Clofazimine for the treatment of tuberculosis

Abstract

Shorter (6–9 months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine’s repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine’s exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine’s precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.

Overcoming Mycobacterium tuberculosis Drug Resistance: Novel Medications and Repositioning Strategies

“…It has been altered for the treatment of drug-resistant TB. In preclinical and clinical trials, it has been shown that adding clofazimine to treatment regimens for MDR-TB and XDR-TB improves treatment outcomes and decreases the time to culture conversion …”

“…It has been altered for the treatment of drug-resistant TB. In preclinical and clinical trials, it has been shown that adding clofazimine to treatment regimens for MDR-TB and XDR-TB improves treatment outcomes and decreases the time to culture conversion Nitazoxanide: An antiparasitic drug, nitazoxanide has shown encouraging antimycobacterial activity against M. tuberculosis .…”

Enhanced Biosynthesis of Phenazine-1,6-dicarboxylic Acid in Streptomyces coelicolor

“…Typical phenazines such as phenazine-1-carboxylic acid (PCA) and phenazine-1-carboxamide (PCN) are promising biopesticides for agricultural diseases while some more highly substituted phenazines display anticancer and radical scavenging properties . Besides, clofazimine is a clinically used antileprotic and antitubercular phenazine drug . Phenazines can also be adopted as components of microbial fuel cells and environmental sensors .…”

“…1 Besides, clofazimine is a clinically used antileprotic and antitubercular phenazine drug. 4 Phenazines can also be adopted as components of microbial fuel cells 5 and environmental sensors. 6 Accordingly, the identification and efficient production of phenazines are of great interest.…”

Appraisal of Fungus-Derived Xanthoquinodins as Broad-Spectrum Anti-Infectives Targeting Phylogenetically Diverse Human Pathogens

“…Selected examples of compounds that exhibit cross-phylum/multikingdom activity against phylogenetically diverse pathogens include nitazoxanide (thiazolide class used to treat Apicomplexa and Metamonada pathogens), paromomycin (amino cyclitol glycoside used to treat Amoebozoa, Euglenozoa, Metamonada, and Platyhelminthes pathogens), and tinidazole (nitroimidazole class used to treat Amoebozoa, Campylobacterota, and Metamonada pathogens) . These and other emerging agents − illustrate the scope of opportunities that exist pertaining to the identification, development, and employment of broad-spectrum anti-infectives …”