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To determine the levels and patterns of resistance to first- and second-line anti-tuberculosis (TB) drugs among new and previously treated sputum smear positive pulmonary TB (PTB) patients.We conducted a nationally representative cross-sectional facility-based survey in June 2017-July 2018 involving 45 clusters selected based on probability proportional to size. The survey aimed to determine the prevalence of anti-TB drug resistance and associated risk factors among smear positive PTB patients in Tanzania. Sputum samples were examined using smear microscopy, Xpert MTB/RIF, culture and drug susceptibility testing (DST). Logistic regression was used to account for missing data and sampling design effects on the estimates and their standard errors.We enrolled 1557 TB patients, including 1408 (90.4%) newly diagnosed and 149 (9.6%) previously treated patients. The prevalence of multidrug-resistant TB (MDR-TB) was 0.85% [95% confidence interval (CI): 0.4-1.3] among new cases and 4.6% (95% CI: 1.1-8.2) among previously treated cases. The prevalence of Mycobacterium tuberculosis strains resistant to any of the four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) was 1.7% among new TB patients and 6.5% among those previously treated. Drug resistance to all first-line drugs was similar (0.1%) in new and previously treated patients. None of the isolates displayed poly-resistance or extensively drug-resistant TB (XDR-TB). The only risk factor for MDR-TB was history of previous TB treatment (odds ratio = 5.7, 95% CI: 1.9-17.2).The burden of MDR-TB in the country was relatively low with no evidence of XDR-TB. Given the overall small number of MDR-TB cases in this survey, it will be beneficial focusing efforts on intensified case detection including universal DST.

Background The main advantage of GeneXpert MTB/RIF® (Xpert) molecular diagnostic technology is the rapid detection of M.tuberculosis DNA and mutations associated with rifampicin (RIF) resistance for timely initiation of appropriate treatment and, consequently, preventing further transmission of the disease. We assessed time to treatment initiation and treatment outcomes of RIF-resistant and RIF-susceptible TB patients diagnosed and treated in Vladimir TB Dispensary, Russia in 2012, before and after implementation of GeneXpert MTB/RIF® diagnostic technology. Methods All adult patients suspected of having TB during February–December 2012 underwent a clinical examination, chest x-ray, microscopy, culture, and phenotypic drug susceptibility testing (DST). Starting August 2012 Xpert diagnostic technology became available in the facility. We used logistic regression to compare treatment outcomes in pre-Xpert and post-Xpert periods. Kaplan-Meier curves and log-rank test were used to compare the time to treatment initiation between the groups. Results Of 402 patients screened for TB during February–December 2012, 338 were diagnosed with TB (280 RIF-susceptible, 58 RIF-resistant). RIF-resistant patients in the post-Xpert group started treatment with second-line drugs (SLD) earlier than those in pre-Xpert group (median 11 vs. 37 days, Log-rank p = 0.02). The hazard ratio for time to SLD treatment initiation was significantly higher in post-Xpert group (HR:2.06; 95%CI:1.09,3.89) compared to pre-Xpert group. Among the 53/58 RIF-resistant TB patients with available treatment outcome, 28 (53%) had successful outcomes (cured/completed treatment) including 15/26 (58%) in post-Xpert group versus 13/27 (48%) in pre-Xpert group. The observed difference, however, was not statistically significant (OR:0.69; 95%CI:0.23,2.06). Among RIF-susceptible TB cases time to treatment initiation was not significantly different between the groups (2 vs. 3 days, Log-rank p = 0.73). Of 252/280 RIF-susceptible TB cases with treatment outcome, 199 (79%) cases had successful outcome including 94/114 (82%) in post-Xpert group versus 105/138 (76%) in pre-Xpert group (OR:0.68; 95%CI:0.36,1.26). Conclusion We observed that availability of Xpert for initial diagnosis significantly reduced the time to SLD treatment for RIF-resistant patients in the Vladimir TB Dispensary. Although implementation of rapid diagnostics did not improve treatment outcomes, early diagnosis of MDR-TB is important for selection of appropriate treatment regimen and prevention of transmission of drug-resistant strains of TB.

