Global Status of Ethambutol Resistance in Mycobacterium tuberculosis Clinical Isolates: An Updated Systematic Review and Meta-Analysis

Abstract

Ethambutol (EMB) serves as a critical first-line antimycobacterial agent pivotal in the management of Mycobacterium tuberculosis. The emergence of resistance to EMB, primarily driven by mutations in the embB gene, constitutes a formidable challenge to global tuberculosis (TB) eradication efforts. This meta-analysis followed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and synthesized data from multiple databases, including PubMed, Embase, MEDLINE, Web of Science, and Elsevier Science, through August 2024. The selection criteria targeted studies reporting the prevalence and patterns of EMB resistance, utilizing both phenotypic and genotypic diagnostic methods. Data were extracted using Microsoft Excel, and statistical analyses were performed with Stata 17.0. Study heterogeneity was evaluated using the I² statistic and Cochran’s Q test. A random-effects model using the DerSimonian–Laird method estimated the pooled prevalence of EMB resistance, with subgroup analyses distinguishing new cases from those with a treatment history exceeding 1 month. Fifty-one studies (34,215 isolates; 2,776 EMB-resistant) were included. The pooled prevalence of EMB resistance was 10% (95% confidence interval [CI]: 8–12%; I² = 92.99%), with substantial regional variation (Africa [15.56%] vs. Southeast Asia [6.60%]). Among multidrug-resistant TB patients, EMB resistance was 54% (95% CI: 45–63%) and reached 68% (95% CI: 65–72%) in the Eastern Mediterranean; previously treated patients had higher resistance than new cases (31% vs. 13%). Only 12 studies reported codon-specific embB data eligible for pooling, with embB306 most frequently reported and notable regional gaps for embB406/497 (e.g., Americas ND; Europe lacking 406/497). The study identifies substantial regional variations in EMB resistance and the prevalence of specific embB mutations. However, uneven regional representation (particularly limited data from Africa and the Americas) may affect the precision of global estimates. Enhancing diagnostic accuracy through molecular methods and developing regional surveillance systems are essential for effective management of EMB-resistant TB. Future research should prioritize comprehensive genomic analyses to identify novel resistance mutations and advance diagnostic methodologies. Future studies should adopt whole-genome sequencing and standardized codon-level reporting to enable comprehensive mutation profiling and improve comparability across surveillance systems.