Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa

MICs are commonly used to assess the in vitro activities of antimicrobial agents; however, they provide minimal information on the pattern of bacterial activities. Time-kill studies with extensive sampling allow assessment of both the rate and extent of bacterial killing and regrowth. We compared imipenem and meropenem by both MIC-MBC testing and a time-kill study with P. aeruginosa 27853. In the time-kill study, concentration/MIC ratios ranging from 0.0625 to 32 times the MIC were studied. The kill rate, time to 99.9% kill, doubling time of regrowth, and area under the bacterial killing curve (AUKC) were evaluated. Degradation during the testing procedure was accounted for by assessing actual drug exposure as determined by the area under the concentration-time curve. Pharmacodynamic parameters were compared by using the Wilcoxon signed-rank test. The modal MIC and MBC for imipenem were 2 and 4 micrograms/ml, respectively, and those for meropenem were 0.25 and 0.5 microgram/ml, respectively. In the time-kill study, both agents displayed concentration-dependent activity over a range of 0.25 to 4 times the MIC. Initial killing (0 to 1 h) was faster with imipenem at the same concentration/MIC ratios (P = 0.0506). The time to 99.9% kill was approximately 5 h for both agents. When regrowth occurred, the doubling rate for imipenem, which was the same as that for the growth control, was twice as rapid as that for meropenem. At the same concentrations, the AUKCs over 24 h were lower for meropenem than for imipenem (P = 0.0280); however, when normalized by MIC, imipenem resulted in smaller AUKCs. Comparison of plots of area under the concentration-time curve versus AUKC, which accounted for drug degradation and actual drug exposure, revealed that meropenem was three times more active than imipenem, rather than the eightfold difference suggested by MICs. Time-kill curves with extensive sampling and measurement of actual drug exposure, rather than traditional MIC testing, may more accurately assess differences in the in vitro activities of antimicrobial agents.