Summary Background Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa. Methods We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa. Findings The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4–16·2) in India, 8·9% (4·5–11·7) in the Philippines, 32·5% (27·0–35·8) in Russia, and 5·7% (3·0–7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1–12·9) in India, 9·0% (4·0–14·7) in the Philippines, 9·0% (4·8–14·2) in Russia, and 8·5% (2·5–14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000–40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040. Interpretation MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis. Funding US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.

Current US guidelines recommend longer treatment for tuberculosis (TB) caused by pyrazinamide-resistant organisms (e.g., Mycobacterium bovis) than for M. tuberculosis TB. We compared treatment response times for patients with M. bovis TB and M. tuberculosis TB reported in the United States during 2006–2013. We included culture-positive, pulmonary TB patients with genotyping results who received standard 4-drug treatment at the time of diagnosis. Time to sputum-culture conversion was defined as time between treatment start date and date of first consistently culture-negative sputum. We analyzed 297 case-patients with M. bovis TB and 30,848 case-patients with M. tuberculosis TB. After 2 months of treatment, 71% of M. bovis and 65% of M. tuberculosis TB patients showed conversion of sputum cultures to negative. Likelihood of culture conversion was higher for M. bovis than for M. tuberculosis, even after controlling for treatment administration type, sex, and a composite indicator of bacillary burden.

Background Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics. Methods In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay. For specific mutations, we performed bivariate analysis to determine relative risk of baseline or acquired resistance to other TB drugs. We compared time to sputum culture conversion (TSCC) using Kaplan-Meier curves and stratified Cox regression. Results In total, 447 participants enrolled from January 2005 to December 2008 from 7 countries were included. Relative to rpoB S531L, isolates with rpoB D516V had less cross-resistance to rifabutin, increased baseline resistance to other drugs, and increased acquired fluoroquinolone resistance. Relative to mutation of katG only, mutation of inhA promoter and katG was associated with baseline extensively drug resistant (XDR) TB, increased acquired fluoroquinolone resistance, and slower TSCC (125.5 vs 89.0 days). Conclusions Specific mutations in inhA and katG are associated with differences in resistance to other drugs and TSCC. Molecular testing may make it possible to tailor treatment and assess additional drug resistance risk according to specific mutation profile.

Multidrug-resistant (MDR) TB is more difficult to diagnose and treat compared with drug-susceptible TB. Young children are at greater risk of severe TB disease and death when treatment is delayed compared to adults. We sought to describe characteristics of children (

