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Dear Editors,
We read with interest the paper by Lee et al., which reviewed the in vitro, in vivo, and clinical data on cefiderocol [1]. However, we would like to address and highlight for your readers, the inaccurate characterization of all-cause mortality (ACM) in the APEKS-NP (NCT03032380, EudraCT 2016-003020-23) clinical trial and the subsequent conclusion drawn from this mischaracterization.
APEKS-NP was specifically designed to assess mortality in the nosocomial pneumonia patient population. Furthermore, APEKS-NP met its primary endpoint of non-inferiority. ACM in the cefiderocol arm was 12.4% versus 11.6% in the high-dose meropenem arm with a treatment difference of 0.8% [95% CI − 6.6 to 8.2] demonstrating that cefiderocol was non-inferior to high-dose meropenem in critically ill patients with nosocomial pneumonia caused by a broad range of Gram-negative bacteria, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae [2, 3]. APEKS-NP subsequently served as the basis of approval by the US Food and Drug Administration (FDA) for use of cefiderocol in hospital-acquired and ventilator-acquired pneumonias (HAP/VAP) due to susceptible Gram-negative microorganisms, and supported removal of the restriction of limited or no alternative treatment options, and limited safety and efficacy data statements from the cefiderocol label [4].
From these results, Lee et al. draw the conclusion that cefiderocol should be limited only to the treatment of cUTIs from Gram-negative bacteria [1]. Our organization, as well as the FDA and European Medicines Agency, examined these results and concluded that cefiderocol can be used in patients with cUTI and HAP/VAP as evidenced by cefiderocol’s current FDA-approved indication as well as the pathogen-focused indication in the European Union [4, 5].
Thank you for the opportunity to respond to Lee et al. We hope this letter helps clarify the design, results and interpretation of APEKS-NP and cefiderocol’s place in therapy.
References
Lee YR, Yeo S. Cefiderocol, a new siderophore cephalosporin for the treatment of complicated urinary tract infections caused by multidrug-resistant pathogens: preclinical and clinical pharmacokinetics, pharmacodynamics, efficacy and safety. Clin Drug Investig. 2020;40:901–13. https://doi.org/10.1007/s40261-020-00955-x.
Wunderink RG, Matsunaga Y, Ariyasu M, Clevenbergh P, Echols R, Kaye KS, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. October 2020 (online).
FDA Antimicrobial Drugs Advisory Committee, Cefiderocol Briefing Document NDA #209445. Shionogi Inc. https://www.fda.gov/media/131705/download. Accessed 27 May 2020.
Fetroja® Prescribing Information: Drugs@FDA, Reference ID: 4676517. revised 20 September 2020.
European Medicines Agency. Fetcroja (cefiderocol) EPAR. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/fetcroja#product-information-section. Accessed 9 Mar 2021.
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Andrew Koren and Andreas Karas are employees of Shionogi Inc. Roger Echols is a consultant for Shionogi and received a consultancy fee for his services.
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Koren, A., Karas, A. & Echols, R. Comment on ‘Cefiderocol, a New Siderophore Cephalosporin for the Treatment of Complicated Urinary Tract Infections Caused by Multidrug-resistant Pathogens: Preclinical and Clinical Pharmacokinetics, Pharmacodynamics, Efficacy and Safety’. Clin Drug Investig 41, 659–660 (2021). https://doi.org/10.1007/s40261-021-01043-4
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DOI: https://doi.org/10.1007/s40261-021-01043-4