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.
A. M. Sánchez-Díaz, European Unionâs Seventh Framework Programme: Grant Investigator , Research grant .
R. Cantón, European Unionâs Seventh Framework Programme: Grant Investigator , Research grant .
V. Tam, European Unionâs Seventh Framework Programme: Grant Investigator , Research grant .