Objective Drug-resistant tuberculosis (TB) threatens global TB control because it is difficult to diagnose and treat. Community-based programmatic management of drug-resistant TB (cPMDT) has made therapy easier for patients, but data on these models are scarce. Bangladesh initiated cPMDT in 2012, and in 2013, we sought to evaluate programme performance. Methods In this retrospective review, we abstracted demographic, clinical, microbiologic and treatment outcome data for all patients enrolled in the cPMDT programme over 6 months in three districts of Bangladesh. We interviewed a convenience sample of patients about their experience in the programme. Results Chart review was performed on 77 patients. Sputum smears and cultures were performed, on average, once every 1.35 and 1.36 months, respectively. Among 74 initially culture-positive patients, 70 (95%) converted their cultures and 69 (93%) patients converted the cultures before the sixth month. Fifty-two (68%) patients had evidence of screening for adverse events. We found written documentation of musculoskeletal complaints for 16 (21%) patients, gastrointestinal adverse events for 16 (21%), hearing loss for eight (10%) and psychiatric events for four (5%) patients; conversely, on interview of 60 patients, 55 (92%) reported musculoskeletal complaints, 54 (90%) reported nausea, 36 (60%) reported hearing loss, and 36 (60%) reported psychiatric disorders. Conclusions The cPMDT programme in Bangladesh appears to be programmatically feasible and clinically effective; however, inadequate monitoring of adverse events raises some concern. As the programme is brought to scale nationwide, renewed efforts at monitoring adverse events should be prioritised. Objectif La tuberculose (TB) resistante aux medicaments menace la lutte mondiale contre la TB, car il est difficile a diagnostiquer et a traiter. La prise en charge programmatique communautaire de la TB resistante aux medicaments (cPMDT) a rendu le traitement plus facile pour les patients, mais les donnees sur ces modeles sont rares. Le Bangladesh a lance la cPMDT en 2012 et en 2013 nous avons cherche a evaluer la performance du programme. Methodes Dans cette analyse retrospective, nous avons extrait les donnees demographiques, cliniques, microbiologiques et les resultats du traitement pour tous les patients inscrits au programme cPMDT depuis plus de six mois dans trois districts du Bangladesh. Nous avons interviewe un echantillon de convenance des patients sur leur experience dans le programme. Resultats L'analyse des dossiers a ete realisee pour 77 patients. Les frottis et cultures d'expectorations ont ete effectues en moyenne une fois tous les 1,35 et 1,36 mois, respectivement. Sur 74 patients initialement a culture positive, 70 (95%) ont vu leurs cultures converties et 69 (93%) ont vu leurs cultures converties avant le sixieme mois. Cinquante-deux (68%) patients avaient des donnees d'investigations pour des evenements indesirables. Nous avons trouve de la documentation ecrite sur des troubles musculosquelettiques pour 16 (21%), des evenements indesirables gastro-intestinaux pour 16 (21%), la perte auditive pour 8 (10%) et des evenements psychiatriques pour 4 (5%) patients. Cependant, dans les entretiens avec 60 patients, 55 (92%) ont declare des troubles musculosquelettiques, 54 (90%) des nausees, 36 (60%) une perte auditive et 36 (60%) des troubles psychiatriques. Conclusions Le programme cPMDT au Bangladesh semble etre realisable du point de vue programmatique et efficace cliniquement. Cependant, une surveillance insuffisante des evenements indesirables souleve des inquietudes. Comme le programme est etendu a l’echelle nationale, des efforts renouveles de suivi des evenements indesirables devraient etre mis en priorite. Objetivo La tuberculosis (TB) resistente a medicamentos pone en peligro el control global de la TB, puesto que es dificil de diagnosticar y de tratar. Los programas comunitarios de manejo de la TB resistente a medicamentos (cMTR) han facilitado el tratamiento para los pacientes, pero son escasos los datos que se tienen sobre este modelo. Bangladesh inicio un cMTR en el 2012 y en el 2013 evaluamos el desempeno del programa. Metodos En esta revision retrospectiva, sustrajimos datos demograficos, clinicos, microbiologicos y de resultados del tratamiento de todos los pacientes que participaron en el programa de cMTR, durante seis meses, en tres distritos de Bangladesh. Entrevistamos a una muestra conveniente de pacientes sobre su experiencia en el programa. Resultados Se realizo una revision de las historias clinicas de 77 pacientes. Se realizaron baciloscopias y cultivos, en promedio, una vez cada 1.35 y 1.36 meses, respectivamente. Entre los 74 pacientes con un cultivo positivo inicial, 70 (95%) tuvieron una conversion del cultivo y 69 (93%) pacientes tuvieron una conversion del cultivo antes de seis meses. Cincuenta y dos (68%) pacientes tenian evidencia de cribado por eventos adversos. Encontramos documentacion escrita de quejas por trastornos musculoesqueleticos en 16 (21%) pacientes, eventos adversos gastrointestinales en 16 (21%), perdida de la audicion en ocho (10%) y eventos psiquiatrico en cuatro (5%) pacientes. Por otro lado, al entrevistar a 60 pacientes, 55 (92%) reportaron trastornos musculoesqueleticos, 54 (90%) reportaron nauseas, 36 (60%) reportaron perdida de la audicion y 36 (60%) reportaron desordenes psiquiatricos. Conclusiones El programa cMTR en Bangladesh parece ser factible y clinicamente efectivo. Sin embargo, la monitorizacion inadecuada de efectos adversos es preocupante. A medida que el programa se amplie a nivel nacional, se deberia priorizar el incrementar esfuerzos en la monitorizacion de los eventos adversos.

We studied the epidemiology of drug-resistant tuberculosis (TB) in Vladimir Region, Russia, in 2012. Most cases of multidrug-resistant TB (MDR TB) were caused by transmission of drug-resistant strains, and >33% were in patients referred for testing after mass radiographic screening. Early diagnosis of drug resistance is essential for preventing transmission of MDR TB.

