Humanized Exposures of Cefiderocol, a Siderophore Cephalosporin, Display Sustained in vivo Activity against Siderophore-Resistant Pseudomonas aeruginosa

Pharmacology
Islam M GhaziD P Nicolau

Abstract

We evaluated the in vivo efficacy of humanized exposures of cefiderocol, a novel siderophore cephalosporin, against a test panel of P. aeruginosa (PSA) previously shown to develop resistance to 2 preclinical candidate siderophores (MB-1 and SMC-3176). In the thigh infection model, the PSA bacterial density in untreated controls grew from 5.54 ± 0.23 to 8.68 ± 0.57 log10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log10 CFU reduction in all 8 isolates, while MB-1 and SMC-3176 exhibited variable activity similar to that previously reported. Humanized exposures of cefepime and levofloxacin, acting as positive antimicrobial controls displayed activity consistent with that of the bacterial phenotypic susceptibility profiles. Cefiderocol manifested in vivo efficacy against all PSA isolates including those resistant to cefepime and levofloxacin in contrast to its predecessor siderophore compounds. These preclinical data are supportive of further evaluation of cefiderocol in the treatment of P. aeruginosa.

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Citations

Nov 15, 2019·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Malcom G P Page
Oct 30, 2019·Antimicrobial Agents and Chemotherapy·James M KiddDavid P Nicolau
Feb 20, 2020·Infectious Diseases and Therapy·Janet Y WuJason M Pogue
Apr 23, 2019·Expert Review of Anti-infective Therapy·Georgios L VoulgarisMatthew E Falagas
Nov 15, 2019·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Takafumi Sato, Kenji Yamawaki
Nov 15, 2019·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Yoshinori Yamano
Oct 18, 2020·Pharmacotherapy·Jacinda C Abdul-MutakabbirMichael J Rybak
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Apr 15, 2021·Expert Review of Clinical Pharmacology·Anselm Jorda, Markus Zeitlinger
Jun 3, 2021·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Elizabeth Marie GavioliEtty Vider
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Dec 31, 2021·Clinical Chemistry·Rucha DatarAlex van Belkum

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