Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models

Objectives: Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacteriumavium complex (MAC) and to identify the optimal clinical dose. Methods: Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also coincubated primary isolated macrophages infectedwithMAC 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-MACmodel was sampled at intervals to determine theminocycline pharmacokinetics andMAC 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. Wethen performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients. Results: The 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. Conclusions: Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation. © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.