Optimum Dosage Regimen Of Amikacin In Pseudomonas Aeruginosa-induced Bloodstream And Lower Respiratory Tract Infection Based On Monte Carlo Simulation

Objective:Pseudomonas aeruginosa is the most common non-fermenting bacteria in the clinic and an important conditional pathogen for hospital-acquired infections.While,Pseudomonas aeruginosa has a high resistance rate to carbapenem antibacterials,and clinical treatment is more difficult.Among aminoglycoside antibacterial drugs,amikacin has the strongest anti-aeruginous activity and higher sensitivity rate.However,there are still some problems to be solved in the clinical treatment of Pseudomonas aeruginosa infection with amikacin.For instance,the recommended doses of amikacin in domestic and foreign guidelines are different,whether the recommended dose of domestic guidelines for Pseudomonas aeruginosa infection is insufficient.There are differences in the epidemiological distribution of drug susceptibility of Pseudomonas aeruginosa in bloodstream and lower respiratory tract infections,and the penetrability of amikacin in lung tissue is low.How to formulate dosing schedules for different infection sites.Therefore,in this study,combined with the epidemiological distribution of Pseudomonas aeruginosa in sputum culture and blood culture specimens in our hospital,the dosage regimen of amikacin which included 6 kinds of intravenous administration and 2 kinds of nebulized administration schemes was optimized and evaluated by Monte Carlo simulation in order to seek the best therapeutic dose of amikacin for different infection sites and different drug sensitivity results.Methods:1.Collect the drug sensitivity distribution of Pseudomonas aeruginosa to amikacin and imipenem in sputum culture and blood culture specimens from 2018.1-2019.12 in our hospital.2.Combining with relevant domestic and foreign guidelines and literature,establish the PK/PD model of amikacin,set the target target value,and select the population pharmacokinetic parameters of the target population.3.Based on the instructions and clinical guidelines of amikacin,combined with the actual clinical situation,formulate the dosing plan.4.Calculate the PTA and CFR of amikacin under different dosing regimens for lower respiratory tract infections and bloodstream infections based on Monte Carlo simulation.Results:1.The resistance rate of Pseudomonas aeruginosa to amikacin and imipenem in blood culture specimens in our hospital（3.95%,17.10%）is lower than that of sputum culture specimens（9.76%,40.70%）.Compared with non-resistant strains of imipenem-resistant strains in sputum culture specimens,the overall tendency of Pseudomonas aeruginosa to amikacin is higher.2.For empirical treatment of bloodstream infections caused by Pseudomonas aeruginosa,CFR≥90%under the regimen of 15.0mg.kg^-1.d^-1or more.When MIC≤1mg.L^-1,PTA≥90%under all simulated dosing schedules;when MIC=2mg.L^-1,only7.5mg.kg^-1.d^-1dosing schedule PTA<90%;When MIC=4mg.L^-1,only PTA≥90%under 17.5mg.kg^-1.d^-1or more dosing schedule;When MIC≥8mg.L^-1,all simulated dosing schedules PTA<90%.3.For the empirical treatment of lower respiratory tract infections caused by Pseudomonas aeruginosa,the CFR of 6 simulated doses is less than 90%,and the CFR value of the 400mg.d^-1nebulization regimen is 100%.When MIC≤0.5mg.L^-1,PTA≥90%under all simulated dosing regimens;When MIC=1mg.L^-1,the PTA under the two dosing regimens of 7.5mg.kg^-1.d^-1and 10.0mg.kg^-1.d^-1is less than 90%;When the treatment MIC≥2mg.L^-1,PTA<90%under all simulated dosing regimens.For Pseudomonas aeruginosa with MIC=64mg.L^-1,the probability of reaching the standard under the 400mg.d^-1dosing regimen of amikacin nebulized is still 100%.Conclusion:In the empirical treatment of Pseudomonas aeruginosa bloodstream infection with amikacin,the dosage regimen of 15.0mg.kg^-1.d^-1should be used.When the MIC≥8mg.L^-1,the combined administration should be selected according to the drug susceptibility.For empirical treatment of lower respiratory tract infections,intravenous administration alone should not be administered.When MIC≥2 mg.L^-1,there is a greater risk of treatment failure.In addition,the 400mg.d^-1atomization regimen has shown good efficacy in lower respiratory tract infections,but its safety still needs further verification.