目的 探討美羅培南在化膿性腦膜炎的新生患兒血漿和腦脊液中的藥動(dòng)學(xué)和藥效學(xué)的關(guān)聯(lián)。方法 試驗(yàn)招募2016年5月—2021年5月在揚(yáng)州大學(xué)附屬醫(yī)院診斷為化膿性腦膜炎的58例新生兒患者，均獲得血漿樣品，其中17人獲得腦脊液樣品。出生后2～4周的新生兒以及4～6周的嬰幼兒使用8 h的劑量間隔，美羅培南使用劑量為40 mg·kg^-1，輸注時(shí)間超過30 min。使用帶有DIGITAL FORTRAN編譯器的NONMEM軟件包分析數(shù)據(jù)。超高效液相色譜聯(lián)用串聯(lián)質(zhì)譜（UHPLC-MS/MS）測(cè)定血漿和腦脊液中的美羅培南濃度。使用最終模型估計(jì)值的蒙特卡羅模擬（n＝1 000）用于生成不同給藥方案的游離血藥濃度水平維持在目標(biāo)菌群的最低抑菌濃度（MIC）之上的時(shí)間（fT＞MIC）占1個(gè)給藥間隔的百分比（% fT＞MIC）和最小抑菌濃度（MIC）值：1、2、4、8 mg·L^-1。結(jié)果 美羅培南在血漿中的峰濃度（C_max）、曲線下面積（AUC）、清除率（CL）、表觀分布容積（V_d）高于腦脊液中的各項(xiàng)數(shù)據(jù)，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）；血漿中的半衰期（t_1/2）低于腦脊液，差異有統(tǒng)計(jì)學(xué)意義（P＜0.05）。用蒙特卡羅模擬10 000例患者目標(biāo)獲得概率，隨著MIC值增加，血漿目標(biāo)獲得概率降低；血漿中40%最低抑菌濃度（MIC）的時(shí)間百分比（40% TMIC）、60% TMIC、80% TMIC、100% TMIC目標(biāo)獲得概率逐漸降低。隨著MIC值增加，腦脊液目標(biāo)獲得概率降低；腦脊液中40% TMIC、60% TMIC、80% TMIC、100% TMIC目標(biāo)獲得概率逐漸降低。結(jié)論 模擬試驗(yàn)表明，當(dāng)MIC為2 μg·mL^-1時(shí)，美羅培南在血漿中的目標(biāo)獲得概率可以達(dá)標(biāo)，其在腦脊液中的目標(biāo)獲得概率不能達(dá)標(biāo)，治療時(shí)需要增加美羅培南的劑量或縮短給藥間隔，以達(dá)到治療目標(biāo)。

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

江蘇省婦幼健康科研項(xiàng)目資助(F201858)