SOUTH AFRICA has one of the highest burdens of multidrug-resistant tuberculosis (MDR-TB; defined as TB with resistance to isoniazid [INH] and rifampin [RMP]) in the world, with 15 419 laboratory-confirmed MDR-TB cases in 2012.1 The World Health Organization (WHO) estimates that 1.8% of new cases and 6.7% of retreatment cases among adults in South Africa are MDR-TB.2 No routine surveillance data on MDR-TB among children are available globally or in South Africa. However, the proportion of MDR-TB among new and retreatment cases is believed to be similar among both adults and children in most countries, based on several mathematical models.1,3,4 In some settings, including South Africa, infants and young children may be at higher risk for MDR-TB than adults.4,5 Estimates of pediatric TB and drug-resistant TB (DR-TB; TB with resistance to any anti-tuberculosis drug) rely on limited data because TB surveillance has historically focused on sputum smear-positive disease and laboratory- confirmed drug resistance, which are much less common in children, who often have difficulty producing sputum and tend to have paucibacillary disease.4–6 The presence of drug resistance or human immunodeficiency virus (HIV) infection compounds diagnostic and treatment challenges in children.7–10 Such challenges are of concern, as infants and young children, especially those with HIV infection, are more likely than adults to progress rapidly from infection to disease and develop more severe forms of TB, such as TB meningitis.7,10–12 The few published reports that describe the epidemiology of pediatric DR-TB have been limited to small case series or cohorts in academic centers. A recent meta-analysis highlighted variations in treatment practices, time to treatment (from 2 days to 46 months), length of treatment (6–34 months), and severity of disease among children, but reported a relatively uniform treatment success rate of 80%.8,13 Studies from major academic centers in Johannesburg and the Western Cape Province provide the most comprehensive description of DR-TB among children in South Africa. In the Western Cape, results from surveys over a 17-year period showed DR-TB and MDR-TB among children with culture-confirmed TB reaching its peak during our study period, at 15.4% and 8.9%, respectively.14–16 In Johannesburg in 2008, 9% of children with a recorded drug susceptibility test (DST) result had MDR-TB.17 Treatment outcomes varied, with higher levels of mortality (31%) among children in Johannesburg than in Western Cape (12%).13,17 A better understanding of the epidemiology of DR-TB in children and adolescents across South Africa can inform whether programmatic and clinical practices meet the needs of children and adolescents. To that end, we reviewed the records of children and adolescents with DR-TB in four provinces in South Africa to describe the clinical features, management, and outcomes of DR-TB among this vulnerable population.

Less toxic and less expensive drugs and shorter treatment regimens are needed., Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5–6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2–4) drugs; 26% retained susceptibility to

Background The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse. Methods We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively. Results The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug. Conclusions Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.

Alternatives to culture are needed in high burden countries to assess whether response to treatment of multidrug-resistant-tuberculosis (MDR-TB) is satisfactory. The objective was to assess the association of weight gain and treatment outcome. The methods included analysis of clinical, bacteriologic, and weight from 439 MDR-TB patients in the Philippines. Odds ratios (ORs) were calculated to determine whether 5% weight gain during the first 6 months of treatment was associated with outcome. Three hundred and ten (71%) patients were cured and 129 (29%) had poor outcomes (death, defaulted, or failed treatment). Fifty-three percent were underweight (body mass index [BMI] < 18.5 kg/m(2)) before treatment. Five percent weight gain after completing 3 months of treatment was associated with good outcome among patients who were underweight before treatment (OR 2.1; 95% confidence interval [CI], 1.05 to 4.4). Baseline weight and degree of weight change during the first 6 months of treatment can help identify persons who are more likely to have poor outcomes and require other interventions.

