Retrospective Study And Pulmonary Pharmacodynamics Of Polymyxin B In HAP/VAP Patients

Background: Hospital acquired pneumonia and ventilator associated pneumonia(HAP/VAP)are common hospital acquired infections in respiratory wards.The main pathogens are multidrug-resistant(MDR)and extensive-resistant(XDR)Gram negative bacteria(GNB),such as Acinetobacter baumannii,Pseudomonas aeruginosa,Klebsiella pneumoniae,etc.Polymyxin B(PMB)is one of the last choices of antibiotics for the treatment of such patients.Many guidelines recommend the intravenous therapy of PMB.However,due to the insufficient evidence of efficacy in inhalation therapy and that the pharmacokinetics of drugs in the lung is still unknown,there is controversy about whether to use aerosol inhalation PMB treatment in clinical practice.Objective: To explore the clinical efficacy and the pulmonary pharmacokinetics of intravenous infusion combining with inhalation of PMB,in order to supplement medical evidence for the inhalation therapy of PMB.Methods:1.We retrospectively compared the clinical efficacy of intravenous or intravenous combining with inhalation of PMB in HAP/VAP patients admitted to our respiratory intensive care unit from March 2018 to December 2022.We evaluated the clinical efficacy with cure,improvement,progress,and failure based on the changes in symptoms,signs,laboratory tests,pathogenic microorganisms,and pulmonary imaging examinations before and after medication,according to the Guidance for Clinical Trials of Anti-bacterial Drugs.We additionally categorized cure,improvement and progress as total effectiveness.2.We prospectively collected lavage fluid samples from HAP/VAP patients,and conducted a preliminary exploration of the concentration changes and pharmacokinetic parameters(Area Under Curve,AUC)of the drug in the alveolar epithelial lung fluid(ELF)during the PMB therapy.We also compared the drug concentration and pharmacokinetic parameters in ELF between patients receiving intravenous therapy and those receiving inhalation therapy.Results:1.1.The retrospective study included a total of 120 courses of HAP/VAP infected with MDR/XDR GNB that treated with PMB,including 75 courses of intravenous therapy and 45 courses of intravenous combining inhalation.The total clinical effectiveness achieved by PMB intravenous combined with inhalation therapy was slightly higher than that achieved by intravenous therapy alone,but the difference was not statistically significant(55.6% vs 50.7%,P=0.604).However,after adjusting for confounding factors using logistic regression models,it was still found that intravenous combined with nebulized inhalation PMB was an independent influencing factor for total clinical efficacy(OR=3.817,95% CI 1.036-14.059,P=0.044).2.A total of 7 patients with PMB intravenous medication and 10 patients with intravenous PMB combining inhalation were included in the pharmacokinetic study.Compared to pure intravenous administration,intravenous combination of 25 mg q12h inhalation of PMB lead to higher concentrations in ELF(ELF concentration 1 hour after administration:3.530 μ g/ml±21.758 μg/ml vs 1.099 μg/ml±0.593 μg/ml,P=0.017;ELF concentration at 12 hours after administration:13.380 μ g/ml±6.115 μg/ml vs 0.423 μg/ml±0.175 μg/ml,P=0.014),and can achieve significantly higher AUC in ELF [intravenous group 27.131(mg·h)/l ± 5.081(mg·h)/l,combined group 476.921(mg·h)/l ± 172.719(mg·h)/l,P=0.011].Conclusion: 1.The combination of PMB intravenous nebulization inhalation therapy is not significantly more effective than intravenous therapy,but it is still an independent factor for achieving positive clinical efficacy;2.After intravenous infusion combined with inhalation of PMB,a higher concentration in ELF is acquired.The research results of these studies supplement medical evidence for the clinical practice of PMB combined with inhalation therapy.