The leaky antibiotic pipeline

Reviewed by Cindy Noyes, MD; University of Vermont Medical Center, Burlington, VT

Prasad et al provide insight regarding issues limiting late-stage development and approval for gram-negative active antibacterial agents based on their review of antibiotic development from 2010-2020.   First, candidate antibiotics frequently do not transition from phase 1 to phase 2 investigation, most commonly due to toxicity concerns.  The authors suggest that in vivo preclinical models are good predictors of efficacy but poor predictors of safety.  Additionally, malalignment of discovery and clinical use is a formidable challenge.  For example, development focuses on a particular pathogen or cellular target, but late-stage trials test the candidate’s efficacy in a particular clinical syndrome and setting.  Given clinical trial participants often have low incidence of drug resistant organisms, performance compared to standard agents with high efficacy against susceptible organisms may not be equivalent.  Finally, data sharing in the industry remains limited, which further reduces the ability to consider alternate modes of delivery or use as a synergistic agent. 

Prasad NH, et al (May 2022).  Leaks in the Pipeline: a failure analysis of gram-negative antibiotic development from 2010-2020.  Antimicrobial Agents and Chemotherapy.

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