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Multidrug-resistant tuberculosis (MDR-TB) has historically required longer treatment regimens that were associated with higher unfavorable outcomes and side effects rates compared with drug susceptible TB (DS-TB). During the last decade, several studies conducted mostly in high-incidence settings have shown that MDR-TB can be successfully treated using all-oral shorter regimens of 6- to 9-month duration. In this article, we review the evolution of MDR-TB treatment from the early long regimens with injectables agents (IAs), followed by the shorter regimens with IA, to the groundbreaking, all-oral, 6- to 9-month regimens. Finally, we propose a framework for implementation of the shorter all-oral regimens in the United States.

Pulmonary infections are important causes of global morbidity and mortality, but diagnostics are often limited by the ability to collect specimens easily, safely, and in a cost-effective manner. We review recent advances in the collection of infectious aerosols from patients with TB and with influenza. Although this research has been focused on assessing the infectious potential of such patients, we propose that these methods have the potential to lead to the use of patient-generated microbial aerosols as noninvasive diagnostic tests of disease and tests of infectiousness.

Background: Undernutrition is the leading cause of tuberculosis (TB) in India and is associated with increased TB mortality. Independent of TB, undernutrition decreases quality of life and economic productivity. Material and Methods: We assessed the cost-effectiveness of providing augmented rations to undernourished Indians through the government’s Targeted Public Distribution System (TPDS) using Markov state transition models which simulated disease progression and mortality among undernourished individuals in three groups: general population, household contacts (HHCs) of people living with TB, and persons with HIV. The models calculate costs and outcomes (TB cases, TB deaths, and quality-adjusted life years, QALYs) associated with a 2600 KCal/day diet for adults with body mass index [BMI] of 16-18.4 kg/m2 until they attain a BMI of 20kg/m2 compared to a “do nothing” scenario wherein TPDS rations are unchanged. We employed deterministic and probabilistic sensitivity analyses to test result robustness. Results: Over 5 years, augmented rations could avert 78% of TB cases and 88% of TB deaths among currently undernourished Indians. Correspondingly, this intervention could forestall 78% and 43% of TB cases among undernourished HHCs and HIV positive persons and prevent 88% and 68% of deaths, respectively. Augmented rations resulted in ten-fold higher resolution of undernutrition. Augmented rations were highly cost-effective (incremental cost effectiveness ratio (ICER): $460/QALY). ICER was lower for HHCs ($437/QALY) and the HIV population ($407/QALY). QALYs gained from improving nutritional status eclipsed those from preventing TB. Conclusions: A robust nutritional intervention would be highly cost-effective in reducing TB incidence and mortality while reducing chronic undernutrition. Funding Information: This work was supported by the National Institutes of Health (grant 5T32AI052074-13) to PS; US Civilian Research and Development Foundation (CRDF; award USB-31150-XX-13 to N. S. H. and C. R. H.); the National Science Foundation (cooperative agreement OISE-9531011 to N. S. H. and C. R. H.), with federal funds from the Government of India’s Department of Biotechnology, the Indian Council of Medical Research, the National Institutes of Health, the National Institute of Allergy and Infectious Diseases, and the Office of AIDS Research and distributed in part by CRDF Global; grant from the Warren Alpert Foundation and Boston University School of Medicine (N.S.H); the Clinical and Translational Sciences Institute (grant 1UL1TR001430 to N.S. H.); the Providence/Boston Center for AIDS Research (grant P30AI042853 to C. R. H.); funding from Boston University Foundation India (to N.S.H.); and the Boston University/Rutgers Tuberculosis Research Unit (grant U19AI111276 to C. R. H.). Declaration of Interests: We do not report any conflicts of interest.

