Tigecycline pharmacodynamics in the hollow fiber system of Mycobacterium avium-complex lung disease and the utility of MICs and time-kill studies in drug development

Background Guideline-based therapy (GBT) drugs for Mycobacterium avium -complex (MAC) lung disease (LD) were chosen in part because they have low minimum inhibitory concentrations (MICs). Despite these low MICs, GBT achieves 6-month sustained sputum culture conversion in only 43% of patients. Methods First, we co-incubated tigecycline with MAC for 7 days in time-kill studies and calculated the exposure mediating 50% of maximal effect (E max ), or EC 50 . Next, we performed tigecycline exposure-effect studies in the hollow fiber system of MAC (HFS-MAC) inoculated with the reference ATCC#700898 isolate. Third, we performed an exposure-effect study in the HFS-MAC inoculated with five clinical isolates. Finally, the target exposure (EC 80 ) was used to identify a clinical dose of inhaled tigecycline for MAC-LD in 10,000 virtual subject Monte Carlo experiments (MCE). Results In time-kill studies, the EC 50 was 0–24 h area under the concentration-time curve-to-MIC (AUC 0–24 /MIC) of 174 for extracellular and 4.56 for intracellular MAC (p < 0.001). In the HFS-MAC inoculated with ATCC#700898, the EC 50 statistically differed between sampling days. However, studies with five different isolates demonstrated a stable and robust day-to-day EC 50 (%CV = 18.18%), with an EC 80 AUC 0–24 /MIC of 33.65. The E max was 4.84 log 10 CFU/mL. In MCE, tigecycline inhalational doses of 35–40 mg/day achieved the EC 80 target in >90% of virtual patients, with an MIC breakpoint of 256 mg/L. Conclusion Instead of static time-kill studies with a reference strain, inclusion of multiple MAC isolates in HFS-MAC studies improves the precision of pharmacokinetic/pharmacodynamic parameter estimates. Tigecycline administered via the inhalational route could contribute to the treatment of MAC-LD.