Exposure-Efficacy Analyses Support Optimal Dosing Regimens of Ceftolozane/Tazobactam in Participants with Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia in ASPECT-NP.

Autor: Gao W; Merck & Co., Inc., Kenilworth, New Jersey, USA., Passarell J; Cognigen Corporation, a Simulations Plus Company, Buffalo, New York, USA., Patel YT; Cognigen Corporation, a Simulations Plus Company, Buffalo, New York, USA., Zhang Z; Merck & Co., Inc., Kenilworth, New Jersey, USA., Lin G; Merck & Co., Inc., Kenilworth, New Jersey, USA., Fiedler-Kelly J; Cognigen Corporation, a Simulations Plus Company, Buffalo, New York, USA., Bruno CJ; Merck & Co., Inc., Kenilworth, New Jersey, USA., Rhee EG; Merck & Co., Inc., Kenilworth, New Jersey, USA., De Anda CS; Merck & Co., Inc., Kenilworth, New Jersey, USA., Feng HP; Merck & Co., Inc., Kenilworth, New Jersey, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 May 17; Vol. 66 (5), pp. e0139921. Date of Electronic Publication: 2022 Apr 26.
DOI: 10.1128/aac.01399-21
Abstrakt: An exposure-efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relationship between plasma exposure of ceftolozane and tazobactam and efficacy endpoints (primary: 28-day all-cause mortality; key secondary: clinical cure at test-of-cure visit) in adult participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Participants ( N  =   231) from the ceftolozane/tazobactam treatment group in the intention-to-treat population who had pharmacokinetic data available and relevant baseline lower respiratory tract (LRT) pathogen(s) susceptibility data were included. Population pharmacokinetic models were used to predict individual ceftolozane and tazobactam plasma exposure measures (percentage of the interdose interval with free drug concentrations above the MIC [% ƒ T>MIC] and % ƒ T above a threshold [% ƒ T>C T = 1 μg/mL], respectively) associated with the last dose using the highest ceftolozane/tazobactam MIC for the relevant baseline LRT pathogens. Efficacy measures were comparable between the baseline LRT pathogens and across MIC cutoffs (1-8 μg/mL). Most participants (82%) had 99% ƒ T>MIC for ceftolozane; 9% ( N  =   21/231) had 0% ƒT>MIC due to high MICs of the LRT pathogen (64-256 μg/mL). The %ƒT>MIC for ceftolozane exceeded 73% for all participants with baseline LRT pathogen(s) MIC ≤4 μg/mL. All 231 participants achieved the tazobactam pharmacokinetic/pharmacodynamic target of >20% ƒ T>C T where C T = 1 μg/mL. For either efficacy endpoint, median ceftolozane %ƒT>MIC was 99% in participants achieving efficacy. No exposure-efficacy trend was observed for ceftolozane or tazobactam. These results further support the recommended ceftolozane/tazobactam dosing regimens evaluated in ASPECT-NP for patients with HABP/VABP.
Databáze: MEDLINE
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