Resistance to Linezolid and Pretomanid in the Era of Modern Drug-Resistant Tuberculosis Treatment in South Africa: A Systematic Review and Meta-Analysis

Abstract

Background: The success of modern drug-resistant tuberculosis (DR-TB) regimens increasingly depends on linezolid (LZD) and pretomanid (Pa), yet the emergence of resistance to these critical agents threatens to reverse recent treatment advances, with limited consolidated evidence available from high-burden settings such as South Africa. Objectives: To systematically review and meta-analyse South African data on LZD and Pa resistance, minimum inhibitory concentrations (MICs), resistance-associated mutations, and treatment outcomes. Eligibility Criteria: We included clinical trials, cohort studies, surveillance studies, and molecular investigations conducted in South Africa from 2013 onward that reported resistance prevalence, MIC data, genotypic mutations, or treatment outcomes related to LZD and/or Pa. Information Sources: PubMed, PubMed, Embase, Web of Science, and grey literature sources were searched from January 2013 to 31 December 2025 in accordance with PRISMA 2020 guidelines. Risk of Bias: Study quality was assessed using the Joanna Briggs Institute (JBI) cohort appraisal checklist. Included Studies: Seventeen studies representing provincial and national cohorts were included. Synthesis of Results: Random-effects meta-analysis was used to estimate pooled baseline resistance. Subgroup, sensitivity, and meta-regression analyses were performed. Results: Random-effects meta-analysis demonstrated a pooled baseline LZD resistance prevalence of 0.53% (95% CI: 0.01–1.83; I2 = 81.1%) in routine South African cohorts, while substantially higher resistance (33%) was observed in treatment-failure populations. Baseline LZD MICs were typically 0.125–1.0 µg/mL, while elevated MICs (up to 8.0 µg/mL) were associated with rplC and rrl mutations, particularly rplC Cys154Arg. No confirmed phenotypic Pa resistance was identified across included South African cohorts, despite the detection of resistance-associated mutations in genomic surveillance studies. MIC values remained within the range of 0.016–1.0 µg/mL. Mutations in ddn, fbiA, fbiC, and fgd1 were reported in genomic studies. Treatment success rates ranged from 63.6% to 99% for LZD-containing regimens and approached 90% for Pa-based regimens. Limitations: Limited study numbers, heterogeneity in laboratory methods, and overrepresentation of certain provinces may affect generalizability. Conclusions: Baseline resistance to LZD and Pa in South Africa remains low, supporting continued programmatic use. Ongoing molecular surveillance is essential to detect resistance amplification and preserve regimen efficacy.