Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: evidence for enhanced resistance resulting from the coexistence of two different resistance mechanisms.
We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbactam against an isogenic series of Klebsiella pneumoniae strains. Both cefoperazone and cefoperazone-sulbactam were active in vitro against a susceptible clinical strain, and the combination was highly effective in the treatment of rat intra-abdominal abscesses. Loss of expression of a 39-kDa outer membrane protein resulted in at least a fourfold increase in the MICs of cefoperazone and cefoperazone-sulbactam but did not appreciably affect the in vivo efficacy of either regimen. Introduction of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the susceptible strain resulted in the loss of in vitro activity and in vivo efficacy for cefoperazone. The in vitro activity of cefoperazone-sulbactam against this strain was diminished, but the antibiotic combination remained highly active in vivo. Introduction of RP4 into the strain lacking the 39-kDa outer membrane protein resulted in a fourfold increase in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a loss of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanisms, neither of which alone results in substantially diminished cefoperazone-sulbactam efficacy in vivo, can cause in vivo resistance to the beta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.
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Research Service, Department of Veterans Affairs Medical Center, Cleveland, Ohio.
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D000038:Abscess / Q000188:drug therapy / Q000382:microbiology; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000096:biosynthesis; D002438:Cefoperazone / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination / Q000494:pharmacology; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008826:Microbial Sensitivity Tests; D018272:Porins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013407:Sulbactam / Q000494:pharmacology*; D001618:beta-Lactamases / Q000096:biosynthesis
D001425:Bacterial Outer Membrane Proteins; D018272:Porins; D002438:Cefoperazone; D001618:beta-Lactamases; D013407:Sulbactam