The Experts below are selected from a list of 35337 Experts worldwide ranked by ideXlab platform
Salmaan Keshavjee - One of the best experts on this subject based on the ideXlab platform.
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multiDrug Resistant Tuberculosis and extensively Drug Resistant Tuberculosis
Cold Spring Harbor Perspectives in Medicine, 2015Co-Authors: Kwonjune J Seung, Michael Rich, Salmaan KeshavjeeAbstract:The continuing spread of Drug-Resistant Tuberculosis (TB) is one of the most urgent and difficult challenges facing global TB control. Patients who are infected with strains Resistant to isoniazid and rifampicin, called multiDrug-Resistant (MDR) TB, are practically incurable by standard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000 deaths because of MDR-TB. Extensively Drug-Resistant (XDR) TB refers to MDR-TB strains that are Resistant to fluoroquinolones and second-line injectable Drugs. The main causes of the spread of Resistant TB are weak medical systems, amplification of resistance patterns through incorrect treatment, and transmission in communities and facilities. Although patients harboring MDR and XDR strains present a formidable challenge for treatment, cure is often possible with early identification of resistance and use of a properly designed regimen. Community-based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence.
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treatment of extensively Drug Resistant Tuberculosis in tomsk russia a retrospective cohort study
The Lancet, 2008Co-Authors: I Y Gelmanova, Sergey P Mishustin, A K Strelis, Salmaan Keshavjee, Paul Farmer, Yevgeny G AndreevAbstract:Summary Background Mycobacterium Tuberculosis strains that cause untreatable Drug-Resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively Drug-Resistant Tuberculosis in Tomsk, Russia. Methods We undertook a retrospective cohort study of 608 patients with multiDrug Resistant Tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively Drug-Resistant (XDR) Tuberculosis and non-extensively Drug-Resistant (non-XDR) Tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. Findings Of 608 patients with multiDrug Resistant Tuberculosis, 29 (4·8%) patients had baseline XDR Tuberculosis. Treatment failure was more common in patients with XDR Tuberculosis than in those with non-XDR Tuberculosis (31% vs 8·5%, p=0·0008). 48·3% of patients with XDR Tuberculosis and 66·7% of patients with non-XDR Tuberculosis had treatment cure or completion (p=0·04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR Tuberculosis. Interpretation The chronic features of Tuberculosis in these patients suggest that extensively Drug-Resistant Tuberculosis may be acquired through previous treatments that include second-line Drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of Drug-Resistant strains of Mycobacterium Tuberculosis . Funding Bill & Melinda Gates Foundation, Eli Lilly Foundation, The Open Society Institute, Frank Hatch Fellowships in Global Health Equity at the Brigham & Women's Hospital, Infectious Disease Society of America, the Heiser Foundation, the United States National Institutes of Health, and the John D and Catherine T MacArthur Foundation.
Michael Rich - One of the best experts on this subject based on the ideXlab platform.
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multiDrug Resistant Tuberculosis and extensively Drug Resistant Tuberculosis
Cold Spring Harbor Perspectives in Medicine, 2015Co-Authors: Kwonjune J Seung, Michael Rich, Salmaan KeshavjeeAbstract:The continuing spread of Drug-Resistant Tuberculosis (TB) is one of the most urgent and difficult challenges facing global TB control. Patients who are infected with strains Resistant to isoniazid and rifampicin, called multiDrug-Resistant (MDR) TB, are practically incurable by standard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000 deaths because of MDR-TB. Extensively Drug-Resistant (XDR) TB refers to MDR-TB strains that are Resistant to fluoroquinolones and second-line injectable Drugs. The main causes of the spread of Resistant TB are weak medical systems, amplification of resistance patterns through incorrect treatment, and transmission in communities and facilities. Although patients harboring MDR and XDR strains present a formidable challenge for treatment, cure is often possible with early identification of resistance and use of a properly designed regimen. Community-based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence.
