1316 - Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol in Critically Ill Patients

Background: Cefiderocol (CFDC), a novel siderophore cephalosporin, has demonstrated potent antibacterial activity against a wide range of Gram-negative bacteria including carbapenem-resistant strains. We aimed to evaluate relationships between drug exposure and outcomes in critically ill patients.

Methods: Sparse pharmacokinetic (PK) samples at steady state from critically ill patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection receiving CFDC in two Phase 3 studies were analyzed. Percent time of dosing interval of free drug concentration exceeding the minimum inhibitory concentration (MIC) in plasma and epithelial lining fluid (ELF) (%fT_>MIC and %fT_>MIC,ELF, respectively) were determined for 60 (CREDIBLE-CR; NCT02714595) and 97 patients (APEKS-NP; NCT03032380), using a 3-compartment population PK model. The %fT_>MIC,ELF was calculated for 125 pneumonia patients based on an intrapulmonary PK model. Relationships between %fT_>MIC, %fT_>MIC,ELF and clinical and microbiological outcomes at test of cure (TOC), or mortality at Day 28 were assessed.

Results: The median (90^th percentile) MICs of Gram-negative pathogens in the PK/pharmacodynamic (PD) analyses were 0.25 (4) µg/mL (CREDIBLE-CR) and 0.25 (2) µg/mL (APEKS-NP), respectively. Individual plasma %fT_>MIC was 100% in ≥95% of patients in each study, and estimated %fT_>MIC,ELF was 100% in 89.3% (25/28 pneumonia patients; CREDIBLE-CR) and 97.9% (95/97 pneumonia patients; APEKS-NP). Clinical cure rates and survival rates in patients with 100% fT_>MIC or %fT_>MIC,ELF were similar between the two studies (Table). No PK/PD relationships between %fT_>MIC, %fT_>MIC,ELF and clinical cure, microbiological eradication, or survival were identified in either study because high %fT_>MIC or %fT_>MIC,ELF was achieved in all patients.Table. Clinical cure and survival rates in patients with 100% fT>MIC or %fT>MIC,ELF in CREDIBLE-CR and APEKS-NP studies


Conclusion: PK/PD relationship was not identified between CFDC plasma or ELF exposure and clinical or microbiological outcomes, or mortality as high %fT_>MIC and %fT_>MIC,ELF were achieved, suggesting the recommended dosing regimen of 2 g q8h or renally adjusted dosage (including augmented renal clearance), infused over 3 hours, provides sufficient exposure to CFDC in critically ill patients.