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 (<13 years) diagnosed with MDR TB between 2008-2010 in three South African provinces and assess factors associated with pre-treatment loss to follow-up. We matched laboratory and medical records at treatment facilities to identify pre-treatment loss and examined demographic and clinical characteristics for association with loss. Categorical variables were examined for association using Pearson's x2 or Fisher's exact test, employing Bonferroni correction for multiple pairwise comparisons. Between 2008-2010, 156 children were diagnosed with laboratory-confirmed MDR TB. Only 44% (n = 69) were documented as having received treatment. Young children (<2 years) (47/59, 80%), children with extrapulmonary (EP) TB (27/34, 79%), and children diagnosed at general hospitals (60/97, 62%) were most likely to be lost before treatment. Children most vulnerable to death from TB are most likely to be lost before treatment, possibly leading to underestimates of disease burden, case notifications, and poor outcomes among this population. Point-of-care diagnosis and robust follow-up may reduce pre-treatment loss in this population.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (-0.20, -0.23 to -0.16), levofloxacin (-0.06, -0.09 to -0.04), moxifloxacin (-0.07, -0.10 to -0.04), or bedaquiline (-0.14, -0.19 to -0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I(2) method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

OBJECTIVE: To describe outcomes of HIV-infected pediatric patients with drug-resistant tuberculosis (DR TB). METHODS: Demographic, clinical, and laboratory data from pediatric patient charts treated for DR TB during 2005-2008 were collected retrospectively from five MDR TB hospitals in South Africa. Data were summarized and Pearson's chi-squared test or Fisher's exact test were used to assess differences in variables of interest by HIV status. A time-to-event analysis was conducted using days from start of treatment to death. Variables of interest were first assessed using the Kaplan-Meier method. Cox proportional hazard models were fit to estimate crude and adjusted hazard ratios. RESULTS: Of 423 eligible participants, 398 (95%) had culture-confirmed DR-TB and 238 (56%) were HIV-infected. A total of 54% were underweight, 42% were male and median age was 10.7 years (IQR: 5.5-15.3). Of the 423 participants, 245 (58%) were successfully treated, 69 (16%) died, treatment failed in 3 (1%), 36 (9%) were lost to follow-up, and 70 (17%) were still on treatment, transferred or had unknown outcomes. Time to death differed by HIV status (p=0.008), sex (p<0.001), year of TB diagnosis (p=0.05) and weight status (p=0.002). Over the two-year risk period, the adjusted rate of death was 2-fold higher among participants with HIV compared to HIV-negative participants (aHR=2.28; 95% CI: 1.11, 4.68). CONCLUSIONS: Male, underweight, and HIV-infected children with DR TB were more likely to experience death when compared to other children with DR TB within this study population.

Background: Multidrug-resistant tuberculosis (MDR TB) is an important global public health threat, but accurate estimates of MDR TB burden among children are lacking. Methods: We analyzed demographic, clinical and laboratory data for newly-diagnosed pediatric (<15 years) TB cases reported to the US National TB Surveillance System (NTSS) during 1993-2014. MDR TB was defined as culture-confirmed TB disease with resistance to at least isoniazid and rifampicin. To ascertain potential under-estimation of pediatric MDR TB, we surveyed high burden states for clinically-diagnosed cases treated for MDR TB. Results: Of 20,789 pediatric TB cases, 5,162 (24.8%) had bacteriologically-confirmed TB. Among 4,862 (94.2%) with drug-susceptibility testing, 82 (1.7%) had MDR TB. Most pediatric MDR TB cases were female (n=51, 62%), median age was 5 years (IQR 1-12), one-third were Hispanic (n=28, 34%), and two-thirds (n=55, 67%) were born in the US. Most cases had additional resistance to ≥1 other first-line drug (n=66; 80.5%) and one-third had resistance to ≥1 second-line drug (24/73 tested). Of 77 who started treatment prior to 2013, 66 (86%) completed treatment and 4 (5%) died. Among the four high TB burden states/jurisdictions surveyed, there was 42-55% under-estimation of pediatric MDR TB cases when using only culture-confirmed case definitions. Conclusions: Only one-quarter of pediatric TB cases had culture-confirmed TB, likely resulting in underestimation of true pediatric MDR TB burden in the US using strictly bacteriologic criteria. Better estimates of pediatric MDR TB burden in the US are needed and should include clinical diagnoses based on epidemiologic criteria.

BACKGROUND: Resistance to second-line drugs (SLD) develops during treatment of multidrug-resistant (MDR) tuberculosis (TB), but the impact on treatment outcome has not been determined. OBJECTIVES: To determine the relationship with treatment outcomes of (1) initial versus acquired drug resistance and (2) treatment regimens. METHODS: MDR-TB patients starting SLD 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 injectables (SLI), and (2) treatment regimens. RESULTS: Of 1,244 MDR-TB patients, 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-TB, 69.7% with initial resistance to either a fluoroquinolone or SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial XDR-TB, and 13.0% with acquired XDR-TB (P<0.0001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of proven effective drugs increased from ≤1 to ≥5 (P<0.0001 for trend); while acquired drug resistance decreased from 12%-16% range, depending on the drug, down to 0%-2% (P<0.0001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (CL 0.56,0.69) 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. CONCLUSION: 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.

Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005-2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received <3 effective drugs than among patients who received >3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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 p<0.0001). 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. INTERPRETATION: 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. FUNDING: 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.

INTRODUCTION: Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis (TB) is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance. SUBJECTS AND METHODS: To assess the GLC's impact, we followed adults with pulmonary MDRTB from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLD) in nine countries that volunteered to participate, five countries that met GLC criteria and four countries that did not apply to the GLC. RESULTS: In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) TB, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLI). The relative risk (95% confidence interval) of acquired resistance was lower at GLC-approved sites: 0.27 (0.16,0.47) for XDRTB, 0.28 (0.17,0.45) for FQ, and 0.15 (0.06,0.39) to 0.60 (0.34,1.05) for three different SLI. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios were 0.21 (0.07,0.62) for acquired XDRTB and 0.23 (0.09,0.59) for acquired FQ resistance. CONCLUSIONS: Treatment of MDRTB involves substantial risk of acquired resistance to SLD, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Following the World Health Organization's endorsement of the Xpert((R)) MTB/RIF assay, which rapidly and simultaneously diagnoses tuberculosis (TB) and detects resistance to rifampin (RMP), the question arises to what extent RMP resistance is an adequate marker for multidrug-resistant TB (MDR-TB). A retrospective analysis of data from >81 countries and subnational settings demonstrated that >40% of RMP-resistant isolates from new TB cases did not display resistance to isoniazid (INH) in settings with relatively low MDR-TB prevalence (one third of all countries and subnational settings). Results indicated the need for INH susceptibility testing in addition to RMP susceptibility testing.