The purpose of this study was to assess the performance of Cepheid® Xpert MTB/RIF® ("Xpert") and TB-Biochip® MDR ("TB-Biochip"). Sputum specimens from adults with presumptive tuberculosis (TB) were homogenized and split for: (1) direct Xpert and microscopy, and (2) concentration for Xpert, microscopy, culture [Lowenstein-Jensen (LJ) solid media and Mycobacteria Growth Indicator Tube® (MGIT)], indirect drug susceptibility testing (DST) using the absolute concentration method and MGIT, and TB-Biochip. In total, 109 of 238 (45.8 %) specimens were culture-positive for Mycobacterium tuberculosis complex (MTBC), and, of these, 67 isolates were rifampicin resistant (RIF-R) by phenotypic DST and 64/67 (95.5 %) were isoniazid resistant (INH-R). Compared to culture of the same specimen, a single direct Xpert was more sensitive for detecting MTBC [95.3 %, 95 % confidence interval (CI), 90.0-98.3 %] than direct (59.6 %, 95 % CI, 50.2-68.5 %) or concentrated smear (85.3 %, 95 % CI, 77.7-91.1 %) or LJ culture (80.8 %, 95 % CI, 72.4-87.5 %); the specificity was 86.0 % (95 % CI, 78.9-91.3 %). Compared with MGIT DST, Xpert correctly identified 98.2 % (95 % CI, 91.5-99.9 %) of RIF-R and 95.5 % (95 % CI, 85.8-99.2 %) of RIF-susceptible (RIF-S) specimens. In a subset of 104 specimens, the sensitivity of TB-Biochip for MTBC detection compared to culture was 97.3 % (95 % CI, 91.0-99.5 %); the specificity was 78.1 % (95 % CI, 61.5-89.9 %). TB-Biochip correctly identified 100 % (95 % CI, 94.2-100 %) of RIF-R, 94.7 % (95 % CI, 76.7-99.7 %) of RIF-S, 98.2 % (95 % CI, 91.4-99.9 %) of INH-R, and 78.6 % (95 % CI, 52.1-94.2 %) of INH-S specimens compared to MGIT DST. Xpert and Biochip were similar in accuracy for detecting MTBC and RIF resistance compared to conventional culture methods.

SETTING Programmatic implementation of decentralized rapid drug susceptibility testing (DST) in Lima, Peru. OBJECTIVE Pre-post analysis compared time to diagnosis, treatment outcome and survival among patients tested with direct nitrate reductase assay (NRA) vs. indirect conventional methods. DESIGN From 2005 to 2009, we prospectively followed all patients referred for DST before (control) and after (intervention) NRA implementation. Among those referred for DST, NRA was used for smear-positive samples of patients with no prior history of multidrug resistance or treatment for multidrug-resistant tuberculosis (TB). Data were abstracted from patient charts and laboratory registers. Endpoints were favorable outcomes, time to result and time to death. RESULTS Of those patients who met the criteria for NRA, 740 underwent NRA and 621 underwent conventional DST. NRA yielded test results for 78.4% of cases vs. 68.8% for conventional DST (P < 0.0001); the median time to result was 44 vs. 133 days, respectively (adjusted HR 0.64, 95%CI 0.56-0.73). Among individuals without previous anti-tuberculosis treatment, NRA was associated with a favorable treatment outcome (adjusted OR 1.39, 95%CI 1.01-1.90) and prolonged survival (adjusted HR 0.53, 95%CI 0.31-0.90). CONCLUSION Direct NRA significantly shortened time to test result and improved treatment outcomes and survival in certain groups.

Summary Background The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. Methods From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. Findings Among 1278 patients, 43·7% showed resistance to at least one second-line drug, 20·0% to at least one second-line injectable drug, and 12·9% to at least one fluoroquinolone. 6·7% of patients had XDR tuberculosis (range across study sites 0·8–15·2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. Interpretation Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. Funding US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare.

Background. Acquired resistance to second-line drugs (SLDs) is a problem in treating patients with drug-resistant tuberculosis worldwide. The objectives of this study were to identify risk factors for acquired resistance (AR) to injectable SLDs (INJ SLDs) and fluoroquinolones in the US National tuberculosis Surveillance System, 1993–2008. Methods. We selected cases for which the initial and final drug susceptibility test (DST) results had been reported. We defined AR as resistance at the final DST but susceptibility to the same drug at the initial DST. We analyzed AR using 2-way frequency tables and multivariable logistic regression. Results. The baseline prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis was 12.6% (1864/14770) and 0.38% (56/14770), respectively. Of 2274 individuals without initial resistance to INJ SLDs, 49 (2.2%) acquired resistance. Of 1141 initially susceptible to fluoroquinolones, 32 (2.8%) acquired resistance. The AR to INJ SLDs was associated with age group 25–44 years (adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2–6.3), positive HIV (human immunodeficiency virus) status (aOR, 2.5; 95% CI, 1.3–4.7), MDR at treatment initiation (aOR, 5.5; 95% CI, 2.9–10.5), and treatment with any SLD (aOR, 2.4; 95% CI,1.2–4.7). The AR to fluoroquinolones was associated with MDR tuberculosis at treatment initiation (aOR, 6.5; 95% CI, 2.9–14.6). Conclusions. Among patients with initial and final DST reported, the risk factors for AR to INJ SLDs included age, positive HIV status, MDR tuberculosis and initial treatment with any SLD, while the only predictor for AR to fluoroquinolones was MDR tuberculosis at treatment initiation. Providers should consider monitoring SLD DST for MDR tuberculosis patients in the indicated subgroups. Antituberculosis drug resistance is a major public health problem around the world. The World Health Organization (WHO) estimates the global burden of multidrug-resistant (MDR) tuberculosis, defined as tuberculosis resistant to at least isoniazid and rifampicin, at approximately 650 000 cases in 2011 [1].

