Cefiderocol MICs fell against Pseudomonas aeruginosa and Klebsiella pneumoniae, and the drug showed marked synergy with LL-37 against resistant Acinetobacter baumannii. Jacinda Abdul-Mutakabbir, PharmD, MPH, AAHIVP, discusses her team's findings around this therapy and these pathogens.
Cefiderocol (Fetroja; Shionogi) showed enhanced in vitro activity under physiologic conditions against multidrug-resistant (MDR) Gram-negative pathogens, according to research presented at
Standard antimicrobial susceptibility testing (AST) relies on bacteriologic media. These media may not reflect drug activity in the host or in the presence of innate immune effectors.¹ The investigators, from the University of California, San Diego (UCSD), included Jacinda C. Abdul-Mutakabbir, PharmD, MPH, AAHIVP, associate professor of Clinical Pharmacy at the University of California San Diego in the Skaggs School of Pharmacy, who discussed the work with Contagion.
The team tested cefiderocol and LL-37 against 30 MDR Gram-negative isolates: 10 K pneumoniae, 10 P aeruginosa, and 10 A baumannii.¹ MIC testing was done in cation-adjusted Mueller-Hinton broth (MHB). It was also done in RPMI cell culture medium supplemented with 10% Luria-Bertani (LB) broth to support equivalent bacterial growth.¹ Checkerboard assays in RPMI plus 10% LB followed on 12 isolates, four per species.
Fractional inhibitory concentration index (FICI) values of 0.5 to 1.0 were defined as additive, and values of 0.5 or lower as synergistic.¹ Compared with MHB, cefiderocol MICs in RPMI plus 10% LB fell 4-fold for P aeruginosa and 2-fold for K pneumoniae. A baumannii isolates remained resistant to cefiderocol in both media.¹
Abdul-Mutakabbir noted RPMI differs from bacteriologic media in pH and contains elements absent from MHB, although it does not fully replicate host blood, serum, or urine. Her mentor and coauthor, Victor Nizet, MD, had earlier observed azithromycin activity in RPMI against species where it showed no activity in MHB.
P aeruginosa and K pneumoniae both showed additive interactions between cefiderocol and LL-37 (FICI 0.5-1.0).¹ In contrast, A baumannii isolates showed marked synergy with the combination (FICI ≤0.5). This held even when MICs for each agent alone exceeded 8 mg/L.¹
Abdul-Mutakabbir explained the drug’s siderophore component exploits nutrient immunity, a host-pathogen interaction conventional AST does not capture. LL-37 is an exogenous form of an endogenous human antimicrobial peptide, typically deployed at the site of infection. Pairing the two agents offers a view of how innate immunity may respond when a patient receives cefiderocol, she said.
“It really coincides with what we see in real-world data for cefiderocol,” said Abdul-Mutakabbir. “[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, she noted.
“My hypothesis is LL-37 may be sensitizing cefiderocol to more increased killing, or the neutrophils to more increased killing by cefiderocol, or vice versa,” Abdul-Mutakabbir said. “So my next step will be sequencing the isolates.”
Sequencing will explore whether the combination helps overcome iron-mediated resistance in these isolates. Abdul-Mutakabbir also raised whether giving cefiderocol before another beta-lactam or a polymyxin could prime host defenses at the infection site.
The authors concluded conventional susceptibility testing may underestimate the in vivo efficacy of cefiderocol, particularly against cefiderocol-resistant A baumannii.¹ They called for a physiology-informed framework for antibiotic evaluation. These findings are preliminary and in vitro, and clinical validation is still needed. Other IDWeek 2026 data, including real-world outcomes from the
