Abstract: For the indigenous population living in remote Australia Streptococcus pyogenes and community-associated MRSA (CA-MRSA) are common causes of skin and soft tissue infections (SSTIs). For S. pyogenes oral sulfamethoxazole/trimethoprim has been shown to be non-inferior to intramuscular benzathine benzylpenicillin for the treatment of impetigo. Since β-lactam-resistant CA-MRSA is a frequent co-pathogen, sulfamethoxazole/trimethoprim is the recommended oral alternative for community-based treatment of impetigo in remote Australia. In Western Australia (WA), a trimethoprim-resistant Panton–Valentine leucocidin-positive ST5-IVc MRSA clone (WA121) has emerged as a frequent cause of SSTIs in the state’s northern regions, causing 941 cases in 2016/2017. The bioMérieux VITEK® 2 ID/AST System, used by the majority of diagnostic microbiology laboratories in WA, classifies WA121 as sulfamethoxazole/trimethoprim resistant. Consequently, it has been recommended that sulfamethoxazole/trimethoprim should not be a first-line oral antibiotic treatment alternative for impetigo in remote Australia.