Anti-tuberculosis treatment strategies and drug development: challenges and priorities

Nature Reviews Microbiology, Journal Year: 2022, Volume and Issue: 20(11), P. 685 - 701

Published: April 27, 2022

Despite two decades of intensified research to understand and cure tuberculosis disease, biological uncertainties remain hamper progress. However, owing collaborative initiatives including academia, the pharmaceutical industry non-for-profit organizations, drug candidate pipeline is promising. This exceptional success comes with inherent challenge prioritizing multidrug regimens for clinical trials revamping trial designs accelerate regimen development capitalize on discovery breakthroughs. Most wanted are markers progression from latent infection active pulmonary response predictors relapse, in vitro tools uncover synergies that translate clinically animal models reliably assess treatment shortening potential new regimens. In this Review, we highlight benefits challenges 'one-size-fits-all' duration versus individualized therapy based disease severity host pathogen characteristics, considering scientific operational perspectives.

Language: Английский

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A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis

Nature Medicine, Journal Year: 2018, Volume and Issue: 24(11), P. 1708 - 1715

Published: Oct. 26, 2018

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 patient-level data with external validation, we identify populations eligible for treatment, define phenotypes that are hard treat and evaluate the impact adherence dosing strategy on outcomes. In 3,405 included in analyses, baseline smear grade 3+ relative <2+, HIV seropositivity ≤90% significant risk factors unfavorable outcome. Four-month non-inferior minimal disease defined by <2+ sputum or non-cavitary A hard-to-treat phenotype, high grades cavitation, may require durations >6 months cure all. Regimen duration can be selected order improve outcomes, providing stratified medicine approach as an alternative 'one-size-fits-all' treatment currently used worldwide.

Language: Английский

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Practical Guidance for Clinical Microbiology Laboratories: Mycobacteria

Clinical Microbiology Reviews, Journal Year: 2018, Volume and Issue: 31(2)

Published: Jan. 30, 2018

SUMMARY Mycobacteria are the causative organisms for diseases such as tuberculosis (TB), leprosy, Buruli ulcer, and pulmonary nontuberculous mycobacterial disease, to name most important ones. In 2015, globally, almost 10 million people developed TB, half a patients suffered from its multidrug-resistant form. 2016, total of 9,287 new TB cases were reported in United States. there 174,608 case leprosy worldwide. India, Brazil, Indonesia cases. World Health Organization 2,037 with being Africa. Pulmonary disease is an emerging public health challenge. The U.S. National Institutes increase 20 47 cases/100,000 persons (or 8.2% per year) among adults aged 65 years or older throughout States, 181,037 national annual estimated 2014. This review describes contemporary methods laboratory diagnosis diseases. Furthermore, considers ever-changing care delivery system stresses laboratory's need adjust embrace molecular technologies provide shorter turnaround times higher quality who we serve.

Language: Английский

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Of tuberculosis and non-tuberculous mycobacterial infections – a comparative analysis of epidemiology, diagnosis and treatment

Journal of Biomedical Science, Journal Year: 2020, Volume and Issue: 27(1)

Published: June 17, 2020

Abstract Pulmonary diseases due to mycobacteria cause significant morbidity and mortality human health. In addition tuberculosis (TB), caused by Mycobacterium (Mtb), recent epidemiological studies have shown the emergence of non-tuberculous (NTM) species in causing lung humans. Although more than 170 NTM are present various environmental niches, only a handful, primarily avium complex M. abscessus , been implicated pulmonary disease. While TB is transmitted through inhalation aerosol droplets containing Mtb, generated patients with symptomatic disease, disease mostly disseminated aerosols originated from environment. However, following inhalation, both Mtb phagocytosed alveolar macrophages lungs. Subsequently, immune cells recruited circulation site infection, which leads granuloma formation. pathophysiology share several fundamental cellular molecular events, host-susceptibility infections different. Striking differences also exist presentation between cases. associated bronchiectasis, this condition rarely predisposing factor for TB. Similarly, Human Immunodeficiency Virus (HIV)-infected individuals, presents as disseminated, extrapulmonary form rather miliary, seen infection. The diagnostic modalities TB, including diagnosis drug-susceptibility testing (DST), advanced possess higher rate sensitivity specificity, compared tools available infections. general, drug-sensitive effectively treated standard multi-drug regimen well-defined first- second-line antibiotics. treatment drug-resistant requires additional, newer class antibiotics combination or without first drugs. contrast, display heterogeneity their susceptibility anti-TB Thus, usually involves use macrolides injectable aminoglycosides. well-established international guidelines available, empirical not entirely successful. duration much longer diseases, resection surgery affected organ(s) part that do respond treatment. Here, we discuss epidemiology, diagnosis,

Language: Английский

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The Diagnosis and Treatment of Tuberculosis

Deutsches Ärzteblatt international, Journal Year: 2019, Volume and Issue: unknown

