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Antipseudomonal activity of simulated infusions of gentamicin alone or with piperacillin assessed by serum bactericidal rate and area under the killing curve

The objectives of this study were to (i) determine which of three simulated dosing regimens (gentamicin alone, simultaneous infusions of gentamicin and piperacillin, or staggered infusions of gentamicin and piperacillin) produced the fastest killing rate of Pseudomonas aeruginosa in serum, using the serum bactericidal rate (SBR) assay; and (ii) describe an alternative method of analysis of killing curves, the area under the killing curve (AUKC). Gentamicin alone or combined with piperacillin was added to heat-inactivated human serum to approximate drug concentrations achieved after the above-mentioned types of infusion. By a microdilution technique, seven strains of P. aeruginosa were exposed to no drug (control) and gentamicin alone or with piperacillin; colony counts were determined at hourly intervals for 5 h, and log10 CFU per milliliter was plotted versus time. Linear regression was used to calculate the slope (SBR) of each timed killing curve for each drug concentration tested alone or in combination. In addition, the AUKC for each curve was calculated. To compare simulated infusion regimens further, the cumulative AUKC (the sum of AUKCs for specific time points along the serum concentration-time curve for each simulated regimen) was calculated. With the SBR assay or AUKC determination, there was a significant increase in the rate of killing of all test strains by the combination compared with gentamicin alone only at gentamicin concentrations which exceeded the MIC (8, 5, and 2.5 micrograms/ml). Mean cumulative AUKC of the simultaneous-infusion regimen was significantly less (indicating faster killing) than either the staggered-infusion regimen or the gentamicin infusion alone. Both the SBR and AUKC have the potential for integration of in vitro microbiologic effects and in vivo pharmacokinetics of antimicrobial agents.