The role of eis mutations in the development of kanamycin resistance in Mycobacterium tuberculosis isolates from the Moscow region

Gikalo, Marina; Nosova, Elena; Krylova, L. Yu.; Moroz, A. M.

doi:10.1093/jac/dks178

Cited by 52 publications

(43 citation statements)

References 4 publications

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“…The other four specimens were KAN s in both DST runs, indicating that these mutants had MICs below the tested KAN critical concentration. While eis promoter mutations have been well documented to confer only low-level KAN resistance (21,44), recent studies have found M. tuberculosis eis mutants to have broad KAN MIC ranges (0.625 to 32 g/ml) via liquid-based DST methods (45,46). As such, the eis promoter mutants identified in our study may have had MICs around the critical concentration.…”

Section: Rifmentioning

confidence: 63%

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Georghiou

Seifert

Catanzaro

et al. 2016

Antimicrob Agents Chemother

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f Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH r ) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH r specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF r ) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF r specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN r ) specimens, respectively. The eis promoter mutation ؊12T was found in 26% of KAN r and 4% of KAN-susceptible (KAN s ) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.) I n 2014, an estimated 9.6 million people developed tuberculosis (TB), and 1.5 million people died of their infection (1). Although global TB incidence rates have fallen an average of 1.5% per year since 2000, the rise of drug-resistant TB (DR-TB) globally has complicated TB control efforts (1). The World Health Organization (WHO) estimates that as many as 1 in every 20 new, active TB infections is now drug resistant (1). One of the major roadblocks in combating this growing problem has been the lack of diagnostic technology for DR-TB. Current growth-based culture and drug susceptibility testing (DST) methods can take several weeks to months to yield results (2). While waiting on culture results, physicians are forced to treat their patients empirically, adjusting treatment regimens only once DST results become available. As a result, many undiagnosed DR-TB patients are being given medications that are ineffective, which amplifies resistance, increases the risk of mortality, and increases the risk of transmitting DR-TB infections in the community.Rapid molecular diagnostic assays for DR-TB have the p...

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Section: Rifmentioning

confidence: 63%

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Georghiou

Seifert

Catanzaro

et al. 2016

Antimicrob Agents Chemother

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“…In recent studies conducted on clinical strains isolated in Estonia, Vietnam, and South Africa, the sensitivity of the assay for the detection of resistance to KAN was very low (reaching 43% at its maximum) (16,22,23), probably due to the high prevalence of Beijing strains harboring mutations in eis genes not recognized by the assay and responsible for conferring resistance to KAN only, as was shown in Vietnam (23). Absence of cross-resistance to AMK and CAP in strains harboring mutations in the eis promoter region has been recently demonstrated in a genomic study of resistance in Samara, Russia (24), and in another study conducted in Russia (25). In a previous large study conducted in Samara, a significant proportion of Beijing KAN-resistant and AMK-sensitive strains was found to contain mutations in the eis gene but not in the rrs gene (24).…”

Section: Discussionmentioning

confidence: 86%

Diagnostic Accuracy of the GenoType MTBDR sl Assay for Rapid Diagnosis of Extensively Drug-Resistant Tuberculosis in HIV-Coinfected Patients

et al. 2013

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cThe Russian Federation is a high-tuberculosis (TB)-burden country with high rates of Mycobacterium tuberculosis multidrug resistance (MDR) and extensive drug resistance (XDR), especially in HIV-coinfected patients. Rapid and reliable diagnosis for detection of resistance to second-line drugs is vital for adequate patient management. We evaluated the performance of the GenoType MTBDRsl (Hain Lifescience GmbH, Nehren, Germany) assay on smear-positive sputum specimens obtained from 90 HIV-infected MDR TB patients from Russia. Test interpretability was over 98%. Specificity was over 86% for all drugs, while sensitivity varied, being the highest (71.4%) for capreomycin and lowest (9.4%) for kanamycin, probably due to the presence of mutations in the eis gene. The sensitivity of detection of XDR TB was 13.6%, increasing to 42.9% if kanamycin (not commonly used in Western Europe) was excluded. The assay is a highly specific screening tool for XDR detection in direct specimens from HIV-coinfected TB patients but cannot be used to rule out XDR TB.

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“…More needs to be understood about the relationships of these mutations and their CAP-specific MICs to improve the clinically relevant predictive value of molecular diagnostics for detecting phenotypic CAP r . Like the INH r that is caused by both katG and inhA promoter mutations, phenotypic KAN r is caused by mutations in both rrs and the eis promoter (40,41). Due to regional variations in the frequencies of eis and rrs mutations in the KAN r isolates that we observed, we predict that rapid diagnostic methods, such as the Hain Lifescience MTBDRsl, which detect only rrs SNPs and not eis promoter SNPs, will underestimate KAN r significantly in countries like Moldova (which had mostly eis mutations in KAN r isolates).…”

Section: Discussionmentioning

confidence: 99%

Predicting Extensively Drug-Resistant Mycobacterium tuberculosis Phenotypes with Genetic Mutations

et al. 2014

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The role of eis mutations in the development of kanamycin resistance in Mycobacterium tuberculosis isolates from the Moscow region

Cited by 52 publications

References 4 publications

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape

Diagnostic Accuracy of the GenoType MTBDR sl Assay for Rapid Diagnosis of Extensively Drug-Resistant Tuberculosis in HIV-Coinfected Patients

Predicting Extensively Drug-Resistant Mycobacterium tuberculosis Phenotypes with Genetic Mutations

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