1409. Evaluation of Alternative Piperacillin-Tazobactam Dosing Strategies against ESBL-producing Enterobacteriaceae using a Hollowfiber Infection Model
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • IDweek2018 Alternative Piperacillin Dosing Strategies_final.pdf (1.2 MB)
  • Background: Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae exhibit variable response to treatment with piperacillin-tazobactam. Current clinical practice with piperacillin-tazobactam involves dosing the components simultaneously at a fixed ratio of 8:1 piperacillin to tazobactam. However, it remains unclear whether this ratio is optimal for enzyme inhibition and bactericidal activity. Using a hollowfiber infection model (HFIM), we evaluated the efficacy of various exposures of piperacillin-tazobactam against ESBL-producing Enterobacteriaceae.

    Methods: A clinical strain of K. pneumoniae expressing CTX-M-15 was used as a reference isolate. Piperacillin minimum inhibitory concentrations (MIC) were determined using a range of tazobactam concentrations and fitted to an inhibitory Emax model. A HFIM was used to simulate and evaluate the impact of escalating tazobactam dosing in the context of a fixed piperacillin exposure (equivalent to 4g every 8h). Serial samples were collected to verify the pharmacokinetic simulations (by LC/MS/MS) and determine bacterial density for up to 120h. Measured drug concentrations were incorporated in the Emax model to determine the free-time above instantaneous MIC (fT>MICi) associated with each experimental exposure. The target fT>MICi associated with growth suppression was subsequently validated using a clinical strain of E. coli (producing SHV-12) and a second K. pneumoniae (producing CTX-M-15).

    Results: For the reference strain, a clinical regimen of 4g piperacillin and 0.5g tazobactam administered every 8h resulted in a fT>MICi of 39.6% and bacterial regrowth. An exposure equivalent to 1.5g tazobactam (fT>MICi of 55.1%) was needed to suppress growth. These regrowth findings were validated with the 2 other ESBL-producers with tazobactam exposures characterized by fT>MICi of 36.8% and 43.8%.

    Conclusion: Improved bacterial killing was observed with increasing tazobactam exposures. As a novel PK/PD index, fT>MICi may be used to characterize response to a β-lactamase inhibitor and provide efficacy targets to guide the development and clinical dosing of these inhibitors.

    Henrietta Abodakpi, Pharm.D, Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, Kai-Tai Chang, Ph.D, Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, Ana Maria Sánchez-Díaz, Ph.D, Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain, Rafael Cantón, Pharm.D, Ph.D, Hospital Universitario Ramon y Cajal, Madrid, Spain and Vincent Tam, Pharm.D, Pharmacological and Pharmaceutical Sciences; Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX

    Disclosures:

    H. Abodakpi, None

    K. T. Chang, None

    A. M. Sánchez-Díaz, European Union’s Seventh Framework Programme: Grant Investigator , Research grant .

    R. Cantón, European Union’s Seventh Framework Programme: Grant Investigator , Research grant .

    V. Tam, European Union’s Seventh Framework Programme: Grant Investigator , Research grant .

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