Beta-lactam resistance mechanisms of methicillin-resistant Staphylococcus aureus

J Infect Dis. 1991 Mar;163(3):514-23. doi: 10.1093/infdis/163.3.514.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / metabolism
  • Binding, Competitive
  • Carrier Proteins / metabolism
  • Drug Resistance, Microbial
  • Endocarditis, Bacterial / blood
  • Endocarditis, Bacterial / drug therapy
  • Female
  • Hexosyltransferases*
  • Methicillin Resistance*
  • Microbial Sensitivity Tests
  • Muramoylpentapeptide Carboxypeptidase / metabolism
  • Penicillin-Binding Proteins
  • Penicillinase
  • Peptidyl Transferases*
  • Protein Binding
  • Rats
  • Rats, Inbred Strains
  • Staphylococcal Infections / blood
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / enzymology
  • beta-Lactams

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carrier Proteins
  • Penicillin-Binding Proteins
  • beta-Lactams
  • Peptidyl Transferases
  • Hexosyltransferases
  • Muramoylpentapeptide Carboxypeptidase
  • Penicillinase