Pharmacodynamic Activity of Fosfomycin Simulating Urinary Concentrations Achieved After a Single 3 Gram Oral Dose versus Escherichia coli Using an In Vitro Model

Authors

George G. Zhanel, University of Manitoba
Kate Parkinson, University of Manitoba
Sean Higgins, University of Manitoba
Andrew Denisuik, University of Manitoba
Heather Adam, University of Manitoba
Johann Pitout, University of Calgary
Ayman Noreddin, Chapman UniversityFollow
James A. Karlowsky, University of Manitoba

Document Type

Article

Publication Date

4-23-2017

Abstract

We assessed the activity of fosfomycin simulating urinary concentrations achieved after a single 3 gram oral dose against Escherichia coli using an in vitro pharmacodynamic model. Eleven urinary isolates of E. coli were studied. Isolates were ESBL-producing or carbapenemase-producing. The in vitro pharmacodynamic model was inoculated with an inoculum of (~1 × 10⁶ cfu/mL). Fosfomycin was administered to simulate maximum free (ƒ) urine (U) concentrations and a t_1/2 obtained after a standard single 3 gram oral dose in healthy volunteers (ƒU_max, 4000 mg/L; t_1/2, 6 h). Sampling was performed over 48 h to assess the rate and extent of bacterial reduction as well as resistance selection. Complete bacterial eradication from the model was defined by no regrowth over the 48 h study period. Fosfomycin MICs ranged from 1 to 4 μg/mL for ESBL producers, while all three carbapenemase-producing E. coli demonstrated a fosfomycin MIC of 2 μg/mL. Fosfomycin ƒT_>MIC of 100% (ƒAUC_0–24/MIC, ≥ ~ 7250) resulted in bacterial killing (reductions in log₁₀ CFU assessed relative to the starting inoculum at 2, 4, 6, 12, 24, and 48 hours of ≥3.0) at each time-point versus all isolates of ESBL-producing and carbapenemase-producing E. coli. We conclude that fosfomycin urinary concentrations obtained after a single 3 gram oral dose were bactericidal as early as 1 h after dosing with complete bacterial eradication at all time-points over the 48 h testing period against urinary isolates of E. coli (including MDR ESBL- and/or carbapenemase-producing strains). Our data help to explain the high (>90%) microbiological and clinical cure rates achieved with fosfomycin when used as a single 3 gram oral dose to treat patients with acute uncomplicated cystitis.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Diagnostic Microbiology and Infectious Disease. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version will be subsequently published in Diagnostic Microbiology and Infectious Disease in 2017. DOI: 10.1016/j.diagmicrobio.2017.04.007

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Recommended Citation

Zhanel George G., Parkinson Kate, Higgins Sean, Denisuik Andrew, Adam Heather, Pitout Johann, Noreddin Ayman, Karlowsky James A., Pharmacodynamic Activity of Fosfomycin Simulating Urinary Concentrations Achieved After a Single 3 Gram Oral Dose versus Escherichia coli Using an In Vitro Model, Diagnostic Microbiology and Infectious Disease (2017), doi: 10.1016/j.diagmicrobio.2017.04.007

Copyright

Elsevier

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.