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ObjectivesOur aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose.MethodsMinocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients.ResultsThe MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments.ConclusionsMinocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.

Original publication

DOI

10.1093/jac/dkz143

Type

Journal article

Journal

The Journal of antimicrobial chemotherapy

Publication Date

07/2019

Volume

74

Pages

1952 - 1961

Addresses

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Keywords

Cell Line, Macrophages, Humans, Mycobacterium avium Complex, Mycobacterium avium-intracellulare Infection, Pneumonia, Bacterial, Minocycline, Anti-Bacterial Agents, Microbial Sensitivity Tests, Monte Carlo Method, Bayes Theorem, Algorithms, Models, Biological