India's National Tuberculosis Elimination Programme (NTEP) covers diagnostic and therapeutic costs of TB treatment. However, persons living with TB (PLWTB) continue to experience financial distress due to direct costs (payment for testing, treatment, travel, hospitalization, and nutritional supplements) and indirect costs (lost wages, loan interest, and cost of domestic helpers).To analyze the magnitude and pattern of TB-related costs from the perspective of Indian PLWTB.We identified relevant articles using key search terms ('tuberculosis,' 'India,' 'cost,' 'expenditures,' 'financing,' 'catastrophic' and 'out of pocket') and calculated variance-weighted mean costs.Indian patients incur substantial direct costs (mean: US$46.8). Mean indirect costs (US$666.6) constitute 93.4% of the net costs. Mean direct costs before diagnosis can be up to four-fold that of costs during treatment. Treatment in the private sector can result in costs up to six-fold higher than in government facilities. As many as one in three PLWTB in India experience catastrophic costs.PLWTB in India face high direct and indirect costs. Priority interventions to realize India's goal of eliminating catastrophic costs from TB include decreasing diagnostic delays through active case finding, reducing the need for travel, improving awareness and perception of NTEP services, and ensuring sufficient reimbursement for inpatient TB care.Le programme national d’élimination de la tuberculose (NTEP) d’Inde couvre les coûts du diagnostic et du traitement de la TB. Les personnes vivant avec le TB (PLWTB) sont cependant toujours confrontées à des graves difficultés financières dues aux coûts directs (paiement des tests, du traitement, des trajets, de l’hospitalisation et des compléments nutritionnels) et aux coûts indirects (perte de revenus, intérêts du prêt, et coût des aides à domicile).Analyser la magnitude et le profil des coûts liés à la TB selon la perspective des PLWTB en Inde.Nous avons identifié les articles pertinents en utilisant les mots clés («Les patients indiens subissent des coûts directs substantiels (moyenne : US$46,8). Les coûts indirects moyens (US$666,6) constituent 93,4% des coûts nets. Les coûts directs moyens avant le diagnostic peuvent être quatre fois plus élevés que les coûts au cours du traitement. Le traitement dans le secteur privé peut coûter jusqu’à six fois plus que dans les structures publiques. Jusqu’à un tiers des PLWTB en Inde subissent des coûts catastrophiques.Les PLWTB en Inde font face à des coûts directs et indirects élevés. Les interventions prioritaires à mettre en œuvre pour réaliser l’objectif de l’Inde d’éliminer les coûts catastrophiques liés à la TB incluent la réduction du délai de diagnostic grâce à une recherche active des cas, la diminution des besoins de trajets, l’amélioration de la sensibilisation et de la perception des services NTEP et l’assurance d’un remboursement suffisant pour la prise en charge en hôpital de la TB.El Programa Nacional de Eliminación de la Tuberculosis de la India (NTEP) cubre los costos del diagnóstico y el tratamiento de la TB. Sin embargo, las personas con TB (PLWTB) aún afrontan dificultades económicas debido a los costos directos (pago de las pruebas, el tratamiento, los desplazamientos, la hospitalización y los suplementos nutricionales) y los costos indirectos (salarios perdidos, intereses de préstamos y remuneración de empleados domésticos).Analizar la magnitud y el tipo de costos relacionados con la TB desde la perspectiva de las PLWTB en la India.Se encontraron artículos pertinentes utilizando términos clave de búsqueda (“En la India, los pacientes asumen gastos directos considerables (promedio: US$46,80). Los costos indirectos promedio (US$666,60) constituyen el 93,4% de los costos netos. Los costos directos promedio antes del diagnóstico pueden corresponder hasta cuatro veces los costos durante el tratamiento. En el sector privado, los costos del tratamiento pueden ser hasta seis veces más altos que en los establecimientos gubernamentales. Una de cada tres PLWTB en la India afronta gastos catastróficos.Las PLWTB en la India afrontan altos costos directos e indirectos. Entre las intervenciones prioritarias que contribuirían a lograr el objetivo de eliminar los costos catastróficos por TB en la India se cuentan el acortar los retrasos diagnósticos mediante la búsqueda activa de casos, disminuir la necesidad de desplazarse, promover la familiarización con los servicios del NTEP y mejorar su percepción y garantizar el reembolso adecuado de la atención hospitalaria de la TB.

