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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 (90th 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. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Grant/Research Support)Merck (Grant/Research Support)Shionogi Inc. (Consultant) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee)

Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach. Methods PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance. Results The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was >90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was >90% against MICs ≤2 μg/mL and >85% against MICs ≤4 μg/mL, regardless of renal function. Table. Probability of Target Attainment for 75% fT>MIC or 75% fT>MIC,ELF Conclusion The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)