Methicillin-resistant Staphylococcus aureus is a frequent cause of hospital-associated infections, including central catheter–associated bacteremia. Vancomycin has been the drug of choice for treating this type of bacteremia for decades in patients who have no contraindications to the antibiotic. However, resistance to vancomycin is an emerging problem. Newer antibiotics approved by the Food and Drug Administration have activity against methicillin-resistant S aureus . Some of the antibiotics also have activity against strains of S aureus that are intermediately susceptible or resistant to vancomycin. This article uses a case study to highlight the clinical signs of vancomycin failure and describes the indications for and appropriate use of alternative antimicrobials such as ceftaroline, daptomycin, linezolid, tigecycline, and telavancin. ( Critical Care Nurse . 2016;36[4]:46–57)