Molecular correlation between in vitro and in vivo activity of beta-lactam and beta-lactamase inhibitor combinations against methicillin-resistant Staphylococcus aureus.
Beta-Lactam resistance in Staphylococcus aureus is associated with beta-lactamase production, with the presence of a new penicillin binding protein (PBP) called PBP2a, with reduced affinity for beta-lactam antibiotics, and with modifications of normal PBPs. We have studied these mechanisms of resistance, in vivo and in vitro, for several beta-lactam antibiotics against both beta-lactamase-producing and non-producing methicillin-resistant S. aureus organisms (MRSA). Our results showed that all tested agents inhibited binding of labeled penicillin G to many PBPs. The combination of cefoperazone and sulbactam was the best combination, and it inhibited radiolabeled penicillin G binding to PBP2a at a lower concentration than that needed for cefoperazone alone. In vivo, the regimen of cefoperazone plus sulbactam was also more effective than cefoperazone alone. For beta-lactamase-negative strains this correlated with an increased binding affinity of cefoperazone plus sulbactam to PBP2a and PBP4. The improved efficacy of cefoperazone plus sulbactam versus cefoperazone with a beta-lactamase producing strain was closely related to cefoperazone hydrolysis by beta-lactamase that was inhibited by sulbactam. This study demonstrates that there is more than one effect of beta-lactamase inhibitors when they are combined with beta-lactam antimicrobial agents, and also that there may be a role for these agents in therapy for MRSA infections.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis.
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EL
Fasola
C E
CE
Fasching
L R
LR
Peterson
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002438:Cefoperazone / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006602:Hexosyltransferases; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism*; D010400:Penicillin G / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D013407:Sulbactam / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D002438:Cefoperazone; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases; D010400:Penicillin G; D013407:Sulbactam