Limited Activity of Clofazimine as a Single Drug in a Mouse Model of Tuberculosis Exhibiting Caseous Necrotic Granulomas

Abstract

New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis. Recently, there has been renewed interest in clofazimine (CFZ). In this study, we utilized the C3HeB/FeJ mouse model, possessing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZ monotherapy in comparison to results with BALB/c mice, which form only multifocal, coalescing cellular aggregates devoid of caseous necrosis. While CFZ treatment was highly effective in BALB/c mice, its activity was attenuated in the lungs of C3HeB/FeJ mice. This lack of efficacy was directly related to the pathological progression of disease in these mice, since administration of CFZ prior to the formation of hypoxic, necrotic granulomas reconstituted bactericidal activity in this mouse strain. These results support the continued use of mouse models of tuberculosis infection which exhibit a granulomatous response in the lungs that more closely resembles the pathology found in human disease.

Effects of clofazimine on planktonic and biofilm growth of Mycobacterium tuberculosis and Mycobacterium smegmatis

“…Of the three types of microbial populations tested, the slowly replicating biofilmproducing bacilli of both mycobacterial species were found to be most susceptible to These findings are essentially in agreement with a recent study reported by Irwin et al who described the differential efficacy of clofazimine monotherapy in several murine models of experimental pulmonary TB [24]. Clofazimine was found to be most effective against the rapidly growing, intracellular bacilli in multifocal, coalescing lesions in the lungs of BALB/c mice as well as extracellular bacilli in the initiation phase of granuloma formation in C3HeB/FeJ mice [24].…”

“…The findings of the current study taken together with those of Irwin et al [24] and others [16,25] suggest that clofazimine and other antimycobacterial agents may be most effective in well aerated environments, seemingly consistent with the involvement of endogenously generated reactive oxygen species in antimicrobial activity. However, alternative mechanisms of clofazimine-mediated antimicrobial activity, probably also negated by dormancy, have also been proposed [15,19].…”

“…Clofazimine was found to be most effective against the rapidly growing, intracellular bacilli in multifocal, coalescing lesions in the lungs of BALB/c mice as well as extracellular bacilli in the initiation phase of granuloma formation in C3HeB/FeJ mice [24]. However, clofazimine was ineffective against extracellular bacilli encased in the well established, hypoxic, caseous, necrotic granulomas in the lungs of C3HeB/FeJ mice [24].…”

Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis

“…Together with prior studies indicating the poor activity of PZA in large caseous lesions (9,22), this study demonstrates the potential value of this heterogeneous disease model for identifying more precisely the lesion microenvironments in which certain drugs exert their activity and contribute to the efficacy of combination therapy. Strategies to increase the proportion of C3HeB/FeJ mice with large caseous lesions are under investigation.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…[350][351][352] However, in C3HeB/FeJ mice that develop large caseous granulomas, clofazimine is less effective, perhaps because of the hypoxic conditions or reduced diffusion through caseous tissue, or both. 353,354 Clofazimine shows no bactericidal activity in patient sputum over the first 14 days of treatment. 355 However, in a phase 2 clinical trial, adding clofazimine at a dose of 100 mg daily for 21 months to multidrug background therapy (ie, the MDR tuberculosis treatment regimen) improved MDR tuberculosis treatment success versus placebo (74% vs 54%).…”