Epidemiological Survey Of Nosocomial Infections In Intensive Care Units And Population Pharmacokinetics Of Ceftriaxone In Critically Ill Patients

Objective:Nosocomial infection(NI)is a major cause of increased morbidity,mortality and economic burden.By conducting studies on the epidemiology and risk factors of NI,it can help doctors to adopt timely strategies to improve the prognosis of patients.Secondly,prognostic assessment studies of NI are conducted to gain a more accurate understanding of the extent to which NI affects the clinical prognosis of critically ill patients.Ceftriaxone is a third-generation semi-synthetic cephalosporin antibacterial drug with a broad antimicrobial spectrum and strong antibacterial ability to effectively cover Grampositive and Gram-negative bacteria as well as some anaerobic bacteria,playing an important role in both empirical and pathogenic treatment of critically ill patients.However,after the selection of antimicrobial drugs for treatment in critically ill patients,understanding the pharmacokinetic characteristics of antimicrobial drugs in critically ill patients to provide a scientific basis for their rational use is a key step in the treatment of infections and an important measure to reduce the risk of NI occurrence.This paper aims to assess the characteristics,risk factors and prognosis of NI in critically ill patients through a study on the epidemiology of NI in intensive care units,and to collect blood from patients using ceftriaxone in ICU for concentration measurement and population pharmacokinetic analysis to provide a basis for the rational use of antimicrobial drugs in clinical practice.Based on the pharmacokinetic parameters of ceftriaxone in severe patients,the reaching probability of different drug administration schemes was simulated to provide basis for rational clinical application of antibiotics.Part 1.Clinical impact and risk factors of intensive care unit-acquired nosocomial infection: a propensity score-matching study from 2018 to 2020 in a teaching hospital in ChinaMethods:Through retrospective analysis,all patients who were hospitalized in the ICU for > 2days in our hospital from 2018 to 2020 were included in the study with reference to the current diagnostic criteria for nosocomial infection in China.General information data,clinical characteristics,medical interventions,hospital infection information and clinical outcomes of the patients were collected.Continuous variables were compared using ttests or non-parametric tests for independent samples,and categorical variables were compared using chi-square tests and Fisher’s exact tests.Variables with p < 0.05 in univariate analysis were selected for inclusion in multivariate logistic regression models to identify independent risk factors for NI.Propensity score matching(PSM)was used to match the NI and without-infected groups with a 1:2 match.The Kruskal-Wallis test was used to analyse differences in clinical outcomes between sites of infection and pathogens.Results:1.Baseline information: A total of 2425 patients were included in this study,of whom 1298 patients stayed in the ICU for at least 48 h.NI occurred in 231(9.53%)patients after admission to the ICU.the median age of the patients was 60 years and was predominantly male.The median APACHE II score for patients admitted for 48 h was10.0.Patients with NI had a significantly higher all-cause mortality rate in the ICU(12.1%)compared to patients without NI.2.Statistics of bacterial pathogens of NI: A total of 389 pathogens were isolated from 231 infections: 293 Gram-negative bacilli,78 Gram-positive cocci,18 fungi and188 multi-drug resistant bacteria(48.3%),of which A.baumannii had the highest resistance rate(60.6 %).The respiratory tract,bloodstream,urinary tract,and intraabdominal events accounted for the majority of the NI(56.3%,22.4%,6.2%,and 6.2%,respectively).Acinetobacter baumannii(31.6%),Pseudomonas aeruginosa(13.4%),and Escherichia coli(8.2%)were the most frequently isolated pathogens.3.Risk factors for NI: 1298 patients were grouped according to the occurrence of NIs.The results showed that long-term immunosuppressive therapy,impaired consciousness,blood transfusion,multiple organ dysfunction syndrome,three or more antibiotic treatments,mechanical ventilation,tracheotomy,urinary catheter,gastric tube and central venous catheter were high risk factors for hospital-acquired infections.Secondly,the results of this study showed a correlation between surgical procedures and a lower incidence of NI.4.Impact of NI on clinical outcomes: After PSM,196 cases were successfully matched in the NI group and 325 cases in the without-infected group,and the distribution of covariates remained balanced between the infected and without-infected groups.Compared to the without-infected group,the median number of ICU days in the infected group increased by 12.0 days,the median number of hospital days increased by 14.0 days,the median cost of hospitalisation increased by 73,596.62,and the median cost of antimicrobial drugs increased by 7,612.44,with antimicrobial drug costs accounting for one percent of hospitalisation costs.ICU mortality increased by 5.8% and predicted mortality in the ICU increased by 11.3%.5.Differences