Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model

Abstract

An in vitro pharmacokinetic model mimicking human serum drug concentrations, based on a dialyzer unit, was developed to study the efficacies of continuous infusion and intermittent administration of ceftazidime over a period of 36 h. The daily dose of ceftazidime was 300 mg/liter/24 h given either as a continuous infusion or as three bolus doses. The intermittent dosing regimen yielded peak and trough concentrations after the fourth dose of 92.3 (standard deviation, 8.0) and 1.4 (standard deviation, 0.9) mg/liter, respectively. Continuous administration yielded concentrations of approximately 20 mg/liter. To study efficacy, three Pseudomonas aeruginosa strains, ATCC 27853, CF4, and CF16, were used. The MICs of ceftazidime for these strains were 1, 4, and 16 mg/liter, respectively. Strain CF16 was killed initially during both regimens and then started to regrow. At the end of the fourth dosing interval, i.e., after 32 h, viable counts showed no difference between the regimens. Strains ATCC 27853 and CF4 were killed initially during both dosing schedules, and after the first dosing interval viable counts were similar. However, after the fourth interval, there was a marked difference between bacterial counts during continuous and intermittent infusion, being 2.2 and 2.8 loglo, respectively, demonstrating a greater efficacy during continuous infusion. The results indicate that, in the absence of other factors, a sustained level of ceftazidime around or slightly above the MIC is not high enough to maintain efficacy over more than one (8-h) dosing interval. When sustained concentrations higher than four times the MIC are employed, continuous administration in this model is more efficacious than intermittent dosing.Time-kill curves for beta-lactam antibiotics against Pseudomonas aeruginosa show time-dependent killing which is maximal at relatively low concentrations (35). Concentrations much higher than the MIC contribute no extra effect. From these experiments, it can be deduced that continuous serum drug concentrations above the MIC of the antibiotic used to combat the microorganism in question should be more efficacious than declining concentrations, as observed after intermittent dosing (8, 10). During the latter regimen, concentrations fall below the MIC during part of the dosing interval. It has been shown in several animal models that continuous infusion is indeed more efficacious than intermittent dosing (14,21, 27). However, the half-life of most drugs is severely shortened in the animals studied, and conclusions regarding the pharmacodynamics in humans are difficult to make (15). For, if the shortened half-life is taken into account, the time during which the concentration is below the MIC applies for almost the entire dosing interval, which is contrary to the situation as observed in humans. This problem has, however, been partly overcome by fractional dosing to mimic human pharmacokinetics (13).In vitro simulation of human pharmacokinetics may thus give additional information with respect to kinetics of kil...

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Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

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Novel Concentration-Killing Curve Method for Estimation of Bactericidal Potency of Antibiotics in an In Vitro Dynamic Model

“…Good quantitative analyses of the pharmacodynamics of antibiotics have been undertaken, in which time-kill curves and the postantibiotic effect are used to estimate the time-killing effect, while MIC and MBC are usually used to estimate the concentration-killing effect. The MIC at which 50% of isolates are inhibited (MIC 50 ), the MIC 90 , and the MIC 99 have sometimes been determined (6,26,29,33,37). However, information on the dynamics of the direct bactericidal effects of antibiotics on bacteria is fragmentary.…”

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