Pharmacokinetics/pharmacodynamics of a ß-lactam and ß-lactamase inhibitor combination: a novel approach for aztreonam/avibactam.
J Antimicrob Chemother
; 70(9): 2618-26, 2015 Sep.
Article
em En
| MEDLINE
| ID: mdl-26024868
ABSTRACT
OBJECTIVES:
The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-ß-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.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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 ß-lactam/ß-lactamase inhibitor combinations.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Aztreonam
/
Infecções por Enterobacteriaceae
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Compostos Azabicíclicos
/
Antibacterianos
Limite:
Animals
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos