Are two really better than one? A retrospective study comparing monotherapy versus combination therapy for <i>Stenotrophomonas maltophilia</i> infections

Management of <i>Stenotrophomonas maltophilia</i> infections is challenging. The Infectious Diseases Society of America recommends up-front combination therapy, though this may increase toxicity without clear benefit. We compared combination therapy (CT) versus monotherapy (MT) in the management of <i>S. maltophilia</i> infections to inform institutional decision-making and microbiology reporting. We conducted a retrospective study of adults with <i>S. maltophilia</i> infections who received ≥72 h of organism-directed, <i>in vitro</i> active therapy between July 1, 2019, and November 30, 2024. Patients were excluded if they lacked evidence of infection, had cystic fibrosis, or had polymicrobial cultures. CT was defined as more than one agent given concomitantly for ≥72 h. The primary outcome was clinical failure, a composite of 30-day all-cause mortality and microbiologically confirmed recurrence. Of 370 patients screened, 103 met the inclusion criteria (86 MT and 17 CT). CT recipients were more often immunocompromised (70.6% vs 22.1%) with bacteremia (58.8% vs 19.8%). Clinical failure occurred in 47.1% versus 36.0% of patients in the CT and MT cohorts, respectively (RD: 15.6%; 95% CI: -9.9% to 41.2%). Resistance developed in 8.7% of isolates, most commonly with levofloxacin. Adverse effects occurred in 26.7% MT and 35.3% CT cohorts. We observed no differences in clinical failure between CT versus MT for the management of <i>S. maltophilia</i> infections. Risks of adverse effects with CT should be balanced with perceived benefit based on host factors, infection source, and risk of resistance. These findings suggest MT is a viable option for select patients with <i>S. maltophilia</i> infections.IMPORTANCEManagement of <i>Stenotrophomonas maltophilia</i> infections is challenging due to intrinsic antimicrobial resistance. Current Infectious Diseases Society of America guidance recommends up-front combination therapy for all cases based on limited observational and <i>in vitro</i> data. In our retrospective cohort study comparing combination therapy with monotherapy, we found no significant differences in 30-day clinical failure but observed a numerically higher rate of adverse events with combination therapy. These results fill an important gap in real-world outcomes and support monotherapy as a viable and potentially safer option. Our findings may guide clinical decision-making and microbiology reporting toward more individualized treatment strategies.