Pharmacokinetics/pharmacodynamics of a β-lactam and β-lactamase inhibitor combination: a novel approach for aztreonam/avibactam

• Published in: Journal of antimicrobial chemotherapy Vol. 70; no. 9; pp. 2618 - 2626
• Main Authors: Singh, Renu, Kim, Aryun, Tanudra, M Angela, Harris, Jennifer J, McLaughlin, Robert E, Patey, Sara, O'Donnell, John P, Bradford, Patricia A, Eakin, Ann E
• Format: Journal Article
• Language: English
• Published: England 01.09.2015
• Subjects: Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Azabicyclo Compounds - administration & dosage; Azabicyclo Compounds - pharmacokinetics; Azabicyclo Compounds - pharmacology; Aztreonam - administration & dosage; Aztreonam - pharmacokinetics; Aztreonam - pharmacology; beta-Lactamase Inhibitors - administration & dosage; beta-Lactamase Inhibitors - pharmacokinetics; beta-Lactamase Inhibitors - pharmacology; beta-Lactams - administration & dosage; beta-Lactams - pharmacokinetics; beta-Lactams - pharmacology; Disease Models, Animal; Enterobacteriaceae - drug effects; Enterobacteriaceae Infections - drug therapy; Female; Mice; Microbial Sensitivity Tests; Models, Biological; Treatment Outcome; NDM-1; PK/PD; hollow-fibre infection model
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv132

The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-β-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains. Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains. MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target. PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for β-lactam/β-lactamase inhibitor combinations.