Pathogen-focused Clinical Development to Address Unmet Medical Need: Cefiderocol Targeting Carbapenem Resistance

Author:

Echols Roger1,Ariyasu Mari2,Nagata Tsutae Den2

Affiliation:

1. Infectious Disease Drug Development Consulting, LLC, Easton, Connecticut

2. Global Development, Shionogi & Co, Ltd, Osaka, Japan

Abstract

AbstractHistorically, the regulatory requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for developing new antibiotics have not addressed pathogen-focused indications for drug approval. The design of the necessary randomized controlled trials traditionally involves the enrollment of patients with site-specific infections caused by susceptible as well as resistant pathogens. Cefiderocol has undergone a streamlined clinical development program to address serious carbapenem-resistant infections. The regulatory approach, and the pivotal clinical trials, differed between the FDA and EMA. In the United States, the APEKS-cUTI (Acinetobacter, Pseudomonas, Escherichia coli, Klebsiella, Stenotrophomonas–complicated urinary tract infection) study was conducted to provide the basis for FDA approval of a site-specific cUTI indication. The EMA, however, preferred the CREDIBLE-CR (A MultiCenter, RandomizED, Open-label ClInical Study of S-649266 or Best AvailabLE Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-negative Pathogens) study, in which patients with nosocomial pneumonia, bloodstream infections, or cUTIs were enrolled if they had a carbapenem-resistant pathogen. The resulting European label will be pathogen focused rather than infection site specific (ie, treatment of gram-negative infection in patients with limited treatment options). The implications and limitations of these different regulatory processes are discussed.

Funder

Shionogi & Co, Ltd

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Microbiology (medical)

Reference24 articles.

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2. Epidemiology and diagnostics of carbapenem resistance in gram-negative bacteria;Nordmann;Clin Infect Dis,2019

3. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017. Available at: http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf. Accessed 1 February 2019.

4. Cefiderocol (S-649266), a new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: structure activity relationship;Aoki;Eur J Med Chem,2018

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