BackgroundReliable estimates of the burden of multidrug-resistant tuberculosis (MDR-TB) are crucial for effective control and prevention of tuberculosis (TB). Papua New Guinea (PNG) is a high TB burden country with limited information on the magnitude of the MDR-TB problem.MethodsA cross-sectional study was conducted in four PNG provinces: Madang, Morobe, National Capital District and Western Province. Patient sputum samples were tested for rifampicin resistance by the Xpert MTB/RIF assay and those showing the presence of resistance underwent phenotypic susceptibility testing to first- and second-line anti-TB drugs including streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide, ofloxacin, amikacin, kanamycin and capreomycin.ResultsAmong 1,182 TB patients enrolled in the study, MDR-TB was detected in 20 new (2.7%; 95% confidence intervals [CI] 1.1-4.3%) and 24 previously treated (19.1%; 95%CI: 8.5-29.8%) TB cases. No case of extensively drug-resistant TB (XDR-TB) was detected. Thirty percent (6/20) of new and 33.3% (8/24) of previously treated cases with MDR-TB were detected in a single cluster in Western Province.ConclusionIn PNG the proportion of MDR-TB in new cases is slightly lower than the regional average of 4.4% (95%CI: 2.6-6.3%). A large proportion of MDR-TB cases were identified from a single hospital in Western Province, suggesting that the prevalence of MDR-TB across the country is heterogeneous. Future surveys should further explore this finding. The survey also helped strengthening the use of smear microscopy and Xpert MTB/RIF testing as diagnostic tools for TB in the country.

BACKGROUND Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

(See the Editorial Commentary by Daley and Horsburgh on pages 1064–5.) Microbial drug resistance has become a major public health concern worldwide. In the case of tuberculosis, the first global drug resistance survey, published in 1997, reported multidrug-resistant (MDR) tuberculosis (ie, resistant to at least isoniazid and rifampicin) in virtually every participating country [1]. Shortly thereafter, the World Health Organization (WHO) and many other partners launched the DOTS (directly observed treatment, short course)–Plus initiative for the programmatic management of MDR tuberculosis in middle- and low-income countries [2–4] because only a small fraction of MDR tuberculosis cases were diagnosed and treated worldwide [5]. Initially, this initiative focused on the availability, affordability, quality, and control of second-line drugs (SLDs) needed to treat MDR tuberculosis [6]. To the extent that the level of MDR tuberculosis in a country was a barometer for the strength of its basic tuberculosis control program, the partners recognized the risk of generating more highly drug-resistant tuberculosis [4]. Suddenly providing access to relatively obscure and toxic SLDs for treatment of MDR tuberculosis would likely lead to the development of widespread resistance to these same drugs. Indeed, in 2010, WHO estimated that 94 000 of 440 000 (21.4%) MDR tuberculosis cases worldwide may be the consequence of recently acquired resistance [5]. Therefore, WHO and its partners planned to introduce second-line treatment for MDR tuberculosis through an expanding series of pilot and demonstration projects [3, 4, 7]. These projects had to meet specific criteria that were developed to maximize cure rates and minimize the extent to which further drug resistance would develop [7, 8]. These criteria included, as examples, robust political commitment and leadership, a strong basic DOTS program, documented proficiency in phenotypic drug susceptibility testing (DST), strong individualized treatment regimens, 100% direct observation of MDR tuberculosis treatment, assiduous management of drug toxicities, and operational infection control measures. To increase access to SLDs and make them affordable, the Green Light Committee (GLC) established a pooled procurement mechanism consolidating demand into larger, more frequent, more predictable purchases [5, 6]. In turn, major pharmaceutical manufacturers offered 60%–90% price reductions for their brands of quality-assured antituberculosis drugs [6, 7, 9, 10]. Projects procured drugs through this mechanism. To prevent acquired resistance, self-selected programs in middle- and low-income countries applied to the GLC, which evaluated, assisted, approved, and monitored applicants. To evaluate whether programs met the criteria for access to SLDs, the GLC ensured that applicants (1) had strong basic DOTS programs and (2) met the criteria established by WHO's Scientific Panel on MDR Tuberculosis [7, 8]. Under these circumstances, the programs would be granted access to procure high-quality, reduced-price SLDs. From 1 January 2000 to 30 June 2011, the GLC approved 138 projects in 90 countries, representing 131 262 patients with MDR tuberculosis [11]. The GLC Secretariat tracked the procurement, distribution, and utilization of drugs, but there was no built-in mechanism to track acquired SLD resistance. To determine whether this GLC process, in the broad sense, could potentially reduce the frequency of acquired drug resistance, we launched the Preserving Effective TB Treatment Study (PETTS) to quantify the emergence of further resistance to SLD in GLC-approved MDR tuberculosis treatment programs, compared concurrently with non-GLC programs in 2 middle-income and 2 high-income countries.

