title: Beta-lactam resistance mechanisms of methicillin-resistant Staphylococcus aureus.
abstract: In vitro and in vivo activity of amoxicillin and penicillin G alone or combined with a penicillinase inhibitor (clavulanate) were tested against five isogenic pairs of methicillin-resistant Staphylococcus aureus (MRSA) producing or not producing penicillinase. Loss of the penicillinase plasmid caused an eight times or greater reduction in the MICs of amoxicillin and penicillin G (from greater than or equal to 64 to 8 micrograms/ml), but not of the penicillinase-resistant drugs methicillin and cloxacillin (greater than or equal to 64 micrograms/ml). This difference in antibacterial effectiveness correlated with a more than 10 times greater penicillin-binding protein 2a affinity of amoxicillin and penicillin G than of methicillin and a greater than or equal to 90% successful amoxicillin treatment of experimental endocarditis due to penicillinase-negative MRSA compared with cloxacillin, which was totally ineffective (P less than .001). Amoxicillin was also effective against penicillinase-producing parent MRSA, provided it was combined with clavulanate. Penicillinase-sensitive beta-lactam antibiotics plus penicillinase inhibitors might offer a rational alternative treatment for MRSA infections.
authors.affiliation: Department of Internal Medicine, CHUV, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Franciolli
authors.forename: J
authors.initials: J
authors.lastname: Bille
authors.forename: M P
authors.initials: MP
authors.lastname: Glauser
authors.forename: P
authors.initials: P
authors.lastname: Moreillon
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004697:Endocarditis, Bacterial / Q000097:blood / Q000188:drug therapy; D005260:Female; D006602:Hexosyltransferases; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010405:Penicillinase; D010458:Peptidyl Transferases; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D047090:beta-Lactams; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D010405:Penicillinase