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comprehensive treatment of extensively Drug Resistant Tuberculosis
The New England Journal of Medicine, 2008Co-Authors: Carol Deane Benedict Mitnick, Sonya Shin, Kwonjune J Seung, Michael Rich, Sidney Atwood, Jennifer Furin, Felix Alcantara A Viru, Sasha C Appleton, Garrett M Fitzmaurice, Jaime BayonaAbstract:Background Extensively Drug-Resistant Tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of Tuberculosis. We describe the management of extensively Drug-Resistant Tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. Methods A total of 810 patients were referred for free individualized therapy, including Drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively Drug-Resistant Tuberculosis and developed regimens that included five or more Drugs to which the infecting isolate was not Resistant. Results Of the 651 patients tested, 48 (7.4%) had extensively Drug-Resistant Tuberculosis; the remaining 603 patients had multiDrug-Resistant Tuberculosis. The patients with extensively Drug-Resistant Tuberculosis had undergone more treatment than the other patients (mean [±SD] number of regimens, 4.2±1.9 vs. 3.2±1.6; P<0.001) and had isolates that were Resistant to more Drugs (number of Drugs, 8.4±1.1 vs. 5.3±1.5; P<0.001). None of the patients with extensively Drug-Resistant Tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively DrugResistant Tuberculosis received daily, supervised therapy with an average of 5.3±1.3 Drugs, including cycloserine, an injectable Drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multiDrug-Resistant Tuberculosis (P = 0.36). Conclusions Extensively Drug-Resistant Tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for Tuberculosis.
Megan Murray - One of the best experts on this subject based on the ideXlab platform.
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mycobacterium Tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of Drug Resistant Tuberculosis
Nature Genetics, 2013Co-Authors: Christopher B Ford, Rupal R Shah, Midori Kato Maeda, Sebastien Gagneux, Ted Cohen, James C Johnston, Megan Murray, Jennifer L GardyAbstract:A critical question in Tuberculosis control is why some strains of Mycobacterium Tuberculosis are preferentially associated with multiple Drug resistances. We demonstrate that M. Tuberculosis strains from Lineage 2 (East Asian lineage and Beijing sublineage) acquire Drug resistances in vitro more rapidly than M. Tuberculosis strains from Lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a Drug susceptible Lineage 2 strain will harbor multiDrug Resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of Drug Resistant Tuberculosis should target bacterial as well as treatment-related risk factors.
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treatment outcomes among patients with extensively Drug Resistant Tuberculosis systematic review and meta analysis
Clinical Infectious Diseases, 2010Co-Authors: Karen R Jacobson, Carol Deane Benedict Mitnick, Megan Murray, Dylan B Tierney, Christie Y JeonAbstract:Background. The treatment of extensively Drug-Resistant Tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial Drugs are less effective, more toxic, and more costly than first-line agents, and XDR TB strains are, by definition, Resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses. Methods. We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes. Results. The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%‐54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%‐27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes ( ). P p .012 Conclusions. This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though Drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of latergeneration fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies.
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emergence of increased resistance and extensively Drug Resistant Tuberculosis despite treatment adherence south africa
Emerging Infectious Diseases, 2010Co-Authors: Alistair Calver, Megan Murray, Elizabeth M. Streicher, Paul D. Van Helden, A Falmer, Odelia J Strauss, Madelene Hanekom, Thelma Liversage, Mothusi Masibi, Robin M. WarrenAbstract:We investigated the emergence and evolution of Drug-Resistant Tuberculosis (TB) in an HIV co-infected population at a South African gold mine with a well-functioning TB control program. Of 128 patients with Drug-Resistant TB diagnosed during January 2003-November 2005, a total of 77 had multiDrug-Resistant (MDR) TB, 26 had pre-extensively Drug-Resistant TB (XDR TB), and 5 had XDR TB. Genotyping suggested ongoing transmission of Drug-Resistant TB, and contact tracing among case-patients in the largest cluster demonstrated multiple possible points of contact. Phylogenetic analysis demonstrated stepwise evolution of Drug resistance, despite stringent treatment adherence. These findings suggested that existing TB control measures were inadequate to control the spread of Drug-Resistant TB in this HIV co-infected population. Diagnosis delay and inappropriate therapy facilitated disease transmission and Drug-resistance. These data call for improved infection control measures, implementation of rapid diagnostics, enhanced active screening strategies, and pharmacokinetic studies to determine optimal dosages and treatment regimens.
