Antibiotic heteroresistance in Mycobacterium tuberculosis isolates: a systematic review and meta-analysis

Abstract

Background Mycobacterium tuberculosis (MTB) is responsible for tuberculosis; that continues to be a public health threat across the globe. Furthermore, increasing heteroresistance (HR)-the presence of resistant and susceptible isolates among MTB strains- has been reported from around the world. This phenomenon can lead to full resistance development and treatment failure. Methods We systematically searched the relevant studies in PubMed, Scopus, and Embase (Until October 21, 2020). The study outcomes revealed the weighted pooled prevalence of antibiotic HR in MTB isolates with subgroup analysis by year, quality of study, and heteroresistance detection method. Results A total of 38 studies which had investigated MTB isolates were included in the meta-analysis. Geographically, the highest number of studies were reported from Asia (n = 24), followed by Africa (n = 5). Nineteen studies reported HR to isoniazid, with a weighted pooled prevalence of 5% (95% CI 0–12) among 11,761 MTB isolates. Also, there is no important trend for the subgroup analysis by the study period (2001–2014 vs 2015–2017 vs 2018–2020). HR to rifampin was reported in 17 studies, with a weighted pooled prevalence of 7% (95% CI 2–14) among 3782 MTB isolates. HR to fluoroquinolone and ethambutol were reported in 12 and 4 studies, respectively, with weighted pooled prevalence of 10% and 1% among 2153 and 1509 MTB isolates, correspondingly. Conclusion Based on our analysis, HR in MTB isolates with different frequency rate is present worldwide. Thus, the selection of appropriate and reliable methods for HR detection is crucial for TB eradication.

Inclusion of minor alleles improves catalogue-based prediction of fluoroquinolone resistance inMycobacterium tuberculosis

“…Importantly, this brings the catalogue performance for detecting fluoroquinolone resistance up to the level of isoniazid and rifampicin 4,5 , where the determinants of resistance are also well understood. The magnitude of improvement in sensitivity correlates with the previously estimated 10% frequency of fluoroquinolone resistance conferred by alleles seen in mixed populations 10 . Resistance from minority populations has likewise been implicated for rifampicin, isoniazid and ethambutol 10 , and should be explored further.…”

“…The magnitude of improvement in sensitivity correlates with the previously estimated 10% frequency of fluoroquinolone resistance conferred by alleles seen in mixed populations 10 . Resistance from minority populations has likewise been implicated for rifampicin, isoniazid and ethambutol 10 , and should be explored further.…”

“…Mixed populations are common in M. tuberculosis infections and have been particularly implicated in fluoroquinolone resistance 8,9 ; the prevalence of mixed populations containing minor resistance-conferring alleles is estimated at c. 10% of fluoroquinolone resistant isolates 10 . WGS bioinformatic pipelines often use filters and thresholds to reduce the effect of sequencing errors 7 , which unfortunately also preclude the detection of minor alleles.…”

Rapid Identification of Drug Resistance and Phylogeny in M. tuberculosis, Directly from Sputum Samples

“…The presence of heteroresistant variants in Mtb isolates has been reported worldwide for several clinically important drugs ( 43 ). However, current molecular methods have limited utility in their detection; Xpert and Xpert Ultra can detect heteroresistance greater than 20% and GenoType greater than 5% ( 44 ).…”

Ultrasensitive Detection of Multidrug-Resistant Mycobacterium tuberculosis Using SuperSelective Primer-Based Real-Time PCR Assays

“…Even with the limitations of current tools, the clinical impact of heteroresistant TB is increasingly recognized [ 8 , 11 , 14 , 16 ]. A recent study reported the weighted pooled prevalence of INH heteroresistance (from 19 studies) to be 5% and RIF heteroresistance (from 17 studies) to be 7% from 2001 to 2020 [ 17 ]. Among South African TB patients, heteroresistant infections identified by the mycobacterial interspersed repetitive units variable number of tandem repeat (MIRU-VNTR) genotyping were associated with a 90% increase in the odds of delayed sputum conversion after 2 months of treatment [ 18 ], a critical treatment endpoint for TB control programs (and related to the risk of ongoing transmission in the community).…”