The most appropriate treatment for this patient is daptomycin. He has a history of methicillin-resistant Staphylococcus aureus (MRSA) skin infections and now presents with injection drug use–associated cellulitis and bacteremia with gram-positive cocci in clusters, presumably MRSA. Because of his history of vancomycin intolerance, daptomycin, an alternative to vancomycin for the empiric treatment of MRSA-associated bacteremia and infective endocarditis, should be given. Daptomycin is a lipopeptide-type antibiotic and is bactericidal against MRSA. He will require echocardiography and repeat blood cultures after intravenous antibiotics have been initiated. Additionally, patients receiving daptomycin should be assessed regularly for clinical or laboratory signs of muscle weakness or pain, particularly in those receiving statin-based lipid-lowering agents or with kidney disease. Intravenous antibiotics must be administered for at least 2 weeks for S. aureus bacteremia.

Ceftriaxone could be used to treat nonpurulent cellulitis because β-hemolytic streptococci are the likely cause. However, it does not provide effective coverage against MRSA.

Imipenem, a broad-spectrum β-lactam antibiotic with activity against many aerobic and anaerobic bacteria, does not provide effective coverage against MRSA.

Additionally, S. aureus that may be resistant to methicillin also may be resistant to oxacillin, nafcillin, and other β-lactam agents, including ceftriaxone and imipenem. Nafcillin or oxacillin would be appropriate choices if the infection were found to be caused by methicillin-susceptible S. aureus. Until that time, however, empiric therapy should reliably target MRSA. The only β-lactam with reliable activity against MRSA is ceftaroline, a fifth-generation cephalosporin approved by the FDA for treatment of skin infections and community-acquired bacterial pneumonia.