THE IMPACT OF PENICILLINASE ON CEFAMANDOLE TREATMENT AND PROPHYLAXIS OF EXPERIMENTAL ENDOCARDITIS DUE TO METHICILLIN-RESISTANT STAPHYLOCOCCUS-AUREUS

beta-lactams active against methicillin-resistant Staphylococcus aureu s (MRSA) must resist penicillinase hydrolysis and bind penicillin-bind ing protein 2A (PBP 2A). Cefamandole might share these properties. Whe n tested against 2 isogenic pairs of MRSA that produced or did not pro duce penicillinase, MICs of cefamandole (8-32 mg/L) were not affected by penicillinase, and cefamandole had a greater than or equal to 40 ti mes greater PBP 2A affinity than did methicillin. In rats, constant se rum levels of 100 mg/L cefamandole successfully treated experimental e ndocarditis due to penicillinase-negative isolates but failed against penicillinase-producing organisms. This suggested that penicillinase p roduced in infected vegetations might hydrolyze the drug. Indeed, cefa mandole was slowly degraded by penicillinase in vitro. Moreover, its e fficacy was restored by combination with sulbactam in vivo. Cefamandol e also uniformly prevented MRSA endocarditis in prophylaxis experiment s, a setting in which bacteria were not yet clustered in the vegetatio ns. Thus, while cefamandole treatment was limited by penicillinase, th e drug was still successful for prophylaxis of experimental MRSA endoc arditis.