1316. Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol in Critically Ill Patients
Authors: Katsube Takayuki , Kawaguchi Nao , Matsunaga Yuko , Ariyasu Mari , Den Nagata Tsutae , Portsmouth Simon , Paterson David , Paterson David , Satlin Michael J , Zeitlinger Markus , Echols Roger , Wajima Toshihiro 
Published: January 2021

Abstract

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&gt;MIC and %fT&gt;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&gt;MIC,ELF was calculated for 125 pneumonia patients based on an intrapulmonary PK model. Relationships between %fT&gt;MIC, %fT&gt;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&gt;MIC was 100% in ≥95% of patients in each study, and estimated %fT&gt;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&gt;MIC or %fT&gt;MIC,ELF were similar between the two studies (Table). No PK/PD relationships between %fT&gt;MIC, %fT&gt;MIC,ELF and clinical cure, microbiological eradication, or survival were identified in either study because high %fT&gt;MIC or %fT&gt;MIC,ELF was achieved in all patients.
Table. Clinical cure and survival rates in patients with 100% fT&gt;MIC or %fT&gt;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&gt;MIC and %fT&gt;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)