Purpose <p>Due to rising antibiotic resistance rates, treating infections becomes more complex. To tackle this, old and new antibiotics will need to be used more frequently for additional indications outside the scope of their original registrations. We aimed to introduce a mixed methods approach to identify off-label indications for antimicrobials in specific settings, and applied this to an antimicrobial not commonly used in the Netherlands, ceftaroline.</p> Methods <p>We developed the Exploratory Positioning of Antimicrobials in New Settings (EXPANS) approach, which includes a systematic literature review, an observational study and an expert meeting. We applied our approach to ceftaroline to explore off-label indications and its potential use in outpatient parenteral antimicrobial therapy (OPAT).</p> Results <p>In both the literature and Dutch hospitals, ceftaroline was mainly prescribed as second-line treatment following treatment failure or side effects, often for endocarditis and bone and joint infections. Combination therapy with daptomycin was common, and ceftaroline was used in OPAT. In Dutch hospitals, only 48 patients were prescribed ceftaroline in the last five years. Experts experienced a lack of evidence, reimbursement issues, and the risk of leukopenia as key barriers to its use. Dutch experts noted potential for off-label use of ceftaroline in endocarditis and as prophylaxis for prosthetic joint revision surgery.</p> Conclusion <p>The components used in our EXPANS approach were complementary, gathering original data on clinical experiences with specific antimicrobials and identifying barriers to their use in practice. We recommend this systematic approach to explore untapped potential of existing antimicrobial agents and optimize their use.</p>