Clinical relevance of topical antibiotic use in co-selecting 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 S. aureus in some settings. In this study, we provide experimental proof of co-selection 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 confer a competitive advantage in the presence of sub-inhibitory concentrations of FA and mupirocin, respectively. Further, we used a porcine skin colonisation model to show that clinically relevant concentrations of topical antibiotics can co-select for presence of unrelated antimicrobial resistance determinants, such as mecA, blaZ, and qacA, in fusC or mupA harbouring S. aureus. These findings provide valuable insights on the role of acquired FA or mupirocin resistance in co-selecting for broader antibiotic resistance in S. aureus, prompting greater need for judicious use of topical antibiotics.

外用抗生素制剂（如夫西地酸（fusidic acid, FA）或莫匹罗星（mupirocin））可用于预防和治疗葡萄球菌引发的浅表皮肤感染。既往基因组流行病学研究表明，在部分场景中，外用抗生素的广泛使用与耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）的出现存在关联。本研究为接触夫西地酸或莫匹罗星后，金黄色葡萄球菌（Staphylococcus aureus, S. aureus）出现多重耐药性的共选择现象提供了实验证据。通过靶向诱变与表型分析，我们证实，在多种金黄色葡萄球菌遗传背景中，携带fusC可赋予对夫西地酸的耐药性，携带mupA可赋予对莫匹罗星的高水平耐药性。体外实验表明，分别在夫西地酸和莫匹罗星的亚抑菌浓度环境下，携带fusC和mupA的菌株可获得竞争优势。此外，我们利用猪皮肤定植模型证实，临床相关浓度的外用抗生素可在携带fusC或mupA的金黄色葡萄球菌中，共选择获得如mecA、blaZ及qacA等非相关抗菌耐药决定因子。本研究结果为获得性夫西地酸或莫匹罗星耐药性在金黄色葡萄球菌中共同选择更广谱抗生素耐药性的作用提供了重要见解，也提示亟需审慎使用外用抗生素。