Detection of Second Line Drug Resistance among Drug Resistant Mycobacterium Tuberculosis Isolates in Botswana

Mogashoa, Tuelo; Melamu, Pinkie; Derendinger, Brigitta; Ley, Serej D.; Streicher, Elizabeth; Iketleng, Thato; Mupfumi, Lucy; Mokomane, Margaret; Kgwaadira, Botshelo; Rankgoane-Pono, Goabaone; Tsholofelo, Thusoyaone T.; Kasvosve, Ishmael; Moyo, Sikhulile; Warren, Robin M.; Gaseitsiwe, Simani

doi:10.3390/pathogens8040208

Cited by 9 publications

(6 citation statements)

References 27 publications

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“…moxifloxacin) can be used at a higher dose. However, if the D94G mutation is present, both levofloxacin and moxifloxacin are ineffective [20]. Additional mutations found in our isolates were S91P, D94A, and D94N/Y.…”

Section: Discussionmentioning

confidence: 64%

Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

et al. 2020

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Background: Fluoroquinolones (FQs) are potential drugs that inhibit DNA synthesis and are used in the treatment of multidrug-resistant tuberculosis (TB) and short-term anti-TB regimens. In recent years, a high proportion of FQ resistance has been observed in Mycobacterium tuberculosis isolates. The development of FQ resistance in multidrug-resistant TB negatively impacts patient treatment outcome and is a serious threat to control of TB. Methods: The study included a total of 562 samples from patients with pulmonary TB that had been on antituberculosis therapy. MTBDRsl assays were performed for the molecular detection of mutations. Sequence analysis was performed for the characterization and mutational profiling of FQ-resistant isolates. Results: FQ resistance was observed in 104 samples (18.5%), most of which were previously treated and treatment failure cases. A total of 102 isolates had mutations in DNA gyrase subunit A (gyrA), while mutations in gyrB were observed in only two isolates. Mutational analysis revealed that the mutations mostly alter codons 94 (replacing aspartic acid with glycine, D94G) and 90 (replacing alanine with valine, A90V). In MDR and treatment failure cases, resistance to FQs was most commonly associated with the D94G mutation. In contract, a high proportion of A90V mutations were observed in isolates that were newly diagnosed. Conclusion: The findings suggest that genotypic assays for FQ resistance should be carried out at the time of initial diagnosis, before starting treatment, in order to rule out mutations that impact the potential use of FQs in treatment and to control drug resistance.

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Section: Discussionmentioning

confidence: 64%

Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

et al. 2020

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“…Among the four genes we considered to describe the molecular characterization of second-line drug resistance of which D94G in the gyrA gene for FQ and A1401G in the rrs gene for IA were the most prevalent resistance-conferring mutations to SLD. Resistance to FQ was conferred by mutations in the QRDR documented by previous studies [ 16 – 18 ].…”

Section: Discussionmentioning

confidence: 89%

Molecular characterisation of second-line drug resistance among drug resistant tuberculosis patients tested in Uganda: a two and a half-year’s review

et al. 2022

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Background Second-line drug resistance (SLD) among tuberculosis (TB) patients is a serious emerging challenge towards global control of the disease. We characterized SLD-resistance conferring-mutations among TB patients with rifampicin and/or isoniazid (RIF and/or INH) drug-resistance tested at the Uganda National TB Reference Laboratory (NTRL) between June 2017 and December 2019. Methods This was a descriptive cross-sectional secondary data analysis of 20,508 M. tuberculosis isolates of new and previously treated patients’ resistant to RIF and/or INH. DNA strips with valid results to characterise the SLD resistance using the commercial Line Probe Assay Genotype MTBDRsl Version 2.0 Assay (Hain Life Science, Nehren, Germany) were reviewed. Data were analysed with STATAv15 using cross-tabulation for frequency and proportions of known resistance-conferring mutations to injectable agents (IA) and fluoroquinolones (FQ). Results Among the eligible participants, 12,993/20,508 (63.4%) were male and median (IQR) age 32 (24–43). A total of 576/20,508 (2.8%) of the M. tuberculosis isolates from participants had resistance to RIF and/or INH. These included; 102/576 (17.7%) single drug-resistant and 474/576 (82.3%) multidrug-resistant (MDR) strains. Only 102 patients had test results for FQ of whom 70/102 (68.6%) and 01/102 (0.98%) had resistance-conferring mutations in the gyrA locus and gyrB locus respectively. Among patients with FQ resistance, gyrAD94G 42.6% (30.0–55.9) and gyrA A90V 41.1% (28.6–54.3) mutations were most observed. Only one mutation, E540D was detected in the gyrB locus. A total of 26 patients had resistance-conferring mutations to IA in whom, 20/26 77.0% (56.4–91.0) had A1401G mutation in the rrs gene locus. Conclusions Our study reveals a high proportion of mutations known to confer high-level fluoroquinolone drug-resistance among patients with rifampicin and/or isoniazid drug resistance. Utilizing routinely generated laboratory data from existing molecular diagnostic methods may aid real-time surveillance of emerging tuberculosis drug-resistance in resource-limited settings.

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“…moxifloxacin can be used at higher dose. But if there is mutation at D94G both levofloxacin and moxifloxacin are ineffective [20] (GLI guideline Line probe assay). S91P, D94A, and D94N/Y were other mutations found in our isolates.…”

Section: Discussionmentioning

confidence: 99%

Fluoroquinolone resistance and mutational profile of gyrA gene in pulmonary MDR tuberculosis patients

Kabir

Tahir

Mukhtar

et al. 2020

Preprint

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Background Flouroquinolones (FQs) are the potential drugs that inhibit DNA synthesis and used in the treatment of MDR-TB and anti-TB short term regimens. In recent year’s high proportion of flouroquinolone (FQs) resistance in Mycobacterium tuberculosis isolates has been observed. The development of FQs resistance among multidrug resistant TB (Pre-XDR TB) negatively impact patient treatment outcome and is a serious threat to control TB. Methods A total of 562 samples were included in the study from patients with pulmonary TB which had been on anti-tuberculosis therapy. MTBDRsl assay was performed for molecular detection of mutations. Sequence analysis was performed for characterization and mutational profiling of FQ resistant isolates. Results FQs resistance was observed in 104 (18.5%) samples and most of them were previously treated and treatment failure cases. A total of 102 isolates had mutations in gyrA gene while gyrB gene mutations were observed in only two isolates. Mutational analysis showed that the mutations mostly alter protein at codon 94 (D94G) (represents the replacement of aspartic acid with glycine) and 90 (A90V) (substitution of alanine with valine). In MDR and treatment failure cases, the FQs-R was most commonly associated with D94G mutation. Whereas, a high proportion of A90V mutation was observed in MTB isolates which were newly diagnosed. Conclusion The findings suggest that the genotypic studies for FQs resistance should be carried out at the time of initial diagnosis, before starting treatment, to rule out all type of mutations for its potential use in treatment to control the resistance.

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Detection of Second Line Drug Resistance among Drug Resistant Mycobacterium Tuberculosis Isolates in Botswana

Cited by 9 publications

References 27 publications

Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

Molecular characterisation of second-line drug resistance among drug resistant tuberculosis patients tested in Uganda: a two and a half-year’s review

Fluoroquinolone resistance and mutational profile of gyrA gene in pulmonary MDR tuberculosis patients

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