in clinical impact between sites of infection and pathogen groups:The Length of ICU stay was 20.0 days,35.0 days and 16.0 days and the Length of hospital stay was 33.5,49.0 and 24.0 days for the A.baumannii,P.aeruginosa and E.coli groups,respectively.The differences in ICU stay and length of stay between the three pathogens were statistically significant(p<0.001)and the E.coli infection group was lower than the other two pathogen groups.No significant differences were found between the different sites of infection.Part 2.Determination of ceftriaxone concentration in human plasma by highperformance liquid chromatographyMethods:The drug concentration of ceftriaxone was determined by HPLC,and the conditions were set as follows: column Venusil MP C18(4.6 mm 150 mm,5 μ m;Agela Technologies),mobile phase selected methanol(20)-0.05mol/L PBS buffer(80),column temperature: 30℃,detection wavelength: 245 nm,flow rate: 1ml / min.Theophylline was selected as the internal standard,and the samples were centrifuged using methanol to determine the ceftriaxone plasma concentration.The specificity,linearity,limit of quantification,precision,accuracy,and stability of the method were investigated.Results:The concentration of ceftriaxone in human plasma showed good linearity in the range of 6.25-400 μg-m L-1 with a lower limit of quantification of 3.125 μg-m L-1.The standard curve equation was y=0.015x-0.049,r=0.9995.The methodological validation showed good specificity with intra-day and inter-day precision <10% and accuracy within ±15%.Stability was good at 4°C,20°C,-80°C and after three repeated freezethaws.Part 3.Population pharmacokinetics of ceftriaxone in critically ill patientsMethods:This study was conducted in an intensive care unit and was a prospective,openended population pharmacokinetic study.All basic information,clinical medication information and biochemical tests were collected from the patients.Blood samples were collected from patients and concentrations were measured by the HPLC method established in Part II.A non-linear mixed-effects model with phoenix software was used to establish a basal model of ceftriaxone.The effects of age,body weight,total bilirubin,albumin,serum creatinine values,urea nitrogen,creatinine clearance,alanine aminotransferase and aspartate aminotransferase on the model were investigated to establish and validate the final ceftriaxone population pharmacokinetic model.Based on the above model,Monte Carlo simulation was used to simulate the target achievement probability of ceftriaxone under different administration schemes,so as to increase the efficacy of ceftriaxone in severe patients.Results:1.Baseline information: A total of 30 critically ill patients were included in this study,25 male patients and 5 female patients.The mean age was 55.57 years.The mean haemoglobin value was 107.55 g/L.Most patients had normal liver and renal function.There were four dosing regimens,with the 2g Qd regimen being the predominant treatment option.2.PPK model for ceftriaxone: The population pharmacokinetic model for ceftriaxone was selected as the final two-compartment model with first-degree linear elimination.The most important covariates in this model were albumin and creatinine clearance.The final model pharmacokinetic parameters were a mean central compartment volume of distribution(V1)of 8.18 L,a central compartment clearance(CL1)of 1.37 L/h,a peripheral compartment volume of distribution(V2)of 6.61 L and an intercompartmental clearance(CL2)of 2.04 L/h.3.According to Monte Carlo simulation results: In patients with high creatinine clearance,increased administration times will increase the efficacy of ceftriaxone,and the administration regimen of 2g q12 h is superior to that of 4g qd.Conclusion:1.Long-term immunosuppressive therapy,consciousness disturbance,transfusion of blood,MODS,three or more antibiotic therapy,MN,tracheotomy,urinary catheter,gastric tube and CVC are high risk factors for NI.2.NI will increase the cost,length of stay and mortality,causing serious adverse consequences to hospital,medical staff and patients.3.This study established a quantitative analysis method with HPLC and highly stable accuracy for ceftriaxone and pharmacokinetic studies.4.In this study,a population pharmacokinetic model of ceftriaxone was established to estimate the pharmacokinetic parameters.Albumin and creatinine clearance were important factors affecting the apparent volume and clearance of patients,respectively.Through the simulation of different protein levels and different renal function of patients dose to achieve individualized administration,improve clinical efficacy.4.In this study,a population pharmacokinetic model of ceftriaxone was established to estimate the pharmacokinetic parameters.Albumin and creatinine clearance were important factors affecting the apparent volume and clearance of patients,respectively.Through the simulation of different protein levels and different renal function of patients dose to achieve individualized administration,improve clinical efficacy.5.In patients with creatinine clearance > 200 m L/min,increased administration times increased the efficacy of ceftriaxone,and the administration regimen of 2g q12 h was superior to 4g qd.