Ana G. Jop Vidal

Antimicrobial resistance (AMR) and virulence have traditionally been viewed as competing traits in bacterial evolution due to fitness costs. However, Streptococcus pneumoniae has emerged as a paradigm of successful coevolution, with multidrug-resistant clones simultaneously maintaining or enhancing pathogenic potential. This review examines the molecular mechanisms, epidemiological patterns, and clinical consequences of the convergence between AMR and virulence in Streptococcus pneumoniae. Resistance to β-lactams is driven by mosaic penicillin-binding protein genes (pbp1a, pbp2b, pbp2x), while macrolide resistance is mediated primarily by the erm(B) gene (MLS phenotype) and mef(A/E)–msr(D) genes encoding an efflux system. These determinants are frequently co-localized on integrative and conjugative elements, ICEs, (e.g., Tn916 family) within successful clonal complexes such as CC271/320 and lineages including ST320 and GPSC10. Contrary to the classical fitness cost hypothesis, compensatory epistasis, capsular recombination, metabolic adaptations, and intra-serotype phenotypic variation enable certain clones to combine high-level resistance to β-lactams, macrolides, and tetracyclines with enhanced colonization, biofilm formation, immune evasion, and invasive capacity. Post-pneumococcal conjugate vaccine (PCV) surveillance reveals the persistence and expansion of these high-risk lineages, contributing to treatment-refractory invasive pneumococcal disease (IPD), increased morbidity, and mortality. Although PCVs have reduced vaccine-type resistant strains in some settings, serotype replacement and emerging metabolic genotypes continue to drive adaptation. This review highlights the need for integrated genomic surveillance, novel therapeutics (e.g., omadacycline, lefamulin, endolysins), monoclonal antibodies, and next-generation vaccines targeting both resistance and conserved virulence determinants. A multifaceted strategy combining antimicrobial stewardship, strengthened surveillance, and innovative interventions is essential to curb the evolving threat of resistant and virulent S. pneumoniae.

Antimicrobial resistance (AMR) and virulence have traditionally been viewed as competing traits in bacterial evolution due to fitness costs. However, Streptococcus pneumoniae has emerged as a paradigm of successful coevolution, with multidrug-resistant clones simultaneously maintaining or enhancing pathogenic potential. This review examines the molecular mechanisms, epidemiological patterns, and clinical consequences of the convergence between AMR and virulence in pneumococci. Resistance to β-lactams is driven by mosaic penicillin-binding proteins (pbp1a, pbp2b, pbp2x), while macrolide resistance is mediated primarily by erm(B) (MLS phenotype) and mef(A/E)–msr(D) efflux systems. These determinants are frequently co-localized on mobile genetic elements (e.g., Tn916 family) within successful clonal complexes such as CC271/320 and lineages including ST320 and GPSC10. Contrary to the classical fitness cost hypothesis, compensatory epistasis, capsular recombination, metabolic adaptations, and intra-serotype phenotypic variation enable certain clones to combine high-level resistance to β-lactams, macrolides, and tetracyclines with enhanced colonization, biofilm formation, immune evasion, and invasive capacity. Post-pneumococcal conjugate vaccine (PCV) surveillance reveals the persistence and expansion of these high-risk lineages, contributing to treatment-refractory invasive pneumococcal disease (IPD), increased morbidity, and mortality. Although PCVs have reduced vaccine-type resistant strains in some settings, serotype replacement and emerging metabolic genotypes continue to drive adaptation. This review highlights the need for integrated genomic surveillance, novel therapeutics (e.g., omadacycline, lefamulin, endolysins), monoclonal antibodies, and next-generation vaccines targeting both resistance and conserved virulence determinants. A multifaceted strategy combining antimicrobial stewardship, strengthened surveillance, and innovative interventions is essential to curb the evolving threat of resistant and virulent S. pneumoniae.

Macrolide antibiotics are recommended for the treatment of pneumococcal pneumonia and invasive pneumococcal disease (IPD). Prior to 2000, ∼10% of Streptococcus pneumoniae strains isolated from IPD cases in Latin American countries were resistant to macrolides. The mechanism of resistance to macrolides was associated mainly with the efflux pump known as the macrolide efflux genetic assembly, since most pneumococcal strains carried the mef(A/E) gene, whereas ermB and mef(A/E). In the first decade of this century, a significant increase in the prevalence of macrolide resistance was observed in pneumococcal strains in both Mexico and Peru. Approximately 30% of S. pneumoniae strains in these countries were already resistant to erythromycin, while the prevalence in Colombia, Argentina, and Brazil remained below 10%. During the last decade, we have been experiencing a worrisome increase in pneumococcal strains carrying resistance to macrolides, with a prevalence of up to 80% for resistance to erythromycin. The mechanism for disseminating macrolide resistance has evolved. Currently, more than 55% of invasive S. pneumoniae macrolide-resistant strains carry both the ermB and the mef(A/E)/mel genes. Lessons learned from the current macrolide resistance crisis in Latin America can inform interventions in other regions.