Population Pharmacokinetic Study of Amoxicillin-Treated Burn Patients Hospitalized at a Swiss Tertiary-Care Center

Abstract

The objective of this study was to investigate the population pharmacokinetics (PK) of amoxicillin in ICU burn patients and the optimal dosage regimens. This was a prospective study involving 21 consecutive burn patients receiving amoxicillin. PK data were analyzed using nonlinear mixed-effects modeling. Monte-Carlo simulations assessed the influence of various amoxicillin dosage regimens with identified covariates on the probability to achieve a target (PTA) value of time during which free amoxicillin concentrations in plasma exceeded the MIC (fT>MIC). A two-compartment model best described the data. Creatinine clearance (CL_CR) and body weight (BW) influenced amoxicillin CL and central volume of distribution (V₁), respectively. The median CL_CR (Cockcroft-Gault formula) was high (128 ml/min), with 25% of patients having CL_CRs of >150 ml/min. The CL, V₁, and half-life (t_1/2) values at steady state for a patient with a CL_CR of 110 ml/min and BW of 70 kg were 13.6 liters/h, 9.7 liters, and 0.8 h, respectively. Simulations showed that a target fT>MIC of ≥50% was achieved (PTA > 90%) with standard amoxicillin dosage regimens (1 to 2 g every 6 to 8 h [q6-8h]) when the MIC was low (<1 mg/liter). However, increased dosages of up to 2 g/4 h were necessary in patients with augmented CL_Rs or higher MICs. Prolonging amoxicillin infusion from 30 min to 2 h had a favorable effect on target attainment. In conclusion, this population analysis shows an increased amoxicillin CL and substantial CL PK variability in burn patients compared to literature data with nonburn patients. Situations of augmented CL_CR and/or high bacterial MIC target values may require dosage increases and longer infusion durations. (This study has been registered at ClinicalTrials.gov under identifier NCT01965340.).

Keywords: amoxicillin; burn patients; pharmacokinetics; population pharmacokinetics.

FIG 1

Model-derived conditional weighted residuals versus population predictions (upper graph) and time (lower graph).

FIG 2

Prediction-corrected visual predictive check obtained with the final model. The open circles represent the observed concentrations. The gray solid and dashed lines represent the median and the 5th/95th percentiles of the observed concentrations, respectively. The dark and light gray areas represent the 95% confidence interval (CI) of the simulated median and 5th/95th percentiles, respectively. Of note, three observations greater than 100 mg/liter are not shown for ease of graphical display (105.7, 134.4, and 198 mg/liter).

FIG 3

Observed versus population/individual predictions (linear scale). White circles represent population predictions, and smaller black circles individual predictions. The line is y = x.

FIG 4

Probability of target attainment as a function of the MIC and dosage regimen for six stages of renal function. IT, infusion time. The left and right sides show the results for the low (fT>MIC ≥ 50%) and high (fT>MIC = 100%) pharmacodynamic targets, respectively.