Omadacycline pharmacokinetics/pharmacodynamics in the hollow fiber model and clinical validation of efficacy to treat pulmonary Mycobacterium abscessus disease

• Published in: International journal of antimicrobial agents 2023-07, Vol.62 (1), p.106847-106847, Article 106847
• Main Authors: Singh, Sanjay, Wang, Jann-Yuan, Heysell, Scott K., McShane, Pamela J., Wadle, Carly, Shankar, Prem, Huang, Hung-Ling, Pasipanodya, Jotam, Boorgula, Gunavanthi D., Philley, Julie V., Gumbo, Tawanda, Srivastava, Shashikant
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Efficacy; Hollow fiber system model; Humans; Lung Diseases - drug therapy; M. abscessus; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous - drug therapy; Pharmacokinetics/pharmacodynamics; Retrospective Studies; Safety; Tetracyclines - pharmacology; Tetracyclines - therapeutic use
• ISSN: 0924-8579; 1872-7913; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.106847

•Omadacycline showed excellent efficacy in HFS-Mab at exposures that could be achieved in >99% of patients on 300 mg/day.•Sustained sputum culture conversion (SSCC) in 8/10 patients on omadacycline 300 mg/day-based combinations vs. 1/9 on guideline-based regimens.•No toxicity was observed in any of the cases vs. 9/9 patients treated with guideline-based regimens.•Omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months in one patient. Guideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS-Mab), which killed ∼1.22 log10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure. First, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS-Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings. Omadacycline efficacy in the HFS-Mab was 2.09 log10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P=0.006), symptom improvement in 8/8 vs. 5/9 (P=0.033), toxicity in 0 vs. 9/9 (P