Bacterial Urinary Tract Infections
Bacterial urinary tract infections (UTIs) typically result from normal skin and GI tract flora ascending the urinary tract and overcoming the normal urinary tract defenses that prevent colonization. Bacterial UTI is the most common infectious disease of dogs, affecting 14% of all dogs during their lifetime. Although UTIs are uncommon in young cats, the incidence of UTI is much higher in older cats, which may be more susceptible to infection because of diminished host defenses secondary to aging or concomitant disease (such as diabetes mellitus, renal failure, or hyperthyroidism). Approximately two-thirds of those cats also have some degree of renal failure. Bacterial UTIs in ruminants are associated with catheterization or parturition in females and as both a cause and consequence of urolithiasis in males. In horses, UTIs are uncommon and typically associated with bladder paralysis, urolithiasis, or urethral damage.
Unlike human patients, veterinary patients are often asymptomatic, and the UTI may be an incidental finding. The consequences of untreated UTI include lower urinary tract 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. Because of the blood-prostate barrier, it is difficult to eradicate bacteria from the prostate, and the urinary tract may be reinfected after 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 UTIs. The other common pathogens include Staphylococcus, Proteus, Streptococcus, Klebsiella, and Pseudomonas spp. In UTIs in horses, E coli, Streptococcus, and Enterococcus spp predominate, whereas Corynebacterium renale and E coli are the most common pathogens in ruminants. In immunocompromised animals, funguria from Candida spp may occur.
Antimicrobials are the cornerstone of UTI therapy, and many animals with recurring UTIs are managed empirically with repeated courses (see Table: 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 emergence of resistant bacteria. With chronic UTI from highly resistant bacteria, therapeutic options are extremely limited.
Drugs Commonly Used to Treat Urinary Tract Infections in Small Animals
Urine culture is the “gold standard” for diagnosis of UTI. Indications to perform urine culture include visualization of bacteria during urine sediment examination, evidence of pyuria, dilute urine (<1.013 SG), immunosuppression, and diabetes mellitus or hyperadrenocorticism. Antimicrobial susceptibility testing should be done with complicated or recurrent cases of UTIs, immunosuppressed animals, animals recently catheterized, or animals treated with antimicrobials within the preceding 3 wk (because of selection for antimicrobial resistance). In addition, culture and susceptibility testing should be performed in cases that do not respond within 7 days of therapy for UTI or in cases associated with multiple pathogens.
High urine concentrations of antimicrobials are correlated with efficacy in 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 100 times 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 urinary tract 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 antimicrobial should be easy for owners to administer, have few adverse effects, and be relatively inexpensive. Once urine culture and sensitivity results are known, the bacterial minimum inhibitory concentration (MIC) can be compared with 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.
Amoxicillin-clavulanic acid has an increased spectrum of activity against gram-negative bacteria because of 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 amoxicillin alone may be as effective as amoxicillin-clavulanic acid to treat UTIs.
Cefadroxil and cephalexin are first-generation cephalosporins. Cefadroxil is a veterinary-labeled suspension product, whereas cephalexin is available in both human and veterinary formulations as tablets, paste, or suspension products. 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 treatment of dogs with a UTI due to E coli or Proteus. In cats, it is only approved for skin infections but may be used in an extra-label manner for UTIs. 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 for skin infections (wounds and abscesses), but it is used extra-label for 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, swine, and cattle and for treatment of canine UTI caused by E coli and Proteus. Ceftiofur has pharmacokinetic properties very different from those of 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 mcg/mL) but is much less active against Staphylococcus spp and has variable activity against Proteus (MIC 0.5–16 mcg/mL). Because of the 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.
Chloramphenicol has a high volume of distribution, and high tissue concentrations can be achieved, including in the prostate of male dogs and cats. It is active against a wide range of gram-positive and many gram-negative bacteria, against which it is usually bacteriostatic. Chloramphenicol is typically active against enterococci, staphylococci, streptococci, E coli, Klebsiella, and Proteus. Pseudomonas are resistant. North American isolates of methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius are typically susceptible. Well known for causing idiosyncratic (non-dose-dependent) anemia in people and dose-dependent bone marrow suppression in animals, its use in both human and veterinary medicine is increasing because of resistance to other antimicrobial drugs.
Enrofloxacin, orbifloxacin, and marbofloxacin are all fluoroquinolones approved to treat UTIs in dogs; although all are used in cats, only some are approved for this use. Pradofloxacin is only approved for skin infections in cats in North America, but it is approved for treatment of UTI in dogs in Europe and is used to treat feline UTI. The fluoroquinolones are bactericidal, amphoteric drugs. They possess acidic and basic properties but are very lipid soluble at physiologic pH (pH 6–8) and thus have a high volume of distribution. All fluoroquinolones 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 UTIs that involve gram-negative bacteria, especially Pseudomonas, and for UTIs in intact male dogs and cats because of their excellent penetration into the prostate gland and activity in abscesses. They are concentration-dependent killers with a long postadministration 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, because this encourages 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 convenient therapeutic options.
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 fluoroquinolones, the aminoglycosides are concentration dependent, bactericidal killers with a long postadministration 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 used only for treatment of UTI in people, because it has a very low volume of distribution, and therapeutic concentrations are attained only in urine. It is considered a carcinogen, so it is banned for use in food-producing animals, but its use in small animals is increasing with the rising rates of antimicrobial resistance to veterinary antimicrobials. Nitrofurantoin is used for infections caused by E coli, enterococci, staphylococci, Klebsiella spp, and Enterobacter spp. It is increasingly indicated for treatment of UTIs caused by multidrug-resistant bacteria, which are otherwise difficult to treat using conventional veterinary antimicrobial agents. The pharmacokinetics and adverse effect profile of nitrofurantoin have not been investigated in dogs, cats, or horses, and the need for multiple daily dosing makes it inconvenient for owners.
