Small-colony variants of Staphylococcus aureus: hidden threat in chronic and recurrent infections.

Staphylococcus aureus small-colony variants (SCVs) are unique phenotypic forms that significantly contribute to the development of chronic, recurrent, and treatment-refractory infections. These variants arise from metabolic defects, most commonly in the menadione, hemin, or thymidine biosynthetic pathways, leading to slow growth, atypical colony morphology, and altered virulence expression. The ability of these bacteria to persist intracellularly, form robust biofilms, and resist multiple antibiotics poses a significant clinical challenge. SCVs have been implicated in osteomyelitis, prosthetic joint infections, bloodstream infections, and cystic fibrosis airway disease, where they are often overlooked because of their atypical features and slow growth in diagnostic cultures. Therapeutically, conventional agents such as vancomycin and β-lactams exhibit limited efficacy against intracellular or biofilm-associated SCVs. In contrast, fluoroquinolones and rifampin achieve intracellular penetration but carry the risk of inducing resistance and selecting for SCVs. Recent experimental strategies, including ATP synthase inhibitors such as tomatidine and resveratrol, nanoparticle-based drug delivery, antibiotic-loaded bone cement, and pH modulation through alkalinization, have demonstrated promising activity, although clinical validation remains limited. Adjunctive measures such as surgical debridement and phage therapy provide additional options but are limited by feasibility and safety concerns. Taken together, SCVs represent an important survival strategy for S. aureus that complicates both diagnosis and treatment. Combination antimicrobial regimens that exploit diverse mechanisms of action remain the cornerstone of current management, while novel therapeutic approaches hold future potential. Continued research into the biology of SCVs and translational studies are essential to develop effective, clinically applicable interventions for these persistent infections.