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Intravenous antibiotics should also be started early upon suspicion of a necrotizing soft tissue infection. For necrotizing fasciitis, initial empiric therapy should cover streptococci, anaerobes, enteric gram-negative rods, and staphylococci. Suggested regimens include combinations of a penicillin or cephalosporin, an aminoglycoside, and anaerobic coverage with either clindamycin or metronidazole. Beta-lactamase inhibitor combinations (e.g., ampicillin/sulbactam) have also been suggested. In nosocomial and some community-acquired settings, infection from methicillin-resistant Staphylococcus aureus is possible, and vancomycin may be considered. Results of Gram stain, cultures, and susceptibility testing can assist in narrowing coverage.

High-dose penicillin is traditionally considered the drug of choice for treatment of group A streptococci, particularly due to Streptococcus pyogenes infections. However, there are theoretical advantages of clindamycin, including its inhibition of bacterial toxin synthesis. In experimental models of deep S. pyogenes infection, clindamycin has been shown to be superior. For this reason, the addition of clindamycin to regimens has been suggested for any possible invasive streptococcal infection.

Patients with suspected clostridial myonecrosis should be treated with high-dose intravenous penicillin. Some sources also recommend the addition of clindamycin for similar reasons as in necrotizing fasciitis. In penicillin-allergic patients, metronidazole has been combined with clindamycin. Given that infections may be polymicrobial and the diagnosis of clostridial myonecrosis may initially be uncertain, broad-spectrum antibiotic coverage, as for necrotizing fasciitis, is prudent pending surgical exploration and microbiologic testing.

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