Clofazimine for the Treatment of Multidrug-Resistant Tuberculosis: Prospective, Multicenter, Randomized Controlled Study in China

Tang, Shenjie; Yao, Lan; Hao, Xiaofei; Liu, Yidian; Zeng, Linhai; Liu, Gang; Li, Mingwu; Li, Fujian; Wu, Meimei; Zhu, Yousheng; Sun, Hsin‐Yun; Gu, Jin; Wang, Xia-Fang; Zhang, Zhanjun

doi:10.1093/cid/civ027

Cited by 95 publications

(114 citation statements)

References 22 publications

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“…This finding was subsequently confirmed in a larger study in Bangladesh (7), and similar results were also reported from observational studies in Niger and Cameroon (8,9). The specific bactericidal and treatment-shortening activity of clofazimine was experimentally evidenced in mouse models of drug-susceptible (10) and drug-resistant (11) TB as well as clinically evidenced in a controlled clinical trial conducted in China (12). Thus, clofazimine appears to have potential as a repurposed drug for improving, i.e., significantly shortening, the treatment of TB.…”

supporting

confidence: 73%

“…Considering the results from these two studies, it is reasonable to expect a treatment-shortening effect of combining clofazimine with first-line drugs in the treatment of patients with TB if the main pharmacokinetic parameters of clofazimine in the mouse are applicable to humans. The decades of experience utilizing clofazimine for multidrug treatment of leprosy patients at daily doses of 50 to 100 mg demonstrate that clofazimine can be safely administered to humans for long periods of time, with the most common adverse reaction being reversible skin discoloration and ichthyosis (12). Thus, clofazimine is extremely unique in that it is an off-patent, available drug that could immediately be evaluated as a repurposed drug for the treatment of TB, and it seems advisable that the contribution of clofazimine as a first-line drug for the treatment of patients with TB should be assessed.…”

Section: Discussionmentioning

confidence: 99%

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Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy

Swanson

Ammerman

Ngcobo³

et al. 2016

Antimicrob Agents Chemother

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dExperimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamideethambutol, or a first-line regimen where clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving clofazimine, either alone or in combination, compared to the mice that did not receive clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum clofazimine levels remained at or above the 0.25-g/ml MIC for M. tuberculosis. Thus, sustained activity of clofazimine may be important in the treatment-shortening effect associated with this drug.

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supporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy

Swanson

Ammerman

Ngcobo³

et al. 2016

Antimicrob Agents Chemother

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“…With the exception of three randomised controlled trials (RCTs) for clofazimine and linezolid [43–45], the evidence used to assess the effects of individual medicines on the outcomes of adult patients on longer MDR-TB regimens originated from observational studies. Meta-analysis were conducted on two datasets: 1) an IPD dataset compiled from studies of 9153 patients treated between the early 1980s and 2009 [41], and 2) a study-level aggregated dataset for over 17 000 MDR-TB and XDR-TB patients in 74 studies published between January 2009 and August 2015 (B astos M, L an Z, M enzies R, personal communication).…”

Section: Resultsmentioning

confidence: 99%

World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update

et al. 2017

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Antimicrobial resistance is a major global concern. Tuberculosis (TB) strains resistant to rifampicin and other TB medicines challenge patient survival and public health. The World Health Organization (WHO) has published treatment guidelines for drug-resistant TB since 1997 and last updated them in 2016 based on reviews of aggregated and individual patient data from published and unpublished studies. An international expert panel formulated recommendations following the GRADE approach. The new WHO guidelines recommend a standardised 9–12 months shorter treatment regimen as first choice in patients with multidrug- or rifampicin-resistant TB (MDR/RR-TB) strains not resistant to fluoroquinolones or second-line injectable agents; resistance to these two classes of core second-line medicines is rapidly detectable with molecular diagnostics also approved by WHO in 2016. The composition of longer regimens for patients ineligible for the shorter regimen was modified. A first-ever meta-analysis of individual paediatric patient data allowed treatment recommendations for childhood MDR/RR-TB to be made. Delamanid is now also recommended in patients aged 6–17 years. Partial lung resection is a recommended option in MDR/RR-TB care. The 2016 revision highlighted the continued shortage of high-quality evidence and implementation research, and reiterated the need for clinical trials and best-practice studies to improve MDR/RR-TB patient treatment outcomes and strengthen policy.

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“…Studies were included if they were randomized and controlled and if sputum smear or culture results were reported. Sputum culture status after 8 weeks of treatment was the preferred endpoint because this is the sole TB biomarker meeting the criteria of Chau et al [15] as a “known valid” predictor of relapse [16, 17] and failure [18, 19]. Sputum acid-fast smear conversion was substituted for culture in 3 studies in which culture was not reported.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D as Adjunctive Host-Directed Therapy in Tuberculosis: A Systematic Review

Wallis

Zumla

2016

Open Forum Infectious Diseases

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Vitamin D plays an important role in innate defenses against intracellular pathogens. Seasonal vitamin D insufficiency (VDI) due to reduced sun exposure far from the equator increases tuberculosis risk. Eight randomized controlled trials examined vitamin D as adjunctive therapy during tuberculosis treatment. The studies varied substantially regarding patient genetic backgrounds, the extent of baseline VDI, the administered dose, the study endpoints, and the quality of the reported data. One carefully performed study in which moderately large vitamin D doses were given to markedly VDI patients found a benefit sufficient to support shortening treatment from 6 to 4 months, although other similar studies did not. Vitamin D is thought to have anti-inflammatory effects. However, 2 studies reported 3 vitamin D recipients with severe paradoxical inflammatory reactions. Future studies of vitamin D in tuberculosis in patients with specific genetic backgrounds must monitor these events closely to determine their risks and underlying mechanisms.

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Clofazimine for the Treatment of Multidrug-Resistant Tuberculosis: Prospective, Multicenter, Randomized Controlled Study in China

Abstract: Using Cfz to treat MDR tuberculosis promotes cavity closure, accelerates sputum culture conversion, and improves treatment success rates.

Cited by 95 publications

References 22 publications

Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy

Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy

World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update

Vitamin D as Adjunctive Host-Directed Therapy in Tuberculosis: A Systematic Review

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