Setting Drug resistance is an increasing threat to tuberculosis (TB) control worldwide. The World Health Organization advises monitoring for drug resistance, with either ongoing surveillance or periodic surveys. Methods The antituberculosis drug resistance survey was conducted in Lesotho in 2008-2009. Basic demographic and TB history information was collected from individuals with positive sputum smear results at 17 diagnostic facilities. Additional sputum sample was sent to the national TB reference laboratory for culture and drug susceptibility testing. Results Among 3441 eligible smear-positive persons, 1121 (32.6%) were not requested to submit sputum for culture. Among 2320 persons submitted sputum, 1164 (50.2%) were not asked for clinical information or did not have valid sputum samples for testing. In addition, 445/2320 (19.2%) were excluded from analysis because of other laboratory or data management reasons. Among 984/3441 (28.6%) persons who had data available for analysis, MDR-TB was present in 24/773 (3.1%) of new and 25/195 (12.8%) of retreatment TB cases. Logistical, operational and data management challenges affected survey results. Conclusion MDR-TB is prevalent in Lesotho, but limitations reduced the reliability of our findings. Multiple lessons learned during this survey can be applied to improve the next drug resistance survey in Lesotho and other resource constrained countries may learn how to avoid these bottlenecks.

Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis.We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling.We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment.Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis.US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.

Setting. Standardised tuberculosis (TB) treatment through directly observed therapy (DOT) is available in South Africa, but the level of adherence to standardised TB treatment and its impact on treatment outcomes is unknown. Objectives. To describe adherence to standardised TB treatment and provision of DOT, and analyse its impact on treatment outcome. Methods. We utilised data collected for an evaluation of the South African national TB surveillance system. A treatment regimen was considered appropriate if based on national treatment guidelines. Multivariate log-binomial regression was used to evaluate the association between treatment regimens, including DOT provision, and treatment outcome. Results. Of 1 339 TB cases in the parent evaluation, 598 (44.7%) were excluded from analysis owing to missing outcome or treatment information. The majority (697, 94.1%) of the remaining 741 patients received an appropriate TB regimen. Almost all patients (717, 96.8%) received DOT, 443 (59.8%) throughout the treatment course and 274 (37.0%) during the intensive (256, 34.6%) or continuation (18, 2.4%) phase. Independent predictors of poor outcome were partial DOT (adjusted risk ratio (aRR) 3.1, 95% confidence interval (CI) 2.2 - 4.3) and previous treatment default (aRR 2.3, 95% CI 1.1 - 4.8). Conclusion . Patients who received incomplete DOT or had a history of defaulting from TB treatment had an increased risk of poor outcomes.

