Ooi Mong How, Ngu Sing Jiat, Chor Yek Kee, Li Jian, Landersdorfer Cornelia B, Nation Roger L
Department of Pediatrics, Sarawak General Hospital, Kuching, Malaysia.
Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Kota Samarahan, Sarawak, Malaysia.
Clin Infect Dis. 2019 Nov 13;69(11):1962-1968. doi: 10.1093/cid/ciz067.
Intravenous colistin is widely used to treat infections in pediatric patients. Unfortunately, there is a paucity of pharmacological information to guide the selection of dosage regimens. The daily dose recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) is the same body weight-based dose traditionally used in adults. The aim was to increase our understanding of the patient factors that influence the plasma concentration of colistin, and assess the likely appropriateness of the FDA and EMA dosage recommendations.
There were 5 patients, with a median age of 1.75 (range 0.1-6.25) years, a median weight of 10.7 (2.9-21.5) kg, and a median creatinine clearance of 179 (44-384) mL/min/1.73m2, who received intravenous infusions of colistimethate each 8 hours. The median daily dose was 0.21 (0.20-0.21) million international units/kg, equivalent to 6.8 (6.5-6.9) mg of colistin base activity per kg/day. Plasma concentrations of colistimethate and formed colistin were subjected to population pharmacokinetic modeling to explore the patient factors influencing the concentration of colistin.
The median, average, steady-state plasma concentration of colistin (Css,avg) was 0.88 mg/L; individual values ranged widely (0.41-3.50 mg/L), even though all patients received the same body weight-based daily dose. Although the daily doses were ~33% above the upper limit of the FDA- and EMA-recommended dose range, only 2 patients achieved Css,avg ≥2mg/L; the remaining 3 patients had Css,avg <1mg/L. The pharmacokinetic covariate analysis revealed that clearances of colistimethate and colistin were related to creatinine clearance.
The FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal functioning is an important determinant of dosing in these patients.
静脉注射黏菌素广泛用于治疗儿科患者的感染。遗憾的是，缺乏药理学信息来指导给药方案的选择。美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）推荐的每日剂量是传统上用于成人的基于体重的相同剂量。目的是加深我们对影响黏菌素血浆浓度的患者因素的理解，并评估FDA和EMA剂量建议的可能适宜性。
有5例患者，中位年龄为1.75岁（范围0.1 - 6.25岁），中位体重为10.7 kg（2.9 - 21.5 kg），中位肌酐清除率为179 mL/min/1.73m²（44 - 384 mL/min/1.73m²），每8小时接受一次多黏菌素甲磺酸钠静脉输注。中位每日剂量为0.21（0.20 - 0.21）百万国际单位/千克，相当于每千克/天6.8（6.5 - 6.9）毫克黏菌素碱基活性。对多黏菌素甲磺酸钠和形成的黏菌素的血浆浓度进行群体药代动力学建模，以探索影响黏菌素浓度的患者因素。
黏菌素的中位、平均稳态血浆浓度（Css,avg）为0.88毫克/升；个体值差异很大（0.41 - 3.50毫克/升），尽管所有患者接受相同的基于体重的每日剂量。虽然每日剂量比FDA和EMA推荐剂量范围的上限高约33%，但只有2例患者的Css,avg≥2毫克/升；其余3例患者的Css,avg<1毫克/升。药代动力学协变量分析显示，多黏菌素甲磺酸钠和黏菌素的清除率与肌酐清除率相关。
FDA和EMA的剂量建议对许多儿科患者可能并非最优。肾功能是这些患者给药的重要决定因素。
