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


CONCLUSIONS
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.
Lee
Su Young
SY
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Kuti
Joseph L
JL
Nicolau
David P
DP
D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D016022:Case-Control Studies; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004926:Escherichia coli / Q000145:classification / Q000187:drug effects / Q000201:enzymology; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D006801:Humans; D007709:Klebsiella / Q000145:classification / Q000187:drug effects / Q000201:enzymology; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077723:Cefepime; D001618:beta-Lactamases