Langhendries J P, Battisti O, Bertrand J M, François A, Darimont J, Ibrahim S, Tulkens P M, Bernard A, Buchet J P, Scalais E
Department of Paediatrics, Children's Hospital, St-Joseph-Espérance-Rocourt, Clinique St-Vincent, Belgium.
Dev Pharmacol Ther. 1993;20(3-4):220-30. doi: 10.1159/000457566.
Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.
众所周知，新生儿尤其是早产儿的肾小球滤过率（GFR）较低。这可能导致在多次使用氨基糖苷类药物（AGs）时血药谷浓度升高，进而可能引发肾毒性和耳毒性反应。在成人和儿童中，AGs每日一次给药已被证明比传统给药方案（每日两次，bid；每日三次，tid）耐受性相同或更好，同时还具有潜在的药效学和护理优势。然而，尚无关于新生儿的相关数据。因此，开展了这项前瞻性研究，以评估与每日两次给药方案相比，每日一次给予阿米卡星的耐受性，并研究这两种给药方案下药物的药代动力学。将22名男性新生儿（胎龄≥34周；出生后年龄≤2天）随机分为两组，一组每日一次（qd）接受阿米卡星（AK）（15mg/kg/天）治疗（n = 10），另一组每日两次（bid）接受治疗（n = 12），两组均联合氨苄西林（50mg/kg/12h）治疗。在治疗的第1、3、5和7天，在下一次给药前（谷浓度）、输液结束后1小时（峰浓度）以及仅在第1天的3和6小时测量AK血浆水平。由于样本量较小，无法评估疗效差异，且疗效本身也不是本研究的目的。通过肌酐清除率评估肾小球功能障碍，通过尿液中蛋白质（视黄醇结合蛋白、β2-微球蛋白、克拉拉细胞蛋白（P1）和微量白蛋白）、酶（N-乙酰-β-D-氨基葡萄糖苷酶、碱性磷酸酶、丙氨酸氨基肽酶和γ-谷氨酰转移酶）以及总磷脂（TPL）的排泄评估肾小管损伤。在治疗的第0、3和9天，通过脑干听觉诱发电位（BAEP）评估耳毒性。选取8名健康新生儿作为对照。所有患者在出生后的头几天GFR均出现正常且相似的升高。蛋白尿未增加，但在两个AK治疗组中，治疗期间酶尿和TPL均显著增加，两组间无显著差异。治疗组和未治疗组患者在第9天的BAEP无显著差异。我们从这项前瞻性研究得出结论，鉴于每日一次给予AK具有潜在优势，在无更多毒性的情况下，对于胎龄≥34周的新生儿，推荐每日一次给药方案而非每日两次给药方案。
