Bacterial urinarytract infections (UTI) typically result from normal skin and GI tract flora ascending the urinarytract and overcoming the normal urinarytract defenses that prevent colonization. Bacterial UTI is the most common infectious disease of dogs, affecting 14% of all dogs during their lifetime. It is less common in cats, and occurs only infrequently in large animals. Young cats with feline lower urinarytract disease usually have bacteriologically sterile urine. However, >50% of geriatric cats with urinarytract disease have a bacterial UTI. Approximately two-thirds of those cats also have renal failure. Bacterial UTI in ruminants are associated with catheterization or parturition in females and as both a cause and consequence of urolithiasis in males. In horses, UTI are uncommon and typically associated with bladder paralysis, urolithiasis, or urethral damage.
Unlike humans, veterinary patients are often asymptomatic, and the UTI may be an incidental finding. The consequences of untreated UTI include lower urinarytract dysfunction, urolithiasis, prostatitis, infertility, septicemia, and pyelonephritis with scarring and eventual kidney failure. Coagulase-positive staphylococci are involved in the formation of struvite (MgNH4PO4) calculi in dogs. In intact male dogs, UTI frequently extends to the prostate gland. Due to the blood-prostate barrier, it is difficult to eradicate bacteria from the prostate, and the urinarytract may be reinfected following appropriate treatment, causing a systemic bacteremia, infecting the rest of the reproductive tract, or causing an abscess within the prostate.
Large retrospective studies have documented the most common species of uropathogens in dogs and cats, with Escherichia coli being the single most common pathogen in both acute and recurrent UTI. In equine UTI, E coli, Streptococcus spp and Enterococcus spp predominate, while Corynebacterium renale and E coli are the most common pathogens in ruminant infections. In dogs and cats, UTI are caused by more than one pathogen ∼30% of the time. In immunocompromised patients, funguria from Candida spp may be seen.
Antimicrobials are the cornerstone of UTI therapy, and many animals with recurring UTI are managed empirically with repeated courses (see Drugs Commonly Used to Treat Urinary Tract Infections in Small Animals). This approach fails if the underlying pathophysiology predisposing the animal to the UTI is not addressed; as well, it encourages the development of resistant bacteria. With chronic UTI from highly resistant bacteria, therapeutic options are extremely limited.
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Upon presentation for a UTI, many veterinary patients are started on empirical antimicrobial therapy without urine culture results. This practice is not recommended because it is impossible to predict the causative pathogen or the antimicrobial that will be most effective.
High urine concentrations of antimicrobials are correlated with efficacy in the treatment of uncomplicated cystitis. But in complicated cases and in pyelonephritis, tissue concentrations may be equally important. Most antimicrobials undergo renal elimination to a great extent, so urine concentrations may be up to 100x peak plasma concentrations. Drug excretion through the kidney involves various processes such as secretion and/or reabsorption in different parts of the nephron depending on the molecular structure of the drug, its pKa, the pH in the tubular fluid, and degree of protein binding. The flow of urine through the urinarytract is part of the defense against invading pathogens, because the flow of fluid rinses the epithelial linings. High urine antimicrobial concentrations are important for eradication of bacteria in the urine, but for infection of the bladder wall or renal tissue it is necessary to use antimicrobials that have active concentrations in the tissues. Serum or plasma concentrations are useful surrogate markers for antimicrobial concentrations in the renal or bladder tissues.
In addition to having the appropriate antimicrobial activity and achieving effective concentrations in urine, the selected anti-microbial should be easy for clients to administer, have few adverse effects, and be relatively inexpensive. Once urine culture and sensitivity results are known, the bacterial MIC can be compared to the mean urinary concentration of the drug and an appropriate antimicrobial chosen.
