2025 年第 8 期 第 20 卷

呼吸机相关肺炎患者头孢哌酮舒巴坦血药浓度不达标的危险因素及给药方案的蒙特卡洛模拟研究

The risk factors of substandard concentration of cefoperazone sulbactam in patients with ventilator-associated pneumonia and Monte Carlo simulation study on dosing regimen

作者：吕博谦1陈彬1吴海明1任仕馨2陆国红1

英文作者：Lyu Boqian1 Chen Bin1 Wu Haiming1 Ren Shixin2 Lu Guohong1

单位：1上海交通大学医学院附属仁济医院药学部，上海201112；2上海妙可堂中医门诊部，上海200042

英文单位：1Department of Pharmacy Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai 201112 China; 2Traditional Chinese Medicine Outpatient Department Shanghai Miaoketang Shanghai 200042 China

关键词：呼吸机相关肺炎；头孢哌酮舒巴坦；血药浓度；蒙特卡洛模拟；给药方案

英文关键词：Ventilator-associatedpneumonia;Cefoperazonesulbactam;Plasmaconcentration;MonteCarlosimulation;Administrationregimen

• 摘要：

• 目的 分析呼吸机相关肺炎（VAP）患者头孢哌酮舒巴坦（SCF）血药浓度不达标相关因素并应用蒙特卡洛模拟（MCS）评价SCF治疗VAP的给药方案。方法 选择2021年4—9月上海交通大学医学院附属仁济医院收治的VAP患者172例作为研究对象。根据SCF稳态血药谷浓度将患者分为不达标组（64例）和达标组（108例），分析VAP患者SCF血药浓度不达标相关影响因素。运用MCS分析各给药方案在不同输注时间下的达标情况。结果  多因素Logistic回归分析结果显示年龄、颅脑损伤、肌酐清除率（CCr）水平及连续性肾脏替代治疗（CRRT）为VAP患者SCF血药浓度不达标的独立影响因素（均P<0.05）。Logistic回归模型预测VAP患者SCF血药浓度不达标内部验证前后曲线下面积分别为0.873（95%置信区间：0.839～0.898）、0.875（95%置信区间：0.844～0.901），预测效能较好。MCS分析结果显示，在不同给药方案和输注时间条件下，随着药物输注时间的增加，目标达成概率（PTA）呈现上升趋势。然而，每种给药方案均存在特定的最小抑菌浓度（MIC）阈值。当病原菌MIC低于该阈值时，可通过调整输注时间来达到PTA>90%的预期药效学目标。当病原菌MIC≤16 μg/ml时，均可通过优化给药方案和延长输注时间实现PTA>90%；然而，当病原菌MIC≥32 μg/ml时，无论采用何种给药方案或输注时间，均无法达到PTA>90%的治疗目标。经验性治疗时，仅3 g（q6 h）给药方案输注时间4 h的情况下，累积反应率达到90%以上。结论  临床选择VAP患者SCF给药方案时，应充分考虑患者年龄、CRRT、颅脑损伤及CCr水平的影响。SCF输注给药方案所产生的药代动力学/药效动力学协同效应表现出对MIC的选择性特征。对于处于敏感性阈值上限或临界高值的病原菌株，可通过优化给药策略，包括调整给药间隔、增加药物剂量以及延长输注时间等方式，以实现有效血药浓度的维持。

• Objective To analyze the related factors of substandard concentration of cefoperazone sulbactam (SCF) in patients with ventilator-associated pneumonia (VAP) and to evaluate the dosing regimen of SCF in the treatment of VAP by Monte Carlo simulation (MCS). Methods A total of 172 VAP patients admitted to Renji Hospital, Shanghai Jiao Tong University School of Medicine from April to September 2021 were selected as the research objects. According to the steady-state trough concentration of SCF in VAP patients, the patients were divided into substandard group (64 cases) and standard group (108 cases), and the related factors of substandard SCF concentration in VAP patients were analyzed. MCS was used to analyze the compliance of each regimen at different infusion times. Results Multivariate Logistic regression analysis showed that age, craniocerebral injury, creatinine clearance rate (CCr) level and continuous renal replacement therapy (CRRT) were independent influencing factors for substandard SCF plasma concentration in VAP patients (all P<0.05). The area under the curve of Logistic regression model for predicting substandard SCF plasma concentration in VAP patients before and after internal verification was 0.873(95% confidence interval: 0.839-0.898) and 0.875(95% confidence interval: 0.844-0.901), respectively, which had a good prediction efficiency. The results  of MCS analysis showed that with the increase of drug infusion time, the target achievement probability (PTA) showed an upward trend under different administration regimens and infusion time. However, each dosing regimen had a specific minimum inhibitory concentration (MIC) threshold. When the pathogen MIC was below this threshold, the infusion time could be adjusted to achieve the desired pharmacodynamic goal of PTA>90%. When the pathogen MIC was ≤16 μg/ml, PTA>90% could be achieved by optimizing the dosing regimen and prolonging the infusion time. However, when the pathogen MIC was ≥32 μg/ml, the therapeutic goal of PTA>90% could not be achieved regardless of the dosing regimen or infusion time. For empirical treatment, the cumulative response rate reached more than 90% when only 3 g(q6 h) regimen was infused for 4 h. Conclusion The age, CRRT, craniocerebral injury and CCr level should be fully considered when selecting SCF dosing regimen for VAP patients. The pharmacokinetic/pharmacodynamic synergism induced by SCF infusion dosing regimen shows a selective characteristic for MIC. For the pathogens at the upper or borderline high sensitivity threshold, the administration strategy can be optimized, including adjusting the administration interval, increasing the drug dose, and prolonging the infusion time, so as to achieve the maintenance of effective blood drug concentration.