Profile and Frequency of Mutations Conferring Drug-Resistant Tuberculosis in the Central, Southeastern and Eastern Ethiopia

Abstract

Purpose Advances in molecular tools that assess genes harboring drug resistance mutations have greatly improved the detection and treatment of drug-resistant tuberculosis (DR-TB). This study was conducted to determine the frequency and type of mutations that are responsible for resistance to rifampicin (RIF), isoniazid (INH), fluoroquinolones (FLQs) and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis (MTB) isolates obtained from culture-positive pulmonary tuberculosis (TB) patients in the central, southeastern and eastern Ethiopia. Patients and Methods In total, 224 stored culture-positive MTB isolates from pulmonary TB patients referred to Adama and Harar regional TB laboratories between August 2018 and January 2019 were assessed for mutations conferring RIF, INH, FLQs and SLIDs resistance using GenoType ® MTBDRplus (MTBDRplus) and GenoType ® MTBDRsl (MTBDRsl). Results RIF, INH, FLQs and SLIDs resistance-conferring mutations were identified in 88/224 (39.3%), 85/224 (38.0%), 7/77 (9.1%), and 3/77% (3.9%) of MTB isolates, respectively. Mutation codons rpoB S531L (59.1%) for RIF, katG S315T (96.5%) for INH, gyrA A90V (42.1%) for FLQs and WT1 rrs (100%) for SLIDs were observed in the majority of the isolates tested. Over a 10th of rpoB mutations detected in the current study were unknown. Conclusion In this study, the most common mutations conferring drug resistance to RIF, INH, FLQs were identified. However, a significant proportion of RIF-resistant isolates manifested unknown rpoB mutations. Similarly, although few in number, all SLID-resistant isolates had unknown rrs mutations. To further elucidate the entire spectrum of mutations, tool such as whole-genome sequencing is imperative. Furthermore, the expansion of molecular drug susceptibility testing services is critical for tailoring patient treatment and preventing disease transmission.

Patterns and profiles of drug resistance-conferring mutations in Mycobacterium tuberculosis genotypes isolated from tuberculosis-suspected attendees of spiritual holy water sites in Northwest Ethiopia

“…Similarly, in the current study, amongst INH-resistant isolates, mutations in the kat G was most frequent at codon Ser315Thr1 (95%), while no inh A gene mutation was observed. In agreement with our findings, a recent multicenter study in Ethiopia reported a prevalence of 91.8% for kat G/Ser315Thr1 mutation ( 45 ), and a meta-analysis study that examined INH conferring gene mutations noted a prevalence of 95.8% for kat G315 mutation ( 21 ). The kat G/Ser315Thr1 gene mutation, causing high-level INH resistance was predominant (95%) in the current study and other earlier studies in different parts of Ethiopia ( 21 , 45–48 , 55 , 56 , 61 ).…”

“…In this study, two RIF-resistant isolates ( rpo BWT6 and rpo BWT7) had shown a mutation or missing WT band, but no corresponding MUT band, and were classified as unknown genetic changes. This proportion of isolates with unknown mutations is similar to other studies from a recent multicenter study, Ethiopia (13.6%) ( 45 ), Addis Ababa, Ethiopia (15.8%) ( 55 ), Southern Ethiopia (14.7%) ( 56 ), and elsewhere, a large, multisite diagnostic study (13%) ( 57 ). This could be due to the mutations occurring outside the analyzed codon regions (drug-resistance determining regions) which LPAs unable to evaluate/detect ( 58 ).…”

“…In line with our result, a higher frequency of mutation at codon S531L was reported in other high TB burden countries like China (58%) ( 50 ), India (62%) ( 51 ), Pakistan (64%) ( 52 ), Sudan (64%) ( 53 ), and Iran (66%) ( 54 ). The other mutation in our study, His526Tyr was previously reported in Ethiopia, which ranged from 6.6–17.2% ( 21 , 44 , 45 , 55 ), Sudan (12.8%) ( 53 ), India (11.1%) ( 51 ), and China (8.9%) ( 50 ). However, a similar or higher proportion to our results was noted in Sudan (12.8%) ( 53 ), India (11.1%) ( 51 ), China (8.9%) ( 50 ), South Africa, at amino acid position 526 (27.9%) ( 36 ).…”

“…In this study, among RIF-resistant TB isolates, the most frequent mutation (80%) associated with RIF resistance was at codon S531L, followed by His526Tyr (6.7%). The gene mutation at codon S531L was noted as the dominant mutation of the rpo B gene responsible for RIF resistance in several previous studies done in different parts of Ethiopia; which includes the Amhara region (73%) ( 46 ), Tigray region (70%) ( 44 ), Somali region (80%) ( 47 ), Addis Ababa (81.3%) ( 48 ), Southwest Ethiopia (82.4%) ( 49 ), a meta-analysis report, Ethiopia (74.2%) ( 21 ), and a recent multicenter study report, Ethiopia (59.1%) ( 45 ). In line with our result, a higher frequency of mutation at codon S531L was reported in other high TB burden countries like China (58%) ( 50 ), India (62%) ( 51 ), Pakistan (64%) ( 52 ), Sudan (64%) ( 53 ), and Iran (66%) ( 54 ).…”

Acquired bedaquiline and fluoroquinolones resistance during treatment follow-up in Oromia Region, North Shewa, Ethiopia

“…Additionally, in this case report, we identified the gyrA mutation at codon A90V , which was responsible for FQs resistance in MTB isolates. This mutation was also the most common type in the previous studies in Central, and Southeastern Ethiopia and a laboratory-based surveillance study in Ethiopia [21] , [22] . In this case report, the development of second-line drug gene mutations in a drug-resistant MTB strain may be due to several factors, such as poor adherence to medication, drug malabsorption, incomplete or irregular treatment, inappropriate drug selection, dosing errors, or treatment duration, which can also contribute to the development of drug resistance [23] .…”