Characterization of mouse models of Mycobacterium avium complex infection and evaluation of drug combinations

Abstract

The Mycobacterium avium complex is the most common cause of nontuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. avium complex infection has not been established. Clarithromycin is accepted as the cornerstone drug for treatment of M. avium lung disease; however, good model systems, especially animal models, are needed to evaluate the most effective companion drugs. We performed a series of experiments to evaluate and use different mouse models (comparing BALB/c, C57BL/6, nude, and beige mice) of M. avium infection and to assess the anti-M. avium activity of single and combination drug regimens, in vitro, ex vivo, and in mice. In vitro, clarithromycin and moxifloxacin were most active against M. avium, and no antagonism was observed between these two drugs. Nude mice were more susceptible to M. avium infection than the other mouse strains tested, but the impact of treatment was most clearly seen in M. avium-infected BALB/c mice. The combination of clarithromycin-ethambutol-rifampin was more effective in all infected mice than moxifloxacin-ethambutol-rifampin; the addition of moxifloxacin to the clarithromycin-containing regimen did not increase treatment efficacy. Clarithromycin-containing regimens are the most effective for M. avium infection; substitution of moxifloxacin for clarithromycin had a negative impact on treatment efficacy.

FIG 1

Gross lung pathology in four strains of mice, 12 weeks after aerosol infection with M. avium (implantation of approximately 5 log₁₀ CFU/lung). Four weeks postinfection, clarithromycin (100 mg/kg/day) was administered to a subgroup of mice.

FIG 2

Lung histopathology in four strains of mice, 12 weeks after aerosol infection with M. avium. Lung sections from untreated mice were stained with Ziehl-Neelsen, and red arrowheads indicate AFB. Images were captured at ×50 (BALB/c) or ×100 (C57BL/6, beige, and nude) magnification.