Ceftriaxone Efficacy for Mycobacterium avium Complex Lung Disease in the Hollow Fiber and Translation to Sustained Sputum Culture Conversion in Patients.

Autor:	Deshpande D; Baylor University Medical Center, Dallas., Magombedze G; Mathematical Modeling and AI Department, Praedicare Inc, Dallas., Boorgula GD; Department of Medicine, School of Medicine, University of Texas at Tyler., Chapagain M; Department of Cellular and Molecular Biology, School of Medicine, University of Texas Health Science Center at Tyler., Srivastava S; Baylor University Medical Center, Dallas.; Department of Medicine, School of Medicine, University of Texas at Tyler.; Department of Cellular and Molecular Biology, School of Medicine, University of Texas Health Science Center at Tyler., Gumbo T; Mathematical Modeling and AI Department, Praedicare Inc, Dallas.; Hollow Fiber System and Experimental Therapeutics Laboratories, Praedicare Inc, Dallas, Texas.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2024 Aug 16; Vol. 230 (2), pp. e230-e240.
DOI:	10.1093/infdis/jiad545
Abstrakt:	Background: Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a β-lactam with a lung-to-serum penetration ratio of 12.18-fold. Methods: We mimicked lung concentration-time profiles of 7 ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS-MAC). Monte Carlo experiments were used for dose selection. We also compared once-daily ceftriaxone monotherapy to 3-drug SOC against 5 MAC clinical isolates in HFS-MAC using γ (kill) slopes, and translated to SSCC rates. Results: Ceftriaxone killed 1.02-3.82 log10 colony-forming units (CFU)/mL, at optimal dose of 2 g once-daily. Ceftriaxone killed all 5 strains below day 0 versus 2 of 5 for SOC. The median γ (95% confidence interval [CI]) was 0.49 (.47-.52) log10 CFU/mL/day for ceftriaxone and 0.38 (.34-.43) log10 CFU/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates (CI) of 39.3% (36%-42%) at 6 months. The SOC SSCC was 50% at 8.18 (3.64-27.66) months versus 3.58 (2.20-7.23) months for ceftriaxone, shortening time to SSCC 2.35-fold. Conclusions: Ceftriaxone is a promising agent for creation of short-course chemotherapy. Competing Interests: Potential conflicts of interest. T. G., G. M., and M. C. are employees of Praedicare Inc, a System of Systems–based drug development company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu