BACKGROUNDCohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODSWe conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTSOf 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group -a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], −7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, −10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONSIn persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.

SummaryBackground Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.

Background-Nosocomial transmission has been described in extensively drug resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about rates of drug-resistant TB among healthcare workers (HCWs) in TB and HIV endemic settings.

The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

Setting KwaZulu-Natal, South Africa a predominantly rural province with high burdens of TB, MDR-TB and HIV infection. Objective To determine the most effective model of care by comparing MDR-TB treatment outcomes at community-based sites with traditional care at a central, specialised hospital. Design A non-randomised observational prospective cohort study comparing community-based and centralised care. Patients at community-based sites were closer to home, had easier access to care and home-based care was available from treatment initiation. Results Four community-based sites treated 736 patients, while 813 were treated at the centralised hospital (a total of 1549 patients). Overall, 75% were HIV co-infected (community: 76% vs. hospitalised: 73%, p=0.45) and 86% received antiretroviral therapy (community: 91% vs. hospitalised: 82%, p=0.22). In multivariate analysis MDR-TB patients were more likely to have a successful treatment outcome if they were treated at a community-based site (adjusted OR=1.43, p=0.01). However, there was heterogeneity in outcomes at the four community-based sites, with Site 1 demonstrating that home-based care was associated with increased treatment success of 72% compared with success of between 52 - 60% at the other three sites. Conclusion Community-based care for patients with MDR-TB was more effective than care in a central, specialised hospital. Home-based care further increased treatment success.