ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1682477
Tigecycline pharmacodynamics in the hollow fiber system of Mycobacterium avium complex lung disease, and the utility of MICs and time-kill studies in drug development
Provisionally accepted
- 1Baylor University Medical Center, Dallas, United States
- 2The University of Texas at Tyler School of Medicine, Tyler, United States
- 3The University of Texas Health Science Center at Tyler, Tyler, United States
- 4IMPI Biotechnology Company Incorporated, Tateguru, Zimbabwe
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Background: Guideline-based therapy (GBT) drugs for Mycobacterium avium-complex (MAC) lung disease (LD) were chosen in part because they have low MICs. Despite these low MICs, GBT achieves six-month sustained sputum culture conversion in only 43% of patients. Methods: First, we co-incubated tigecycline with MAC for seven days in time-kill studies and calculated the exposure mediating 50% of maximal effect (Emax) or EC50. Next, we performed tigecycline exposure-effect studies in the hollow fiber system of MAC (HFS-MAC) inoculated with the reference ATCC#700898 isolate. Third, we performed an exposure-effect study in the HFS-MAC inoculated with five clinical isolates. Finally, the target exposure (EC80) was used to identify a clinical dose of inhaled tigecycline for MAC-LD in 10,000 virtual subject Monte Carlo experiments (MCE). Results: In time-kill studies the EC50 was 0-24h area under the concentration-time curve-to-MIC (AUC0-24/MIC) of 62.24 for extracellular and 0.14 for intracellular MAC (p<0.001). In the HFS-MAC inoculated with ATCC#700898, the EC50 statistically differed between sampling days. However, studies with five different isolates demonstrated a stable and robust day-to-day EC50 (%CV=18.18%), with an EC80 AUC0-24/MIC of 33.65. The Emax was 4.84 log10 CFU/mL. In MCE, tigecycline inhalational doses of 35-40 mg/day achieved the EC80 target in >90% of virtual patients, with an MIC breakpoint of 256 mg/L. Conclusion: Instead of static time-kill studies with reference strain, inclusion of multiple MAC isolates in HFS-MAC studies improves precision of pharmacokinetic/pharmacodynamic parameter estimates. Tigecycline via the inhalational route could contribute to treatment of MAC-LD.
Keywords: Tetracycline, Nontuberculous Mycobacteria, pulmonary disease, PK/PD, probability of target attainment
Received: 08 Aug 2025; Accepted: 08 Oct 2025.
Copyright: © 2025 Deshpande, Srivastava and Gumbo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Tawanda Gumbo, wegona@impibiotechcity.com
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