To characterize antimicrobial susceptibility profiles, multidrug resistance (MDR) patterns, and geographic variation among clinical Streptococcus isolates collected from a multicenter surveillance network in China during 2021–2022. We further characterized species-specific resistance patterns and appropriate susceptibility interpretations for Streptococcus pneumoniae ( S. pneumoniae) . We analyzed 1,518 non-duplicate clinical Streptococcus isolates collected from 66 hospitals in China during 2021–2022. Minimum inhibitory concentrations (MICs) were determined by broth microdilution (BMD) and interpreted according to CLSI M100, 36th edition. Resistance rates, MIC 50 /MIC 90 values, and MDR phenotypes were summarized by species group. Regional differences in categorical resistance and MIC distributions were evaluated, with analyses involving small regional subgroups interpreted as exploratory. The impact of different CLSI breakpoint scenarios on susceptibility classification was specifically evaluated for S. pneumoniae . Streptococcus agalactiae ( group B Streptococcus [GBS]) and S. pneumoniae were the predominant groups. Overall, β-lactams retained high activity against β-hemolytic streptococci, but resistance to erythromycin, clindamycin, and tetracycline was frequent across major species groups. GBS showed high resistance rates to erythromycin (80.77%), clindamycin (77.04%), and tetracycline (64.66%), while Streptococcus pyogenes ( S. pyogenes ) and Streptococcus dysgalactiae ( S. dysgalactiae) remained highly susceptible to β-lactams. Viridans group streptococci (VGS) displayed heterogeneous susceptibility profiles, with variable resistance patterns among regions. MDR phenotypes were common within individual species groups, with significant regional variation observed particularly among GBS isolates. For S. pneumoniae , antimicrobial susceptibility classification was strongly influenced by breakpoint selection: among the same 413 non-meningitis isolates, penicillin resistance increased from 1.94% (8/413) using non-meningitis breakpoints to 76.03% (314/413) using meningitis breakpoints ( P < 0.0001). This multicenter surveillance study demonstrates substantial variation in antimicrobial susceptibility patterns among clinical Streptococcus isolates in China. Interpretation of streptococcal antimicrobial resistance requires consideration of both bacterial species and clinical breakpoint scenarios, because breakpoint selection may substantially influence categorical susceptibility classification. Clinically contextualized surveillance provides a meaningful framework for monitoring and interpreting antimicrobial resistance among streptococci .
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