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

Devyani Deshpande; Shashikant Srivastava; Tawanda Gumbo

doi:10.1016/j.ijantimicag.2024.107204

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

Int J Antimicrob Agents. 2024 May 14:107204. doi: 10.1016/j.ijantimicag.2024.107204. Online ahead of print.

Authors

Devyani Deshpande¹, Shashikant Srivastava², Tawanda Gumbo³

Affiliations

¹ Baylor University Medical Center, Dallas, Texas, USA.
² 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 at Tyler, Tyler, Texas, USA.
³ Hollow Fiber System & Experimental Therapeutics Laboratories, Irving, Texas, USA; Mathematical Modeling and AI Department, Praedicare Inc., Irving, Texas, USA. Electronic address: rozvi1@praedicareinc.com.

PMID: 38754528
DOI: 10.1016/j.ijantimicag.2024.107204

Abstract

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 fiber 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 (E₅₀, EC₈₀) were identified. The EC₈₀ 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±0.80h in the HFS-MAC and killed a maximum of 2.17 log₁₀ CFU/mL below day 0. The EC₅₀ was %T_MIC of 75.9% (95% confidence interval: 68.43% to 86.54%) and the EC₈₀ 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.

Keywords: drug degradation; efficacy; hollow fiber system model; novel regimens.