there is no recurrence. Although not ideal, this approach can be used in cases that have underlying disease that cannot be eliminated or successfully managed, but practitioners and clients must be aware of the potential hazards of bacterial resistance.
In some cases clinicians are faced with dogs that have repeated positive cultures but no clinical signs. This scenario is referred to as asymptomatic bacteriuria in humans and subclinical bacteriuria in dogs. In women with recurrent UTI, it has been shown that treatment of asymptomatic bacteriuria (ASB) is associated with higher rates of symptomatic UTI and higher drug resistance. Additionally, untreated ASB in diabetic humans has not been associated with increased complications.2,3 In humans, the strains causing the ASB have been shown to be non-virulent and may compete with uropathogenic E. coli, and have been used therapeutically in some cases.6 Subclinical bacteriuria has been reported in healthy female dogs and was found to be a non-progressive condition in one recent study.25 In the current state of increasing bacterial resistance it will be more and more important to consider not reaching for antibiotics in cases of subclinical disease. More animal studies are needed, but this is something to be aware of in our veterinary patients.
Finally, in addition to standard antibiotic therapy, ancillary therapies have been used to help in UTI prevention. Cranberry contains proanthocyanidins which inhibit attachment of bacterial fimbriae (E. coli) to the uroepithelium. Use in dogs is anecdotal but consumption of cranberry was shown to decrease UTI recurrence rates over one year by 35% in young to middle aged women.9 Urinary antiseptics such as methenamine mandelate have also been used. Methenamine is converted to formaldehyde in the bladder, but this requires an acidic pH. Urinary acidifiers may be needed to achieve an appropriate urine pH (5-6). There is currently insufficient evidence to support the use of these ancillary therapies in dogs.22
Probiotics have also been evaluated in two veterinary studies to determine if the vaginal microbiota is different in dogs with recurrent UTI, and if oral probiotic therapy could change the vaginal microbiota. No difference was found between groups and oral therapy had no effect on resident flora. More studies are needed to determine the role of probiotics in dogs with recurrent UTI.10,11
In summary, bacterial UTI is a common condition in dogs. Urine cultures are key to successful diagnosis and management of UTI. Recurrent infections can be challenging and require a thorough diagnostic work-up to identify and eliminate underlying causes of UTI, when possible. Thoughtful antibiotic strategies may improve efficacy of therapy in difficult cases, and consideration should be given to not treating positive cultures in dogs without clinical disease.
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