Population pharmacokinetics and probability of target attainment of tigecycline in critically ill children.

Abstract

Background and objectives: Tigecycline is not usually recommended for patients under 18 years due to limited safety data and adverse events, and dosing guidelines for children under 8 remain undefined. However, it remains a critical treatment option for life-threatening multidrug-resistant infections in critically ill children. This study aimed to characterize the population pharmacokinetics (PopPK) of tigecycline in children, identify key covariates affecting PK variability and propose optimized dosing regimens tailored to specific infection types.

Materials and methods: This study enrolled 20 children receiving intravenous tigecycline. One- and two-compartment models were explored. Monte Carlo simulations with age-stratified tigecycline dosing regimens were performed to evaluate the probability of target attainment (PTA) for various dosing regimens.

Results: A two-compartment model incorporating allometric scaling and a sigmoidal maturation function best described tigecycline PK. PTA analyses indicated that the standard dose was sufficient for children with infections caused by susceptible Streptococcus groups (breakpoint 0.125 mg/L) across community-acquired pneumonia (CAP), complicated intra-abdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI). For susceptible Enterobacterales, Staphylococcus spp. or Enterococcus spp. (breakpoint 0.5 mg/L), the standard dose reached PK/pharmacodynamic (PD) targets for CAP, while cIAI required twice the standard dose. cSSSI necessitated higher dosing (150 mg) in adolescents; however, potential toxicity concerns necessitate extreme caution with such escalation. Infections caused by Enterobacteriaceae with intermediate resistance (breakpoint 4 mg/L) failed to achieve PK/PD targets even with increased doses exceeding 4.8 mg/kg.

Conclusions: Overall, these results suggest that current dosing recommendations may be insufficient for less susceptible pathogens.