Brandt, Claudia M.

The efficacy of azithromycin or clarithromycin was compared to that of amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus experimental endocarditis. Rabbits with catheter-induced aortic valve vegetations were given no antibiotics or two doses of amoxicillin at 25 mg/kg of body weight, azithromycin at 10 mg/kg, clarithromycin at 10 mg/kg, clindamycin at 40 mg/kg followed by clindamycin at 20 mg/kg, or erythromycin at 10 mg/kg. Antibiotics were administered 0.5 h before and 5.5 h after intravenous infusion of 5 x 10(5) CFU of Streptococcus milleri. Forty-eight hours after bacterial inoculation, the rabbits were killed and aortic valve vegetations were aseptically removed and cultured for bacteria. Infective endocarditis occurred in 88% of untreated animals, 1% of animals receiving amoxicillin, 9% of animals receiving erythromycin, 0% of animals receiving clindamycin, 2.5% of animals receiving clarithromycin, and 1% of animals receiving azithromycin. All five regimens were more effective (P < 0.001) than no prophylaxis. Erythromycin was less effective (P < 0.05) than amoxicillin or clindamycin. Azithromycin or clarithromycin was as effective as amoxicillin, clindamycin, or erythromycin for the prevention of viridans group streptococcus experimental endocarditis in this model.

The efficacy of ceftriaxone or penicillin alone or combined with gentamicin at different dosing intervals was evaluated in experimental endocarditis due to a penicillin-susceptible, ceftriaxone-tolerant strain of Streptococcus sanguis I. The difference between monotherapy with ceftriaxone and procaine penicillin approached statistical significance (P = 0.052). Ceftriaxone combined with gentamicin administered as a single daily dose was less effective than was procaine penicillin combined with gentamicin administered in a single daily dose or in three divided doses.

The efficacy of cefazolin or cefpirome alone or combined with rifampin was compared with that of vancomycin alone or combined with rifampin in an experimental model of methicillin-resistant, beta-lactamase-producing, coagulase-negative staphylococcal endocarditis. Phenotypically, the mecA gene-positive strain used in vivo did not exhibit methicillin resistance by the agar dilution or disk susceptibility method but was resistant in vitro (oxacillin MIC, 64 micrograms/ml) by the microtiter dilution method with 2% NaCl supplementation. Macrodilution broth susceptibilities of standard inocula failed to demonstrate cross-resistance of staphylococci to cefazolin (MIC, 8 micrograms/ml) or cefpirome (MIC, 4 micrograms/ml). In vivo, vancomycin and cefpirome had similar activities, and both regimens were more effective than was cefazolin alone. While the MIC of rifampin was low (0.031 micrograms/ml), monotherapy with rifampin resulted in a bimodal distribution of outcomes due to the expected emergence of resistant mutants. The results in vitro of time-kill synergy studies using rifampin in combination with cefazolin or cefpirome varied with the antimicrobial concentrations tested and did not reliably predict activities in vivo of rifampin-beta-lactam combination therapies. Cefpirome, but not cefazolin or vancomycin, in combination with rifampin was synergistic in vivo. Cefpirome in combination with rifampin was more effective than was cefazolin in combination with rifampin. Both cephalosporin-rifampin regimens were significantly more effective than was cephalosporin or vancomycin monotherapy and were as effective as vancomycin combined with rifampin. These data support further evaluation of rifampin-beta-lactam combinations as possible alternative therapies to vancomycin-containing regimens for selected methicillin-resistant coagulase-negative staphylococcal infections.

Results of in vitro time-kill synergy studies using subinhibitory, inhibitory, or suprainhibitory concentrations of bactericidal agents were compared with treatment outcomes of experimental infective endocarditis due to a methicillin-susceptible strain of Staphylococcus aureus. For rifampin-cephalosporin combinations, in vitro synergy testing using recommended fractions of the MIC failed to predict antagonism in vivo while concentrations above the MIC corresponded with antagonism in vivo.