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

Islam M. Ghazi, Marguerite L. Monogue, Masakatsu Tsuji, David P. Nicolau

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 log 10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log 10 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.

Original languageEnglish (US)
Pages (from-to)278-284
Number of pages7
JournalPharmacology
Volume101
Issue number5-6
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Fingerprint

Siderophores
Cephalosporins
Pseudomonas aeruginosa
Levofloxacin
Thigh
Infection
cefepime
SMC-3176

Keywords

  • Cefiderocol
  • Humanized exposure
  • In vivo activity
  • Pseudomonas aeruginosa
  • Siderophore

ASJC Scopus subject areas

  • Pharmacology

Cite this

Humanized Exposures of Cefiderocol, a Siderophore Cephalosporin, Display Sustained in vivo Activity against Siderophore-Resistant Pseudomonas aeruginosa. / Ghazi, Islam M.; Monogue, Marguerite L.; Tsuji, Masakatsu; Nicolau, David P.

In: Pharmacology, Vol. 101, No. 5-6, 01.04.2018, p. 278-284.

Research output: Contribution to journalArticle

@article{87e0e675960c44f291fe620b614853b6,
title = "Humanized Exposures of Cefiderocol, a Siderophore Cephalosporin, Display Sustained in vivo Activity against Siderophore-Resistant Pseudomonas aeruginosa",
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 log 10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log 10 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.",
keywords = "Cefiderocol, Humanized exposure, In vivo activity, Pseudomonas aeruginosa, Siderophore",
author = "Ghazi, {Islam M.} and Monogue, {Marguerite L.} and Masakatsu Tsuji and Nicolau, {David P.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1159/000487441",
language = "English (US)",
volume = "101",
pages = "278--284",
journal = "Pharmacology",
issn = "0031-7012",
publisher = "S. Karger AG",
number = "5-6",

}

TY - JOUR

T1 - Humanized Exposures of Cefiderocol, a Siderophore Cephalosporin, Display Sustained in vivo Activity against Siderophore-Resistant Pseudomonas aeruginosa

AU - Ghazi, Islam M.

AU - Monogue, Marguerite L.

AU - Tsuji, Masakatsu

AU - Nicolau, David P.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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 log 10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log 10 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.

AB - 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 log 10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log 10 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.

KW - Cefiderocol

KW - Humanized exposure

KW - In vivo activity

KW - Pseudomonas aeruginosa

KW - Siderophore

UR - http://www.scopus.com/inward/record.url?scp=85042354055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042354055&partnerID=8YFLogxK

U2 - 10.1159/000487441

DO - 10.1159/000487441

M3 - Article

C2 - 29471305

AN - SCOPUS:85042354055

VL - 101

SP - 278

EP - 284

JO - Pharmacology

JF - Pharmacology

SN - 0031-7012

IS - 5-6

ER -