Stenotrophomonas maltophilia: the need for randomized controlled trials to evaluate treatment options

The most optimal treatment for serious Stenotrophomonas maltophilia infections remains undetermined based on current evidence. The evolution of Infectious Diseases Society of America (IDSA) guidance from 2022 to 2024 reflects growing support for combination therapy and a shift away from agents with unfavorable pharmacokinetic/pharmacodynamic profiles, such as tigecycline. No randomized controlled trials (RCTs) have been conducted to date, and existing observational comparative studies have yielded heterogeneous results. Despite efforts to adjust for bias and confounders, definitive conclusions remain elusive, largely due to methodological limitations inherent in retrospective designs, such as immortal time bias. For serious S. maltophilia infections, a multi-arm trial is likely necessary to generate robust evidence; however, challenges, such as large sample size requirements, difficult patient recruitment, and high implementation costs remain significant barriers. To overcome these obstacles, innovative trial designs and analytic approaches have emerged. Target trial emulation, for instance, seeks to approximate RCT-level evidence using observational data. Several other designs aim to improve the flexibility and efficiency of clinical trials, including: multi-arm, multi-stage (MAMS) trial designs; embedding a multi-arm trial within a larger platform trial; an analysis method known as PRACTical method composed of personalized randomization treatment options relevant to individuals; and Bayesian analytic frameworks, enabling simultaneous comparison across multiple treatment arms. As we seek answers to complex clinical dilemmas, such as the life-threatening S. maltophilia infection reported by Qadabashi and colleagues in a recent article in ASM Case Reports (ASM Case Rep 1:e00005-25, 2025, https://doi.org/10.1128/asmcr.00005-25), these forward-looking trial designs and analytic methodologies will be critical in shaping the future of evidence-based treatment strategies.