Setting In early studies, Xpert® MTB/RIF accurately detected culture-proven pulmonary tuberculosis (TB). Recent reports have, however, found a lower than expected specificity in previously treated TB patients. Objective To investigate the diagnostic accuracy of Xpert in presumptive pulmonary TB patients in Southwestern Uganda. Design We obtained demographic and clinical information and collected three sputum samples from each patient for smear microscopy, Xpert and culture. We estimated Xpert sensitivity and specificity against culture, and stratified the analysis by previous treatment and sputum quality status. Results We analyzed results from 860 presumptive TB patients, including 109 (13%) with a previous history of anti-tuberculosis treatment; 205 (24%) were culture-positive. Xpert specificity was lower (91.8%, 95%CI 84.9-96.2) in previously treated than in new TB patients (97.5%, 95%CI 96.1-98.5; P = 0.01). In an adjusted analysis, patients with culture-, Xpert+ results were more likely to have been previously treated for TB (OR 8.3, 95%CI 2.1-32.0; P = 0.002), and to have mucosalivary sputum (OR 4.1, 95%CI 1.1-14.6; P = 0.03), but were less likely to self-report fever (OR 0.23, 95%CI 0.1-0.7; P = 0.008) than patients with concordant positive results. Conclusion Xpert specificity was lower in previously treated patients with suspected TB. The clinical and programmatic impact of culture-, Xpert+ results requires evaluation in future studies.

The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from AUC values of 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy.

Background Epidemiologic data suggests that only a minority of tuberculosis (TB) patients are infectious. Cough aerosol sampling is a novel quantitative method to measure TB infectiousness. Methods We analyzed data from three studies conducted in Uganda and Brazil over a 13-year period. We included sputum acid fast bacilli (AFB) and culture positive pulmonary TB patients and used a cough aerosol sampling system (CASS) to measure the number of colony-forming units (CFU) of Mycobacterium tuberculosis in cough-generated aerosols as a measure for infectiousness. Aerosol data was categorized as: aerosol negative (CFU = 0) and aerosol positive (CFU > 0). Logistic regression models were built to identify factors associated with aerosol positivity. Results M. tuberculosis was isolated by culture from cough aerosols in 100/233 (43%) TB patients. In an unadjusted analysis, aerosol positivity was associated with fewer days of antituberculous therapy before CASS sampling (p = .0001), higher sputum AFB smear grade (p = .01), shorter days to positivity in liquid culture media (p = .02), and larger sputum volume (p = .03). In an adjusted analysis, only fewer days of TB treatment (OR 1.47 per 1 day of therapy, 95% CI 1.16-1.89; p = .001) was associated with aerosol positivity. Conclusion Cough generated aerosols containing viable M. tuberculosis, the infectious moiety in TB, are detected in a minority of TB patients and rapidly become non-culturable after initiation of antituberculous treatment. Mechanistic studies are needed to further elucidate these findings., In this aggregated analysis of three cohorts of sputum smear and culture positive pulmonary TB patients, we found that only a minority of individuals have viable aerosolized M. tuberculosis, the infectious moeity in TB. Infectiousness is markedly reduced shortly after antituberculous therapy is initiated, as indicated by a sharp decrease in M. tuberculosis growth in cultures of cough-generated aerosols.

