Pharmacokinetics of cefiderocol during extracorporeal membrane oxygenation: A case report

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Abstract

Patients with extracorporeal membrane oxygenation (ECMO) support do frequently receive broad-spectrum antibiotics, due to the high frequency of infection by multidrug resistant microorganisms. The extracorporeal circuit can alter the pharmacokinetics (PK) of administered drugs, and in the case of antibiotics this may lead to treatment failure. Cefiderocol is a new cephalosporin that exhibits excellent in vitro activity against many multidrug-resistant (MDR) microorganisms, but there is no published data about the modifications of its PK in patients with ECMO support. Herein we report the results of a pharmacokinetic investigation of cefiderocol in a critically ill patient receiving extracorporeal respiratory support.

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Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

Yutaka Saisho, Takayuki Katsube, Scott White … (2018)

ABSTRACT Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration (C max), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of C max and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

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Optimising drug dosing in patients receiving extracorporeal membrane oxygenation

Vesa Cheng, Mohd-Hafiz Abdul-Aziz, Jason A Roberts … (2018)

Optimal pharmacological management during extracorporeal membrane oxygenation (ECMO) involves more than administering drugs to reverse underlying disease. ECMO is a complex therapy that should be administered in a goal-directed manner to achieve therapeutic endpoints that allow reversal of disease and ECMO wean, minimisation of complications (treatment of complications when they do occur), early interruption of sedation and rehabilitation, maximising patient comfort and minimising risks of delirium. ECMO can alter both the pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs and our understanding of these alterations is still evolving. Based on available data it appears that modern ECMO circuitry probably has a less significant impact on PK when compared with critical illness itself. However, these findings need further confirmation in clinical population PK studies and such studies are underway. The altered PD associated with ECMO is less understood and more research is indicated. Until robust dosing guidelines become available, clinicians will have to rely on the principles of drug dosing in critically ill and known PK alterations induced by ECMO itself. This article summarises the PK alterations and makes preliminary recommendations on possible dosing approaches.

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Intrapulmonary pharmacokinetic profile of cefiderocol in mechanically ventilated patients with pneumonia

Takayuki Katsube, David Nicolau, Keith A Rodvold … (2021)

Objectives Lung penetration of cefiderocol, a novel siderophore cephalosporin approved for treatment of nosocomial pneumonia, has previously been evaluated in healthy subjects. This study assessed the intrapulmonary pharmacokinetic profile of cefiderocol at steady state in hospitalized, mechanically ventilated pneumonia patients. Methods Patients received cefiderocol 2 g (or ≤1.5 g if renally impaired), administered IV q8h as a 3 h infusion, or 2 g q6h if patients had augmented renal function (estimated CL CR > 120 mL/min). After multiple doses, each patient underwent a single bronchoalveolar lavage (BAL) procedure either at the end of the infusion or at 2 h after the end of infusion. Plasma samples were collected at 1, 3, 5 and 7 h after the start of infusion. After correcting for BAL dilution, cefiderocol concentrations in epithelial lining fluid (ELF) for each patient and the ELF/unbound plasma concentration ratio (R C, E/P ) were calculated. Safety was assessed up to 7 days after the last cefiderocol dose. Results Seven patients received cefiderocol. Geometric mean ELF concentration of cefiderocol was 7.63 mg/L at the end of infusion and 10.40 mg/L at 2 h after the end of infusion. R C, E/P was 0.212 at the end of infusion and 0.547 at 2 h after the end of infusion, suggesting delayed lung distribution. There were no adverse drug reactions. Conclusions The results suggest that cefiderocol penetrates the ELF in critically ill pneumonia patients with concentrations that are sufficient to treat Gram-negative bacteria with an MIC of ≤4 mg/L.

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Author and article information

Contributors

Jordi Riera: (View ORCID Profile)

Alba Pau: (View ORCID Profile)

Journal

Title: Perfusion

Abbreviated Title: Perfusion

Publisher: SAGE Publications

ISSN (Print): 0267-6591

ISSN (Electronic): 1477-111X

Publication date Created: May 2023

Publication date (Electronic): February 28 2023

Publication date (Print): May 2023

Volume: 38

Issue: 1_suppl

Pages: 40-43

Affiliations

[1 ]Critical Care Department, Vall d’Hebron University Hospital, Barcelona, Spain

[2 ]Sepsis, Organ Dysfunction and Resuscitation (SODIR) Research Group, Vall d’Hebron Research Institute, Barcelona, Spain

[3 ]Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

[4 ]Pharmacy Department, Vall D’Hebron University Hospital, Barcelona, Spain

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DOI: 10.1177/02676591231160462

SO-VID: 97ed11e1-4f72-4a5b-a1c6-d9c41d7a999c

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Pharmacokinetics of cefiderocol during extracorporeal membrane oxygenation: A case report

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Most cited references 6

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

Optimising drug dosing in patients receiving extracorporeal membrane oxygenation

Intrapulmonary pharmacokinetic profile of cefiderocol in mechanically ventilated patients with pneumonia

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