Abstract
Pakistan ranks 5th among the world's highest tuberculosis (TB) burden countries alongside the 6th among countries with the highest burden of drug-resistant TB, including multi-drug resistant (MDR)-TB. Methods for rapid and reliable drug susceptibility testing (DST) are prerequisite for the prompt institution of effective anti-TB treatment. The aim of this study was to evaluate the efficiency of Genotype MTBDRplus and MTBDRsl assays for the detection of MDR and (pre-) extensively drug-resistant (XDR-TB) isolates in Pakistan. The study included 47 pre-XDR and 6 XDR-TB isolates, recovered from 53 patients from Pakistan. Conventional DST was performed using the standard 1% proportion method on the Löwenstein-Jensen medium. For molecular determination of drug resistance, GenoType MTBDRplus and GenoType MTBDRsl assays (Hain Lifescience, Germany) were used. To evaluate discrepancies between conventional and molecular DST results, mutation profiling was performed by amplifying and sequencing seven genetic loci, i.e., katG, inhA, and mabA-inhA promoter, rpoB, gyrA, embB, rrs. The sensitivity of Genotype MTBDRplus was 71.7% for isoniazid (INH) and 79.2% for rifampicin (RIF). Sequence analysis revealed non-synonymous mutations in 93.3 and 27.3% of isolates phenotypically resistant to INH and RIF, respectively, albeit susceptible when tested by GenoType MTBDRplus. GenoType MTBDRsl had a sensitivity of 73.6, 64.7, 20, 25, and 100% for the detection of fluoroquinolones, ethambutol, kanamycin, amikacin, and capreomycin resistance, respectively. Upon sequencing, mutations were detected in 20, 77.8%, and all isolates phenotypically resistant to aminoglycosides, ethambutol, and fluoroquinolones, respectively, yet declared as susceptible with GenoType MTBDRsl. Low sensitivities seriously impede the large-scale application of the Genotype MTBDRplus and MTBDRsl assays. Unless further optimized, the currently available line-probe assays should rather be auxiliary to the conventional, phenotype-based methods in the detection of MDR- and XDR-TB in Pakistan.
Highlights
Tuberculosis (TB) remains an inglorious leader among infectious diseases in mortality, with its annual toll of 1.5 million lives worldwide (Ullah et al, 2016)
The aim of the study was to evaluate the efficiency of Genotype MTBDRplus and MTBDRsl assays in the detection of drug
Forty-seven (47/53; 88.7%) isolates were resistant to OFX and not to any other secondline injectable drug (SLID), meeting the definition of pre-XDR-TB
Summary
Tuberculosis (TB) remains an inglorious leader among infectious diseases in mortality, with its annual toll of 1.5 million lives worldwide (Ullah et al, 2016). According to a most recent World Health Organization (WHO) report, every seventeenth TB patient expels MDR bacilli. One in sixteen of such patients expel strains of XDR phenotype (World Health Organization, 2017). Pakistan, with a population of 193 million people, continues to be on the top of the list high TB-burden countries (HBCs), in terms of total TB caseload (TB incidence rate, 268 per 100,000 population) and in terms of DRTB, including MDR-TB (MDR-TB incidence rate, 14 per 100,000 population), globally (World Health Organization, 2017). Studies on the prevalence of DR-TB, including MDR-TB and XDRTB in Pakistan are quite scarce and fragmentary (Ali et al, 2011, 2015; Farooqi et al, 2012; Javaid et al, 2016). The true prevalence of DR-TB is thought to be underestimated, mostly due to a limited number of facilities offering drug susceptibility testing (DST) and poor availability of modern and advanced technologies, allowing for fast and reliable drug resistance profiling (Domínguez et al, 2016)
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