Neel R Gandhi - One of the best experts on this subject based on the ideXlab platform.
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modeling missing cases and transmission links in networks of extensively Drug Resistant Tuberculosis in kwazulu natal south africa
bioRxiv, 2019Co-Authors: Kristin N. Nelson, Neel R Gandhi, Barun Mathema, James C.m. Brust, Tyler S. Brown, Shaheed V. Omar, Sara C. Auld, Benjamin A Lopman, Nazir Ahmed Ismail, Salim AllanaAbstract:The transmission patterns of Drug-Resistant Tuberculosis (TB) remain poorly understood, despite over half a million incident cases in 2017. Modeling TB transmission networks can provide insight into the nature and drivers of transmission, but incomplete and non-random sampling of TB cases can pose challenges to making inferences from epidemiologic and molecular data. We conducted a quantitative bias analysis to assess the effect of missing cases on a transmission network inferred from Mtb sequencing data on extensively Drug-Resistant (XDR) TB cases in South Africa. We tested scenarios in which cases were missing at random, differentially by clinical characteristics, or differentially by transmission (i.e., cases with many links were under or over-sampled). Under the assumption cases were missing at random, cases in the complete, modeled network would have had a mean of 20 or more transmission links, which is far higher than expected, in order to reproduce the observed, partial network. Instead, we found that the most likely scenario involved undersampling of high-transmitting cases, and further models provided evidence for superspreading behavior. This is, to our knowledge, the first study to define and assess the support for different mechanisms of missingness in a study of TB transmission. Our findings should caution interpretation of results of future studies of TB transmission in high-incidence settings, given the potential for biased sampling, and should motivate further research aimed at identifying the specific host, pathogen, or environmental factors contributing to superspreading.
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High Prevalence of inhA Promoter Mutations among Patients with Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa
PLOS ONE, 2015Co-Authors: Abraham Johannes Niehaus, Neel R Gandhi, Koleka Mlisana, Barun Mathema, James C.m. BrustAbstract:Background Drug-Resistant Tuberculosis (TB) remains extremely difficult to treat because there are often few remaining active medications and limited diagnostic options to detect resistance. Resistance to isoniazid is typically caused by mutations in either katG or the inhA promoter. inhA mutations confer low-level resistance to isoniazid and cross-resistance to ethionamide while katG mutations confer high-level isoniazid resistance and no cross-resistance. Line Probe Assays (LPAs) that detect mutations in katG and inhA are currently performed on all positive TB cultures in KwaZulu-Natal province, South Africa, but the frequency of inhA mutations in Drug-Resistant TB patients has not been examined. Methods We sought to determine the proportion of patients who could potentially benefit from highdose isoniazid and who may be Resistant to ethionamide. We reviewed 994 LPA (Hain MTBDRplus) results at the TB reference laboratory in KwaZulu-Natal to determine the frequency of mutations in either katG or the inhA promoter. We stratified these results by Drugresistance category (i.e., MDR-TB, pre-XDR-TB, and XDR-TB) as determined by phenotypic Drug-susceptibility testing.
