BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons initiate treatment and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, six-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200 mg linezolid. After U.S. FDA approval in 2019, some U.S. clinicians rapidly implemented BPaL using an initial linezolid 600 mg dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from U.S. patients treated with BPaL between 10/14/2019 and 4/30/2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider-driven, and most had linezolid adjusted by therapeutic drug monitoring (TDM). RESULTS: Of 70 patients starting BPaL, two changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and two of these 68 (2.9%) patients relapsed after completion. Using an initial 600 mg linezolid dose daily adjusted by TDM and careful clinical and laboratory monitoring for side effects, supportive care, and expert consultation throughout BPaL treatment, three (4.4%) patients with hematologic toxicity and four (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in ATS/CDC/ERS/IDSA 2019 guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the U.S. is feasible.

SETTING: Mulago Hospital, Kampala, Uganda.OBJECTIVE: To quantify Mycobacterium tuberculosis in sputum during the first 8 weeks of pulmonary multidrug-resistant TB (MDR-TB) treatment.DESIGN: We enrolled consecutive adults with pulmonary MDR-TB treated according to national guidelines. We collected overnight sputum samples before treatment and weekly. Sputum samples were cultured on Middlebrook 7H11S agar to measure colony-forming units per mL (cfu/mL) and in MGIT™ 960™ media to measure time to detection (TTD). Linear mixed-effects regression was used to estimate the relational change in log(10) cfu/mL and TTD.RESULTS: Twelve adults (median age: 27 years) were enrolled. Half were women, and two-thirds were HIV-positive. At baseline, median log(10) cfu/mL was 5.1, decreasing by 0.29 log(10) cfu/mL/week. The median TTD was 116.5 h, increasing in TTD by 36.97 h/week. The weekly change was greater in the first 2 weeks (-1.04 log(10) cfu/mL/week and 120.02 h/week) than in the remaining 6 weeks (-0.17 log(10) cfu/mL/week and 26.11 h/week).CONCLUSION: Serial quantitative culture measures indicate a slow, uneven rate of decline in sputum M. tuberculosis over 8 weeks of standardized pulmonary MDR-TB treatment.

BACKGROUND: As new drugs are developed for multidrug-resistant tuberculosis (MDR-TB), the role of currently used drugs must be reevaluated. METHODS: We combined individual-level data on patients with pulmonary MDR-TB published during 2009-2016 from 25 countries. We compared patients receiving each of the injectable drugs and those receiving no injectable drugs. Analyses were based on patients whose isolates were susceptible to the drug they received. Using random-effects logistic regression with propensity score matching, we estimated the effect of each agent in terms of standardized treatment outcomes. RESULTS: More patients received kanamycin (n = 4330) and capreomycin (n = 2401) than amikacin (n = 2275) or streptomycin (n = 1554), opposite to their apparent effectiveness. Compared with kanamycin, amikacin was associated with 6 more cures per 100 patients (95% confidence interval [CI], 4-8), while streptomycin was associated with 7 (95% CI, 5-8) more cures and 5 (95% CI, 4-7) fewer deaths per 100 patients. Compared with capreomycin, amikacin was associated with 9 (95% CI, 6-11) more cures and 5 (95% CI, 2-8) fewer deaths per 100 patients, while streptomycin was associated with 10 (95% CI, 8-13) more cures and 10 (95% CI, 7-12) fewer deaths per 100 patients treated. In contrast to amikacin and streptomycin, patients treated with kanamycin or capreomycin did not fare better than patients treated with no injectable drugs. CONCLUSIONS: When aminoglycosides are used to treat MDR-TB and drug susceptibility test results support their use, streptomycin and amikacin, not kanamycin or capreomycin, are the drugs of choice.

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.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Setting: Tuberculosis (TB) treatment facilities in Haiti. Objective: To assess factors associated with loss to follow-up (LTFU) among patients receiving treatment for tuberculosis (TB) in Haiti. Design: We analyzed Haiti's national surveillance data for patients started on anti-tuberculosis treatment from 2011 to 2015 to determine factors associated with LTFU using multivariable logistic regression and describe LTFU in terms of subnational units to target future intervention strategies. We also conducted a survival analysis to estimate hazard ratios of factors associated with time to LTFU. Results: Of 81 490 TB cases reported, 7423 (9.1%) were LTFU during anti-tuberculosis treatment, increasing from 7.1% in 2011 to 10.3% in 2015. Six high-volume facilities had significantly higher rates of LTFU (14.3-31.9%) than the rest of the country, accounting for 18.8% of all TB cases reported, but 41.7% of all LTFU patients. Male sex, previous treatment history, and human immunodeficiency virus infection were associated with higher rates of LTFU. The median time to LTFU was 94 days. Conclusion: A small number of facilities accounted for disproportionately high rates of LTFU. These results identify characteristics of facilities and individuals leading to concentrated interventions to reduce LTFU and improve treatment success.

