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To analyse the clonal dynamics and clinical characteristics of adult invasive pneumococcal disease (IPD) caused by MDR and penicillin-non-susceptible (PNS) pneumococci in Spain. All adult IPD episodes were prospectively collected (1994-2018). Streptococcus pneumoniae isolates were serotyped, genotyped and tested for antimicrobial susceptibility. Changes in the incidence of IPD were analysed and risk factors contributing to MDR were assessed by logistic regression. Of 2095 IPD episodes, 635 (30.3%) were caused