title: Pharmacokinetics-pharmacodynamics of cefepime and piperacillin-tazobactam against Escherichia coli and Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases: report from the ARREST program.
abstract: The frequency of resistance to beta-lactams among nosocomial isolates has been increasing due to extended-spectrum beta-lactamase (ESBL)-producing enteric bacilli. Although clinical outcome data are desirable, assessment of clinical efficacy has been limited due to the lack of a statistically meaningful number of well-documented cases. Since time above the MIC (T>MIC) is the pharmacokinetic-pharmacodynamic (PK-PD) measure that best correlates with in vivo activity of beta-lactams, a stochastic model was used to predict the probability of PK-PD target attainment ranging from 30 (P30) to 70% (P70) T>MIC, for standard dosing regimens of both piperacillin-tazobactam and cefepime against Escherichia coli and Klebsiella pneumoniae ESBL phenotypes. The P70/30 T>MIC for cefepime at 2 g every 12 h against E. coli and K. pneumoniae was 0.99/1.0 and 0.96/1.0 and for a regimen of 1 g every 12 h was 0.96/1.0 and 0.93/0.99, respectively. For piperacillin-tazobactam at 3.375 g every 4 h against E. coli and K. pneumoniae, the P70/30 T>MIC was 0.77/0.96 and 0.48/0.77 and for a regimen of 3.375 g every 6 h was 0.28/0.91 and 0.16/0.69, respectively. These data suggest that the probability of achieving T>MIC target attainment rates is generally higher with cefepime than with piperacillin-tazobactam for present-day ESBL-producing strains when one uses contemporary dosing regimens.
authors.affiliation: Cognigen Corporation, Buffalo, New York, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: S M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: R N
authors.initials: RN
authors.lastname: Jones
mesh_terms: D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D010878:Piperacillin / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077725:Piperacillin, Tazobactam Drug Combination; D011336:Probability; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D002511:Cephalosporins; D000077725:Piperacillin, Tazobactam Drug Combination; D000077723:Cefepime; D010397:Penicillanic Acid; D001618:beta-Lactamases; D010878:Piperacillin