Moine Pierre, Mueller Scott W, Schoen Jonathan A, Rothchild Kevin B, Fish Douglas N
University of Colorado Denver, School of Medicine, Department of Anesthesiology, Aurora, Colorado, USA
Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.
Antimicrob Agents Chemother. 2016 Sep 23;60(10):5885-93. doi: 10.1128/AAC.00585-16. Print 2016 Oct.
The objective of this study was to determine the pharmacokinetics and pharmacodynamics (PK/PD) of a weight-based cefoxitin dosing regimen for surgical prophylaxis in obese patients. Patients received a single dose of cefoxitin at 40 mg/kg based on total body weight. Cefoxitin samples were obtained over 3 h from serum and adipose tissue, and concentrations were determined by validated high-performance liquid chromatography. Noncompartmental pharmacokinetic analysis was performed, followed by Monte Carlo simulations to estimate probability of target attainment (PTA) for Staphylococcus aureus, Escherichia coli, and Bacteroides fragilis over 4-h periods postdose. Thirty patients undergoing bariatric procedures were enrolled. The body mass index (mean ± standard deviation [SD])was 45.9 ± 8.0 kg/m(2) (range, 35.0 to 76.7 kg/m(2)); the median cefoxitin dose was 5 g (range, 4.0 to 7.5 g). The mean maximum concentrations were 216.15 ± 41.80 μg/ml in serum and 12.62 ± 5.89 in tissue; the mean tissue/serum ratio was 8% ± 3%. In serum, weight-based regimens achieved ≥90% PTA (goal time during which free [unbound] drug concentrations exceed pathogen MICs [fT>MIC] of 100%) for E. coli and S. aureus over 2 h and for B. fragilis over 1 h; in tissue this regimen failed to achieve goal PTA at any time point. The 40-mg/kg regimens achieved higher PTAs over longer periods in both serum and tissue than did the standard 2-g doses. However, although weight-based cefoxitin regimens were better than fixed doses, achievement of desired pharmacodynamic targets was suboptimal in both serum and tissue. Alternative dosing regimens and agents should be explored in order to achieve more favorable antibiotic performance during surgical prophylaxis in obese patients.
本研究的目的是确定基于体重的头孢西丁给药方案在肥胖患者手术预防中的药代动力学和药效学（PK/PD）。患者根据总体重接受40mg/kg的单剂量头孢西丁。在3小时内从血清和脂肪组织中获取头孢西丁样本，并通过经过验证的高效液相色谱法测定浓度。进行非房室药代动力学分析，随后进行蒙特卡罗模拟，以估计给药后4小时内金黄色葡萄球菌、大肠杆菌和脆弱拟杆菌的达标概率（PTA）。纳入了30例接受减肥手术的患者。体重指数（平均值±标准差[SD]）为45.9±8.0kg/m²（范围为35.0至76.7kg/m²）；头孢西丁的中位剂量为5g（范围为4.0至7.5g）。血清中的平均最大浓度为216.15±41.80μg/ml，组织中的平均最大浓度为12.62±5.89μg/ml；平均组织/血清比值为8%±3%。在血清中，基于体重的给药方案在2小时内对大肠杆菌和金黄色葡萄球菌以及在1小时内对脆弱拟杆菌实现了≥90%的PTA（游离[未结合]药物浓度超过病原体最低抑菌浓度[fT>MIC]的目标时间为100%）；在组织中，该方案在任何时间点均未达到目标PTA。40mg/kg的给药方案在血清和组织中比标准的2g剂量在更长时间内实现了更高的PTA。然而，尽管基于体重的头孢西丁给药方案优于固定剂量，但在血清和组织中实现理想的药效学目标均未达到最佳效果。应探索替代给药方案和药物，以在肥胖患者手术预防期间实现更有利的抗生素疗效。
