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

Lyu Boqian; Chen Bin; Wu Haiming; Ren Shixin; Lu Guohong

doi:10.3760/j.issn.1673-4777.2025.08.005

Abstract：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.