Clinical Relevance of Topical Antibiotic Use in Coselecting for Multidrug-Resistant Staphylococcus Aureus: Insights from in Vitro and Ex Vivo Models

Topical antibiotic preparations, such as fusidic acid (FA) or mupirocin, are used in the prevention and treatment of superficial skin infections caused by staphylococci. Previous genomic epidemiology work has suggested an association between the widespread use of topical antibiotics and the emergence of methicillin-resistant Staphylococcus aureus in some settings. In this study, we provide experimental proof of coselection for multidrug resistance in S. aureus following exposure to FA or mupirocin. Through targeted mutagenesis and phenotypic analyses, we confirmed that fusC carriage confers resistance to FA and mupA carriage confers high-level resistance to mupirocin in multiple S. aureus genetic backgrounds. In vitro experiments demonstrated that carriage of fusC and mupA confers a competitive advantage in the presence of subinhibitory concentrations of FA and mupirocin, respectively. Further, we used a porcine skin colonization model to show that clinically relevant concentrations of topical antibiotics can coselect for the presence of unrelated antimicrobial resistance determinants, such as mecA, blaZ, and qacA, in fusC- or mupA-harboring S. aureus. These findings provide valuable insights on the role of acquired FA or mupirocin resistance in coselecting for broader antibiotic resistance in S. aureus, prompting a greater need for judicious use of topical antibiotics.