Wittau Mathias, Paschke Stephan, Kurlbaum Max, Scheele Jan, Ly Neang S, Hemper Evelyn, Kornmann Marko, Henne-Bruns Doris, Bulitta Jürgen B
Department of Visceral Surgery, University of Ulm, Ulm, Germany
Department of Visceral Surgery, University of Ulm, Ulm, Germany.
Antimicrob Agents Chemother. 2016 Dec 27;61(1). doi: 10.1128/AAC.00952-16. Print 2017 Jan.
Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.).
厄他培南对多种病原体具有广谱抗菌活性，其在接受手术的病态肥胖患者的感染预防和治疗中具有应用价值。然而，其在这些患者中的药代动力学和组织穿透情况尚不明确。我们评估了厄他培南在病态肥胖患者血浆、皮下组织和腹水中的群体药代动力学及目标达标情况。6名女性患者（体重指数为43.7至55.9kg/m²）在0小时和26小时接受15分钟静脉输注1000mg厄他培南。在第2天，通过微透析测定血浆、皮下组织和腹水中未结合的厄他培南浓度；同时对血浆总浓度进行定量。通过蒙特卡洛模拟预测在至少40%的给药间隔内未结合的厄他培南浓度高于最低抑菌浓度（MIC）的目标达标概率。群体药代动力学模型包含两个处置室，并同时描述了所有浓度。对于未结合的厄他培南，在无脂肪体重为53kg的患者中，总清除率为12.3升/小时（变异系数，患者间变异为21.6%），稳态分布容积为57.8升。厄他培南在皮下组织中的浓度-时间曲线下面积（AUC）比血浆中未结合的AUC低49%，在腹水中低25%。组织穿透迅速（平衡半衰期<15分钟），且在皮下组织中存在差异。短期厄他培南输注（每24小时1000mg）在血浆中对高达1mg/L的MIC、皮下组织中对0.25至0.5mg/L的MIC以及腹水中对0.5mg/L的MIC实现了较高（>90%）的目标达标概率。对于与接受手术的病态肥胖患者相关的许多病原体，厄他培南是一个有吸引力的选择。（本研究已在ClinicalTrials.gov注册，标识符为NCT01407965。）
