The future of drug-resistant tuberculosis treatment: learning from the past and the 2019 World Health Organization consolidated guidelines

The World Health Organization (WHO) recently launched the consolidated guidelines on drug-resistant tuberculosis (DR-TB) treatment [1]. They include a new drug classification to manage rifampicin-resistant (RR) and multidrug-resistant (MDR)-TB, while proposing either a shorter regimen (including injectable drugs) or a longer all-oral one as the recommended treatment options. Efficient diagnostic tools are presently available to diagnose resistance to second-line drugs within a few hours (instead of the weeks previously needed) [2]. Therefore, the challenge for National TB Programmes is now to capture these new recommendations in their national guidelines. The aim of this article is to contribute to the ongoing discussion on RR-/MDR-TB treatment considering the lessons learnt over the past 70 years of anti-TB chemotherapy. Other important topics raised in the 2019 WHO drug-resistant treatment guidelines, such as the treatment of isoniazid-resistant TB or the comparison between the two WHO-approved regimens for MDR-TB, have not been addressed within the constraints of this short editorial.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Editorials Source Type: research

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Abstract Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and fastidious procedure that delays progression of drugs down the pipeline and towards the clinic. In this investigation, we report the construction, optimization and characterization of genetically engineered near-i...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
ABSTRACT: Introduction: The mortality rate among tuberculosis patients (TB fatality) has been attributed to irregular chemotherapy, delay in diagnosis, multidrug resistance, and HIV coinfection. Objective: To analyze TB fatality rates by sex, clinical presentation and HIV coinfection in Campinas, S ão Paulo, Brazil. Methods: Cohorts of residents in the city of Campinas who either died during treatment for tuberculosis or had the disease confirmed after death were divided into three intervals: 2001-2003, 2004-2006, and 2007-2009. Data were obtained from the database of the Tuberculosis Surve illance System of the Uni...
Source: Revista Brasileira de Epidemiologia - Category: Epidemiology Source Type: research
Abstract Multidrug-resistant tuberculosis is an alarming threat and targeted deep sequencing (DS) may be an effective method for rapid identification of drug-resistant profiles, including detection of heteroresistance. We evaluated sensitivity and specificity of targeted DS vs. phenotypic drug susceptibility testing (pDST) among patients starting first-line anti-TB therapy in Botswana. Overall, we found high concordance between DS and pDST. Lower sensitivity of DS, which targets established high-confidence resistance variants, was observed for detecting isoniazid-resistance among HIV-infected patients. PMID: ...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
Authors: Méchaï F, Bouchaud O Abstract Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. In 2017, approximately 10 million people developed TB worldwide, of whom more than 100,000 new cases of TBM are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. GeneXpert represents the most significant advance in TBM diagnostics over the past decade, but it lacks sensitivity and cannot be used to rule out ...
Source: Revue Neurologique - Category: Neurology Tags: Rev Neurol (Paris) Source Type: research
We report steady-state CSF concentrations from three patients receiving DLM as part of multidrug-treatment who underwent therapeutic drug monitoring. Drug was quantified using LCMS/MS. In rabbits and humans, mean CSF concentrations (rabbit [1.26 ng/mL at 9h, 0.47 ng/mL at 24h]; human [48 ng/mL at 4h]) were significantly lower than plasma (rabbits [124 ng/mL at 9h, 14.5 ng/mL at 24h]; human [726 ng/mL at 4h]), but estimated free CSF/plasma ratio were>1. In rabbits, brain DLM concentrations were 5-fold higher than in plasma (mean 518 ng/mL at 9h, 74.0 ng/mL at 24h). All patients with XDR-TBM receiving DLM experienced clin...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
In this study, we investigated the potential of RUTI vaccine to control mycobacterial growth ex vivo and demonstrated the capacity of MGIA to aid the identification of essential immune mechanism. We found an association between the peak response of vaccine-induced growth inhibition and a shift in monocyte phenotype following RUTI vaccination in healthy mice. The vaccination significantly increased the frequency of non-classical Ly6C− monocytes in the spleen after two doses of RUTI. Furthermore, mRNA expressions of Ly6C−-related transcripts (Nr4a1, Itgax, Pparg, Bcl2) were upregulated at the peak vaccine respons...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Abstract The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog TBI-166 was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. In...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
This study characterized the pharmacokinetics of novel 100 mg levofloxacin dispersible tablets in 24 children aged
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research
Conclusion: Carrying out a full course of chemotherapy taking into account drug sensitivity MBT with the use of a new generation drug and linezolid allows achieving 82% recovery from tuberculosis.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Tuberculosis Source Type: research
Conclusions: Lower educational levels, immunosuppression, previous TB episodes, other complications (depression, hepatitis, drug use, diabetes and HIV co-infection) had been shown to be associated with disease progression and mortality among MDR-TB cases. New strategies need to be implemented for appropriate MDR-TB detection as well as guarantee for a complete adherence to therapy.
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Tuberculosis Source Type: research
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