Prevalence, Antimicrobial Resistance, and Genetic Diversity of Non‐Typeable Streptococcus pneumoniae Carriage: A Systematic Review and Meta‐Analysis

Background Non‐typeable Streptococcus pneumoniae (NT‐Sp) strains lack detectable capsules and are often missed by traditional serotyping. While associated primarily with asymptomatic carriage, NT‐Sp has emerged as a key player in antimicrobial resistance (AMR) gene dissemination and serotype replacement in the post‐vaccine era. This systematic review and meta‐analysis synthesize global evidence on NT‐Sp carriage, its prevalence, antimicrobial resistance patterns, and genetic diversity. Methods A systematic search of PubMed, Scopus, Web of Science, Google Scholar, and ScienceDirect was conducted up to May 2025. Eligible studies reporting NT‐Sp carriage, molecular typing, or AMR profiles were included. Data extraction and quality assessment followed PRISMA guidelines. A meta‐analysis was performed to estimate pooled prevalence of NT‐Sp carriage and resistance, with subgroup and meta‐regression analyses exploring heterogeneity. Methodological quality was assessed using the Newcastle–Ottawa Scale adapted for cross‐sectional studies. Only open‐access and free full‐text articles were included, which may have introduced selection bias. Results Forty studies from 23 countries were included. The pooled NT‐Sp carriage prevalence was 4.64% (95% CI: 2.78%–6.92%), with substantial heterogeneity ( I 2 = 97.1%, 95% CI: 96.6%–97.5%). Subgroup analyses revealed geographic variation, with Oceania showing the highest prevalence (7.24%, 95% CI: 1.39%–17.04%) and North America the lowest (0.44%, 95% CI: 0.05%–1.11%). Age‐stratified analysis showed that studies, including all ages had the highest estimate (29.88%, 95% CI: 0.00%–100.00%), while children had a pooled prevalence of 4.05% (95% CI: 0.00%–15.80%). Vaccination era did not significantly influence NT‐Sp carriage ( p = 0.312). Resistance was highest for co‐trimoxazole (67.21%, 95% CI: 49.92%–82.73%), penicillin (44.57%, 95% CI: 24.45%–65.50%), and erythromycin (39.85%, 95% CI: 19.58%–61.77%). Meta‐regression identified the “all ages” participant category as a significant predictor of lower NT‐Sp prevalence ( p = 0.034). Molecular tools revealed substantial genomic diversity, with dominant clonal complexes varying by region. Conclusion NT‐Sp is a globally distributed and genetically diverse pneumococcal subset with considerable AMR potential. Its persistence post‐PCV introduction and resistance gene carriage highlights the need for improved detection, molecular surveillance, and consideration in next‐generation vaccine development. Specifically, clinical laboratories in high‐prevalence settings should adopt molecular methods (e.g., PCR or WGS) to detect NT‐Sp in carriage surveillance; empirical antibiotic guidelines for pediatric respiratory infections should consider NT‐Sp resistance patterns, particularly the high prevalence of co‐trimoxazole resistance (67%) and next‐generation PCV trials should include NT‐Sp carriage as an exploratory endpoint. Integrating NT‐Sp into global pneumococcal control strategies is essential.