Clonal complex 4821 (CC4821) Neisseria meningitidis , usually resistant to quinolones but susceptible to penicillin and third-generation cephalosporins, is increasing worldwide. To characterize the penicillin-nonsusceptible (Pen NS ) meningococci, we analyzed 491 meningococci and 724 commensal Neisseria isolates in Shanghai, China, during 1965–2020. The Pen NS proportion increased from 0.3% in 1965–1985 to 7.0% in 2005–2014 and to 33.3% in 2015–2020. Of the 26 Pen NS meningococci, 11 (42.3%) belonged to the CC4821 cluster; all possessed mutations in penicillin-binding protein 2, mostly from commensal Neisseria . Genetic analyses and transformation identified potential donors of 6 penA alleles. Three Pen NS meningococci were resistant to cefotaxime, 2 within the CC4821 cluster. With 96% of the Pen NS meningococci beyond the coverage of scheduled vaccination and the cefotaxime-resistant isolates all from toddlers, quinolone-resistant CC4821 has acquired penicillin and cefotaxime resistance closely related to the internationally disseminated ceftriaxone-resistant gonococcal FC428 clone, posing a greater threat especially to young children.

Invasive meningococcal disease (IMD) due to serogroup Y Neisseria meningitidis (NmY) is rare in China; recently, an invasive NmY isolate, Nm512, was discovered in Shanghai with decreased susceptibility to penicillin (Pen NS ). Here, we investigated the epidemiology of NmY isolates in Shanghai and explored the potential commensal Neisseria lactamica donor of the Pen NS NmY isolate.