Pharmacokinetics of Ampicillin/Sulbactam in Critically Ill Patients with Acute Kidney Injury undergoing Extended Dialysis

Abstract

SummaryBackground and objectives The fixed antibacterial combination of ampicillin and sulbactam is frequently used for various infections. Intact kidneys eliminate approximately 71% of ampicillin and 78% of sulbactam. Patients on thrice-weekly low-flux hemodialysis exhibit an ampicillin t 1/2 of 2.3 hours on and 17.4 hours off dialysis. Despite its frequent use in intensive care units, there are no available dosing recommendations for patients with AKI undergoing renal replacement therapy. The aims of this study were to evaluate the pharmacokinetics of ampicillin/ sulbactam in critically ill patients with AKI undergoing extended dialysis (ED) and to establish a dosing recommendation for this treatment method.Design, setting, participants, & measurements Twelve critically ill patients with anuric AKI being treated with ED were enrolled in a prospective, open-label, observational pharmacokinetic study. Pharmacokinetics after a single dose of ampicillin/sulbactam (2 g/1 g) was obtained in 12 patients. Multiple-dose pharmacokinetics after 4 days of twice-daily ampicillin/sulbactam (2 g/1 g) was obtained in three patients. ResultsThe mean dialyzer clearance for ampicillin/sulbactam was 80.167.7/83.3612.1 ml/min. The t 1/2 of ampicillin and sulbactam in patients with AKI undergoing ED were 2.860.8 hours and 3.561.5 hours, respectively. There was no significant accumulation using a twice-daily dosage of 2 g/1 g ampicillin/sulbactam.Conclusions Our data suggest that in patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m 2 ; blood and dialysate flow, 160 ml/min; treatment time, 480 minutes), a twice-daily dosing schedule of at least 2 g/1 g ampicillin/sulbactam, with one dose given after ED, should be used to avoid underdosing.

Adding to the Armamentarium

“…In patients with severe critical illness, it can be challenging to predict when ED will begin. The present study suggests that ampicillin/sulbactam should be given 3 hours before ED (7). However, these same researchers recently studied daptomycin and a similar ED regimen, and they recommended that daptomycin administration should occur within 8 hours of ED (22).…”

“…More importantly, the work by Lorenzen et al (7) links their pharmacokinetic findings to projected pharmacodynamic effects. These investigators measured ampicillin and sulbactam plasma concentrations achieved in critically ill patients receiving an extended dialysis (ED) treatment and then determined whether the plasma concentrations would yield bactericidal values that might result in infection cure.…”

“…With these drug administration parameters and ED operating characteristics, Lorenzen et al (7) correctly conclude that the pharmacodynamic target (time greater than minimum inhibitory concentration (MIC) of at least 50% of the dosing interval) for most pathogens would not be met. As the work by Lorenzen et al (7) mentions, the problem is that the same ampicillin/sulbactam 2/1-g dose administered at a time other than the time studied would give considerably different pharmacokinetic and pharmacodynamic results. For example, if the same ampicillin/sulbactam dose is administered .3 hours before ED, less drug would be removed by ED, resulting in a longer time above MIC.…”

“…(19), and they use different dialyzer types, treatment durations, and blood/dialysate flow rates (25). Before applying the ampicillin/sulbactam recommendations from the present study, one must ensure that the same ED regimen is used in your institution (7). Finally, ED pharmacokinetic studies have been conducted for very few drugs.…”

“…Pharmacokinetic and pharmacodynamic studies like the one by Lorenzen et al (7) need to continue to be conducted for all types RRT, to begin to reduce the infectious mortality rate in this vulnerable patient population.…”