Susceptibility Testing Is Key for the Success of Cefiderocol Treatment: A Retrospective Cohort Study

Abstract

Cefiderocol is a novel siderophore cephalosporin, which has proven in vitro activity against carbapenem-resistant (CR) Gram-negative pathogens and stability towards all carbapenemases. The aim of this study was to describe the first cases of prescriptions and the efficacy of cefiderocol for compassionate use in the 2 months following its access in France. We performed a national retrospective study of all patients who received at least one dose of cefiderocol from 2 November 2018 to 5 November 2019. We collected clinical characteristics and outcome through a standard questionnaire. Bacterial isolates from 12 patients were centralized and analyzed in the French National Reference Center for Antimicrobial Resistance, and sequenced using Illumina technology. Finally, 13 patients from 7 French university hospitals were included in the study. The main type of infection treated by cefiderocol was respiratory tract infections (RTI, n = 10). The targeted bacteria were Pseudomonas aeruginosa (n = 12), including carbapenemase-producing P. aeruginosa (n = 9), Acinetobacter baumannii (n = 2), Klebsiella pneumoniae (n = 1), and Enterobacter hormaechei (n = 1). Overall, of the 12 patients whose samples were analyzed, 5 P. aeruginosa strains were not susceptible to cefiderocol (4 categorized as resistant and 1 as intermediate) according to Clinical and Laboratory Standards Institute (CLSI) breakpoints. If considering susceptible strains, the cure rate was 6/7, while being 0/5 among not-susceptible strains. This study underlines the necessity to test strains in adequate conditions.

Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections

“…Therefore, our study, in agreement with previous studies, 12 , 13 confirms that inadequate source control together with failing to achieve adequate drug exposure still represents a crucial risk factor for death related to infection. To date, no real-world evidence regarding the administration of cefiderocol during ECMO exists and optimizing the drug dosage in this emerging clinical scenario could be extremely difficult.…”

“…All these factors could affect the antibiotic pharmacodynamic and pharmacokinetic aspects and may influence clinical outcome. Finally, these favourable outcomes are even more relevant since almost 90% of the patients were admitted to intensive care and they all had an extended follow-up of 90 days, significantly longer than other published case series, 11 , 13 and 30% of our cases were critically ill COVID-19 patients with a VAP due to XDR/DRT-P, associated per se with a significantly increased 28 day mortality rate. 14 …”

“… 12 Only Bleibtreu et al . 13 reported 9 of 12 cases (75%) of XDR P. aeruginosa , and 5 of them were non-susceptible to cefiderocol at baseline, contributing to the 55% overall clinical failure. Second, the clinical pictures of patients included were particularly challenging.…”

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

“…We identified 30 case reports and case series including 78 patients who had recalcitrant infections caused by MDR Gram-negative bacteria, and treated with salvage treatment or compassionate use of cefiderocol in real-world settings ( Edgeworth et al, 2019 ; Stevens and Clancy, 2019 ; Trecarichi et al, 2019 ; Alamarat et al, 2020 ; Contreras et al, 2020 ; Dagher et al, 2020 ; Kufel et al, 2020 ; Lampejo et al, 2020 ; Oliva et al, 2020 ; Siméon et al, 2020 ; Zingg et al, 2020 ; Bavaro et al, 2021a ; Bavaro et al, 2021b ; Bleibtreu et al, 2021 ; Bodro et al, 2021 ; Borghesi et al, 2021 ; Carney et al, 2021 ; Chavda et al, 2021 ; Cipko et al, 2021 ; Falcone et al, 2021 ; Fratoni et al, 2021 ; Grande Perez et al, 2021 ; Grasa et al, 2021 ; Klein et al, 2021 ; König et al, 2021 ; Mabayoje et al, 2021 ; Martinez et al, 2021 ; Mc Gann et al, 2021 ; Warner et al, 2021 ; Zaidan et al, 2021 ). The detailed characteristics of these cases are summarized in Supplementary Table S3 .…”

Cefiderocol-Based Combination Therapy for “Difficult-to-Treat” Gram-Negative Severe Infections: Real-Life Case Series and Future Perspectives

“…This is among the most extensive case series describing the real-life use of cefiderocol for the treatment of severe XDR gram-negative bacterial infections, along with the multicentric experience by Bleibtreu and colleagues [17] and the monocentric experience of Falcone et al [18]. In addition, this series enrolled "difficult-to-treat" patients, due to their important comorbidities, severe clinical conditions requiring ICU admission or deep immunocompromission.…”