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 (I² = 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.