Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

Abstract

bOver the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.

The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection

“…Early studies confirmed that most immunocompetent mouse strains result in clearance of Mabs in the first weeks after infection with Mabs isolates (Ordway et al, 2008; Bernut et al, 2014b; Obregón-Henao et al, 2015), making model development and selection challenging. In these earlier studies, C57BL/6 and leptin-deficient (Ob/Ob) mice infected with Mabs with a low-dose aerosol inoculum (LDA, ~100 bacilli per mouse) did not develop a sustained progressive infection.…”

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

“…Regarding M. abscessus infection, in vitro DST studies demonstrated a low MIC of CFZ and in vitro synergy between CFZ and other antibiotics, such as clarithromycin (CLR), AMK, or tigecycline (23)(24)(25)(26)(27)(28). The antimycobacterial activity of CFZ against M. abscessus was also demonstrated in vivo with Drosophila melanogaster and mouse models of infection (29,30).…”

New Insights in the Treatment of Nontuberculous Mycobacterial Pulmonary Disease

“…Bedaquiline also showed activity in the lung tissue of M. abscessus-infected mice [11]. The combination of bedaquiline and clofazimine showed a stronger synergistic effect; this combination therapy significantly lowered bacterial burden of M. abscessus in organs of interferongamma knockout (GKO) mice [8]. These animal models mimic disseminated rather than pulmonary NTM disease and like the HFM findings for MAC and M. abscessus, they still await confirmation in clinical trials.…”

“…The new antituberculosis drug bedaquiline proved bacteriostatic against M. avium in a mouse model, but it did not add to the activity of macrolides [7]. Perhaps, in synergistic combinations (like the bedaquiline-clofazimine combination already proven synergistic in mouse models of M. abscessus disease) [8] bedaquiline might still prove helpful in MAC pulmonary disease (MAC-PD) treatment.…”