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nosocomial transmission of extensively Drug Resistant Tuberculosis in a rural hospital in south africa
The Journal of Infectious Diseases, 2013Co-Authors: Neel R Gandhi, Barun Mathema, Barry N. Kreiswirth, Elena Shashkina, Darren Weissman, Prashini Moodley, Melissa Ramathal, Inga Elson, Richard RothenbergAbstract:Background. Extensively Drug-Resistant Tuberculosis (XDR-Tuberculosis) is a global public health threat, but few data exist elucidating factors driving this epidemic. The initial XDR-Tuberculosis report from South Africa suggested transmission is an important factor, but detailed epidemiologic and molecular analyses were not available for further characterization. Methods. We performed a retrospective, observational study among XDR-Tuberculosis patients to identify hospital-associated epidemiologic links. We used spoligotyping, IS6110-based restriction fragment–length polymorphism analysis, and sequencing of resistance-determining regions to identify clusters. Social network analysis was used to construct transmission networks among genotypically clustered patients. Results. Among 148 XDR-Tuberculosis patients, 98% were infected with human immunodeficiency virus (HIV), and 59% had smear-positive Tuberculosis. Nearly all (93%) were hospitalized while infectious with XDR-Tuberculosis (median duration, 15 days; interquartile range: 10–25 days). Genotyping identified a predominant cluster comprising 96% of isolates. Epidemiologic links were identified for 82% of patients; social network analysis demonstrated multiple generations of transmission across a highly interconnected network. Conclusions. The XDR-Tuberculosis epidemic in Tugela Ferry, South Africa, has been highly clonal. However, the epidemic is not the result of a point-source outbreak; rather, a high degree of interconnectedness allowed multiple generations of nosocomial transmission. Similar to the outbreaks of multiDrug-Resistant Tuberculosis in the 1990s, poor infection control, delayed diagnosis, and a high HIV prevalence facilitated transmission. Important lessons from those outbreaks must be applied to stem further expansion of this epidemic.
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extensively Drug Resistant Tuberculosis as a cause of death in patients co infected with Tuberculosis and hiv in a rural area of south africa
The Lancet, 2006Co-Authors: Neel R Gandhi, Anthony P Moll, Willem A Sturm, Robert Pawinski, Thiloshini Govender, Kimberly Zeller, Umesh G Lalloo, Jason R. AndrewsAbstract:Summary Background The epidemics of HIV-1 and Tuberculosis in South Africa are closely related. High mortality rates in co-infected patients have improved with antiretroviral therapy, but Drug-Resistant Tuberculosis has emerged as a major cause of death. We assessed the prevalence and consequences of multiDrug-Resistant (MDR) and extensively Drug-Resistant (XDR) Tuberculosis in a rural area in KwaZulu Natal, South Africa. Methods We undertook enhanced surveillance for Drug-Resistant Tuberculosis with sputum culture and Drug susceptibility testing in patients with known or suspected Tuberculosis. Genotyping was done for isolates Resistant to first-line and second-line Drugs. Results From January, 2005, to March, 2006, sputum was obtained from 1539 patients. We detected MDR Tuberculosis in 221 patients, of whom 53 had XDR Tuberculosis. Prevalence among 475 patients with culture-confirmed Tuberculosis was 39% (185 patients) for MDR and 6% (30) for XDR Tuberculosis. Only 55% (26 of 47) of patients with XDR Tuberculosis had never been previously treated for Tuberculosis; 67% (28 of 42) had a recent hospital admission. All 44 patients with XDR Tuberculosis who were tested for HIV were co-infected. 52 of 53 patients with XDR Tuberculosis died, with median survival of 16 days from time of diagnosis (IQR 6–37) among the 42 patients with confirmed dates of death. Genotyping of isolates showed that 39 of 46 (85%, 95% CI 74–95) patients with XDR Tuberculosis had similar strains. Conclusions MDR Tuberculosis is more prevalent than previously realised in this setting. XDR Tuberculosis has been transmitted to HIV co-infected patients and is associated with high mortality. These observations warrant urgent intervention and threaten the success of treatment programmes for Tuberculosis and HIV.
Carol Deane Benedict Mitnick - One of the best experts on this subject based on the ideXlab platform.
