Infection risk in myelodysplastic syndromes is dynamic and immune driven.

Infection is a major cause of morbidity and mortality in myelodysplastic syndromes (MDS), yet infection risk remains incompletely defined in the contemporary treatment era. We conducted a retrospective study of 708 patients with MDS to characterize the incidence, microbiology, temporal dynamics, and predictors of infection-related hospitalization over two decades. Overall, 78.8% (n=558) of patients required hospitalization, of which 69.9% were infection related. Infection-related hospitalization was independently associated with inferior overall survival. In multivariable Cox proportional hazards model, comorbidity burden, red blood cell transfusion dependence, higher IPSS-R risk, exposure to chemotherapy or stem cell transplantation, and severe neutropenia independently predicted infection. Among azacitidine-treated patients, 71.4% experienced infection-related hospitalization, with nearly three-quarters occurring within the first six cycles, identifying a critical early vulnerability window. Neutropenia remained the dominant driver of infection risk; however, immune dysfunction independently increased susceptibility. Low monocyte counts, cytokine dysregulation, and TP53 mutations identified high-risk patients despite preserved neutrophil counts, reflecting impaired myeloid reserve. Consistent with this dynamic vulnerability, recent infection or severe neutropenia (<0.5×10⁹/L) increased subsequent infection risk by 2.47-fold. We observed a concerning shift in antimicrobial resistance, with 14% of Gram-negative infections producing extended-spectrum beta-lactamases, 21% of Pseudomonas aeruginosa isolates resistant to piperacillin-tazobactam, and vancomycin-resistant enterococci prevalence increasing from 14% to 46%. Together, these findings identify infection in MDS as a dynamic, prognostically important complication driven by cytopenia, treatment, and immune dysfunction. This supports time-adapted risk stratification, targeted prevention, and antimicrobial stewardship, particularly during early treatment and high-risk disease phase.