title: In VivoPharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
abstract: Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrum-beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5Escherichia coli, 3Klebsiella pneumoniae, and 2Pseudomonas aeruginosastrains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC0-∞) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R2= 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 forE. coli,K.,pneumoniaeandP. aeruginosa, respectively. For theEnterobacteriaceaegroup, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected withE. coli145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due toEnterobacteriaceaeandPseudomonas.
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lepak
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.|William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: VanScoy
authors.affiliation: Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Taylor
authors.affiliation: Zavante Therapeutics, Inc., San Diego, California, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ellis-Grosse
authors.affiliation: Institute for Clinical Pharmacodynamics, Schenectady, New York, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA dra@medicine.wisc.edu.|Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, USA.|William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity*; D005260:Female; D005578:Fosfomycin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000472:pathogenicity*; D051379:Mice; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity*; D013848:Thigh / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin
keywords: PK/PD; fosfomycin