A programme to create short-course chemotherapy for pulmonary Mycobacterium avium disease based on pharmacokinetics/pharmacodynamics and mathematical forecasting.

Objectives: Pulmonary Mycobacterium avium complex (MAC) prevalence is on the rise worldwide. The average therapy duration is 1.5 years, which is associated with poor cure rates. Our objective was to develop a programme to design a combination therapy regimen for pulmonary MAC to be administered for 6 months or less with efficacy in > 90% of patients.

Methods: We performed a literature search for the following MeSH headings 'Mycobacterium avium' AND 'pharmacokinetics/pharmacodynamics' in PubMed up to 2016. The findings were then used to identify steps in the programme to design new regimens with faster microbial kill rates than the current standard regimen.

Results: First, we designed a strategy for rapid in vitro screening of all antibiotic classes for repurposing against pulmonary MAC. Secondly, we identified and compared maximal microbial kill rates (Emax), and optimal exposures of eight different antibiotics. These studies had all been performed in the hollow-fibre system model of pulmonary MAC (HFS-MAC). Thirdly, all drugs with a high Emax at clinically achievable optimal exposures will be chosen, and exposures associated with synergy or additivity for two/three drugs identified based on Bliss independence. Fourthly, the time-kill slopes and resistance suppression of the chosen combinations will be compared with those of standard combination therapy in the HFS-MAC. Finally, we will identify the clinical doses best able to achieve synergistic or additive combination exposures by taking into account pharmacokinetic variability.

Conclusions: Our stepwise pharmacokinetics/pharmacodynamics approach provides a scientific rationale and a strategy for achieving short-course chemotherapy for pulmonary MAC disease within a few years.