Ethambutol (EMB) continues to be used as part of a standard drug regimen for the treatment of tuberculosis (TB). Mutations in the embB gene and those within its conserved EMB resistance determining region (ERDR) in particular have repeatedly been associated with resistance to EMB in Mycobacterium tuberculosis. The aim of this study was to examine the mutational “hot spots” in the embB gene, including the ERDR, among multidrug-resistant (MDR) M. tuberculosis clinical isolates and to find a possible association between embB mutations and resistance to EMB. An 863-bp fragment of the embB gene was sequenced in 17 EMB-resistant and 33 EMB-susceptible MDR-TB isolates. In total, eight embB mutation types were detected in 6 distinct codons of 27 (54%) M. tuberculosis isolates. Mutations in codon 306 were most common, found in both EMB-resistant (9) and EMB-susceptible (11) isolates. Only mutations in codons 406 and 507 were found exclusively in four and one EMB-resistant isolates, respectively. Sequence analysis of the ERDR in the embB gene is not sufficient for rapid detection of EMB resistance, and the codon 306 mutations are not good predictive markers of resistance to EMB.

/pdf/mutations-in-the-embb-gene-and-their-association-with-54k8txio58.pdf

Mutations in the embB gene and their association with ethambutol resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates from Poland.

Analysisof embCAB mutations associated with ethambutol resistance inmultidrug-resistant Mycobacterium tuberculosis isolates from China

Ethambutol (EMB) is a first-line antituberculosis drug; however, drug resistance to EMB has been increasing. Molecular drug susceptibility testing (DST), based on the embB gene, has recently been used for rapid identification of EMB resistance. The aim of this meta-analysis was to establish the accuracy of molecular assay for detecting drug resistance to EMB. PubMed, Embase, and Web of Science were searched according to a written protocol and explicit study selection criteria. Measures of diagnostic accuracy were pooled using a random effects model. A total of 34 studies were included in the meta-analysis. The respective pooled sensitivities and specificities were 0.57 and 0.93 for PCR-DNA sequencing that targeted the embB 306 codon, 0.76 and 0.89 for PCR-DNA sequencing that targeted the embB 306, 406, and 497 codons, 0.64 and 0.70 for detecting Mycobacterium tuberculosis isolates, 0.55 and 0.78 for detecting M. tuberculosis sputum specimens using the GenoType MTBDRsl test, 0.57 and 0.87 for pyrosequencing, and 0.35 and 0.98 for PCR-restriction fragment length polymorphism. The respective pooled sensitivities and specificities were 0.55 and 0.92 when using a lower EMB concentration as the reference standard, 0.67 and 0.73 when using a higher EMB concentration as the reference standard, and 0.60 and 1.0 when using multiple reference standards. PCR-DNA sequencing using multiple sites of the embB gene as detection targets, including embB 306, 406, and 497, can be a rapid method for preliminarily screening for EMB resistance, but it does not fully replace phenotypic DST. Of the reference DST methods examined, the agreement rates were the best using MGIT 960 for molecular DST and using the proportion method on Middlebrook 7H10 media.

Diagnostic Accuracy of a Molecular Drug Susceptibility Testing Method for the Antituberculosis Drug Ethambutol: a Systematic Review and Meta-Analysis

Underestimation of the resistance of Mycobacterium tuberculosis to second-line drugs by the new GenoType MTBDRsl test.

Molecular characterization of drug-resistant and -susceptible Mycobacterium tuberculosis isolated from patients with tuberculosis in Korea.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE. METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards. RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research. CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Clinical standards for the management of adverse effects during treatment for TB

OBJECTIFS: Mener une enquete basee sur la population pour caracteriser le genotype et le phenotype des bacilles tuberculeux resistants aux medicaments pendant l'annee 2004/2005 dans deux comtes ruraux en Chine ou la duree d'implantation du DOTS etait differente: Deqing et Guanyung METHODES: Les souches de Mycobacterium tuberculosis ont ete isolees chez respectivement 164 et 187 patients enregistres dans les dispensaires de tuberculose (TB) locaux a Deqing et Guanyung On a realise sur ces isolats le profil de la sensibilite aux medicaments et le sequencage de l'ADN RESULTATS: Au total, une resistance aux medicaments de premiere ligne a ete mise en evidence dans 223 isolats provenant de 223 patients et parmi ceux-ci, une multi-resistance (MDR, resistance simultanee a l'isoniazide [INH] et a la rifampicine [RMP]) dans 53 isolats On a mis en evidence des mutations du katG, toujours au niveau du codon 315 dans 81 des 131 isolats resistants a l'INH (61,8%) Les mutations en rapport avec la resistance a la RMP sont survenues principalement au niveau des codons 531, 526 et 516 du gene rpoB Une mutation du gene rpsL au niveau des codons 43 ou 88 existait dans 78 des 115 isolats resistants a la streptomycine Une mutation au niveau du codon 306 de embB existait respectivement dans 21 isolats resistants a l'ethambutol et dans 19 isolats sensibles a ce medicament CONCLUSIONS: Nos donnees demontrent qu'en Chine rurale le sequencage de l'ADN au niveau des codons specifiques du gene rpoB peut permettre de predire efficacement la resistance a la RMP et la MDR

Genetic characterisation of drug-resistant Mycobacterium tuberculosis in rural China: a population-based study

1The Fifth People’s Hospital of Suzhou, Infectious Disease Hospital Affiliated to Soochow University, Suzhou, 2School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai, China; 3Faculty of Medicine and Health, School of Pharmacy, University of Sydney, Sydney, NSW, 4Westmead Hospital, Sydney, NSW, 5Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia

Successful treatment of patients severely ill with COVID-19.

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Clinical standards for the management of adverse effects during treatment for TB

Genetic characterisation of drug-resistant Mycobacterium tuberculosis in rural China: a population-based study

Successful treatment of patients severely ill with COVID-19.