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.

Background: Rare diseases affect more than 400 million people globally with only a small number having currently approved treatments. Drugs for rare diseases (medications developed to treat conditions affecting small patient populations), which may include innovative drugs (medications with novel mechanisms/new active ingredients) can face access challenges as they are often found not to be cost-effective under conventional health technology assessment methods. In this review we provide a comprehensive and up-to-date understanding of challenges associated with the economic evaluation of innovative drugs for severe-rare diseases, and any proposed solutions and associated barriers to solution adoption. Methods: This review included searches of electronic databases and select health technology assessment agency websites to identify relevant publications, guidelines or recommendations from 1st January 2014 to 29th July 2024. A pre-authorised protocol, including detailed eligibility criteria, was used to ensure robust methodology in the capture of materials. Relevant data extracted from included publications were synthesised thematically to support identification of the most prominent concepts within current literature. Results: Of the 1,803 records identified, 31 publications and eight health technology assessment guidance were included. Main challenges were related to the utilitarian principle underlying cost-effectiveness analysis, the limited scope of the quality-adjusted life year and the value elements assessed. Associated solutions included the incorporation of a societal willingness-to-pay or inclusion of equity in healthcare decision making, reduced weighting of the economic evaluation in resource allocation, consideration of additional value elements, and introducing a quality-adjusted life year weighting or alternative measures of health outcomes. While some payers have implemented modifications to economic evaluation guidelines in an attempt to address the challenges, for example including the consideration of additional value elements, the solutions employed are not consistent across payers and often do not address the root issue. Economic evaluation as part of health technology assessment therefore remains challenging for manufacturers of drugs for rare diseases. Conclusion: Conventional methods of economic evaluation contribute to the access challenge for innovative drugs for rare diseases. Collaboration between payers, manufacturers, and healthcare decision makers to foster greater understanding of how to evolve and adopt these novel solutions will be key to ensuring timely patient access.