Amoxicillin and ampicillin are bactericidal and relatively nontoxic, with a spectrum of antibacterial activity greater than that of penicillin G. They have excellent activity against staphylococci, streptococci, enterococci, and Proteus, and may achieve urinary concentrations high enough to be effective against E coli and Klebsiella. Pseudomonas and Enterobacter are resistant. Amoxicillin is more bioavailable in dogs and cats (better absorbed from the GI tract) than ampicillin, hence the lower dosage. Absorption of ampicillin is also affected by feeding, so therapeutic success may be easier to achieve with amoxicillin. As penicillins, they are weak acids with a low volume of distribution, so they do not achieve therapeutic concentrations in prostatic fluid of dogs or accessory sex glands of large animals.
Amoxicillin/clavulanic acid has an increased spectrum of activity against gram-negative bacteria due to the presence of clavulanic acid. Clavulanic acid irreversibly binds to β-lactamases, allowing the amoxicillin fraction to interact with the bacterial pathogen. This combination usually has excellent bactericidal activity against β-lactamase producing staphylococci, E coli, and Klebsiella. Pseudomonas and Enterobacter remain resistant. However, clavulanic acid undergoes some hepatic metabolism and excretion, so much of the antimicrobial activity in the bladder may be due to the high concentrations of amoxicillin achieved in urine. Thus, despite an unfavorable susceptibility report for amoxicillin, clinically it may be as effective as amoxicillin/clavulanic acid in treating UTI.
Cefadroxil and cephalexin are first-generation cephalosporins. Cefadroxil is the veterinary-labeled suspension product, while cephalexin is a human formulation available as tablets or as a suspension. Like the penicillins, they are bactericidal, acidic drugs with a low volume of distribution and are relatively nontoxic. Vomiting and other GI signs may occur in dogs and cats treated with cephalosporins. Cephalosporins have greater stability to β-lactamases than penicillins, so they have greater activity against staphylococci and gram-negative bacteria. They have excellent activity against Staphylococcus spp, Streptococcus spp, E coli, Proteus, and Klebsiella. Pseudomonas, enterococci, and Enterobacter are resistant.
Cefovecin is an injectable third-generation cephalosporin approved for the treatment of UTI due to E coli and Proteus. With SC dosing, therapeutic concentrations are achieved for 14 days, making this an attractive treatment choice for fractious animals.
Cefpodoxime is an oral third-generation cephalosporin approved for use in dogs in the USA for skin infections (wounds and abscesses), but it is used extra-label for the treatment of canine UTI. Cefpodoxime has a relatively long half-life in dogs, so it is dosed once daily.
Ceftiofur is an injectable cephalosporin approved for respiratory disease in horses and cattle and for treatment of canine UTI caused by E coli and Proteus. Ceftiofur has pharmacokinetic properties that are very different from other cephalosporins. After injection, ceftiofur is immediately metabolized to desfuroylceftiofur, which has different antimicrobial activity than the parent compound. Desfuroylceftiofur has equivalent activity to ceftiofur against E coli (MIC 4 μg/mL), but is much less active against Staphylococcus spp and has variable activity against Proteus (MIC 0.5–16 μg/mL). Due to instability of desfuroylceftiofur, microbiology services use a ceftiofur disk when performing susceptibility testing, so a false expectation of therapeutic efficacy may result for some pathogens. Pseudomonas, enterococci, and Enterobacter spp are resistant to ceftiofur and desfuroylceftiofur. Ceftiofur is associated with a duration- and dose-related thrombocytopenia and anemia in dogs, which would not be expected with the recommended dosage regimen.
Enrofloxacin, orbifloxacin, difloxacin, and marbofloxacin are all fluoroquinolones approved to treat UTI in dogs; although all are used in cats, only some are approved for this use. The fluoroquinolones are bactericidal, amphoteric drugs. They possess acidic and basic properties but are very lipid soluble at physiologic pH (pH 6.0–8.0) and thus have a high volume of distribution. All fluoroquinolone drugs usually have excellent activity against staphylococci and gram-negative bacteria, but they may have variable activity against streptococci and enterococci. The therapeutic advantages of these drugs are their gram-negative antimicrobial activity and high degree of lipid solubility. They are the only orally administered antimicrobials effective against Pseudomonas. Therefore, fluoroquinolones should be reserved for UTI that involve gram-negative bacteria, especially Pseudomonas, and for UTI in intact male dogs because of their excellent penetration into the prostate gland and activity in abscesses. They are concentration-dependent killers with a long post-antibiotic effect, so once daily, high-dose therapy for a relatively short duration of treatment is effective.
