Association of Pneumococcal Serotype With Susceptibility to Antimicrobial Drugs: A Systematic Review and Meta-analysis

Background Pneumococcal serotypes differ in antimicrobial susceptibility. However, patterns and causes of this variation are not comprehensively understood. Methods We undertook a systematic review of epidemiologic studies of pneumococci isolated from carriage or invasive disease among children globally from 2000-2019. We evaluated associations of each serotype with nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. We evaluated differences in the prevalence of nonsusceptibility to major antibiotic classes across serotypes using random-effects meta-regression models and assessed changes in prevalence of nonsusceptibility after implementation of pneumococcal conjugate vaccines (PCVs). We also evaluated associations between biological characteristics of serotypes and their likelihood of nonsusceptibility to each drug. Results We included data from 129 studies representing 32 187 isolates across 52 countries. Within serotypes, the proportion of nonsusceptible isolates varied geographically and over time, in settings using and those not using PCVs. Factors predicting enhanced fitness of serotypes in colonization as well as enhanced pathogenicity were each associated with higher likelihood of nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole. Increases in prevalence of nonsusceptibility following PCV implementation were evident among non-PCV serotypes, including 6A, 6C, 15A, 15B/C, 19A, and 35B; however, this pattern was not universally evident among non-PCV serotypes. Postvaccination increases in nonsusceptibility for serotypes 6A and 19A were attenuated in settings that implemented PCV13. Conclusions In pneumococci, nonsusceptibility to penicillin, macrolides, and trimethoprim/sulfamethoxazole is associated with more frequent opportunities for antibiotic exposure during both prolonged carriage episodes and when serotypes cause disease. These findings suggest multiple pathways leading to resistance selection in pneumococci. Serotypes with greater capacity to persist in the upper respiratory tract and to cause disease were each more likely to exhibit antimicrobial nonsusceptibility. Amid PCV implementation, nonsusceptibility to antimicrobial drugs increased among non-PCV serotypes associated with upper respiratory tract carriage.