Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone β-Lactamase Inhibitor.

Abstract

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. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes 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 various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (n = 5), Escherichia coli (n = 2), and Enterobacter cloacae (n = 1) strains, which produced a wide 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, and 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 β-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 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.

• Authors: Paul G Ambrose, Brian D VanScoy, Michael Trang, Jennifer McCauley-Miller, Haley Conde, Sujata M Bhavnani, Dylan C Alexander, Lawrence V Friedrich
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 61 Issue 12 (12 2017) ISSN: 1098-6596 [Electronic] United States
• PMID: 28947474 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society for Microbiology.

Chemical References

• Anti-Bacterial Agents
• Cephalosporins
• Thienamycins
• beta-Lactamase Inhibitors
• ceftolozane
• Cefepime
• Ceftazidime
• beta-Lactamases
• Meropenem

Topics

• Anti-Bacterial Agents (pharmacology)
• Cefepime
• Ceftazidime (pharmacology)
• Cephalosporins (pharmacology)
• Computer Simulation
• Enterobacter cloacae (drug effects)
• Escherichia coli (drug effects)
• Humans
• Klebsiella pneumoniae (drug effects)
• Meropenem
• Microbial Sensitivity Tests
• Thienamycins (pharmacology)
• beta-Lactamase Inhibitors (pharmacokinetics, pharmacology)
• beta-Lactamases (metabolism)