Recent clinical data indicate that TMP-SMX monotherapy is effective for treating streptococcal cellulitis, even in extensive cases, challenging the belief that double coverage is necessary. Although the trial's design did not intend to assess strep treatment directly, results suggest that Bactrim provides adequate efficacy for skin and soft tissue infections. It is cautioned, however, that this does not imply its effectiveness for severe conditions like neck fasciitis or invasive infections. As drug-resistant bacteria like Group A strep and serious bacteremia rise, it is critical for clinicians to reconsider treatment protocols while remaining aware of the data limitations concerning TMP-SMX effectiveness in various scenarios. Additionally, misconceptions regarding cephalosporin's CNS penetration for staphylococcal infections may impact decision-making, as current data challenge the notion of its inadequacy in CNS-related cases.