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 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 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.

Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives.

INTRODUCTION: The number of patients with pulmonary disease caused by non-tuberculous mycobacteria (NTM) is increasing globally. Poor resistance against infections, for example, due to pre-existing lung diseases, immune deficiency and immune-modulating treatment, predisposes the population to developing pulmonary NTM disease. The incidence of pre-existing lung diseases such as chronic obstructive pulmonary disease and bronchiectasis has also increased. NTM disease diagnosis is often delayed due to non-specific symptoms. The therapeutic arsenal is limited and adherence to treatment guidelines is often low since the treatment regimens are complex, lengthy and side effects are common. Thus, current disease management is far from satisfactory and needs to be improved. Areas covered: This review provides an overview of the current knowledge of NTM infections and includes pathogenesis, disease patterns, epidemiology, disease management, unmet needs and future perspectives. Expert commentary: NTM disease is becoming more prevalent, in part with our increased awareness and improved diagnostic methods. However, our understanding of the disease pathogenesis is limited and treatment decisions are challenging, with difficult to employ drug regimens. Optimal management requires collaboration between healthcare providers, patients and expert centers.