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.

Multidrug-resistant (MDR) tuberculosis (TB) emerged shortly after introduction of rifamycins in the 1960s; isoniazid resistance had already emerged by the mid-1950s. Without these two drugs, tuberculosis is very difficult and costly to treat, with unacceptably high rates of treatment failure, death, loss to follow-up, and no known preventive treatment. Global attention first focused on MDR TB in the early 1990s when nosocomial outbreaks with high case fatality rates were reported in many countries. Prevalence data for MDR TB on a global scale first became available in 1997. In 2016, about 4.1% of estimated ~10.4 million new TB patients plus 19% of ~1 million previously treated patients, that is ~600,000 people develop MDR TB or rifampicin resistant TB; 250,000 die annually. Ten years ago, <5% of them were diagnosed and enrolled on treatment, increasing to about 21.6% in 2016, leaving much room for improvement. Over that same period of time, momentum has been building to combat MDR TB, including advances in diagnostics, therapeutics, and care; decentralizing patient-centered care coupled with social support; growing improvements in prevention of transmission; increasing use of highly effective antiretroviral treatment; communications, advocacy, and social mobilization; leadership and updated policy guidance. Taking into account long-term epidemiological trends, all of these factors coupled with funding from the Global Fund and other major donors, suggest we may be on the verge of accelerating declines in MDR TB morbidity and mortality. Extreme poverty, which allows tuberculosis to flourish, has actually decreased by about one billion people over the past 25 years. What is needed now is political will on the part of national governments to apply these advances diligently and further reductions in poverty, pushing epidemiological trends past the inflection point to the downward slope. All these can be accelerated with increased support for science leading to better diagnosis, treatment and an effective vaccine to sustain and accelerate the meager declines reported thus far.

BACKGROUND: The well-documented association between underweight and increased incidence of active tuberculosis (TB) has not been extended to incidence or prevalence of latent tuberculous infection (LTBI). DESIGN: After identifying studies that reported a categorical measure of body mass index (BMI) and used the tuberculin skin test (TST) or QuantiFERON(R)-TB Gold In-Tube (QFT) to measure LTBI, a maximum likelihood random-effects model was used to examine the pooled association between LTBI and low BMI (<18.5 kg/m2), compared with 1) normal BMI (18.5-25 kg/m2) and 2) a complementary group of all others, i.e., non-underweight subjects (BMI >/=18.5 kg/m2). RESULTS: Among studies using TST, the odds ratios (ORs) showed a slight, non-statistically significant decrease in the odds of TST positivity in underweight persons compared with both groups (non-underweight, OR 0.88, 95%CI 0.73-1.05; normal weight, OR 0.96, 95%CI 0.77-1.20). Among studies using QFT, the OR suggested slightly decreased, yet non-significant, odds of QFT positivity in underweight compared with non-underweight subjects (OR 0.92, 95%CI 0.68-1.26), and significantly decreased odds of QFT positivity in underweight compared with normal weight subjects (OR 0.84, 95%CI 0.73-0.98). CONCLUSION: These results suggest that underweight persons are not at an increased risk of LTBI. Screening this population for LTBI would not increase the yield of identified LTBI.

We assessed characteristics associated with all-cause mortality among U.S. patients with multidrug-resistant tuberculosis. Mortality decreased from 31% during 1993-2002 to 11% during 2003-2013. Directly observed therapy coverage increased from 74% to 95% and was protective against all-cause mortality after accounting for demographics, clinical characteristics, HIV status, and period of treatment.

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.

We analyzed data for a retrospective cohort of patients treated for extensively drug-resistant tuberculosis in 2 provinces in South Africa and compared predictors of treatment outcome in HIV-positive patients who received or had not received antiretroviral drugs with those for HIV-negative patients. Overall, 220 (62.0%) of 355 patients were HIV positive. After 2 years, 34 (10.3%) of 330 patients with a known HIV status and known outcome had a favorable outcome. Multivariate analysis showed that predictors of favorable outcome were negative results for acid-fast bacilli by sputum microscopy at start of treatment and weight >50 kg. HIV-positive patients were more likely to have an unfavorable outcome. The strongest predictor of unfavorable outcome was weight <50 kg. Overall outcomes were poor. HIV status was not a predictor of favorable outcome, but HIV-positive patients were more likely to have an unfavorable outcome. These results underscore the need for timely and adequate treatment for tuberculosis and HIV infection.

