Cefepime pharmacodynamics in patients with extended spectrum beta-lactamase (ESBL) and non-ESBL infections

J Infect. 2007 May;54(5):463-8. doi: 10.1016/j.jinf.2006.09.004. Epub 2006 Oct 24.

Abstract

Objective: This study was designed to compare cefepime exposures with microbiological outcomes in ESBL and non-ESBL infections and determine the pharmacodynamic profiles associated with successful outcome.

Methods: Cefepime pharmacodynamic exposures of unbound drug [time above MIC (fT>MIC), minimal concentration over MIC (fC(min)/MIC), and area under the curve over MIC (fAUC/MIC)] for 18 patients with ESBL and non-ESBL infections were determined by using a published population pharmacokinetic model. Classification and regression tree analysis was used to identify pharmacodynamic breakpoints that predicted eradication. A 5000-patient Monte Carlo Simulation was conducted to estimate the probability of target attainment for the goal pharmacodynamic exposures.

Results: Eradication was 80% when fT>MIC was 50% compared with 0% when T>MIC was less than 50% (p<0.05). The median fC(min)/MIC ratio for ESBL group was statistically lower than that for the non-ESBL group (1.54 versus 138, p<0.001). Regardless of ESBL production, all pathogens were eradicated when fC(min)/MIC>7.6 and only 33.3% were eradicated when fC(min)/MIC< or =7.6 (p<0.05). Pharmacodynamic exposures of 50% fT>MIC and fAUC/MIC>1654 were also predictive of eradication. While conventional dosage regimens of 2g q 12h and q 8h failed to achieve adequate target attainment, 4 g continuous infusion and 2g q 6-8h prolonged infusion could attain more than 90% of target attainment at the MIC of 2 microg/ml for the breakpoint of fCmin/MIC=7.6.

Conclusion: Microbiological eradication in patients receiving cefepime was best predicted by fCmin/MIC ratio greater than 7.6 regardless of the presence of an ESBL. Continuous or prolonged infusion regimens provided the greatest probability of attaining this exposure.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Anti-Bacterial Agents* / administration & dosage
  • Anti-Bacterial Agents* / pharmacokinetics
  • Anti-Bacterial Agents* / therapeutic use
  • Case-Control Studies
  • Cefepime
  • Cephalosporins* / administration & dosage
  • Cephalosporins* / pharmacokinetics
  • Cephalosporins* / therapeutic use
  • Escherichia coli / classification
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • Female
  • Humans
  • Klebsiella / classification
  • Klebsiella / drug effects
  • Klebsiella / enzymology
  • Klebsiella Infections / drug therapy*
  • Klebsiella Infections / microbiology
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Monte Carlo Method
  • Treatment Outcome
  • beta-Lactamases / biosynthesis*

Substances

  • Anti-Bacterial Agents
  • Cephalosporins
  • Cefepime
  • beta-Lactamases