What individual antimicrobials add to Mycobacterium avium complex therapies; an in vitro perspective
Objective: For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence based combination therapy we assessed the in vitro activity of six drugs - clarithromycin (CLR), rifampicin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CFZ), and minocycline (MIN) alone and in combinations against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. Methods: The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed time-kill kinetic assays (TKA) of all single drugs and clinically relevant two, three, four and five drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Results: Adding a second drug yielded an average increase of the effect size (E) of 18.7 ± 32.9% log10 cfu/mL*day, though antagonism was seen in some combinations. Adding a third drug showed a lower increase in effect size (+12.2 ± 11.5%). The rifampicin-clofazimine-clarithromycin (E=102 log10 cfu/mL*day), rifampicin-amikacin-clarithromycin (E=101 log10 cfu/mL*day) and amikacin-minocycline-ethambutol (E=97.8 log10 cfu/mL*day) regimens proved more active than the recommended rifampicin-ethambutol-clarithromycin regimen (E=89.1 log10 cfu/mL*day). The addition of a fourth drug had little impact on effect size (+4.54 ± 3.08%). Conclusions: In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be rifampicin-amikacin-macrolide or rifampicin-clofazimine-macrolide.