Antimicrobial Therapy - The Merck Veterinary Manual

Antimicrobial Therapy

Urine concentrations of antimicrobials are more important than plasma concentrations. Clinical efficacy correlates with maintaining urine antimicrobial concentrations that are 4 times the minimum inhibitory concentration (MIC) of the pathogen(s) throughout the dosage interval. Most antimicrobials undergo renal elimination to a great extent, so urine concentrations may be up to 100 times peak plasma concentrations. Drugs such as the penicillins and tetracycline may be effective against gram-negative pathogens in the urinary tract, even when they would be ineffective elsewhere in the body.

In addition to having the appropriate antimicrobial activity and achieving effective concentrations in urine, the selected antimicrobial 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 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 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 batericidal 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. Both are available in tablet and liquid formulations that are used in small animals. Cefadroxil is the veterinary-labeled product, while cephalexin is a human formulation. Like the penicillins, they are bactericidal, acidic drugs with a low volume of distribution and are relatively nontoxic. Vomiting and other GI signs may develop 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 , Streptococcus , E coli , Proteus , and Klebsiella . Pseudomonas , enterococci, and Enterobacter are resistant.

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 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 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 for 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 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 with efficacy 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 owner.

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 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 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 .

Tetracyclines are bacteriostatic, amphoteric drugs with a high volume of distribution. Tetracyclines are broad-spectrum antmicrobials, 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 achieves therapeutic concentrations in the prostate, but it is eliminated in bile and directly excreted into the intestine, so is not useful for most UTI.

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.