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"Multidrug-resistant tuberculosis"
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Phantom plague : how tuberculosis shaped history
\"The definitive social history of tuberculosis, from its origins as a haunting mystery to its modern reemergence that now threatens populations around the world. It killed novelist George Orwell, Eleanor Roosevelt, and millions of others - rich and poor. Desmond Tutu, Amitabh Bachchan, and Nelson Mandela survived it, just. For centuries, tuberculosis has ravaged cities and plagued the human body. In Phantom Plague, Vidya Krishnan, traces the history of tuberculosis from the slums of 19th-century New York to modern Mumbai. In a narrative spanning century, Krishnan shows how superstition and folk-remedies, made way for scientific understanding of TB, such that it was controlled and cured in the West. The cure was never available to black and brown nations. And the tuberculosis bacillus showed a remarkable ability to adapt -- so that at the very moment it could have been extinguished as a threat to humanity, it found a way back, aided by authoritarian governments, the toxic kindness of philanthropists, science denialism, and medical apartheid. Krishnan's original reporting paints a granular portrait of the post-antibiotic era as a new, aggressive, drug resistant strain of TB takes over. Phantom Plague is an urgent, riveting and fascinating narrative that deftly exposes the weakest links in our battle against this ancient foe.\"--Front jacket flap.
BOOK
A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis
Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide.
Analysis of tuberculosis drug trials identifies features to stratify patients for longer or shorter treatment duration than the standard of care, in order to improve therapeutic outcomes.
Journal Article
Management of drug-resistant tuberculosis
Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9–24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.
Journal Article
Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test
Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.
Journal Article
Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis
In this randomized, controlled trial involving children with household exposure to multidrug-resistant tuberculosis, levofloxacin led to a lower incidence of tuberculosis than placebo, but the difference was not significant.
Journal Article
Evaluation of High-Dose Isoniazid in Multidrug-Resistant Tuberculosis Treatment
High-dose isoniazid is recommended to treat multidrug-resistant tuberculosis (MDR TB). Among 958 MDR TB isolates identified in France during 2008-2022, 93.1% exhibited high-level isoniazid resistance, and molecular testing showed limited diagnostic accuracy in predicting resistance. Clinicians should reconsider using high-dose isoniazid in MDR TB treatment because of suboptimal effect and toxicity concerns.
Journal Article
Drug-resistant tuberculosis: a persistent global health concern
Drug-resistant tuberculosis (TB) is estimated to cause 13% of all antimicrobial resistance-attributable deaths worldwide and is driven by both ongoing resistance acquisition and person-to-person transmission. Poor outcomes are exacerbated by late diagnosis and inadequate access to effective treatment. Advances in rapid molecular testing have recently improved the diagnosis of TB and drug resistance. Next-generation sequencing of Mycobacterium tuberculosis has increased our understanding of genetic resistance mechanisms and can now detect mutations associated with resistance phenotypes. All-oral, shorter drug regimens that can achieve high cure rates of drug-resistant TB within 6–9 months are now available and recommended but have yet to be scaled to global clinical use. Promising regimens for the prevention of drug-resistant TB among high-risk contacts are supported by early clinical trial data but final results are pending. A person-centred approach is crucial in managing drug-resistant TB to reduce the risk of poor treatment outcomes, side effects, stigma and mental health burden associated with the diagnosis. In this Review, we describe current surveillance of drug-resistant TB and the causes, risk factors and determinants of drug resistance as well as the stigma and mental health considerations associated with it. We discuss recent advances in diagnostics and drug-susceptibility testing and outline the progress in developing better treatment and preventive therapies.In this Review, Pai and colleagues examine the global landscape of drug-resistant tuberculosis, exploring its epidemiology, causes, risk factors, stigma and associated mental health burden as well as discussing the most recent developments in diagnostics, treatment and preventive regimens.
Journal Article
Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline
In this phase 2 study, the addition of bedaquiline to routine therapy for multidrug-resistant tuberculosis showed significant efficacy, with accelerated sputum-culture conversion and increased culture conversion at 24 and 120 weeks.
The World Health Organization (WHO) estimates that the global incidence of tuberculosis in 2012 was 8.6 million cases, with 1.3 million deaths, predominantly occurring in developing countries.
1
Although there has been some progress in reducing tuberculosis cases and deaths in the past 20 years, multidrug-resistant tuberculosis (i.e., with resistance to at least isoniazid and rifampin) remains a major challenge. The 2012 global incidence of multidrug-resistant tuberculosis was 450,000 cases.
1
Therapy for multidrug-resistant tuberculosis is a long, arduous regimen of antiquated drugs that are mainly bacteriostatic and have an unfavorable side-effect profile.
2
The WHO reports that major efforts are needed to . . .
Journal Article
Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis
Sarah Fortune and colleagues report that
Mycobacterium tuberculosis
strains from lineage 2 acquire drug resistance
in vitro
more rapidly than strains from lineage 4 and show that this correlates with a higher
in vivo
mutation rate, as estimated from whole-genome sequencing of clinical isolates. They develop a stochastic mathematical model of the within-host evolution of drug resistance, using these mutation rate estimates to predict the rates of emergence of resistance in individuals with tuberculosis.
A key question in tuberculosis control is why some strains of
M. tuberculosis
are preferentially associated with resistance to multiple drugs. 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.
Journal Article
The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis—lessons from the South African experience
Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6–9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa.
Journal Article