A recent study presented at IDWeek 2026 found that Cefiderocol (Fetroja; Shionogi) exhibits improved in vitro activity against multidrug-resistant Gram-negative pathogens under physiologic conditions. The research revealed that the median minimum inhibitory concentrations (MICs) of cefiderocol decreased significantly – by a factor of 4 for Pseudomonas aeruginosa and by a factor of 2 for Klebsiella pneumoniae – when tested in a modified culture medium compared to standard testing conditions. Furthermore, cefiderocol demonstrated marked cooperation with the antimicrobial peptide LL-37 against Acinetobacter baumannii isolates that were resistant to cefiderocol alone.
Conventional antimicrobial susceptibility testing typically utilizes bacteriologic media, which may not accurately reflect the activity of antimicrobial agents within the host or in the presence of innate immune effectors. To address this limitation, investigators from the University of California, San Diego (UCSD) conducted MIC testing of cefiderocol and LL-37 against 30 multidrug-resistant Gram-negative isolates – comprising 10 K. pneumoniae, 10 P. aeruginosa, and 10 A. baumannii isolates – in both cation-adjusted Mueller-Hinton broth (MHB) and RPMI cell culture medium supplemented with 10% Luria-Bertani (LB) broth.
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Checkerboard assays were performed on 12 isolates (four per species) in RPMI medium supplemented with 10% LB broth. In contrast, A. baumannii isolates remained resistant to cefiderocol in both media types. The fractional inhibitory concentration index (FICI) values indicated additive interactions between cefiderocol and LL-37 for P. aeruginosa and K. pneumoniae, but marked cooperation for A. baumannii isolates.
According to Jacinda C. Abdul-Mutakabbir, PharmD, MPH, an associate professor of Clinical Pharmacy at UCSD, the siderophore component of cefiderocol exploits nutrient immunity, a host-pathogen interaction. LL-37 is an exogenous form of an endogenous human antimicrobial peptide that is typically deployed at infection sites. The combination of cefiderocol and LL-37 provides insight into how innate immunity may respond when a patient receives cefiderocol. Abdul-Mutakabbir stated, “[The] MIC test may say it won’t work, but then when we treat them inpatient, we may see a difference in terms of [the] clinical outcome.” Ongoing, more dynamic testing by the team continues to show increased killing with LL-37 and cefiderocol against Acinetobacter compared with the other Gram-negative pathogens studied.