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

Autor: Singh S; Department of Medicine, University of Texas School of Medicine, Tyler, Texas, USA., Wang JY; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan., Heysell SK; Division of Infectious Diseases and International Health, University of Virginia, USA., McShane PJ; Section of Pulmonary and Critical Care, University of Texas at Tyler, Tyler, Texas, USA., Wadle C; Section of Pulmonary and Critical Care, University of Texas at Tyler, Tyler, Texas, USA., Shankar P; Department of Medicine, University of Texas School of Medicine, Tyler, Texas, USA., Huang HL; Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan., Pasipanodya J; Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc., Dallas, Texas., Boorgula GD; Department of Medicine, University of Texas School of Medicine, Tyler, Texas, USA., Philley JV; Section of Pulmonary and Critical Care, University of Texas at Tyler, Tyler, Texas, USA., Gumbo T; Quantitative Preclinical & Clinical Sciences Department, Praedicare Inc., Dallas, Texas; Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc, Dallas, TX., Srivastava S; Department of Medicine, University of Texas School of Medicine, Tyler, Texas, USA; Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas, USA; Center for Biomedical Research, University of Texas Health Science Centre at Tyler, Tyler, Texas, USA. Electronic address: Shashi.kant@uthct.edu.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2023 Jul; Vol. 62 (1), pp. 106847. Date of Electronic Publication: 2023 May 13.
DOI: 10.1016/j.ijantimicag.2023.106847
Abstrakt: Background: 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 log 10 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.
Methods: 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.
Results: Omadacycline efficacy in the HFS-Mab was 2.09 log 10 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<0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P<0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months.
Conclusion: Based on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease.
(Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
Databáze: MEDLINE
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