title: Activity of cefpirome combined with beta-lactamase inhibitors and affinity for the penicillin-binding proteins of methicillin-resistant Staphylococcus aureus.
abstract: The susceptibility of 47 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) to cefpirome, ceftazidime and methicillin was determined with Isosensitest media, with/without 5% NaCl and incubation at 30 degrees, 37 degrees and 44 degrees C for 24 and 48 h. At 24 h the MIC50 of cefpirome was 8 mg/l compared to 64 mg/l ceftazidime; at 48 h this increased to 32 mg/l cefpirome. The addition of 10 mg/l clavulanic acid or sulbactam lowered the MIC of cefpirome (at 48 h) by greater than four-fold in 23% and 11% of the strains, respectively. Cefpirome had primary affinity for penicillin-binding protein (PBP) 1 and 2 in five MRSA and one methicillin-susceptible Staphylococcus aureus. PBP 2a was present in all MRSA and was not saturated by 64 mg/l cefpirome. Clavulanic acid at a concentration of 10 mg/l bound to PBP 2 by greater than 50% in all strains, and when combined with cefpirome, the density of PBP 2a was also reduced but not completely abolished. The data from this study suggests that the mechanism of synergy of a beta-lactamase inhibitor plus a cephalosporin for MRSA may be due to an additive effect against PBPs and not just inhibition of a beta-lactamase. No cefpirome-resistant mutants could be selected from a methicillin-susceptible Staphylococcus aureus, but mutants were selected from an MRSA (expressing homogeneous methicillin resistance) for which MICs of cefpirome were 8 to 32 mg/l.
authors.affiliation: Department of Medical Microbiology, University of Birmingham, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Piddock
authors.forename: E A
authors.initials: EA
authors.lastname: Traynor
authors.forename: D J
authors.initials: DJ
authors.lastname: Griggs
mesh_terms: D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002442:Ceftazidime / Q000494:pharmacology*; D002511:Cephalosporins / Q000378:metabolism / Q000494:pharmacology*; D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D006602:Hexosyltransferases; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013407:Sulbactam / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D000097572:Cefpirome
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D002442:Ceftazidime; D002511:Cephalosporins; D019818:Clavulanic Acid; D002969:Clavulanic Acids; D004338:Drug Combinations; D006602:Hexosyltransferases; D008712:Methicillin; D002267:Muramoylpentapeptide Carboxypeptidase; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D013407:Sulbactam; D065093:beta-Lactamase Inhibitors; D000097572:Cefpirome