Abstract
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. An HFIM was used to simulate and evaluate the impact of escalating tazobactam dosing in the context of a fixed piperacillin exposure (equivalent to 4 g every 8 hours). Serial samples were collected to verify the pharmacokinetic simulations (by LC–MS/MS) and determine bacterial density for up to 120 hours. 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 4 g piperacillin and 0.5 g tazobactam administered every 8 hours resulted in a fT > MICi of 39.6% and bacterial regrowth. An exposure equivalent to 1.5 g tazobactam (fT > MICi of 55.1%) was needed to suppress growth. These regrowth findings were validated with the two 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.
Disclosures
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.
Session: 145. PK/PD Studies
Friday, October 5, 2018: 12:30 PM