Background For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen. Methods and Findings We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph. In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen). The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial sputum culture conversion, not reversion or long-term relapse. Conclusions MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens., In this prospective cohort study, Courtney Yuen and colleagues examine the association between regimen composition and treatment response in patients with multidrug-resistant tuberculosis., Editors' Summary Background Tuberculosis (TB)—a contagious bacterial disease that usually infects the lungs—is a global public health problem. The World Health Organization (WHO) estimates that, in 2014, about 9.6 million people developed TB and 1.5 million people died from the disease. Mycobacterium tuberculosis, the organism that causes TB, is spread in airborne droplets when people with TB cough. The symptoms of TB include persistent cough, fever, and weight loss; diagnostic tests for TB include the culture (growth) of M. tuberculosis from sputum samples (mucus coughed up from the lungs) and chest X-rays. TB can be cured by taking several antibiotics (including rifampicin and isoniazid) every day for six months. However, the emergence of multidrug-resistant tuberculosis (MDR TB; TB with resistance to at least both rifampicin and isoniazid) and extensively drug-resistant TB (MDR TB with additional resistance to at least quinolones and to second-line injectable antibiotics) is now threatening TB control efforts—about 5% of the cases of TB that occurred in 2014 were caused by MDR TB. Why Was This Study Done? WHO guidelines for the treatment of MDR TB recommend a regimen that includes pyrazinamide and at least four second-line drugs (amikacin or other second-line injectable drugs and fluoroquinolones such as ofloxacin) that are likely to be effective. When bacterial drug susceptibility testing (DST) is not available, determination of the likely effectiveness of drugs is based on patients’ previous exposure to antibiotics and the background drug resistance levels in the community. Although the guidelines state that regimens based on DST results are only marginally more effective than regimens determined without such results, recent evidence suggests that DST results predict regimen effectiveness and that regimens containing more drugs than currently recommended by the guidelines might be beneficial. Here, the researchers undertake a prospective cohort study (an observational study that compares outcomes in non-randomized groups of patients given different treatments) to gain insights into how regimen design affects treatment response among people with MDR TB. Specifically, the researchers analyze the association between both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen and the time to sputum culture conversion (the time between treatment initiation and having two consecutive negative sputum cultures). What Did the Researchers Do and Find? The researchers used a statistical approach called multivariable analysis to analyze data (including baseline DST results and information on the time to sputum culture conversion) collected from 1,137 adults with MDR TB who participated in the Preserving Effective Tuberculosis Treatment Study (PETTS). Receiving an average of at least six potentially effective drugs per day (drugs without a baseline DST result indicating resistance) was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day. Inclusion of more drugs to which baseline DST results indicated susceptibility was associated with a 65% higher likelihood of sputum culture conversion per drug, and inclusion of pyrazinamide was associated with a doubling of the likelihood of sputum culture conversion, Inclusion of more drugs to which baseline DST results indicated resistance was associated with only a 33% higher likelihood of sputum culture conversion per drug. Finally, inclusion of more drugs for which DST had not been performed was beneficial only if the regimen already contained a minimum of three likely effective drugs. What Do These Findings Mean? These findings suggest that regimens that include more potentially effective drugs than currently recommended by WHO might improve the response of patients with MDR TB to treatment. In addition, these findings suggest that rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. However, because this study was based on observational data, these findings do not prove that increasing the number of drugs in treatment regimens or basing drug choice on DST results improves outcomes. It is possible that all the patients who received a particular treatment shared an unknown, non-drug-related characteristic that was actually responsible for their response to treatment. Additionally, the authors were not able to assess the effects of individual drugs, and the analysis assumed equivalent efficacy for all drugs in a particular category, which may not be true in reality. The authors also did not have data on adherence or long-term follow-up to assess relapse or sputum culture reversion. Thus, although these findings suggest that changes to the current WHO guidelines for the treatment of MDR TB might be beneficial, randomized controlled trials should be undertaken first to confirm whether individualized regimens that include more than five drugs can achieve better cure rates than the currently recommended regimens. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001932. The World Health Organization (WHO) provides information (in several languages) on tuberculosis and on multidrug-resistant tuberculosis (in several languages); its Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update and the Global Tuberculosis Report 2015, which provides up-to-date information about tuberculosis around the world, are available The Stop TB Partnership is working towards tuberculosis elimination and provides personal stories about tuberculosis (in English and Spanish) The US Centers for Disease Control and Prevention provides information about tuberculosis and about drug-resistant tuberculosis (in English and Spanish), including a brief description of PETTS The US National Institute of Allergy and Infectious Diseases also has detailed information on tuberculosis, including a drug-resistant tuberculosis visual tour TB & Me, a collaborative blogging project run by patients being treated for MDR TB and Médecins Sans Frontières, provides more patient stories MedlinePlus has links to further information about tuberculosis (in English and Spanish)