Research has implicated low 25-hydroxyvitamin D (25(OH)D) level as a risk factor for infection; however, results have not been consistent. To further determine the nature of this relationship, we conducted a cohort study using Medicare beneficiaries participating in the 2001-2002 and 2003-2004 cycles of the National Health and Nutrition Examination Survey with data individually linked to hospital records from the Centers for Medicare and Medicaid Services. The primary exposure was a 25(OH)D level of <15 ng/mL versus ≥15 ng/mL. The outcomes were a hospitalization with or without an infection within 1 year of participation in the National Health and Nutrition Examination Survey, as determined from the final hospital discharge codes (International Classification of Diseases, Ninth Revision, Clinical Modification). Of 1,713 individuals, 348 had a baseline serum 25(OH)D level of <15 ng/mL, 77 experienced a hospitalization with an infection, and 287 experienced a hospitalization without an infection. In multivariable analyses, a serum 25(OH)D level of <15 ng/mL was associated with a higher risk of hospitalization with an infection (risk ratio = 2.8, 95% confidence interval: 1.3, 5.9, P < 0.01) but not of hospitalization without an infection (risk ratio = 1.4, 95% confidence interval: 0.9, 2.1, P = 0.1). In this study, we found an association between a serum 25(OH)D concentration of <15 ng/mL and a higher subsequent risk for hospitalization with an infection among Medicare beneficiaries.

BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis deaths have decreased worldwide over the past decade. We sought to evaluate the effect of HIV status on tuberculosis mortality among patients undergoing treatment for tuberculosis in Lima, Peru, a low HIV prevalence setting. METHODS: We conducted a prospective cohort study of patients treated for tuberculosis between 2005 and 2008 in two adjacent health regions in Lima, Peru (Lima Ciudad and Lima Este). We constructed a multivariate Cox proportional hazards model to evaluate the effect of HIV status on mortality during tuberculosis treatment. RESULTS: Of 1701 participants treated for tuberculosis, 136 (8.0 %) died during tuberculosis treatment. HIV-positive patients constituted 11.0 % of the cohort and contributed to 34.6 % of all deaths. HIV-positive patients were significantly more likely to die (25.1 vs. 5.9 %, P < 0.001) and less likely to be cured (28.3 vs. 39.4 %, P = 0.003). On multivariate analysis, positive HIV status (hazard ratio [HR] = 6.06; 95 % confidence interval [CI], 3.96-9.27), unemployment (HR = 2.24; 95 % CI, 1.55-3.25), and sputum acid-fast bacilli smear positivity (HR = 1.91; 95 % CI, 1.10-3.31) were significantly associated with a higher hazard of death. CONCLUSIONS: We demonstrate that positive HIV status was a strong predictor of mortality among patients treated for tuberculosis in the early years after Peru started providing free antiretroviral therapy. As HIV diagnosis and antiretroviral therapy provision are more widely implemented for tuberculosis patients in Peru, future operational research should document the changing profile of HIV-associated tuberculosis mortality.

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.

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.

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.

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 <2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens.

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.

We thank Metcalfe et al, Alffenaar et al, Soman et al, and Raoult for their interest in our study [1]. Metcalfe et al raise 2 issues about the analysis and reporting of results [2]. Alffenaar and colleagues raise issues related to drug dosing [3]. Soman and colleagues raise concern about standardized treatment regimens [4]. Raoult refers to the potential utility of existing drugs that are not standard antituberculosis drugs [5]. We respond to each of these letters in turn. | Metcalfe and colleagues suggest that patients who remain culture negative after 1 month of treatment could not have acquired drug resistance and therefore might have been included in the denominator when calculating the proportion of patients with acquired drug resistance [2]. However, the reality and the math are more complicated for at least 3 reasons. First, we disagree that the target population “is presented as all patients with MDR [multidrug-resistant] tuberculosis starting treatment with [second-line drugs].” The target population for this analysis was patients with at least one positive follow-up cultures as displayed in our Figure 1 [1]. Second, we described the excluded subset of patients as having no positive follow-up cultures rather than as having all negative follow-up cultures because these are not the same: 20.8% of the excluded group of patients did not complete treatment (ie, were classified as defaulting) after a median of <12 months (interquartile range, 5–16 months). Because “default” is a World Health Organization (WHO)–defined standard outcome category [6], it was the endpoint in our follow-up of these patients, and we cannot know whether these patients had any subsequent positive cultures. However, the duration of treatment for this group of patients is inadequate. These patients would be at high risk for again becoming culture positive and for acquired drug resistance. Third, many of these patients already had baseline resistance to fluoroquinolones, second-line injectable drugs, or both. It would not be appropriate to include them in the denominator when calculating the frequency of acquired resistance to these same drugs. The exact percentages are uncertain because we did not receive baseline cultures for all these patients and did not recover viable mycobacteria from all cultures received. However, of the 340 viable baseline isolates we received among patients with no positive follow-up cultures, 6.8% had fluoroquinolone resistance, 8.5% had resistance to 1 or more second-line injectable drugs, 11.8% had resistance to either, and 3.5% had resistance to both.

