Data on antimicrobial resistance profiles of CoNS from companion animals with skin lesions and their owners remain limited. This study examined the resistance profiles of these isolates and the molecular characteristics of mecA-positive Staphylococcus epidermidis. Skin lesion swab samples were collected from 160 dogs and cats, and nasal swabs were obtained from 100 owners in Wuhan, China. Among 268 staphylococcal isolates, 163 (60.8%) were CoNS, predominantly S. epidermidis (n = 90) and S. felis (n = 22). S. epidermidis exhibited high resistance rates to trimethoprim–sulfamethoxazole (SXT, 75.6%), penicillin (PEN, 72.2%), and erythromycin (ERY, 50.0%), with 39/90 (43.3%) isolates classified as multidrug-resistant (MDR). The most frequently detected resistance genes in S. epidermidis were blaZ (90.0%), ermC (32.2%), mecA (n = 24, 26.7%), tetK (25.6%), and aacA-aphD (24.4%). S. felis likewise showed the highest resistance rates for SXT (81.8%), PEN (72.7%), and ERY (50.0%), and 14/22 (63.6%) isolates were classified as MDR; blaZ (81.8%) and ermC (54.6%) were the most frequently detected resistance genes. Multilocus Sequence Typing (MLST), Staphylococcal Cassette Chromosome mec (SCCmec) typing of the 24 mecA-positive Staphylococcus epidermidis isolates revealed 12 sequence types and diverse SCCmec profiles. Minimum spanning tree (MST) analysis showed that ST59 was connected with multiple sequence types within the analyzed mecA-positive S. epidermidis sequence-type network. ST59 and ST130 were each detected in isolates of both human and companion animal origin. These findings provide baseline epidemiological information on antimicrobial-resistant CoNS among human- and companion animal-derived isolates and support the inclusion of companion animals in One Health antimicrobial resistance surveillance.
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