Safety Profiles of Polymyxins, Aminoglycosides, and Imipenem/Cilastatin/Relebactam (IMI/REL) in the Treatment of Gram-Negative Infections: A Literature Review

Background/objectives: Gram-negative bacterial infections are associated with significant morbidity and mortality. This targeted literature review (TLR) aimed to descriptively synthesise safety outcomes reported for polymyxins, aminoglycosides, and imipenem/cilastatin/relebactum (IMI/REL) in adult patients with Gram-negative infections. Methods: A TLR was conducted to identify published literature from 2015 to 2025. A database search was conducted on 14 February 2025, using the OVID® platform and grey literature search reviewed publications from the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) and Infectious Disease (ID) Week. Safety outcomes included nephrotoxicity, other toxicities (e.g., haematological, hepatological), renal impairment, treatment-related (i.e., explicitly related to the antimicrobial treatment or its complications) discontinuation, and treatment-related mortality. Results: Sixty-eight publications were included. Definitions of nephrotoxicity varied between publications; RIFLE and KDIGO classifications were typically used. Definitions of renal impairment included renal risk/injury/failure and acute kidney injury (AKI). Colistin (n = 63) showed nephrotoxicity rates of 30.8–56.4%; renal impairment of 15.0–53.8%; treatment-related discontinuation of 12.5–23.0%; and treatment-related mortality from 20.0 to 39.1%. Polymyxin B showed nephrotoxicity rates of 14.6–54.9%; renal impairment rates ranging from 5.3 to 58.1%; and treatment-related mortality of 7.0% (n = 1). Aminoglycoside data were limited (n = 2) but showed nephrotoxicity rates of 77.8% and renal impairment of 18.8%. IMI/REL (n = 6) demonstrated nephrotoxicity of 10.3–17.2%; renal impairment of 0.0–20.7%; treatment-related discontinuation of 0.0–2.3%; and treatment-related mortality of 0.0–0.7%. Conclusions: Polymyxins/aminoglycosides had more frequently reported safety events. Fewer safety events were reported for IMI/REL across studies. These findings support the clinical use of IMI/REL and may inform Health Technology Assessment (HTA) decisions.