OBJECTIVE: To compare trends in direct annual risk of tuberculous infection (ARTI) during 1991-2005 in relation to tuberculosis (TB) incidence and to indirect estimates of ARTI derived from the prevalence of tuberculin skin test (TST) positivity in schoolchildren in Orel Oblast, Russia. DESIGN: In 2005, we abstracted annual TST results and vaccination histories from a representative sample of schoolchildren in Orel Oblast, Russia, where bacille Calmette-Guerin (BCG) vaccination and annual TST of children are nearly universal. We calculated direct ARTI based on the percentage of children tested with TST conversions each year, excluding conversions following BCG vaccination. RESULTS: We analysed records from 13 206 children, with a median of 10 recorded TST results per child. The ARTI increased from 0.2% in 1991 to 1.6% in 2000, paralleling trends in TB incidence. Similar results were observed when the ARTI was estimated based on prevalence of infection among children aged 3-5 years using a 12 mm cut-off to define TST positivity. Results differed substantially when 10 or 15 mm cut-offs were used or when prevalence was determined among children aged 6-8 years. CONCLUSION: ARTI measured through TST conversion increased as TB incidence increased in Orel Oblast. ARTI measured through serial TSTs can thus provide an indicator of changing trends in TB incidence.

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.

OBJECTIVES: We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. METHODS: In 1996, we mapped reported TB cases (1985-1995) and positive tuberculin skin test (TST) reactors (1993-1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. RESULTS: Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. CONCLUSIONS: Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States.

BACKGROUND: Resistance to second-line anti-tuberculosis drugs (SLD) severely compromises treatment options of drug-resistant tuberculosis (TB). We assessed the association between acquisition of resistance (AR) to second-line injectable drugs (SLI) or fluoroquinolones (FQ) and mortality among TB cases confirmed by positive culture results with available initial and final drug susceptibility test (DST) results. METHODS: We analyzed data from U.S. National TB Surveillance System, 1993-2008. Acquired resistance was defined as drug susceptibility at initial DST but resistance to the same drug at final DST. We compared survival with Kaplan-Meier curves and analyzed the association between AR and mortality using a univariate extended Cox proportional hazards model adjusted for age. RESULTS: Of 2,329 cases with both initial and final DST to SLI, 49 (2.1%) acquired resistance; 13/49 (26.5%) had treatment terminated by death versus 222 (10.0%) of those without AR to SLI (P<0.001). Of 1,187 cases with both initial and final DST to FQ, 32 (2.8%) acquired resistance; 12/32 (37.5%) had treatment terminated by death versus 121 (10.9%) of those without AR to FQ (P=0.001). Controlling for age, mortality was significantly greater among cases with AR to SLD than among cases without AR (adjusted hazard ratio (aHR)[SLI], 2.8; 95% confidence interval (CI),1.4-5.4; aHR[FQ], 1.9; 95% CI,1.0-3.5). MDR TB at treatment initiation, positive HIV status, and extrapulmonary disease were also significantly associated with mortality. CONCLUSION: Mortality was significantly greater among TB cases with AR to SLD. Providers should consider AR to SLD early in treatment, monitor DST results, and avoid premature deaths.

BACKGROUND: Development of resistance to antituberculosis drugs during treatment (i.e., acquired resistance) can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance. METHODS: We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004-2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins. RESULTS: M. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96-24.14) adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29-15.90) adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56-23.83). CONCLUSIONS: We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management.