Sputum acid-fast bacilli (AFB) smear microscopy has suboptimal sensitivity but remains the most commonly used laboratory test to diagnose pulmonary tuberculosis (TB). We prospectively evaluated the small membrane filtration (SMF) method that concentrates AFB in a smaller area to facilitate detection to improve the diagnostic performance of microscopy. We enrolled adults with suspicion of pulmonary TB from health facilities in southwestern Uganda. Clinical history, physical examination, and 3 sputum samples were obtained for direct fluorescent AFB smear, SMF, Xpert MTB/RIF, and MGIT culture media. Sensitivity and specificity were estimated for SMF, AFB smear, and Xpert MTB/RIF, using MGIT as the reference standard. The analysis was stratified according to HIV status. From September 2012 to April 2014, 737 participants were included in the HIV-infected stratum (146 [20.5%] were culture positive) and 313 were in the HIV-uninfected stratum (85 [28%] were culture positive). In HIV-infected patients, the sensitivity of a single SMF was 67.4% (95% confidence interval [CI], 59.9% to 74.1%); for AFB, 68.0% (95% CI, 60.6% to 74.6%); and for Xpert MTB/RIF, 91.0% (95% CI, 85.0% to 94.8%). In HIV-uninfected patients, the corresponding sensitivities were 72.5% (95% CI, 62.1% to 80.9%), 80.3% (95% CI, 70.8% to 87.2%), and 93.5% (95% CI, 85.7% to 97.2%). The specificity for all 3 tests in both HIV groups was ≥96%. In this setting, the SMF method did not improve the diagnostic accuracy of sputum AFB. The Xpert MTB/RIF assay performed well in both HIV-infected and -uninfected groups.

Background Tuberculosis disease develops in only 5%-10% of humans infected with Mycobacterium tuberculosis The mechanisms underlying this variability remain poorly understood. We recently demonstrated that colony-forming units of M. tuberculosis in cough-generated aerosols are a better predictor of infection than the standard sputum acid-fast bacilli smear. We hypothesized that cough aerosol cultures may also predict progression to tuberculosis disease in contacts. Methods We conducted a retrospective cohort study of 85 patients with smear-positive tuberculosis and their 369 household contacts in Kampala, Uganda. Index case patients underwent a standard evaluation, and we cultured M. tuberculosis from cough aerosols. Contacts underwent a standard evaluation at enrollment, and they were later traced to determine their tuberculosis status. Results During a median follow-up of 3.9 years, 8 (2%) of the contacts developed tuberculosis disease. In unadjusted and adjusted analyses, incident tuberculosis disease in contacts was associated with sputum Mycobacterial Growth Indicator Tube culture (odds ratio, 8.2; 95% confidence interval, 1.1-59.2; P = .04), exposure to a high-aerosol tuberculosis case patient (6.0, 1.4-25.2; P = .01), and marginally, human immunodeficiency virus in the contact (6.11; 0.89-41.7; P = .07). We present data demonstrating that sputum and aerosol specimens measure 2 related but different phenomena. Conclusions We found an increased risk of tuberculosis progression among contacts of high-aerosol case patients. The hypothesis that a larger infectious inoculum, represented by high aerosol production, determines the risk of disease progression deserves evaluation in future prospective studies.

Background Mycobacterium tuberculosis cultures of cough-generated aerosols from patients with pulmonary tuberculosis (TB) are a quantitative method to measure infectiousness and to predict secondary outcomes in exposed contacts. However, their reproducibility has not been established. Objective To evaluate the predictive value of colony-forming units (CFU) of M.Tuberculosis in cough aerosols on secondary infection and disease in household contacts in Brazil. Methods Adult sputum smear+ and culture+ pulmonary TB cases underwent a standard evaluation and were categorized according to aerosol CFU. We evaluated household contacts for infection at baseline and at 8 weeks with TST and IGRA, and secondary disease. Results We enrolled 48 index TB cases; 40% had negative aerosols, 27% low aerosols (

BACKGROUND: Household contacts of smear-positive tuberculosis (TB) patients are at increased risk of TB infection, however the risk of TB infection and disease in relation to the intensity of exposure remains unknown. METHODS: In the setting of a household contact study in Vitoria, Brazil, we studied smear positive, culture-proven pulmonary TB cases and their household contacts (HHCs). Tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT) were performed on HHCs. Clinical, demographic and radiographic variables were obtained. Intensity of exposure was measured using the Mandalakas score and the sleep location in relation to the index TB case. TB infection was defined by TST ≥ 1o mm or QFT ≥ 0.35 UI/ml. Secondary TB cases were identified by reviewing local and nationwide databases 21 months after conclusion of enrollment. Generalized estimating equations (GEE) models were constructed to evaluate the association between intensity of exposure and TB infection and disease. RESULTS: 160 TB index cases and 894 HHCs were included. TB infection defined by both TST and QFT was more common with high intensity exposures. TST+/IGRA- discordance was associated with less intense exposures measured by the modified Mandalakas score (p < 0.000). 23 (2.6%) of exposed household contacts developed secondary incident TB. The modified Mandalakas score was associated with increased risk of TB disease (OR 1.65 95% CI 1.25 – 2.08 p < 0.000). Diagnostic performance of the modified Mandalakas score was poor to predict TB infection and moderate for TB disease. CONCLUSION: Intensity of exposure improved TST+/IGRA+ concordance and increased risk of TB disease among HHCs, however their diagnostic performance is still suboptimal. A biomarker to guide preventive therapy is urgently needed in this at-risk population.

