Efficacy of cefiderocol in murine models of ventilator-associated pneumonia caused by carbapenem-resistant non-fermenting Gram-negative bacilli, with pharmacokinetic evaluation

Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant non-fermenting Gram-negative bacilli poses a serious clinical challenge due to limited treatment options. Cefiderocol (CFDC) is a novel cephalosporin with a catechol moiety that mimics siderophore function, enabling targeted antimicrobial activity against these pathogens. We evaluated the <i>in vivo</i> efficacy of CFDC against carbapenem-resistant <i>Pseudomonas aeruginosa</i> (CR-Pa) and <i>Acinetobacter baumannii</i> (CR-Ab) using murine models of VAP. VAP was induced in neutropenic mice by intratracheal inoculation of bacterial suspension, following endotracheal tube placement to mimic VAP. Pharmacokinetics (PK) analysis was performed to determine CFDC dosing regimens that achieved 70% of the time above the minimum inhibitory concentration (fT > MIC) over 24 h in plasma, which was the average value reported in previous non-clinical studies. In VAP caused by a strain of CR-Ab, CFDC significantly improved the survival rate and reduced bacterial load in the lungs with fT > MIC of 70%. However, in VAP caused by a strain of CR-Pa, CFDC did not significantly improve the survival rate or reduce bacterial load in the lungs, even with fT > MIC of 70%. To evaluate whether a higher fT > MIC of CFDC would enhance <i>in vivo</i> efficacy, we assessed the bactericidal effect at higher fT > MIC values. A significant reduction in bacterial load in the lungs was observed in VAP caused by CR-Pa when fT > MIC exceeded 90%. These findings suggest that the optimal CFDC dosing regimen for VAP may differ depending on the causative pathogen, with higher fT > MIC targets potentially necessary for infections caused by <i>P. aeruginosa</i>.IMPORTANCEVentilator-associated pneumonia (VAP) caused by drug-resistant non-fermenting bacteria, such as <i>Pseudomonas aeruginosa</i> and <i>Acinetobacter baumannii,</i> is difficult to treat. Cefiderocol is active against these pathogens, but the amount of drug exposure needed to work in the lung has been uncertain. Using mouse models that mimic VAP, we linked cefiderocol exposure to benefit. <i>Acinetobacter</i> infections improved at moderate exposure, whereas <i>Pseudomonas</i> infections required much higher exposure to show clear killing in the lungs. These pathogen-specific requirements help explain variable clinical responses and offer actionable targets for selecting doses and schedules. By turning complex pharmacology into simple guidance, our work supports antibiotic stewardship and informs the design of future studies aimed at improving outcomes for patients with difficult-to-treat VAP.