Ertapenem's therapeutic potential for Mycobacterium avium lung disease in the hollow fibre model.

Autor: Deshpande D; Baylor University Medical Center, Dallas, Texas, USA., Srivastava S; Department of Medicine, School of Medicine, the University of Texas at Tyler, Tyler, Texas, USA; Department of Cellular and Molecular Biology, Center for Biomedical Research, University of Texas Health Science Center, Tyler, Texas, USA., Gumbo T; Hollow Fiber System & Experimental Therapeutics Laboratories, Irving, Texas, USA; Mathematical Modeling and AI Department, Praedicare Inc., Irving, Texas, USA. Electronic address: rozvi1@praedicareinc.com.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2024 Sep; Vol. 64 (3), pp. 107204. Date of Electronic Publication: 2024 May 15.
DOI: 10.1016/j.ijantimicag.2024.107204
Abstrakt: Introduction: Guideline-based therapy for Mycobacterium avium complex (MAC) pulmonary disease achieves sustained sputum conversion rates in only 43-53% of patients. Repurposing of β-lactam antibiotics such as ertapenem could expedite design of more efficacious regimens, compared to developing new drugs.
Methods: We performed an ertapenem exposure-response study in the hollow fibre system model of intracellular MAC (HFS-MAC). We recapitulated human-like intrapulmonary concentration-time profiles of eight once-daily intravenous doses of ertapenem over 28 days and performed repetitive sampling for drug concentration-time profiles and MAC burden. The % of time concentration persisted above MIC (%T MIC ) mediating either 50% or 80% of maximal effect (E 50 , EC 80 ) were identified. The EC 80 was used as target exposure in a 10 000 subject Monte Carlo experiments for ertapenem doses of 1G, 2G, or 4G administered once versus twice daily.
Results: The ertapenem MIC ranged from 0.5 to 2 mg/L on three occasions. Ertapenem achieved a half-life of 4.04 ± 0.80 h in the HFS-MAC and killed a maximum of 2.17 log 10 CFU/mL below day 0. The EC 50 was %T MIC of 75.9% (95% confidence interval: 68.43%-86.54%) and the EC 80 was %T MIC of 100%. Target attainment probability was >90% for 1G twice daily up to an MIC of 2 mg/L, while for 2G twice daily the susceptibility MIC breakpoint was 4-8 mg/L.
Conclusions: Ertapenem microbial kill below day 0 burden was better than guideline-based therapy drugs in the HFS-MAC in the past. Ertapenem is a promising drug for novel combination therapies for MAC lung disease.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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