Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane and Meropenem: The Pharmacological Basis for a Stand-Alone {beta}-Lactamase Inhibitor [PublishAheadOfPrint]

A major challenge in treating patients is the selection of the "right" antibiotic regimen. Given that the optimal β-lactam-β-lactamase inhibitor pair is dependent upon the spectrum of β-lactamase enzymes produced and the frequency of resistance to the β-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the "right" β-lactam rather than only in a fixed combination. In this communication, we describe a one-compartment in vitro infection model studies conducted to identify the magnitude of the pharmacokinetic-pharmacodynamic (PK-PD) index for a β-lactamase inhibitor, CB-618, that would restore the activity of four β-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with varying dose (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (5), Escherichia coli (2), and Enterobacter cloacae (1), which produced a large variety of β-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each partner β-lactam. The CB-618 ratio of the area under the concentration-time curve from 0 to 24 hours to the minimum inhibitory concentration (AUC:MIC ratio) associated with net bacterial stasis and 1- and 2-log₁₀ CFU/mL reduction from baseline at 24 hours was 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone β-lactamase inhibitor.

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