Optimizing bactericidal exposure for beta-lactams using prolonged and continuous infusions in the pediatric population.
BACKGROUND
Administration of beta-lactams via prolonged or continuous infusion has been utilized in adults to optimize drug exposure and clinical outcomes. As children exhibit increased drug clearance, this may further the benefit of prolonged or continuous infusions. This dosing approach was applied to several beta-lactams commonly utilized in children.


METHODS
A variety of cefepime, ceftazidime, imipenem/cilastatin, meropenem, and piperacillin/tazobactam regimens using administration times of 0.5, 3, or 24 hr infusions were simulated in populations of 2- and 12-year-old children using Monte Carlo techniques. The probability of target attainment (PTA) was calculated for each dosing regimen. Minimum inhibitory concentration (MIC) frequencies for Pseudomonas aeruginosa were obtained for two pediatric acute care institutions in order to calculate cumulative fractions of response (CFR).


RESULTS
Standard 0.5 hr infusions resulted in poor PTA for most study agents at their susceptibility breakpoint, whereas 3 hr infusions markedly improved PTA for cefepime (79 to 100%), ceftazidime (80 to 100%), imipenem (41 to 91%), and meropenem (33 to 97%). Piperacillin/tazobactam could not achieve a PTA > 21% for any dosing regimen at its breakpoint, though large improvements were observed at lower MICs. Continuous infusion regimens resulted in similar PTA results to the same dose administered as 3 hr infusions. CFR values for all drugs at both institutions improved when 3 hr or continuous infusions were employed.


CONCLUSIONS
Prolonged and continuous infusion dosing strategies improved the likelihood of obtaining bactericidal targets for these beta-lactams in a simulated pediatric population. Based on these data, pediatric studies employing these strategies are warranted.
Connecticut Children's Medical Center, Hartford, Connecticut, USA.
Joshua D
JD
Courter
Joseph L
JL
Kuti
Jennifer E
JE
Girotto
David P
DP
Nicolau
D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D002648:Child; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D011336:Probability; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D047090:beta-Lactams / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams