title: The impact of penicillinase on cefamandole treatment and prophylaxis of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.
abstract: Beta-lactams active against methicillin-resistant Staphylococcus aureus (MRSA) must resist penicillinase hydrolysis and bind penicillin-binding protein 2A (PBP 2A). Cefamandole might share these properties. When tested against 2 isogenic pairs of MRSA that produced or did not produce penicillinase, MICs of cefamandole (8-32 mg/L) were not affected by penicillinase, and cefamandole had a > or =40 times greater PBP 2A affinity than did methicillin. In rats, constant serum levels of 100 mg/L cefamandole successfully treated experimental endocarditis due to penicillinase-negative isolates but failed against penicillinase-producing organisms. This suggested that penicillinase produced in infected vegetations might hydrolyze the drug. Indeed, cefamandole was slowly degraded by penicillinase in vitro. Moreover, its efficacy was restored by combination with sulbactam in vivo. Cefamandole also uniformly prevented MRSA endocarditis in prophylaxis experiments, a setting in which bacteria were not yet clustered in the vegetations. Thus, while cefamandole treatment was limited by penicillinase, the drug was still successful for prophylaxis of experimental MRSA endocarditis.
authors.affiliation: Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Y A
authors.initials: YA
authors.lastname: Que
authors.forename: J M
authors.initials: JM
authors.lastname: Entenza
authors.forename: P
authors.initials: P
authors.lastname: Francioli
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D002435:Cefamandole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002511:Cephalosporins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004696:Endocarditis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D006602:Hexosyltransferases; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000032:analysis / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010405:Penicillinase / Q000378:metabolism*; D010458:Peptidyl Transferases; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D002435:Cefamandole; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D010405:Penicillinase