TB Elimination Requires Discovery and Development of Transformational Agents

Lienhardt, Christian; Raviglione, Mario C.

doi:10.3390/app10072605

Cited by 5 publications

(5 citation statements)

References 18 publications

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“…Third, a vaccine would be the ultimate solution if found to be highly effective, safe, able to prevent pre-exposure, infection as well as reactivation. 39,40 Since the existing anti-tubercular regimens made before the current advance in pharmacokinetic-pharmacodynamic (PK-PD), we are lacking evidence of exposure-response relationships even in today's tuberculosis pharmacotherapy. 41 Owing to this gap WHO developed a technical report on the PK and PD of drugs used for tuberculosis treatment.…”

Section: Discussionmentioning

confidence: 99%

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

Sileshi¹,

Tadesse²,

Makonnen³

et al. 2021

CPAA

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Background: Tuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line anti-TB drugs. The cure rate, however, varies from patient to patient. Various factors have been related to anti-TB treatment failure. In recent years, studies associating lower plasma concentrations of anti-TB drugs with poor treatment outcomes are emerging although the results are inconclusive. Objective: Investigate the impact of first-line anti-tubercular drugs pharmacokinetics on treatment outcome. Methods: A systematic search of Pubmed, EMBASE, Web of Science, and the Cochrane Library for articles published in the English language between January 2010 to June 2020 was conducted to identify eligible studies describing associations of first-line anti-tubercular drug pharmacokinetics with treatment outcomes. The primary outcomes considered were pharmacokinetics parameter results and its association with treatment outcome. Results: The search identified 1754 articles of which twelve articles; ten prospective observational studies and two controlled clinical trials fulfilled the eligibility criteria. The majority of the studies showed target concentrations for the first-line anti-tubercular drugs below the current standard range. Among the twelve studies, eleven studies assessed rifampicin pharmacokinetics of which eight reported association of drug concentration and treatment outcomes. Similarly, four out of eight and three out of seven reported drug concentration and treatment outcome association for isoniazid and pyrazinamide, respectively. Despite the low plasma concentration, a favorable treatment outcome was achieved for the bulk of the patients. Irrespective of the inconsistency, an increase in exposure to rifampicin improved the outcome, and lower rifampicin, isoniazid, and pyrazinamide concentration are associated with poor outcome. No data are available for ethambutol associating its pharmacokinetics with treatment outcomes. Conclusion: The pharmacokinetics of first-line antitubercular drugs can influence treatment outcomes. Further controlled clinical studies are, however, required to establish these relationships.

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Section: Discussionmentioning

confidence: 99%

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

Sileshi¹,

Tadesse²,

Makonnen³

et al. 2021

CPAA

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“…In addition, the authors describe validated and promiscuous drug targets in the context of their experience at AstraZeneca R&D, Bangalore, India. In their article, Lienhardt and Raviglione discuss the ambitious aim of the WHO to reduce TB incidence by 90% by the year 2030 [8], whereas Iacobino and co-authors review the increasing global challenge represented by drug-resistant TB [9]. An interesting paper by Mazzarello closes the initial section by presenting a historical perspective focused on Carlo Forlanini, who invented pneumothorax for TB treatment in 1882, in the same year when Robert Koch identified M. tuberculosis as the causative agent of human TB [10].…”

Section: The Present Special Issue On "Tuberculosis Drug Discovery Anmentioning

confidence: 99%

Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

2020

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“…In this review, we discuss traditional and nontraditional antibacterial agents that were being evaluated in clinical trials on 30 June 2021 for the treatment of infections caused by the WHO priority pathogens Mycobacterium tuberculosis ( 38 ) and nontuberculosis mycobacteria (NTM) ( 39 ) and C. difficile , which is not a WHO priority pathogen but is considered by the CDC to be an urgent threat ( 11 ). A brief overview of the drug development process and drug regulatory agencies are provided in the supplemental information.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed

Butler

Gigante²,

Sati³

et al. 2022

Antimicrob Agents Chemother

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145

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There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

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TB Elimination Requires Discovery and Development of Transformational Agents

Cited by 5 publications

References 18 publications

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed

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