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 better tolerated in cats and reaches therapeutic concentrations in the prostate, so it may be useful for some UTIs. Doxycycline may also be effective to treat methicillin-resistant staphylococcal UTIs. If capsules are administered, it is critical to have the animal drink afterward 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 two very different drugs that act synergistically on different steps in the bacterial folic acid pathway. Trimethoprim is a bacteriostatic, basic drug with a high volume of distribution and a short elimination half-life, whereas 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.
Currently, the duration of therapy for UTI is controversial. Although animals are routinely treated with antimicrobial drugs for 10–14 days, shorter duration antimicrobial regimens are routinely prescribed in human patients, including single-dose fluoroquinolone therapy. A clinical comparison of 3 days of therapy with a once-daily high dose of enrofloxacin with 2 wk of twice daily amoxicillin-clavulanic acid showed equivalence in the treatment of simple UTI in dogs. However, further studies are needed to determine the optimal dosage regimens for different classes of antimicrobials, and it is inappropriate to use fluoroquinolones as first-line therapy for simple UTIs. Animals with complicated UTI may require longer courses of therapy, and underlying pathology must be addressed. Chronic complicated cases of UTI, pyelonephritis, and prostatitis may require antimicrobial treatment for 4–6 wk, with the risk of selecting for antimicrobial resistance. A follow-up urine culture should be performed after 4–7 days of therapy to determine efficacy. If the same or a different pathogen is seen, 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 whether the UTI has resolved or recurred.
In dogs and cats, if UTI occurs only once or twice yearly, each episode may be treated as an acute, uncomplicated UTI. If episodes occur more often, and predisposing causes of UTI cannot be identified or corrected, chronic low-dose therapy may be necessary. Low antimicrobial concentrations in the urine may interfere with fimbriae production by some pathogens and prevent their adhesion to the uroepithelium. In dogs, recurrent UTIs are due to a different strain or species of bacteria ~80% of the time; therefore, antimicrobial culture and susceptibility is still indicated. Antimicrobial therapy should be started as previously described and when urine culture is negative, continued daily at ⅓ the total daily dose. The antimicrobial should be administered last thing at night to ensure that the bladder contains urine with a high antimicrobial concentration for as long as possible.
Appropriate antimicrobials for chronic, low-dose therapy include amoxicillin, ampicillin, amoxicillin-clavulanic acid, doxycycline, cephalexin, cefadroxil, and nitrofurantoin. A trimethoprim-sulfonamide can be used, but folate supplementation should be provided (15 mg/kg, bid) to prevent bone marrow suppression; there is also the risk of keratoconjunctivitis sicca developing with longterm use. Although attractive for owner convenience, third-generation cephalosporins such as cefpodoxime and cefovecin and fluoroquinolones should not be used for longterm therapy. During longterm 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 longterm, low-dose antimicrobial therapy may be discontinued, and many animals will not have additional recurrences. In some cases, longterm therapy may be continued for years in animals that continue to have recurrent UTIs.
Treatment failures may be due to poor owner compliance, inappropriate choice of antimicrobials, inappropriate dose or duration of treatment, antimicrobial resistance, superinfection, or an underlying predisposing cause (eg, urolithiasis, neoplasia, urachal diverticula). If treatment for a simple or complicated UTI fails, a thorough evaluation should be performed to determine and, when possible, address the cause of failure. When faced with a therapeutic failure, the practitioner must consider whether the UTI is due to a relapse or a reinfection. Relapses due to infection by uropathogens with enhanced intrinsic virulence occur with what should be effective antimicrobial therapy. Strains of uropathogenic E coli have a number of virulence mechanisms that enable them to invade, survive, and multiply within the uroepithelium. The sequestration of uropathogenic E coli within the bladder uroepithelium presents a great therapeutic challenge in both human and veterinary patients. There is no clear consensus in the human medical literature about how to approach these recurrent and persistent UTIs.
Acquired resistance to antimicrobials by uropathogens is of great concern in both human and veterinary medicine. The prevalence of multidrug resistance in uropathogens is increasing, particularly in infections in dogs and cats. Extended-spectrum β-lactamase genes are increasingly identified in E coli isolates from companion animals. Increases in the occurrence of fluoroquionolone-resistant E coli in dogs have been widely reported. Because the mechanism of resistance to fluoroquinolones frequently involves efflux pumps, it also conveys multidrug resistance. Fluoroquinolone resistance is also increasing in other uropathogens, including enterococci, Proteus mirabilis, and Staphylococcus pseudintermedius isolates. Methicillin-resistant staphylococci have been identified in cases of canine UTI. There is increasing evidence that animals are an important reservoir of antimicrobial-resistant bacteria causing infections in people. Enterococci isolated from canine UTIs have been associated with several different resistant phenotypes, with most exhibiting resistance to three or more antimicrobials. One Enterococcus faecium isolate displayed high-level resistance to vancomycin and gentamicin. Sequence analysis suggested that resistance was due to gene exchange between human and canine enterococci. The use of “last resort” human antimicrobials in veterinary patients with resistant infections is controversial. Vancomycin, imipenem-cilastatin, meropenem, fosfomycin, quinupristin-dalfopristin, and tigecycline should not be used routinely in treatment of UTI in animals. Nonantimicrobial control of infection should be considered whenever feasible. Custom-made vaccines, cranberry juice/extract, probiotics and adherence/colonization inhibitors, and establishment of asymptomatic bacteriuria may help preserve the efficacy of antimicrobials.