Pharmacodynamics of cefiderocol, a novel siderophore cephalosporin, explored in a pseudomonas aeruginosa neutropenic murine thigh model
2017
Ghazi, Islam M. | Monogue, Marguerite L. | Tsuji, Masakatsu | Nicolau, David P.
Cefiderocol is a siderophore cephalosporin that displays potent in vitro activity against multi-drug resistant (MDR) Gram-negative bacteria. We aimed to describe cefiderocol's pharmacokinetics, pharmacodynamics, and 24-hour efficacy using dose-ranging methods in the neutropenic murine thigh infection model.Infection was established in neutropenic mice (administered cyclophosphamide 150 mg/kg and 100 mg/kg 4 and 1 days prior to inoculation respectively) with 8 Pseudomonas aeruginosa isolates (MIC range: 0.063-0.5 µg/mL) that have displayed variable in vivo activity against previously tested β-lactam with siderophore moieties. Renal excretion was controlled by administration of 5mg/kg of uranyl nitrate 3 days prior to inoculation. Cefiderocol was administered in subcutaneously in 8 escalating doses (4.2- 166.7 mg/kg every 8 hours).In PK studies, cefiderocol manifested similar pharmacokinetics across tested doses (4, 100, and 250 mg/kg) with a mean half-life 0.86h. In PD studies, the change in CFU after 24h from the initial inoculum ranged from +3.4 to -3.1 log10 with doses of 4.2 to 166.7 mg/kg q8h. Dose-response curves for the eight isolates assumed the characteristic sigmoidal shape with greater CFU reductions as the dose increased. Focusing on the previously defined efficacy parameter of fT>MIC for this compound, targets for stasis, 1 log10 reduction, and 2 log10 reductions ranged from 44.4-94.7, 50.2-97.5 and 62.1-100, respectively.Cefiderocol displayed sustained antibacterial effects against these MDR P. aeruginosa isolates. These data support the cefiderocol dose selected for clinical trials.
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