Solithromycin (CEM-101) is a novel fluoroketolide with high potency against Gram-positive and Gram-negative bacteria commonly associated with community-acquired respiratory tract infections and skin and skin-structure infections. In this study, solithromycin and comparator antimicrobials were tested against a contemporary collection of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, Enterococcus faecium and other Enterococcus spp. collected in the SENTRY Antimicrobial Surveillance Program. Solithromycin was active against S. aureus [minimum inhibitory concentration for 50% of the organisms (MIC 50 )=0.12μg/mL] and was two-fold more active than telithromycin (MIC 50 =0.25μg/mL). Solithromycin was more potent against meticillin (oxacillin)-susceptible S. aureus [MIC 50 =0.06μg/mL and MIC for 90% of the organisms (MIC 90 )=0.12μg/mL) compared with meticillin (oxacillin)-resistant S. aureus (MIC 50 =0.12μg/mL and MIC 90 >16μg/mL). Solithromycin activity was reduced amongst heterogeneous vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus (MIC 50 >16μg/mL). Against strains with defined susceptibilities to erythromycin, clindamycin and telithromycin, solithromycin showed potent inhibition against all combinations (MIC 50 =0.06μg/mL) except those with non-susceptibility to telithromycin (>2μg/mL) (MIC 50 >16μg/mL). The solithromycin MIC 50 for E. faecium (1μg/mL) was four-fold higher than the MIC 50 for E. faecalis (0.25μg/mL). In summary, solithromycin demonstrated high potency against many Staphylococcus and Enterococcus spp. isolated from contemporary infections worldwide.