Background: Stenotrophomonas maltophilia is an uncommon but increasingly recognized cause of healthcare-associated infections, known for its intrinsic resistance to many broad-spectrum antibiotics. While it primarily affects immunocompromised individuals, its role in chronic wound infections such as diabetic foot ulcers remain underreported. This case underscores the clinical significance of S. maltophilia in diabetic foot osteomyelitis, especially in the context of polymicrobial infection with drug-resistant Gram-negative organisms.

Case Presentation: A 64-year-old woman with longstanding type 2 diabetes and peripheral neuropathy presented with a draining ulcer over her left lateral ankle, months after an inadequately treated ankle injury. Initial evaluation revealed a necrotic ulcer with underlying bone exposure. Imaging demonstrated advanced osseous destruction involving the distal tibia and tarsal bones, consistent with osteomyelitis. Deep tissue cultures identified S. maltophilia resistant to trimethoprim-sulfamethoxazole (TMP-SMX) and intermediately susceptible to fluoroquinolones, as well as an extended-spectrum beta-lactamase (ESBL) producing Escherichia coli strain. Initial antibiotic therapy was adjusted multiple times due to resistance patterns and hepatotoxicity. Despite appropriate antimicrobial management with cefiderocol, subsequent imaging revealed a progressing infection with abscess formation and talar necrosis. Surgical consultation resulted in a below-the-knee amputation to manage infection and preserve functional mobility.

Discussion: Although rare in diabetic foot osteomyelitis, S. maltophilia may contribute to more severe disease and poorer outcomes, particularly when co-infecting with resistant organisms such as ESBL-producing E. coli. The pathogen’s resistance to most β-lactams and increasing non-susceptibility to standard agents like TMP-SMX limit therapeutic options. Evidence suggests that S. maltophilia may be independently associated with a greater likelihood of major amputation in limb-threatening diabetic foot infections. This case highlights the importance of early pathogen identification, consideration of atypical organisms in non-healing ulcers, and the need for timely, individualized treatment approaches when managing complex diabetic foot infections.