Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil.

Although clofazimine is used to treat multidrug-resistant tuberculosis (MDR-TB), there is scant information on its effectiveness and safety. The aim of this retrospective, observational study was to evaluate these factors as well as the tolerability of clofazimine in populations in Brazil, where it was administered at a daily dose of 100 mg·day-1 (body weight ≥45 kg) as part of a standardised MDR-TB treatment regimen until 2006 (thereafter pyrazinamide was used).All MDR-TB patients included in the Sistema de Informação de Tratamentos Especiais da Tuberculose (SITETB) individual electronic register were analysed. The effectiveness of clofazimine was assessed by comparing the treatment outcomes of patients undergoing clofazimine-containing regimens against those undergoing clofazimine-free regimens and its safety by describing clofazimine-attributed adverse events. A total of 1446 patients were treated with clofazimine-containing regimens and 1096 with pyrazinamide-containing regimens.Although success rates were similar in patients treated with clofazimine versus those treated with pyrazinamide (880 out of 1446, 60.9%, versus 708 out of 1096, 64.6%; p=0.054), clofazimine-treated cases exhibited higher death rates due to tuberculosis than pyrazinamide-treated ones (314 out of 1446, 21.7%, versus 120 out of 1096, 10.9%) but fewer failures (78 out of 1446, 5.4%, versus 95 out of 1096, 8.7%) and less loss to follow-up (144 out of 1446, 10.0%, versus 151 out of 1096, 13.8%). No relevant differences were detected when comparing adverse events in patients treated with clofazimine-containing regimens to those treated with clofazimine-free regimens. However, the incidence of side-effects was less than previously reported (gastro-intestinal complaints: 10.5%; hyper-pigmentation: 50.2%; neurological disturbances: 9-13%).

Clinical and therapeutic features of pulmonary nontuberculous mycobacterial disease, Brazil, 1993-2011.

To identify clinical and therapeutic features of pulmonary nontuberculous mycobacterial (PNTM) disease, we conducted a retrospective analysis of patients referred to the Brazilian reference center, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, who received a diagnosis of PNTM during 1993­2011 with at least 1 respiratory culture positive for NTM. Associated conditions included bronchiectasis (21.8%), chronic obstructive pulmonary disease (20.7%), cardiovascular disease (15.5%), AIDS (9.8%), diabetes (9.8%), and hepatitis C (4.6%).Two patients had Hansen disease; 1 had Marfan syndrome. Four mycobacterial species comprised 85.6% of NTM infections: Mycobacterium kansasii, 59 cases (33.9%); M. avium complex, 53 (30.4%); M. abscessus, 23 (13.2%); and M. fortuitum, 14 (8.0%). A total of 42 (24.1%) cases were associated with rapidly growing mycobacteria. In countries with a high prevalence of tuberculosis, PNTM is likely misdiagnosed as tuberculosis, thus showing the need for improved capacity to diagnose mycobacterial disease as well as greater awareness of PNTM disease prevalence.

Integrated analysis of ethionamide resistance loci in Mycobacterium tuberculosis clinical isolates.

Tuberculosis patients taking second line drugs such as ethionamide (ETH) have often experienced previous treatment failure and usually have a complex history of disease and treatment that can span decades. Mutations in the ETH activating enzyme, EthA, confer resistance through undescribed mechanisms. To explore the impact of EthA mutations on ETH resistance, data from a total of 160 ETHR isolates was analysed. The most frequently mutated positions are within regions that display sequence conservation with the active site of OTEMO, another FAD-containing NADH-binding Baeyer-Villiger monooxygenase (BVMO), or with the sugar binding site of galectin-4N. Additionally, to look at a possible role of EthR on ETH resistance we purified an EthR mutant identified in a clinical isolate, F110L, and found it to bind the ethA-ethR intergenic region with higher affinity than the wild type regulator in gel shift assays. The ability of cyclic di-GMP to enhance DNA binding is maintained in the EthR mutant. To our knowledge, this is the first ETH resistance study that combines sequence and resistance data of clinical isolates with functional and structural information.