Frequency and patterns of first- and second-line drug resistance-conferring mutations in Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in a cross-sectional study in Tigray Region, Ethiopia

Welekidan, Letemichael Negash; Skjerve, Eystein; Dejene, Tsehaye Asmelash; Gebremichael, Mengistu Welday; Brynildsrud, Ola Brønstad; Tønjum, Tone; Yimer, Solomon Abebe

doi:10.1016/j.jgar.2020.11.017

Cited by 14 publications

(34 citation statements)

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“…Our findings may help clinicians in managing patients carrying isolates with disputed rpoB mutations to halt transmission of DR-TB and ultimately contribute to the attainment of 100% DST coverage for TB patients, as per the WHO End TB Strategy. According to the WGS analysis, 96.2% of mutations that confer INH-resistance occurred at katG codon S315T, which differed from our previous study that reported a 78% mutation at katG codon S315T and 19.5% unknown mutations using LPA (Welekidan et al, 2021).…”

Section: Discussioncontrasting

confidence: 95%

“…In sub-Saharan Africa, studies reporting the occurrences of disputed rpoB mutations by utilizing WGS are very limited. In the current study, a significant proportion of disputed mutations (16%) that cause RIF-resistance was observed at rpoB codons H445N, D435Y, and L430P, which were not detected in our previous study using the WHO recommended LPA analysis ( Welekidan et al, 2021 ). The 20% of RIF resistance-conferring mutations were unknown using LPA ( Welekidan et al, 2021 ).…”

Section: Discussioncontrasting

confidence: 63%

“…In the current study, a significant proportion of disputed mutations (16%) that cause RIF-resistance was observed at rpoB codons H445N, D435Y, and L430P, which were not detected in our previous study using the WHO recommended LPA analysis ( Welekidan et al, 2021 ). The 20% of RIF resistance-conferring mutations were unknown using LPA ( Welekidan et al, 2021 ). The occurrence of disputed rpoB mutations is clinically and epidemiologically highly relevant ( Van Deun et al, 2013 ).…”

Section: Discussioncontrasting

confidence: 63%

“…In our previous study report, DR-conferring mutations to 2nd-line anti-TB drugs developed at gyr A gene codon D94G, D94Y/N, and A90V, but mutations that confer resistance to SLIDs were not reported by LPA ( Welekidan et al, 2021 ). However, the present study showed mutations at gyr A gene codon D94G and mutations to SLIDs.…”

Section: Discussionmentioning

confidence: 99%

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Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia

et al. 2021

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Background: Tuberculosis, mainly caused by Mycobacterium tuberculosis (Mtb), is an ancient human disease that gravely affects millions of people annually. We wanted to explore the genetic diversity and lineage-specific association of Mtb with drug resistance among pulmonary tuberculosis patients.Methods: Sputum samples were collected from pulmonary tuberculosis patients at six different healthcare institutions in Tigray, Ethiopia, between July 2018 and August 2019. DNA was extracted from 74 Mtb complex isolates for whole-genome sequencing (WGS). All genomes were typed and screened for mutations with known associations with antimicrobial resistance using in silico methods, and results were cross-verified with wet lab methods.Results: Lineage (L) 4 (55.8%) was predominant, followed by L3 (41.2%); L1 (1.5%) and L2 (1.5%) occurred rarely. The most frequently detected sublineage was CAS (38.2%), followed by Ural (29.4%), and Haarlem (11.8%). The recent transmission index (RTI) was relatively low. L4 and Ural strains were more resistant than the other strains to any anti-TB drug (P < 0.05). The most frequent mutations to RIF, INH, EMB, SM, PZA, ETH, FLQs, and 2nd-line injectable drugs occurred at rpoB S450L, katG S315T, embB M306I/V, rpsL K43R, pncA V139A, ethA M1R, gyrA D94G, and rrs A1401G, respectively. Disputed rpoB mutations were also shown in four (16%) of RIF-resistant isolates.Conclusion: Our WGS analysis revealed the presence of diverse Mtb genotypes. The presence of a significant proportion of disputed rpoB mutations highlighted the need to establish a WGS facility at the regional level to monitor drug-resistant mutations. This will help control the transmission of DR-TB and ultimately contribute to the attainment of 100% DST coverage for TB patients as per the End TB strategy.