Fluoroquinolones should be avoided for chronic, low-dose therapy, as this encourages the emergence of resistant bacteria that are cross-resistant to other antimicrobial drugs as well. Cases that involve Pseudomonas should be carefully investigated for underlying pathology, which must corrected if at all possible. Once Pseudomonas spp become resistant to the fluoroquinolones, there are no other therapeutic options that are convenient for the animal and client.
Gentamicin and the other aminoglycosides are very large polar (water soluble) molecules, so they have a low volume of distribution and do not penetrate the blood-prostate barrier. They are not absorbed orally and must be given by SC, IM, or IV injection. The aminoglycosides have a similar spectrum of activity to that of the fluoroquinolones, but their use for UTI is limited because of the necessity of parenteral injections and the risk of toxicity with anything but short-term use. Like the fluoroquino-lones, the aminoglycosides are concentration-dependent, bactericidal killers with a long post-antibiotic effect, so once-daily therapy of short duration is effective and minimizes the risk of nephrotoxicity. They can be considered for in-hospital or outpatient treatment of UTI due to fluoroquinolone-resistant pathogens; however, the importance of identifying and correcting underlying pathology must be emphasized.
Nitrofurantoin is a human product available as tablets, capsules, and a pediatric suspension. It is not commonly used in veterinary medicine. It is typically only used for treatment of UTI in people, as it has a very low volume of distribution and therapeutic concentrations are attained only in urine. It is used for infections caused by E coli, enterococci, staphylococci, Klebsiella, and Enterobacter. Resistance to nitrofurantoin does not confer resistance to other antimicrobials. However, the need for multiple daily dosing makes it inconvenient for clients to use.
Tetracyclines are bacteriostatic, amphoteric drugs with a high volume of distribution. Tetracyclines are broad-spectrum antimicrobials, but because of plasmid-mediated resistance, susceptibility is variable in staphylococci, enterococci, Enterobacter, E coli, Klebsiella, and Proteus. In most tissues, Pseudomonas spp are resistant. However, the tetracyclines are excreted unchanged in urine, so high urinary concentrations may result in therapeutic efficacy. Doxycycline is a very lipid-soluble tetracycline that is better tolerated in cats and reaches therapeutic concentrations in the prostate, so it may be useful for some UTI. If capsules are administered, it is critical to have the animal drink afterwards to ensure passage into the stomach. If capsules remain in the esophagus, severe local necrosis with subsequent esophageal stricture can occur.
Trimethoprim/sulfonamides (TMP/sulfas) are combinations of 2 very different drugs that act synergistically on different steps in the bacterial folic acid pathway. Trimethoprim is a bacteriostatic, basic drug that has a high volume of distribution and a short elimination half-life, while the sulfonamides are bacteriostatic, acidic drugs with a medium volume of distribution and long half-lives (ranging from 6 to >24 hr). These drugs are formulated in a 1:5 ratio of TMP to sulfa, although the optimal bactericidal concentration is a ratio of 1:20 TMP:sulfa. Microbiology services use the 1:20 ratio in susceptibility testing, however the widely varying pharmacokinetic properties of this drug combination make it difficult to determine a therapeutic regimen that achieves the 1:20 ratio at the infection site. Although the combination does penetrate the blood-prostate barrier, sulfa drugs are ineffective in purulent material because of freely available para-aminobenzoic acid from dead neutrophils. The combination of TMP/sulfa is synergistic and bactericidal against staphylococci, streptococci, E coli, and Proteus. Activity against enterococci and Klebsiella is variable, and Pseudomonas is resistant. TMP/sulfas are associated with a number of adverse effects, and chronic low-dose therapy may result in bone marrow suppression and keratoconjunctivitis sicca in dogs.
