目的 探讨美罗培南在化脓性脑膜炎的新生患儿血浆和脑脊液中的药动学和药效学的关联。方法 试验招募2016年5月—2021年5月在扬州大学附属医院诊断为化脓性脑膜炎的58例新生儿患者，均获得血浆样品，其中17人获得脑脊液样品。出生后2～4周的新生儿以及4～6周的婴幼儿使用8 h的剂量间隔，美罗培南使用剂量为40 mg·kg^-1，输注时间超过30 min。使用带有DIGITAL FORTRAN编译器的NONMEM软件包分析数据。超高效液相色谱联用串联质谱（UHPLC-MS/MS）测定血浆和脑脊液中的美罗培南浓度。使用最终模型估计值的蒙特卡罗模拟（n＝1 000）用于生成不同给药方案的游离血药浓度水平维持在目标菌群的最低抑菌浓度（MIC）之上的时间（fT＞MIC）占1个给药间隔的百分比（% fT＞MIC）和最小抑菌浓度（MIC）值：1、2、4、8 mg·L^-1。结果 美罗培南在血浆中的峰浓度（C_max）、曲线下面积（AUC）、清除率（CL）、表观分布容积（V_d）高于脑脊液中的各项数据，差异有统计学意义（P＜0.05）；血浆中的半衰期（t_1/2）低于脑脊液，差异有统计学意义（P＜0.05）。用蒙特卡罗模拟10 000例患者目标获得概率，随着MIC值增加，血浆目标获得概率降低；血浆中40%最低抑菌浓度（MIC）的时间百分比（40% TMIC）、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。随着MIC值增加，脑脊液目标获得概率降低；脑脊液中40% TMIC、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。结论 模拟试验表明，当MIC为2 μg·mL^-1时，美罗培南在血浆中的目标获得概率可以达标，其在脑脊液中的目标获得概率不能达标，治疗时需要增加美罗培南的剂量或缩短给药间隔，以达到治疗目标。

Objective To investigate the relationship between the pharmacokinetics and pharmacodynamics of meropenem in plasma and cerebrospinal fluid in newborns and infants with suppurative meningitis. Methods 58 patients diagnosed with suppurative meningitis in The Affiliated Hospital of Yangzhou University from May 2016 to May 2021 were enrolled. Plasma samples were obtained from all patients, and cerebrospinal fluid samples were obtained from 17 of them. For gestational age < 32 weeks and postnatal age < 2 weeks, a 12 h dose interval was used, and for all other patients an 8h dose interval was used. Meropenem was given at a dose of 40 mg·kg^-1 over 30 min. Data was analyzed using NONMEM software package with DIGITAL FORTRAN compiler. Ultra Performance liquid chromatography coupled with Tandem Mass spectrometry UHPLC-MS/MS) was used to determine meropenem concentration in plasma and cerebrospinal fluid. Monte Carlo simulations (n=1 000) using the final model estimates were used to generate % fT>MIC curves and the following Minimal Inhibitory Comentration (MIC) values for different drug administration regiments: 1, 2, 4, 8 mg·L^-1. Results The peak concentration (C_max), area under curve (AUC), clearance rate (CL) and apparent volume of distribution (V_d) of meropenem in plasma were higher than those in cerebrospinal fluid, with statistical significance (P<0.05). The half-life in plasma (t_1/2) was lower than that in CSF, and the difference was statistically significant (P<0.05). The probability of reaching the standard of 10 000 patients was simulated by Monte Carlo. With the increase of MIC value, the probability of reaching the standard of plasma decreased; The probability of reaching the standard of 40% TMIC, 60% TMIC, 80% TMIC and 100% TMIC in plasma decreased gradually. With the increase of MIC value, the probability of cerebrospinal fluid reaching the standard decreased. The probability of reaching the standard of 40% TMIC, 60% TMIC, 80% TMIC and 100% TMIC in cerebrospinal fluid decreased gradually. Conclusion The simulation shows that when the MIC is 2 mg·L^-1, the probability of reaching the standard of meropenem in plasma can reach the standard, and the probability of reaching the standard in the cerebrospinal fluid cannot reach the standard. It is necessary to increase the dose of meropenem or shorten the dosing interval during treatment to achieve treatment goals.

R969

江苏省妇幼健康科研项目资助(F201858)