Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in an In Vitro Infection Model

Abstract

cThe usefulness of ␤-lactam antimicrobial agents is threatened as never before by ␤-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum ␤-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 ␤-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 ␤-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 log 10 CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC 0 -24 ), maximum concentration (C max ), 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 AUC 0 -24 (r 2 ‫؍‬ 0.835) and C max (r 2 ‫؍‬ 0.826). Using the CB-618 AUC 0 -24 indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log 10 CFU/ml at 24 h and CB-618 AUC 0 -24 /MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC 0 -24 /MIC ratio associated with net bacterial stasis and the 1-and 2-log 10 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.

New β-Lactamase Inhibitors in the Clinic

“…40 CB-618 tested in combination with meropenem displays activity against clinical isolates of Enterobacteriaceae expressing the KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and/or TEM-1 beta-lactamases.…”

Treatment of Infections by OXA-48-Producing Enterobacteriaceae

“…It is unclear whether the novel DBO BLI zidebactam is effective at inhibiting OXA-48 due to it being combined in one study with cefepime, which is known to be stable against . Compound CB-618 is another novel DBO BLI that has shown promise, with in vitro susceptibility of OXA-48 producers when combined with meropenem (40). Compound ETX2514 is yet another broad-spectrum DBO with activity against class D beta-lactamases and is currently in clinical development in combination with sulbactam for the treatment of Acinetobacter baumannii infections (41).…”

In Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae

“…The pharmacodynamic behavior of ␤-lactamase inhibitors has not been well established (11). Recent pharmacodynamic studies have begun to identify the exposureresponse relationships of the ␤-lactamase inhibitor component required to restore activity of the ␤-lactam (9,10,(12)(13)(14). Notably, the pharmacodynamic index may be different for these inhibitors; fTϾthreshold has been identified for tazobactam in combination with ceftolozane, cefepime, and piperacillin, with different threshold concentrations as a fraction of the MIC identified dependent on the ␤-lactam backbone.…”

“…That said, the variability in CFU reductions observed during the clavulanate-containing experiments could be due to different exposure-response relationships for the ESBL-producing isolates or, if our assumptions were correct, to the steep ceftibuten response-exposure curve (Fig. 2), where the difference between 50 and 66% fTϾMIC could result in stasis to Ͼ1-log 10 CFU reductions at 24 h. Other in vitro pharmacodynamic studies assessed exposure-response relationships of the inhibitor using a human-simulated concentration profile for the ␤-lactam component based on the commonly used dosing regimen (10,(12)(13)(14). A different approach to ceftibuten dosing was applied in this study because alternative dosing regimens might be advantageous when combining ceftibuten with a ␤-lactamase inhibitor.…”