Determination of the In Vivo Pharmacodynamic Profile of Cefepime against Extended-Spectrum-Beta-Lactamase-Producing Escherichia coli at Various Inocula

Abstract

Cefepime was evaluated in vivo against two inoculum sizes of four strains of Escherichia coli that produced extended-spectrum beta-lactamases (ESBLs) in a murine neutropenic thigh infection model to characterize the pharmacodynamic activity of cefepime in the presence of ESBL-producing bacteria and to evaluate if differences in lengths of cefepime exposure are required with various inocula. Three strains possessed a single enzyme each: TEM-10, TEM-12, and TEM-26. The fourth strain possessed two TEM-derived ESBLs and a third uncharacterized enzyme. Two non-ESBL-producing E. coli strains were included for comparison. Mice received various doses of cefepime to achieve a spectrum of percentages of time the drug was above the MIC (%T>MICs) for each isolate at both inocula. No significant difference in cefepime exposure was required to achieve similar bactericidal effects for ESBL-and non-ESBL-producing isolates when the starting inoculum was 10 5 CFU of E. coli per thigh. The increased MICs observed in vitro for the ESBL-producing strains at 10 7 CFU/ml did not predict the amount of exposure required to achieve a comparable level of bactericidal activity in vivo at the corresponding starting inoculum of 10 7 CFU/thigh. Compared to the cefepime exposure in tests with the lower inoculum (10 5 CFU/thigh), less exposure was required when the starting inoculum was 10 7 CFU/thigh (%T>MIC, 6% versus 26%), such that similar doses (in milligrams per kilogram of body weight) produced similar bactericidal effects with both inocula of ESBL-producing isolates. Equivalent exposures of cefepime produced similar effects against the microorganisms regardless of the presence of ESBL production. Pharmacodynamic profiling undertaken with conventional cefepime MIC determinations predicted in vivo microbial outcomes at both inoculum sizes for the ESBL-producing isolates evaluated in this study. These data support the use of conventional MIC determinations in the pharmacodynamic assessment of cefepime.

Pharmacokinetic–pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications

“…Interestingly, in the previous study, regrowth was observed of an isolate with a MIC of 8 mg l 21 even when the %f TwMIC remained above 40 % (50-69 %), leading to the conclusion that specific or co-existent resistance mechanisms may alter the pharmacodynamics of meropenem. However, in vivo studies demonstrated that, regardless of the production of b-lactamases and other meropenem resistance mechanisms, the desired bactericidal effect can still be achieved as long as the drug exposure is 40 % f TwMIC, as also found with the VIM-1-producing isolates used in the present study (Maglio et al, 2004). Our in vivo data are in line with previous data in a neutropenic animal model of thigh infection by extended-spectrum b-lactamase-producing K. pneumoniae isolates treated with meropenem, where c.f.u.…”

Optimizing Echinocandin Dosing and Susceptibility Breakpoint Determination via In Vivo Pharmacodynamic Evaluation against Candida glabrata with and without fks Mutations

“…More specifically, the in vivo murine model and pharmacodynamic analyses of results were used to discern the impacts of echinocandin dose, MIC, and fks-1 or fks-2 mutation on treatment effect. These approaches have recently demonstrated utility in defining the clinical relevance of bacterial resistance mutations, design of susceptibility breakpoints, and optimal treatment strategies (4,33,34).…”

Extended-Spectrum β-Lactamases: a Clinical Update

“…Those in favor of changing cephalosporin breakpoints dispute that the inoculum effect is important (231). A final argument in favor of ongoing efforts aimed at ESBL detection is the infection control significance of detecting plasmid-mediated multidrug resistance.…”