Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of gram-negative bacteria in a murine thigh infection model

Marguerite L. Monogue, Masakatsu Tsuji, Yoshinori Yamano, Roger Echols, David P. Nicolaua

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol’s efficacy with humanized exposures of meropenem and cefepime against a subset of these pheno-typically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

Original languageEnglish (US)
Article numbere01022-17
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number11
DOIs
StatePublished - Nov 2017
Externally publishedYes

Fingerprint

meropenem
Acinetobacter baumannii
Enterobacteriaceae
Thigh
Gram-Negative Bacteria
Pseudomonas aeruginosa
Siderophores
Cephalosporins
Infection
Population
Growth
cefepime

Keywords

  • Acinetobacter
  • Cefiderocol
  • Escherichia coli
  • Gram-negative bacteria
  • Klebsiella
  • Pseudomonas aeruginosa
  • Siderophore

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Efficacy of humanized exposures of cefiderocol (S-649266) against a diverse population of gram-negative bacteria in a murine thigh infection model. / Monogue, Marguerite L.; Tsuji, Masakatsu; Yamano, Yoshinori; Echols, Roger; Nicolaua, David P.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 11, e01022-17, 11.2017.

Research output: Contribution to journalArticle

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abstract = "Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol’s efficacy with humanized exposures of meropenem and cefepime against a subset of these pheno-typically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85{\%} of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.",
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