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BACKGROUNDFifteen- and 20-valent pneumococcal conjugate vaccines (PCVs) offer broader protection against invasive pneumococcal disease (IPD) than PCV13. Adopting these vaccines may result in decreasing IPD incidence, antibiotic use and antimicrobial resistance (AMR) rates. If the additional serotypes in PCV15 and PCV20 are associated with AMR, AMR rate reduction could be greater than expected from reduced antibiotic consumption alone.AIMThis retrospective analysis assessed the association between AMR and non-PCV13 serotypes in PCV15 and PCV20.METHODSLaboratory-based surveillance data on 8,123 IPD isolates were obtained retrospectively from the Belgian Reference Centre for invasive Streptococcus pneumoniae. Isolates (n = 8,088) were serotyped and tested for AMR. Associations between vaccine serotype groups and AMR were evaluated by multinomial logistic regression. Where associations varied with patients' age, ranges of odds ratios (ORs) are presented.RESULTSPCV15-non-PCV13 and PCV20-non-PCV13 serotypes accounted for 7.4% (n = 597) and 37% (n = 2,992) of IPD isolates respectively. Of non-PCV20 serotypes, 24% (508/2,125) were penicillin resistant. Compared with non-PCV20 serotypes, PCV15-non-PCV13 serotypes were more often associated with erythromycin (ORs: 3.59-9.43) and tetracycline (OR: 2.00) resistance, and with trimethoprim/sulfamethoxazole (OR: 0.11) susceptibility. PCV20-non-PCV15 serotypes were more often associated with amoxicillin (OR: 9.45) and cefotaxime (ORs: 5.06-82.38) resistance, and with erythromycin (ORs: 0.13-0.18), tetracycline (OR: 0.71) and penicillin (ORs: 0.05-0.46) susceptibility.CONCLUSIONPCV20 may lead to a larger decrease in overall IPD incidence than PCV15. Although the PCV20 vaccination impact on AMR may be limited, some resistant or difficult to treat infections could be avoided. Serotype replacement might lead to infections with low level penicillin resistance increasing, but most of these should remain treatable.