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world health organization group 5 Drugs for the treatment of Drug Resistant Tuberculosis unclear efficacy or untapped potential
The Journal of Infectious Diseases, 2013Co-Authors: Kelly E Dooley, Carol Deane Benedict Mitnick, Ekwaro A Obuku, Nadza Durakovic, Vera Belitsky, Eric NuermbergerAbstract:The World Health Organization (WHO) estimates that more than 1.3 million people with multiDrug-Resistant (MDR) Tuberculosis caused by Mycobacterium Tuberculosis Resistant to isoniazid and rifampin will require treatment in the 27 countries with the highest MDR-Tuberculosis burden between 2010 and 2015 [1]. Extensively Drug-Resistant Tuberculosis (XDR-Tuberculosis; caused by M. Tuberculosis Resistant to isoniazid, rifampin, fluoroquinolones, and at least one injectable agent), a more difficult-to-treat form of Tuberculosis, is widespread [2]. Second-line Drugs used to treat Drug-Resistant (DR) Tuberculosis have undesirable toxicity profiles and/or lack potency, and current MDR-Tuberculosis treatment requires at least 18 months of multiDrug therapy. To improve treatment of DR-Tuberculosis with existing Drugs and identify optimized background regimens for trials with new compounds, the Drug Efficacy Subgroup of Research Excellence to Stop Tuberculosis Resistance (RESIST-Tuberculosis; http://www.resisttb.org) reviewed the extant literature on second-line Tuberculosis Drugs to ascertain the contribution of individual agents to DR-Tuberculosis treatment. This review summarizes the evidence and gaps in knowledge for Drugs that are classified by WHO as “group 5”—not recommended for routine use for treatment of DR-Tuberculosis because of unclear efficacy (Table (Table1)1) [3]. This group includes clofazimine, linezolid, amoxicillin-clavulanate, carbapenems, thiacetazone, and clarithromycin. We highlight and prioritize key research questions about these Drugs. Table 1. Grouping of Drugs for Tuberculosis by the World Health Organization
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treatment outcomes among patients with extensively Drug Resistant Tuberculosis systematic review and meta analysis
Clinical Infectious Diseases, 2010Co-Authors: Karen R Jacobson, Carol Deane Benedict Mitnick, Megan Murray, Dylan B Tierney, Christie Y JeonAbstract:Background. The treatment of extensively Drug-Resistant Tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial Drugs are less effective, more toxic, and more costly than first-line agents, and XDR TB strains are, by definition, Resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses. Methods. We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes. Results. The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%‐54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%‐27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes ( ). P p .012 Conclusions. This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though Drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of latergeneration fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies.
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comprehensive treatment of extensively Drug Resistant Tuberculosis
The New England Journal of Medicine, 2008Co-Authors: Carol Deane Benedict Mitnick, Sonya Shin, Kwonjune J Seung, Michael Rich, Sidney Atwood, Jennifer Furin, Felix Alcantara A Viru, Sasha C Appleton, Garrett M Fitzmaurice, Jaime BayonaAbstract:Background Extensively Drug-Resistant Tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of Tuberculosis. We describe the management of extensively Drug-Resistant Tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. Methods A total of 810 patients were referred for free individualized therapy, including Drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively Drug-Resistant Tuberculosis and developed regimens that included five or more Drugs to which the infecting isolate was not Resistant. Results Of the 651 patients tested, 48 (7.4%) had extensively Drug-Resistant Tuberculosis; the remaining 603 patients had multiDrug-Resistant Tuberculosis. The patients with extensively Drug-Resistant Tuberculosis had undergone more treatment than the other patients (mean [±SD] number of regimens, 4.2±1.9 vs. 3.2±1.6; P<0.001) and had isolates that were Resistant to more Drugs (number of Drugs, 8.4±1.1 vs. 5.3±1.5; P<0.001). None of the patients with extensively Drug-Resistant Tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively DrugResistant Tuberculosis received daily, supervised therapy with an average of 5.3±1.3 Drugs, including cycloserine, an injectable Drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multiDrug-Resistant Tuberculosis (P = 0.36). Conclusions Extensively Drug-Resistant Tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for Tuberculosis.
