topical antibiotic use coselects for the carriage of mobile genetic elements conferring resistance to unrelated antimicrobials in staphylococcus aureus topical antibiotics such as mupirocin and fusidic acid are commonly used in the prevention and treatment of skin infections particularly those caused by staphylococci however the widespread use of these agents is associated with increased resistance to these agents potentially limiting their efficacy of particular concern is the observation that resistance to topical antibiotics is often associated with multidrug resistance suggesting that topical antibiotics may play a role in the emergence of multidrugresistant mdr strains new zealand nz has some of the highest globally recorded rates of topical antibiotic usage and resistance using a combination of pacific biosciences singlemolecule realtime smrt wholegenome sequencing illumina shortread sequencing and bayesian phylogenomic modeling on 118 new multilocus sequence type 1 st1 community staphylococcus aureus isolates from new zealand and 61 publically available international st1 genome sequences we demonstrate a strong correlation between the clinical introduction of topical antibiotics and the emergence of mdr st1 s aureus we also provide in vitro experimental evidence showing that exposure to topical antibiotics can lead to the rapid selection of mdr s aureus isolates carrying plasmids that confer resistance to multiple unrelated antibiotics from within a mixed population of competitor strains these findings have important implications regarding the impact of the indiscriminate use of topical antibiotics