Persistent and recurrent Staphylococcus aureus infection: Biofilms, antibiotic tolerance, protected lesion niches, and therapeutic strategies

Staphylococcus aureus ( S. aureus ) causes acute invasive disease as well as persistent and recurrent infections involving skin and soft tissue, the bloodstream and endovascular structures, bone and joints, and implanted devices. Eradication failure reflects antimicrobial resistance together with biofilm formation, host–microbe aggregate formation, intracellular survival, phenotypic antibiotic tolerance, and retention of residual bacteria within protected lesion niches. In this review, we integrate evidence across the disease course, from colonization, barrier disruption, tissue entry, and incomplete early clearance to stable adhesion, protected lesion formation, and recurrence. We examine how surface-attached biofilms, host–microbe aggregates, fibrin-encased abscesses, intracellular reservoirs, and bone-associated microstructures create heterogeneous microenvironments characterized by hypoxia, nutrient limitation, acidification, immune pressure, and uneven antimicrobial exposure. These conditions enrich slow-growing, small-colony variant-like, persister-enriched, and other antibiotic-tolerant populations, with different contributions across clinical syndromes. We also discuss how host–pathogen interactions shape early invasion and later clearance failure through impaired phagocyte access, immune evasion, sustained inflammation, disordered tissue repair, and incomplete eradication of residual bacteria. Finally, we outline therapeutic implications of protected lesion niches, emphasizing that successful management requires active antimicrobial agents, source control, lesion accessibility, drug penetration, and activity against persistence-associated bacterial states within protected niches.