Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, The Netherlands.
Department of Hospital Pharmacy, Division of Clinical Pharmacology, Academic Medical Center, University of Amsterdam, The Netherlands.
Clin Infect Dis. 2018 Apr 3;66(8):1261-1269. doi: 10.1093/cid/cix961.
In intensive care (ICU) patients, systemic exposure of β-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking.
We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios.
One hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively.
Severely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.
在重症监护病房（ICU）患者中，β-内酰胺类抗生素的全身暴露可能会发生变化，阳性临床结局与增加 fT > MIC 比值有关。在撒哈拉以南非洲的医院中，苄青霉素（PEN）常被用于经验性治疗严重肺炎球菌感染。非 ICU 住院人群的药代动力学数据尚缺乏。
我们于 2014 年 10 月至 2015 年 11 月在莫桑比克的一家成人医院中进行了一项静脉注射 PEN 的成人人群的群体药代动力学（PPK）研究。每位患者采集 4 份血样以测量总 PEN（PENt）和游离 PEN（PENu）浓度。我们通过非线性混合效应分析建立了 PPK 模型，并针对不同的患者变量、剂量和药效学靶标场景进行了模拟。
112 名参与者共获得 387 份 PENt 和 53 份 PENu 浓度数据。中位数的体重指数为 18.3（范围为 10.5-31.3）kg/m2，中位数白蛋白浓度和肌酐清除率（CrCl）分别为 29（范围为 12-44）g/L 和 80（范围为 3-195）mL/min。在单室模型中，CrCl 与 PENt 清除率呈正相关。对于 MIC 为 1 mg/L 的微生物感染，模拟结果表明，每 6 小时给予 300 万 IU（1.8 g）时，74.1%的 PENu 浓度在给药间隔的一半时间内（fT > MIC = 50%）将大于 MIC，而 fT > MIC = 100%的目标则为 24.8%。对于 MIC 为 0.06 mg/L 的病原体，这两个百分比分别为 98.2%和 72.3%。
严重感染的撒哈拉以南非洲成年患者在常规间歇性推注给药时 PENu 可能存在暴露不足的风险，尤其是当他们的肾功能完好且感染的病原体对 PEN 具有中度敏感性时。