Published: Oct. 25, 2019

Around 10 million people worldwide contract tuberculosis every year. According to the World Health Organization (WHO), approximately one-quarter of world's population is latently infected with Mycobacterium tuberculosis. In Ger- many, incidence was in decline over several decades but rose 2015 7.3 new cases per 100 000 persons. 2018, a total 5429 were documented, corresponding 6.5 persons.This article based on literature retrieved by selective search PubMed and authors' clinical experience.Tuberculosis involves lungs almost 75% patients can generally involve any organ. Germany, majority come from high-incidence countries. If patient's differential diagnosis includes tuberculosis, main tests for detection pathogen sputum tissue samples are culture (the gold standard), microscopy, nucleic acid amplification tests. Imaging studies also used follow-up. The standard treatment consists combination isoniazid, rifampicin, ethambutol, pyrazinamide, followed isoniazid rifampicin only. Liver damage one more common adverse effects this treatment, arising 2.4% patients. Multidrug-resistant which rare Germany (around year), should be treated special- ized centers.Rapid targeted essential prevent an unfavorable course disease as well its transmission other individuals. presenting unclear symptoms, always considered diagnosis. latent decision-making regarding difficult because lack specific biomarkers relevant data trials.

Language: Английский

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Spinal tuberculosis: a comprehensive review for the modern spine surgeon

The Spine Journal, Journal Year: 2019, Volume and Issue: 19(11), P. 1858 - 1870

Published: May 15, 2019

Language: Английский

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Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial

The Lancet, Journal Year: 2019, Volume and Issue: 393(10177), P. 1216 - 1224

Published: Feb. 21, 2019

Summary

Background

Directly observed treatment (DOT) has been the standard of care for tuberculosis since early 1990s, but it is inconvenient patients and service providers. Video-observed therapy (VOT) conditionally recommended by WHO as an alternative to DOT. We tested whether levels observation were improved with VOT.

Methods

did a multicentre, analyst-blinded, randomised controlled superiority trial in 22 clinics England (UK). Eligible participants aged at least 16 years active pulmonary or non-pulmonary who eligible DOT according local guidance. Exclusion criteria included not have access charging smartphone. randomly assigned either VOT (daily remote using smartphone app) (observations done three five times per week home, community, clinic settings). Randomisation was SealedEnvelope minimisation. involved health-care lay worker, any remaining daily doses self-administered. provided centralised London. Patients trained record send videos every dose ingested 7 days app. Trained observers viewed these through password-protected website. also encouraged report adverse drug events on videos. Smartphones data plans free charge study investigators. records completed until end. The primary outcome completion 80% more scheduled observations over first 2 months following enrolment. Intention-to-treat (ITT) restricted (including only completing 1 allocated arm) analyses done. Superiority determined 15% difference proportion (60% vs 75%). This registered International Standard Randomised Controlled Trials Number registry, number ISRCTN26184967.

Findings

Between Sept 1, 2014, Oct 2016, we 226 patients; 112 114 Overall, 131 (58%) had history homelessness, imprisonment, use, alcohol problems mental health problems. In ITT analysis, 78 (70%) achieved ≥80% successfully during compared 35 (31%) (adjusted odds ratio [OR] 5·48, 95% CI 3·10–9·68; p<0·0001). (77%) 101 (63%) 56 OR 2·52; 1·17–5·54; p=0·017). Stomach pain, nausea, vomiting most common reported (in [14%] nine [8%] DOT).

Interpretation

effective approach than likely be preferable many across broad range settings, providing acceptable, effective, cheaper option supervision multiple

Funding

National Institute Health Research.

Language: Английский

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Xpert^®MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance

Cochrane library, Journal Year: 2018, Volume and Issue: unknown

Published: Aug. 27, 2018

Language: Английский

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Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Kidney International, Journal Year: 2018, Volume and Issue: 93(3), P. 545 - 559

Published: Feb. 3, 2018

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex and comorbid as well injury resulting from prolonged exposure to antiretroviral therapy or opportunistic infections. Clinical guidelines disease prevention treatment in largely extrapolated studies the general population, do not fully incorporate existing knowledge of unique HIV-related pathways genetic factors that contribute this population. We convened an international panel experts nephrology, renal pathology, infectious diseases define pathology setting HIV infection; describe role genetics natural history, diagnosis, individuals; characterize risk-benefit prevention; best practices management individuals.

Language: Английский

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Central Nervous System Tuberculosis

Microbiology Spectrum, Journal Year: 2017, Volume and Issue: 5(2)

Published: March 10, 2017

ABSTRACT Central nervous system tuberculosis (CNS-TB) takes three clinical forms: meningitis (TBM), intracranial tuberculoma, and spinal arachnoiditis. TBM predominates in the western world presents as a subacute to chronic syndrome with prodrome of malaise, fever, headache progressing altered mentation focal neurologic signs, followed by stupor, coma, death within five eight weeks onset. The CSF formula typically shows lymphocytic pleocytosis, low glucose high protein concentrations. Diagnosis rests on serial samples for smear culture, combined PCR. Brain CT MRI aid diagnosis, assessment complications, monitoring course. In patient compatible features, combination meningeal enhancement any degree hydrocephalus is strongly suggestive TBM. Vasculitis leading infarcts basal ganglia occurs commonly major determinant morbidity mortality. Treatment most effective when started early stages disease, should be initiated promptly basis strong suspicion without waiting laboratory confirmation. initial 4 drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol) covers possibility infection resistant strain, maximizes antimicrobial impact, reduces likelihood emerging resistance therapy. Adjunctive corticosteroid therapy has been shown reduce mortality all but late stage disease.

Language: Английский

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