SummaryBackgroundPyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available.MethodsIn a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system.FindingsPyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0–42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0–16·6% for ofloxacin, to 0·5–12·4% for levofloxacin, and 0·9–14·6% for moxifloxacin when tested at 0·5 μg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 μg/mL was low in all countries.InterpretationAlthough pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19–63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness.FundingBill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Mycobacterium tuberculosis is a clonal pathogen proposed to have co-evolved with its human host for millennia, yet our understanding of its genomic diversity and biogeography remains incomplete. Here we use a combination of phylogenetics and dimensionality reduction to reevaluate the population structure of M. tuberculosis, providing an in-depth analysis of the ancient Indo-Oceanic Lineage 1 and the modern Central Asian Lineage 3, and expanding our understanding of Lineages 2 and 4. We assess sub-lineages using genomic sequences from 4939 pan-susceptible strains, and find 30 new genetically distinct clades that we validate in a dataset of 4645 independent isolates. We find a consistent geographically restricted or unrestricted pattern for 20 groups, including three groups of Lineage 1. The distribution of terminal branch lengths across the M. tuberculosis phylogeny supports the hypothesis of a higher transmissibility of Lineages 2 and 4, in comparison with Lineages 3 and 1, on a global scale. We define an expanded barcode of 95 single nucleotide substitutions that allows rapid identification of 69 M. tuberculosis sub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of the M. tuberculosis phylogeny and biogeography.

ObjectiveTo determine the risk factors for developing multidrug resistant tuberculosis in Bangladesh.MethodsThis case-control study was set in central, district and sub-district level hospitals of rural and urban Bangladesh. Included were 250 multidrug resistant tuberculosis (MDR-TB) patients as cases and 750 drug susceptible tuberculosis patients as controls. We recruited cases from all three government hospitals treating MDR-TB in Bangladesh during the study period. Controls were selected randomly from those local treatment units that had referred the cases. Information was collected through face-to-face interviews and record reviews. Unadjusted and multivariable logistic regression were used to analyse the data.ResultsPrevious treatment history was shown to be the major contributing factor to MDR-TB in univariate analysis. After adjusting for other factors in multivariable analysis, age group “18–25” (OR 1.77, CI 1.07–2.93) and “26–45” (OR 1.72, CI 1.12–2.66), some level of education (OR 1.94, CI 1.32–2.85), service and business as occupation (OR 2.88, CI 1.29–6.44; OR 3.71, CI 1.59–8.66, respectively), smoking history (OR 1.58, CI 0.99–2.5), and type 2 diabetes (OR 2.56 CI 1.51–4.34) were associated with MDR-TB. Previous treatment was not included in the multivariable analysis as it was correlated with multiple predictors.ConclusionPrevious tuberculosis treatment was found to be the major risk factor for MDR-TB. This study also identified age 18 to 45 years, some education up to secondary level, service and business as occupation, past smoking status, and type 2 diabetes as comorbid illness as risk factors. National Tuberculosis programme should address these risk factors in MDR-TB control strategy. The integration of MDR-TB control activities with diabetes and tobacco control programmes is needed in Bangladesh.

ObjectivesIn Bangladesh, private healthcare is common and popular, regardless of income or area of residence, making the private sector an important player in health service provision. Although the private sector offers a good range of health services, tuberculosis (TB) care in the private sector is poor. We conducted research in Dhaka, between 2004 and 2008, to develop and evaluate a public–private partnership (PPP) model to involve private medical practitioners (PMPs) within the National TB Control Programme (NTP)'s activities. Since 2008, this PPP model has been scaled up in two other big cities, Chittagong and Sylhet. This paper reports the results of this development, evaluation and scale-up.DesignMixed method, observational study design. We used NTP service statistics to compare the TB control outcomes between intervention and control areas. To capture detailed insights of PMPs and TB managers about the process and outcomes of the study, we conducted in-depth interviews, focus group discussions and workshops.SettingUrban setting, piloted in four areas in Dhaka city; later scaled up in other areas of Dhaka and in two major cities.FindingsThe partnership with PMPs yielded significantly increased case finding of sputum smear-positive TB cases. Between 2004 and 2010, 703 participating PMPs referred 3959 sputum smear-positive TB cases to the designated Directly Observed Treatment, Short-course (DOTS) centres, contributing about 36% of all TB cases in the project areas. There was a steady increase in case notification rates in the project areas following implementation of the partnership.ConclusionsThe PPP model was highly effective in improving access and quality of TB care in urban settings.