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Section: Discussioncontrasting

confidence: 95%

Section: Discussioncontrasting

confidence: 63%

Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia

et al. 2021

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“…ahpC mutations as compensatory mutations associated with katG Ser315Thr) [35] and successful transmission and clonal expansion of these drug-resistant strains [36]. Our findings are in line with the acquisition of drug resistance-conferring mutations in KZN [19] where the introduction of INH in the 1950s [37] and ineffective single drug treatments allowed clonal expansion of INH-resistant strains [36]. The introduction of RIF without systematic screening for drug resistance contributed to the MDR-TB epidemic and the introduction of SLIDs and FQs [38] for treatment of MDR-TB in the absence of an efficient DST programme gave rise to the first XDR-TB outbreak in 2006.…”

Section: Discussion Transmission Dynamicsmentioning

confidence: 99%

Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa

et al. 2022

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Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance to at least isoniazid (INH), rifampicin (RIF), a fluoroquinolone (FQ) and a second-line injectable drug (SLID), is difficult to treat and poses a major threat to TB control. The transmission dynamics and distribution of XDR Mycobacterium tuberculosis (Mtb) strains have not been thoroughly investigated. Using whole genome sequencing data on 461 XDR-Mtb strains, we aimed to investigate the geographical distribution of XDR-Mtb strains in the Western Cape Province of South Africa over a 10 year period (2006–2017) and assess the association between Mtb sub-lineage, age, gender, geographical patient location and membership or size of XDR-TB clusters. First, we identified transmission clusters by excluding drug resistance-conferring mutations and using the 5 SNP cutoff, followed by merging clusters based on their most recent common ancestor. We then consecutively included variants conferring resistance to INH, RIF, ethambutol (EMB), pyrazinamide (PZA), SLIDs and FQs in the cluster definition. Cluster sizes were classified as small (2–4 isolates), medium (5–20 isolates), large (21–100 isolates) or very large (>100 isolates) to reflect the success of individual strains. We found that most XDR-TB strains were clustered and that including variants conferring resistance to INH, RIF, EMB, PZA and SLIDs in the cluster definition did not significantly reduce the proportion of clustered isolates (85.5–82.2 %) but increased the number of patients belonging to small clusters (4.3–12.4 %, P=0.56). Inclusion of FQ resistance-conferring variants had the greatest effect, with 11 clustered isolates reclassified as unique while the number of clusters increased from 17 to 37. Lineage 2 strains (lineage 2.2.1 typical Beijing or lineage 2.2.2 atypical Beijing) showed the large clusters which were spread across all health districts of the Western Cape Province. We identified a significant association between residence in the Cape Town metropole and cluster membership (P=0.016) but no association between gender, age and cluster membership or cluster size (P=0.39). Our data suggest that the XDR-TB epidemic in South Africa probably has its origin in the endemic spread of MDR Mtb and pre-XDR Mtb strains followed by acquisition of FQ resistance, with more limited transmission of XDR Mtb strains. This only became apparent with the inclusion of drug resistance-conferring variants in the definition of a cluster. In addition to the prevention of amplification of resistance, rapid diagnosis of MDR, pre-XDR and XDR-TB and timely initiation of appropriate treatment is needed to reduce transmission of difficult-to-treat TB.

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

Diriba,

Alemu,

Ayano

et al. 2024

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Frequency and patterns of first- and second-line drug resistance-conferring mutations in Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in a cross-sectional study in Tigray Region, Ethiopia

Cited by 14 publications

References 33 publications

Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia

Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia

Transmission, distribution and drug resistance-conferring mutations of extensively drug-resistant tuberculosis in the Western Cape Province, South Africa

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

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