The purpose of this study was to assess the performance of Cepheid(R) Xpert MTB/RIF(R) ("Xpert") and TB-Biochip(R) 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(R) (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.

BACKGROUND: Pyrazinamide (PZA) is essential in tuberculosis (TB) treatment. We describe the prevalence, trends and predictors of PZA resistance in Mycobacterium tuberculosis complex (MTBC) in the U.S. METHODS: We analyzed culture-positive MTBC cases with reported drug susceptibility tests (DST) for PZA in 38 jurisdictions routinely testing for PZA susceptibility from 1999-2009. National TB Genotyping Service data for 2004-2009 were used to distinguish Mycobacterium tuberculosis from Mycobacterium bovis and determine phylogenetic lineage. RESULTS: Overall 2.7% (2,167/79,321) of MTBC cases had PZA resistance, increasing annually from 2.0% to 3.3% during 1999-2009 (P<0.001), largely due to an increase in PZA monoresistance. PZA-monoresistant MTBC (versus drug-susceptible) was associated with age 0-24 years (adjusted prevalence ratio [aPR]=1.50, 95% CI 1.31-1.71), Hispanic ethnicity (aPR=3.52, 2.96-4.18), HIV infection (aPR=1.43, 1.15-1.77), extrapulmonary disease (aPR=3.02, 2.60-3.52), and normal chest radiograph (aPR=1.88, 1.63-2.16), and inversely associated with Asian (aPR=0.59, 0.47-0.73) and Black (aPR=0.37, 0.29-0.49) race. Among multidrug-resistant (MDR) cases 38.0% were PZA-resistant; PZA resistance in MDR MTBC was associated with female sex (aPR=1.25, 1.08-1.46) and previous TB diagnosis (aPR=1.37, 1.16-1.62). Of 28,080 cases with genotyping data, 925 (3.3%) had PZA resistance; 465/925 (50.3%) were M. bovis. In non-MDR M. tuberculosis cases, PZA resistance was higher in the Indo-Oceanic than the East Asian lineage (2.2% versus 0.9%; respectively; aPR=2.26, 1.53-3.36), but in MDR cases it was lower in the Indo-Oceanic lineage (22.0% versus 43.4%, respectively; aPR=0.54, 0.32-0.90). CONCLUSIONS: Specific human and mycobacterial characteristics were associated with pyrazinamide-resistant MTBC, reflecting both specific subgroups of the population and phylogenetic lineages of the mycobacteria.

OBJECTIVES: Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. METHODS: During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. RESULTS: Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5kg/m(2) (p<0.05). In patients without and with previous TB treatment, the prevalence of multidrug-resistant TB was 23% and 26%, respectively, among patients without diabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. CONCLUSIONS: Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome.

BACKGROUND: Foreign-born individuals comprise >50% of tuberculosis (TB) cases in the U.S. Since anti-TB drug resistance is more common in most other countries, when evaluating a foreign-born individual for TB, one must consider the risk of drug resistance. Naturally, clinicians query The Global Project on Anti-tuberculosis Drug Resistance Surveillance (Global DRS) which provides population-based data on the prevalence of anti-TB drug resistance in 127 countries starting in 1994. However, foreign-born persons in the U.S. are a biased sample of the population of their countries of origin, and Global DRS data may not accurately predict their risk of drug resistance. Since implementing drug resistance surveillance in 1993, the U.S. National TB Surveillance System (NTSS) has accumulated systematic data on over 130,000 foreign-born TB cases from more than 200 countries and territories. Our objective was to determine whether the prevalence of drug resistance among foreign-born TB cases correlates better with data from the Global DRS or with data on foreign-born TB cases in the NTSS. METHODS AND FINDINGS: We compared the prevalence of resistance to isoniazid and rifampin among foreign-born TB cases in the U.S., 2007-2009, with US NTSS data from 1993 to 2006 and with Global DRS data from 1994-2007 visually with scatterplots and statistically with correlation and linear regression analyses. Among foreign-born TB cases in the U.S., 2007-2009, the prevalence of isoniazid resistance and multidrug resistance (MDR, i.e. resistance to isoniazid and rifampin), correlated much better with 1993-2006 US surveillance data (isoniazid: r = 0.95, P<.001, MDR: r = 0.75, P<.001) than with Global DRS data, 1994-2007 (isoniazid: r = 0.55, P = .001; MDR: r = 0.50, P<.001). CONCLUSION: Since 1993, the US NTSS has accumulated sufficient data on foreign-born TB cases to estimate the risk of drug resistance among such individuals better than data from the Global DRS.