The Other Face of Stenotrophomonas maltophilia in Hospitalized Patients: Insights from over Two Decades of Non-Cystic Fibrosis Cohort

Background: Stenotrophomonas maltophilia is an intrinsically multidrug-resistant, biofilm- forming, non-fermenter increasingly implicated in hospital-acquired infections. Evidence from non-cystic fibrosis populations, especially in the Middle East, remains sparse. Methods: We conducted a retrospective observational cohort study at a tertiary academic center (Al-Khobar, Saudi Arabia) spanning 1 May 2001–30 April 2023. Hospitalized adults (≥18 years) with culture-confirmed, clinically diagnosed S. maltophilia infection and ≥72 h of antibiotic therapy were included. The primary outcome was all-cause mortality (14-day, 30-day, 1-year). Secondary outcomes were clinical response, microbiological eradication, and infection recurrence. Predictors of 30-day mortality were assessed using multivariable logistic regression; 14-day mortality was analyzed by Kaplan–Meier/log-rank according to susceptibility-guided versus alternative therapy. Results: Of 539 patients with positive cultures, 436 met the inclusion criteria. Mean age was 60.5 ± 19.3 years; 62.2% were male. Most infections were hospital-acquired (92.9%); pneumonia composed 64.7% and bloodstream infection 15.4%. Polymicrobial growth occurred in 55.5% (predominantly Gram-negative co-isolation). Susceptibility was 95.1% to trimethoprim–sulfamethoxazole, 76.4% to levofloxacin, and 43.6% to ceftazidime. Mortality at 14 days, 30 days, and 1 year was 22.8%, 37.9%, and 57.2%, respectively. On multivariable modelling, intensive care unit (ICU) admission, leukocytosis, neutrophilia, anemia, and thrombocytopenia independently predicted 30-day mortality. Susceptibility-guided therapy was associated with improved 14-day survival (log-rank p = 0.033). Conclusions: In this large, long-running non-cystic fibrosis cohort, host acuity and early alignment of treatment to susceptibility data were dominant drivers of outcome. High polymicrobial burden and limited reliably active agents underscore the need for meticulous stewardship, robust infection prevention, and cautious interpretation of S. maltophilia antimicrobial susceptibility testing.