We used a beta-lactamase-producing (beta L+) strain of Streptococcus faecalis that also had high levels of resistance to all aminoglycosides to induce experimental endocarditis in rats. The rats were treated for five or 10 days with procaine penicillin, vancomycin, gentamicin, rifampin, or ciprofloxacin (alone or in various combinations), or with penicillin plus clavulanic acid. The levels of penicillin in serum and vegetations declined rapidly in the beta L+-infected rats treated with procaine penicillin alone, unlike the sustained levels of penicillin in either beta L- -infected rats treated with procaine penicillin or beta L+-infected rats treated with penicillin plus clavulanic acid. For the beta L+-infected rats, the enterococcal counts in vegetations were significantly reduced (greater than 3 log10 cfu/g) only by vancomycin and by penicillin plus clavulanic acid. The efficacy of the latter regimen probably resulted from the inhibition of penicillin inactivation by clavulanic acid in vegetations infected with the beta L+ strain. Our in vivo findings document the biologic significance of beta-lactamase production.

The efficacy of ciprofloxacin, BMY-28142, and ceftazidime was compared in vitro and in experimental left-sided endocarditis due to Pseudomonas aeruginosa in the rat. The dose, dosing interval, and duration of therapy were varied, and the resulting antibiotic levels in serum and vegetations were correlated with bacterial clearance from vegetations. These studies demonstrated that beta-lactams such as BMY exhibited a slow rate of bactericidal action and had no postantibiotic effect against P. aeruginosa in vitro or in vivo. As a consequence, BMY had to be given in multiple doses at relatively short intervals during which concentrations of antibiotics in vegetations were continuously in excess of the MBC for the pathogen. The earlier onset of rapid bactericidal action and the prolonged postantibiotic effect of ciprofloxacin (demonstrated in vivo and in vitro) were, in all likelihood, the factors that allowed the successful use of fewer doses of this antimicrobial agent at relatively longer dosing intervals.