Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M. abscessus infection in mice

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 137; p. 102268
• Main Authors: Sriram, Divya, Wahi, Rishi, Maggioncalda, Emily C., Panthi, Chandra M., Lamichhane, Gyanu
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.12.2022
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Clofazimine; Clofazimine - pharmacology; Clofazimine - therapeutic use; Humans; Lung Diseases - drug therapy; M. abscessus, experimental therapeutics; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium tuberculosis; Pneumonia; Positive control; Rifabutin; M. abscessus, experimental therapeutics; Rifabutin; Clofazimine; Positive control
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2022.102268

Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) can cause chronic pulmonary disease in the setting of structural lung conditions. Current treatment recommendations require at least one year of daily therapy with repurposed antibiotics. Yet these therapies are often ineffective and associated with significant adverse events. To address this challenge, research efforts are underway to develop new antibiotics and regimens. During the preclinical phase of treatment development, experimental agents require testing and comparison alongside positive controls that are known agents with clinical history. As there are no FDA approved treatments for this indication, here, we have considered repurposed antibiotics currently included in the recommendation for treating Mab disease as candidates for selection of an ideal standard comparator that can serve as a positive control in preclinical studies. Clofazimine meets the criteria for an ideal positive control as it can be administered via the least invasive route, requires only once-daily dosing, is well tolerated, and is widely available in high purity from independent sources. Using a mouse model of pulmonary Mab disease, we assessed for ideal dosages of clofazimine in C3HeB/FeJ and BALB/c mice in a six-week treatment window. Clofazimine, 25 mg/kg, once daily, produced desired reduction in Mab burden in the lungs of C3HeB/FeJ and BALB/c mice. Based on these findings, we conclude that clofazimine meets the criteria for a positive control comparator in mice for use in preclinical efficacy assessments of agents for treatment of Mab pulmonary disease. Although not included in the current standard-of-care for treating Mab disease, rifabutin, 20 mg/kg, also produced desired reduction in Mab lung burden in C3HeB/FeJ mice but not in BALB/c mice. Mycobacteroides abscessus can cause life-threatening infections in patients with chronic lung conditions. New treatments are needed as cure rate using existing drugs is low. During pre-clinical phase of treatment development, it is important to compare the efficacy of the experimental drug against existing ones with known history. Here, we demonstrate that clofazimine, one of the antibiotics repurposed for treating Mab disease, can serve as a positive control comparator for efficacy assessments of experimental drugs and regimens to treat M. abscessus disease in mice. •Existing antibiotics to treat M. abscessus (Mab) disease are not optimal.•There is an urgent need for new effective treatments for Mab disease.•New treatments need to be compared with existing antibiotics.•An existing antibiotic that can serve as a comparator is needed.•Clofazimine has ideal attributes to serve as a positive control comparator.