Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial - PubMed (original) (raw)

Randomized Controlled Trial

. 2007 Sep;51(9):3304-10.

doi: 10.1128/AAC.01318-06. Epub 2007 Jul 9.

Affiliations

Randomized Controlled Trial

Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial

Samir G Sakka et al. Antimicrob Agents Chemother. 2007 Sep.

Abstract

Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT(>MIC)) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT(>MIC) value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT(>MIC). The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT(>MIC) of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.

PubMed Disclaimer

Figures

FIG. 1.

FIG. 1.

Observed concentrations in plasma (average ± SD) and typical predicted concentration-time profiles for imipenem after continuous and intermittent treatment of critically ill patients with normal renal function (see Materials and Methods for details on dosage regimens). The typical concentration-time profile based on the median pharmacokinetic parameters was predicted for the continuous-infusion group (continuous line) and for the intermittent-treatment group (dashed line). Importantly, this line is not equivalent to the average predicted concentrations for a large number of simulated patients. The two lines fall on top of each other during the first 4 h.

FIG. 2.

FIG. 2.

Observed-predicted plot for imipenem for all modes of administration. The line of best fit was determined as follows: observed = 1.023 × predicted + 0.262; _r_2 = 0.919; P ≪ 0.001.

FIG. 3.

FIG. 3.

Probability of target attainment for imipenem administered as intermittent 40-min infusions at a dose of 1 g q8h (3 g/day) (A) or as continuous infusion at a dose of 2 g/day (B). We studied the _fT_>MIC targets of 20%, 30%, and 40% of the dosing interval.

Similar articles

Cited by

References

    1. Ambrose, P. G., S. M. Bhavnani, C. M. Rubino, A. Louie, T. Gumbo, A. Forrest, and G. L. Drusano. 2007. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it's not just for mice anymore. Clin. Infect. Dis. 44:79-86. - PubMed
    1. Boucher, B. A., W. L. Hickerson, D. A. Kuhl, A. M. Bombassaro, and G. S. Jaresko. 1990. Imipenem pharmacokinetics in patients with burns. Clin. Pharmacol. Ther. 48:130-137. - PubMed
    1. Craig, W. A. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin. Infect. Dis. 26:1-12. - PubMed
    1. Craig, W. A., and S. C. Ebert. 1992. Continuous infusion of beta-lactam antibiotics. Antimicrob. Agents Chemother. 36:2577-2583. - PMC - PubMed
    1. Craig, W. A., S. Ebert, and Y. Watanabe. 1993. Abstr. 33rd Intersci. Conf. Antimicrob. Agents Chemother., abstr 86. American Society for Microbiology, Washington, DC.

Publication types

MeSH terms

Substances

LinkOut - more resources