Patricia M. Dowling,     Saskatoon, Canada

Concentration-Dependent Antimicrobials

For antimicrobials whose efficacy is concentration dependent, high plasma concentrations relative to the MIC of the pathogen (Cmax : MIC) and the area under the plasma concentration–time curve that is above the bacterial MIC during the dosing interval (area under the inhibitory curve, AUC_0-24 hr : MIC) are the major determinants of clinical efficacy (Figure 260-1). These drugs also have prolonged postantibiotic effects, which allows once-daily dosing with maintenance of maximum clinical efficacy. For fluoroquinolones (enrofloxacin, orbifloxacin, pradofloxacin, marbofloxacin), clinical efficacy is associated with achieving either an AUC_0-24 hr : MIC of more than 125 or a Cmax : MIC of more than 10. For aminoglycosides (gentamicin, amikacin), achieving a Cmax : MIC of more than 10 is considered optimal for efficacy. Other antimicrobials that appear to have concentration-dependent activity are metronidazole (Cmax : MIC > 10 to 25) and azithromycin (AUC_0-24 hr : MIC > 25). These PK : PD targets are met when antimicrobials are administered at label dosages for the pathogens indicated on the label. For extralabel pathogens with high MIC values, such as Pseudomonas aeruginosa, achieving the optimum PK : PD ratios systemically may be impossible with label or even higher than label dosages. In such cases, underdosing is ineffective and merely contributes to antimicrobial resistance.

Time-Dependent Antimicrobials

For antimicrobials whose efficacy is time dependent, the time during which the antimicrobial concentration exceeds the MIC of the pathogen (T > MIC) determines clinical efficacy (Figure 260-2). How much above the MIC and for what percentage of the dosing interval concentrations should be above the MIC still is being debated and likely is specific for individual bacteria-drug combinations. Typically, exceeding the MIC by one to five multiples for between 40% and 100% of the dosing interval is appropriate for time-dependent antimicrobial agents. The time that the concentration exceeds MIC should be closer to 100% for bacteriostatic antimicrobials and for patients that are immunosuppressed. Therefore these drugs typically require frequent dosing or constant-rate infusions for appropriate therapy. An exception is cefovecin; this third-generation cephalosporin maintains concentrations above the target MIC for 7 days because of its high degree of protein binding. In sequestered infections, penetration of the antimicrobial to the site of infection may require high plasma concentrations to achieve a sufficient concentration gradient. In such cases, the AUC_0-24 hr : MIC or Cmax : MIC, or both, also may be important in determining the efficacy of an otherwise time-dependent antimicrobial. The penicillins, cephalosporins, most macrolides and lincosamides, tetracyclines, chloramphenicol, and potentiated sulfonamides are considered time-dependent antimicrobials.

Urinary Tract Infections

Bacterial urinary tract infection (UTI) results when normal skin and gastrointestinal tract flora ascend the urinary tract and overcome the normal urinary tract defenses that prevent colonization. Large retrospective studies have documented the most common species of uropathogens in dogs and cats, with Escherichia coli being the single most common isolate in both acute and recurrent UTIs (Ball et al, 2008). Gram staining and determination of pH of a urine sample help direct empiric antimicrobial therapy. If the urine is persistently alkaline, a urease-producing pathogen such as Staphylococcus spp. should be suspected if Gram-positive cocci are seen, and Proteus if Gram-negative rods are seen. If the urine is acidic, the most likely pathogens are E. coli if Gram-negative rods are seen, and Enterococcus spp. or Streptococcus canis if Gram-positive cocci are seen. Initial treatment of uncomplicated UTIs is straightforward because most antimicrobials undergo renal elimination to a great extent, so urine concentrations may be up to 100 times peak plasma concentrations. All of the first-choice treatments are time-dependent antimicrobials, so frequent dosing is important for efficacy. Amoxicillin has excellent activity against staphylococci, streptococci, enterococci, and Proteus and can achieve high enough urinary concentrations to be effective against E. coli and Klebsiella if dosed frequently. Therefore amoxicillin every 8 hours is the most rational empiric therapy for bacterial UTI while culture and susceptibility results are pending. Amoxicillin/clavulanic acid has excellent bactericidal activity against β-lactamase–producing staphylococci, E. coli, and Klebsiella. However, clavulanic acid undergoes some hepatic metabolism and excretion, so the efficacy of amoxicillin/clavulanic acid may be due primarily to the high concentrations of amoxicillin achieved in urine; therefore it is not preferred over amoxicillin for first-line therapy.

First-generation cephalosporins, such as cephalexin or cefadroxil, have greater stability to β-lactamases than penicillins and therefore have greater activity against staphylococci and Gram-negative bacteria. They have excellent activity against staphylococci, streptococci, E. coli, Proteus, and Klebsiella. Pseudomonas, enterococci, and Enterobacter are resistant, and the use of cephalosporins predisposes patients to nosocomial enterococcal infections. Thus cephalexin and cefadroxil are suitable empiric alternatives to amoxicillin, as long as enterococcal infection has been ruled out by the Gram stain results and urine pH. Nitrofurantoin is an old antimicrobial approved only for treatment of UTIs in people because therapeutic concentrations are not attained in plasma or tissues. It is also a good first-line treatment for UTIs caused by E. coli, enterococci, staphylococci, Klebsiella, and Enterobacter. Bacterial resistance to nitrofurantoin usually does not convey resistance to other antimicrobial classes, so this old antimicrobial is increasingly recommended as a first-line treatment in women. Similarly, recommendations for its use in veterinary medicine are increasing, but good PK : PD studies have not been carried out in dogs and cats, and its adverse effects profile in dogs and cats is not well documented.

Tetracyclines are broad-spectrum antimicrobials that can be used empirically for the treatment of UTIs, but because of plasmid-mediated resistance, staphylococci, enterococci, Enterobacter, E. coli, Klebsiella, and Proteus have variable susceptibility. However, the tetracyclines are excreted unchanged in the urine, so high urinary concentrations may result in therapeutic efficacy despite susceptibility test results that indicate resistance. Doxycycline is a very lipid-soluble tetracycline that is better tolerated in cats and achieves therapeutic concentrations in the prostatic and renal tissues. Because of biliary elimination, it was thought initially not to be useful for treatment of uncomplicated UTIs, but effective concentrations for treatment of the most common pathogens are achieved in the urine of dogs and cats. Combinations of trimethoprim or ormetoprim with a sulfonamide are synergistic and bactericidal against staphylococci, streptococci, E. coli, and Proteus. Activity against Klebsiella is variable, and Enterococcus spp. and Pseudomonas are resistant. Although their spectrum of activity makes the potentiated sulfonamides rational first-line treatment choices, they are associated with a number of adverse effects that discourage more frequent selection. Enrofloxacin, orbifloxacin, and marbofloxacin are all fluoroquinolones approved for treatment of UTIs in dogs and some are approved for cats, but all are used in cats. All fluoroquinolones have excellent activity against staphylococci and Gram-negative bacteria but have variable activity against streptococci and enterococci. The therapeutic advantage of these drugs is their Gram-negative antimicrobial activity and excellent penetration into the prostate gland and activity in infected tissues. Their concentration-dependent killing allows for client-convenient once-daily dosing. However, it is inappropriate to use these important antimicrobials for empiric treatment of uncomplicated UTIs. Their use should be reserved for complicated UTIs, such as cases of pyelonephritis that involve Gram-negative bacteria, and for UTIs in intact male dogs in which prostatic involvement is likely.