Background In household contact investigations of tuberculosis (TB), a second tuberculin skin test (TST) obtained several weeks after a first negative result consistently identifies individuals that undergo TST conversion. It remains unclear whether this delay in M. tuberculosis infection is related to differences in the infectious exposure, TST boosting, partial host resistance, or some other factor. Methods We conducted a household contact study Vitória, Brazil. Between 2008 and 2013, we identified culture-positive pulmonary TB patients and evaluated their household contacts with both a TST and interferon gamma release assay (IGRA), and identified TST converters at 8–12 weeks post study enrollment. Contacts were classified as TST-positive (≥10 mm) at baseline, TST converters, or persistently TST-negative. We compared TST converters to TST-positive and to TST-negative contacts separately, using generalized estimating equations. Results We enrolled 160 index patients and 838 contacts; 523 (62.4%) were TST+, 62 (7.4%) TST converters, and 253 (30.2%) TST−. TST converters were frequently IGRA− at 8–12 weeks. In adjusted analyses, characteristics distinguishing TST converters from TST+ contacts (no contact with another TB patient and residence ownership) were different than those differentiating them from TST− contacts (stronger cough in index patient and contact BCG scar). Conclusions The individual risk and timing of M. tuberculosis infection within households is variable and dependent on index patient, contact and environmental factors within the household, and the surrounding community. Our findings suggest a threshold effect in the risk of infection in humans. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2675-3) contains supplementary material, which is available to authorized users.

Excessive prescribing of vancomycin among patients admitted to inpatient wards is a challenge for antimicrobial stewardship programs, especially in the setting of expanded screening programs for methicillin-resistant Staphylococcus aureus (MRSA). Studies examining factors associated with longer duration of vancomycin use are limited.We conducted a retrospective cohort study to assess the impact of universal MRSA admission screening on duration of vancomycin use at the VA Boston Healthcare System during the period from January 2013-November 2015.A total of 2,910 patients were administered intravenous vancomycin during the study period. A clinical culture positive for MRSA was strongly associated with vancomycin administration lasting72 hours (odds ratio [OR], 2.72; 95% confidence interval [CI], 1.86-3.97; P .001). After controlling for clinical culture results, admission MRSA colonization was not associated with vancomycin use past 72 hours (OR, 0.94; 95% CI, 0.8-1.1). A negative MRSA nasal swab on admission had a high negative predictive value for all MRSA infections evaluated (99.6% for pneumonia, 99.6% for bloodstream infection, and 98.1% for skin and soft tissue infection).Admission surveillance for MRSA nasal colonization is not a major driver of prolonged vancomycin use. A negative admission MRSA nasal screen may be a useful tool for antimicrobial stewardship programs to limit vancomycin use, particularly in noncritically ill patients.

The World Health Organization recommends for tuberculosis retreatment a regimen of isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S) for 2 months, followed by H, R, E, and Z for 1 month and H, R, and E for 5 months. Using data from the National Tuberculosis and Leprosy Program registry, this study determined the long-term outcome under programmatic conditions of patients who were prescribed the retreatment regimen in Kampala, Uganda, between 1997 and 2003. Patients were traced to determine their vital status; 62% (234/377) patients were found dead. Having ≤ 2 treatment courses and not completing retreatment were associated with mortality in adjusted analyses.