Evolution of penicillin and macrolide resistance in vaccine serotypes of Streptococcus pneumoniae (6B, 9V, 19F) in the era of conjugate vaccines

Introduction. Serotypes 6B, 9V and 19F of Streptococcus pneumoniae are traditionally associated with increased resistance to beta-lactams and macrolides, the development of multidrug resistance (MDR), and high epidemiological significance. This review systematically analyses the molecular genetic mechanisms of resistance, the evolution of resistance in the era of conjugated pneumococcal vaccines (PCV7, PCV10, PCV13), regional patterns of dissemination of these serotypes, and their clinical significance, including detailed data for the Russianian Federation.

Objective of the study. A systematic analysis of the evolution of antibiotic resistance in vaccine serotypes of Streptococcus pneumoniae 6B, 9V, and 19F in the context of the global introduction of conjugated pneumococcal vaccines; the study of molecular genetic mechanisms of resistance to penicillin and macrolides; regional patterns of dissemination of these serotypes; the role of clonal complexes in the spread of resistance; and an assessment of clinical implications and prospects for developing new therapeutic strategies.

Materials and methods. A systematic review of published literature was conducted using the PubMed, Scopus, eLibrary, and Web of Science databases for the period 2020–2026. Selection criteria included publications in Russia and English on national surveillance systems for invasive pneumococcal infections in Europe, North America, Asia, and Russia, as well as results of molecular epidemiological studies using PCR methods, capsular gene sequencing, analysis of penicillin-binding protein genes (pbp1a, pbp2x, and pbp2b), detection of macrolide resistance genes (erm(B) and mef(A)), and clonal typing by multilocus sequence typing.

Results. Based on the analysis of literature data, it was established that Serotype 6B is traditionally associated with the clonal complex ST81 and demonstrates moderate resistance to penicillin with an MIC of 0,12–1 mg/L, a macrolide resistance rate of 50–70%, and predominance of the MLSB phenotype caused by the erm(B) gene. After the introduction of PCV7 and PCV13, a significant decrease in the frequency of this serotype was observed in developed countries with high vaccination coverage. However, serogroup dynamics persist, with replacement by serotype 6C, which is not included in vaccines. Serotype 9V was identified as a marker of pronounced multidrug resistance, dominated by the ST156 clone. This clone is characterised by high penicillin MICs of up to 3 mg/L and extreme erythromycin MICs exceeding 256 mg/L. More than 90% of isolates exhibit the MLSB phenotype, and the MDR rate exceeds 50%. Serotype 19F has formed a global resistant core of the pneumococcal population due to the clonal complex ST271/CC271. This complex demonstrates 100% resistance to erythromycin, 94% to clindamycin, 92% to tetracycline, and 76,6% to cefotaxime. It combines triple mosaic pbp genes with erm(B), mef(A), tet(M), and cat. A resistant mutation on a “favourable” genetic background ensures minimal fitness costs of resistance and stable global spread, regardless of vaccine pressure. Significant regional differences were identified in the persistence of target serotypes, with the greatest decline observed in North America and Western Europe (vaccination coverage > 90%) and continued high circulation in Asian countries, including China, India, and Russia. In these regions, serotype 19F remains a leading cause among invasive isolates, with macrolide resistance rates of up to 85% and penicillin resistance of up to 60%. It was demonstrated that the phenomenon of serotype replacement has led to the spread of highly resistant non-vaccine serotypes 19A and 6C, with resistance profiles comparable to those of vaccine serotypes. The clinical significance of detecting serotypes 9V and 19F as prognostic markers of multidrug resistance was established, necessitating empirical therapy with reserve antibiotics. It was shown that expanding vaccine valency to PCV20 – which includes serotype 19F along with other resistant serotypes – provides a basis for controlling the spread of antibiotic-resistant pneumococci, provided that molecular epidemiological surveillance, including clonal typing and analysis of resistance mechanisms, is maintained.

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