Use Of Monte Carlo Pk/pd Model To Optimize Dosing Regimens For β-Lactam Antibiotics Against Gram-negative Bacteria

Objectives:To evaluate pharmacodynamic profiling of prolonged, continuous and traditional dosing regimens of sevenβ-lactam antibiotics against gram-negative bacteria, and achieve optimum regimens in order to instruct the rational clinical application of antibiotics. Then we apply optimum regimen to clinic so as to check the exactitude of this theropy.Methods:Minimum inhibitory concentrations for 524 gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter cloacae) including 188 isolates from intensive care unit from Jan 2008 to Jun 2008 in two hospitals were determined. Pharmacokinetic parameters for ceftazidime, cefepime, piperacillin-tazobactam, cefoperazone-sulbactam, imipenem, meropenem and biapenem were obtained from a published study. Monte Carlo simulation was performed to calculate cumulative fraction of response(CFR) for prolonged, continuous and traditional dosing regimens of sevenβ-lactam antibiotics against five gram-negative bacteria and isolates from intensive care unit. Then we applied optimum regimen to clinic and observed clinical therapeutic effect.Results:1.Against Enterobacteriaceae, carbapenems attained optima CFR. Against Acinetobacter baumannii, cefoperazone-sulbactam 2g every 8h (3h infusion) achieved the highest CFR (47.4%). No regimen achieved an optimum CFR for Pseudomanas aeruginosa.2.Against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter cloacae, the 3-h prolonged infusion of ceftazidime, piperacillin-tazobactam, imipenem and biapenem was better than traditional infusion, and continuous infusion of piperacillin-tazobactam and biapenem was also better than traditional infusion.3. Against bacteria from intensive care unit, increases in CFR were observed when infusion time of all dosing regimens was prolonged to 3 hour. It was noted that increase of CFR was maximum for piperacillin-tazobactam 4.5g every 8 hour.4.In clinical study, the effective rate was 68.6% for prolonged infusion piperacillin-tazobactam compared with 41.9% for traditional infusion. There were statistically significant differences (P<0.05).Conclusions:Prolonged and continuous dosing regimen is superior to traditional dosing regimen. Optimized regimen through Monte Carlo PK/PD model is able to be applied to clinic derectly and increase clinical therapeutic effect.