Dosage Regimens for UTI
Therapy for a UTI is usually recommended for 7–21 days, depending on the animal (eg, intact vs neutered male dog), activity of the antimicrobial and concentration attained in the urine, and the relationship of patient pathology and pathogen virulence. The fluoroquinolones and aminoglycosides are generally effective with a short course of therapy, while the antimicrobials with time-dependent killing activity usually require a more prolonged course. Dogs with prostatitis or animals with complicating pathology (eg, pyelonephritis, cystic calculi) require 4–6 wk of treatment for microbiologic cure. For dogs, antimicrobials should be administered just before bedtime or confinement, in order to maintain high urine concentrations for the longest possible time.
A followup urine culture should be performed after 4–7 days, while the animal is still on therapy, to determine antimicrobial efficacy. If the same or a different pathogen is observed, then an alternative therapy should be chosen and the culture repeated again after 4–7 days. Urine should also be cultured 7–10 days after completing antimicrobial therapy to determine if the UTI is cured or has recurred.
Managing Multiple Episodes of UTI
If episodes occur only once or twice yearly, each may be treated as an acute, uncomplicated UTI. If they occur more often, and predisposing causes of UTI cannot be identified or corrected, chronic low-dose therapy may be necessary to manage the patient. Low antimicrobial concentrations in the urine may interfere with fimbriae production by some pathogens and prevent their adhesion to the uroepithelium.
Recurrent UTI are due to a different strain or species of bacteria ~80% of the time; therefore, antimicrobial culture and susceptibility testing is still indicated. Initiate therapy as before; then, when urine culture is negative, continue antimicrobial therapy sid at ⅓ of the total daily dose. The antimicrobial should be administered at night to maximize antimicrobial concentration in the bladder. Appropriate antimicrobials for chronic, low-dose therapy include amoxicillin, ampicillin, amoxicillin-clavulanic acid, doxycycline, cephalexin, cefadroxil, cefpodoxime, and cefovecin. A trimethoprim/sulfa can be used in dogs, but folate supplementation should be provided (15 mg/kg, bid) to prevent bone marrow suppression, and there is a risk of keratoconjunctivitis sicca developing with chronic use. During chronic therapy, urine culture should be repeated every 4–6 wk. As long as the culture is negative, therapy is continued for 6 mo. If bacteriuria occurs, the infection is treated as an acute episode with an appropriate antimicrobial. After 6 mo of bacteria-free urine, the chronic low-dose antimicrobial therapy may be discontinued, and many animals will not have additional recurrences. In some cases, chronic therapy may be continued for years in patients with recurrent UTI.
Although most UTI respond readily to initial antimicrobial therapy, some animals do not respond or suffer recurrent episodes. A therapeutic failure may be due to a relapse or a reinfection. Relapses are recurrences of the UTI due to the same species of bacteria shortly after discontinuing antimicrobial therapy. Reasons for relapses include inappropriate antimicrobial choice, development of bacterial resistance, a mixed UTI in which all organisms were not eliminated, an inadequate dosage regimen (dose, duration, or frequency), or poor client adherence to the treatment regimen. In cases with sequestered infections, such as prostatitis or pyelonephritis, an appropriate antimicrobial may fail to reach adequate tissue concentrations.
Reinfections are recurrent infections caused by different species of bacteria than previously involved in the UTI. Reasons for reinfection include impaired bacteriostatic nature of urine (eg, glucosuria), disruption of the uroepithelial barrier, reduced immunocompetence, altered urethral function or structure, and urinary retention. If these problems cannot be corrected, chronic antimicrobial therapy is required to prevent further episodes of UTI. Following cessation of antimicrobial therapy, reinfections usually occur at a longer interval than relapses.
Last full review/revision March 2012 by Patricia M. Dowling, DVM,MSc, DACVIM, DACVCP