Comparison of the activity of a human simulated, high-dose, prolonged infusion of meropenem against Klebsiella pneumoniae producing the KPC carbapenemase versus that against Pseudomonas aeruginosa in an in vitro pharmacodynamic model.

摘要

We have previously demonstrated that a high-dose, prolonged-infusion meropenem regimen (2 g every 8 h [q8h]; 3-hour infusion) can achieve 40% free drug concentration above the MIC against Pseudomonas aeruginosa with MICs of or=3 log CFU reduction against all KPC isolates within 6 h, followed by regrowth in all but two isolates. The targeted %fT>MIC (percent time that free drug concentrations remain above the MIC) exposure was achieved against both of these KPC isolates (100% fT>MIC versus MIC=2 microg/ml, 75% fT>MIC versus MIC=8 microg/ml). Against KPC isolates with MICs of 8 and 16 microg/ml that did regrow, actual meropenem exposures were significantly lower than targeted due to rapid in vitro hydrolysis, whereby targeted %fT>MIC was reduced with each subsequent dosing. In contrast, a >or=3 log CFU reduction was maintained over 24 h for all Pseudomonas isolates with meropenem MICs of 8 and 16 microg/ml. Although KPC and P. aeruginosa isolates may share similar meropenem MICs, the differing resistance mechanisms produce discordant responses to a high-dose, prolonged infusion of meropenem. Thus, predicting the efficacy of an antimicrobial regimen based on MIC may not be a valid assumption for KPC-producing organisms.