Staphylococcus aureus and MRSA biofilms in persistent and device-related infections: immune evasion, antimicrobial tolerance, relapse, and therapeutic strategies

Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is a major cause of persistent, device-related, and deep-seated infections that are difficult to eradicate and may relapse after apparently appropriate treatment. Genetic resistance alone does not explain this recalcitrance. In this review, we examine how lesion architecture, antimicrobial exposure, bacterial physiological state, and host clearance interact to shape incomplete clearance and post-treatment relapse in persistent and device-related S. aureus infection. Within biofilm-associated lesions, matrix and host-derived material can restrict antimicrobial and immune-effector access, while oxygen- and nutrient-limited microenvironments alter bacterial physiology and reduce susceptibility to killing. These processes generate spatially and physiologically heterogeneous populations in which productive phagocyte engagement, effective antimicrobial exposure, and bacterial susceptibility to killing can vary within the same lesion. Genetic resistance, insufficient effective antimicrobial exposure, antimicrobial tolerance, and bacterial persistence are biologically distinct, although they can coexist within a single infection. Residual populations may persist in deep biofilm regions, intracellular compartments, retained infected material, or protected tissue niches, but neither phenotype nor location alone reveals whether these survivors can seed relapse. Across persistent and device-related infection, incomplete clearance and post-treatment relapse can reflect four interacting lesion-level determinants: inadequate effective antimicrobial exposure, reduced bacterial killability after exposure, impaired host clearance, and retention of relapse-capable bacterial populations. Durable control depends on effective source control and infection-specific antimicrobial therapy. The clinical value of matrix-disrupting, bacterial-state-directed, host-directed, and phage-based adjuncts will depend on whether they improve bacterial clearance within infected lesions and reduce post-treatment relapse.