title: Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model.
abstract: The usefulness of β-lactam antimicrobial agents is threatened as never before by β-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum β-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartment in vitro infection model to determine the exposure measure for CB-618, a novel β-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel included Enterobacteriaceae clinical isolates, which collectively produced a wide range of β-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challenge Klebsiella pneumoniae isolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0-24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0-24 (r(2) = 0.835) and Cmax (r(2) = 0.826). Using the CB-618 AUC0-24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10 CFU/ml at 24 h and CB-618 AUC0-24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0-24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: VanScoy
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Trang
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCauley
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Conde
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.affiliation: Merck and Co., Kenilworth, New Jersey, USA.
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Friedrich
authors.affiliation: Merck and Co., Kenilworth, New Jersey, USA.
authors.forename: Dylan C
authors.initials: DC
authors.lastname: Alexander
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA University of Oxford, Oxford, United Kingdom PAmbrose@ICPD.com.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000378:metabolism; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D000077731:Meropenem