Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Cefepime in an In Vitro Infection Model

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (% T > threshold). Using data from studies of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs), a relationship between tazobactam % T > threshold and reduction in log(10) CFU/ml from baseline, for which the tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship used to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized, and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae isolates, known to produce CTX-M-15 beta-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/liter in the presence of 4 mg/liter tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625x to 1x the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam % T > threshold and change in log10 CFU/ml from the baseline at 24 h was the product of 0.125 and the cefepime-tazobactam MIC (R-2 = 0.813). The magnitudes of % T > threshold associated with net bacterial stasis and a 1-log(10) CFU/ml reduction from baseline at 24 h were 21.9% and 52.8%, respectively. These data will be useful in supporting the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies.