Abstract
Treatment outcomes using the standard regimen (a macrolide, ethambutol, and rifampicin) for Mycobacterium avium complex-pulmonary disease (MAC-PD) remain unsatisfactory. Thus, improved treatment regimens for MAC-PD are required. Clofazimine has recently been revisited as an effective drug against mycobacterial infection. We performed a comparison between the standard regimen and an alternative regimen (replacing the rifampicin of the standard regimen with clofazimine) based on the intracellular anti-MAC activities of the individual drugs in a murine model of chronic progressive MAC-pulmonary infection (MAC-PI). The intracellular anti-MAC activities of the individual drugs and their combinations in murine bone marrow-derived macrophages (BMDMs) were determined. The treatment efficacies of the standard and clofazimine-containing regimens were evaluated in mice chronically infected with M. avium by initiating 2- and 4-week treatment at 8 weeks post-infection. Bacterial loads in the lung, spleen, and liver were assessed along with lung inflammation. Insufficient intracellular anti-MAC activity of rifampicin in BMDMs was recorded despite its low in vitro minimum inhibitory concentrations (MICs), whereas optimal intracellular killing activity against all tested MAC strains was achieved with clofazimine. Compared to the standard regimen, the clofazimine-containing regimen significantly reduced CFUs in all organs and achieved marked reductions in lung inflammation. The replacement of rifampicin with clofazimine in the treatment regimen resulted in more favorable outcomes in an animal model of chronic progressive MAC-PI. Intriguingly, 2 weeks of treatment with the clofazimine-containing regimen reduced bacterial loads more effectively than 4 weeks of treatment with the standard regimen in M. avium-infected mice. Thus, the clofazimine-containing regimen also had a treatment-shortening effect.
Highlights
Non-tuberculous mycobacteria (NTM), which are ubiquitous and opportunistic pathogens, comprise all the members of Mycobacterium except the Mycobacterium tuberculosis complex and Mycobacterium leprae (Baldwin et al, 2019; Daley et al, 2020)
To investigate whether the lack of intracellular anti-Mycobacterium avium complex (MAC) activity of RIF was due to specific characteristics of macrophages from BALB/c mice, bone marrow-derived macrophages (BMDMs) from C57BL/6 mice were infected with M. avium American Type Culture Collection (ATCC) 700898, M. avium 104 (CP000479.1) and M. intracellulare ATCC 13950 and treated with 10 mg/L RIF
Previous studies showed that a treatment regimen containing CFZ resulted in favorable outcomes for patients with MAC-pulmonary disease (PD), there have been few studies elucidating its effect on macrophages and relevant animal models
Summary
Non-tuberculous mycobacteria (NTM), which are ubiquitous and opportunistic pathogens, comprise all the members of Mycobacterium except the Mycobacterium tuberculosis complex and Mycobacterium leprae (Baldwin et al, 2019; Daley et al, 2020). The Mycobacterium avium complex (MAC), which comprises slow-growing Mycobacterium species, has been ranked as the most common group of NTM pathogens worldwide (Hoefsloot et al, 2013; Daley et al, 2020). Patients with drugsusceptible MAC-PD generally receive at least three antibiotics, a macrolide [azithromycin or clarithromycin (CLR)], ethambutol (EMB), and rifampicin (RIF), as a standard regimen for at least 12 months based on previous empirical clinical investigations (Griffith et al, 1996; Wallace et al, 1996; Wallace et al, 2014; Griffith, 2018). The minimum inhibitory concentrations (MICs) of EMB and RIF are associated with treatment efficacy, and 85.3% of patients whose MAC isolates have MICs of
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