9 May 2019

In Journal of Antimicrobial Chemotherapy Mike Ruth, Jakko van Ingen and colleagues showed, using the hollow fiber pharmacodynamic model, that minocycline may be useful to treat pulmonary diseases caused by Mycobacterium avium complex bacteria. This opportunistic infection is increasing in prevalence and outcomes of current treatment regimens are very poor. Minocycline is an old, safe and well tolerated antibiotic that may improve treatment outcomes.

Abstract

Objectives
Our 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.

Methods 
Minocycline 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 10 000 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.

publication
Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.
Ruth MM, Magombedze G, Gumbo T, Bendet P, Sangen JJN, Zweijpfenning S, Hoefsloot W, Pennings L, Koeken VACM, Wertheim HFL, Lee PS, van Ingen J, Deshpande D.

Mike Ruth and Jakko van Ingen are members of theme Infectious disease and global health

 

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