Analysis Of Risk Factors And Evaluation Of Antimicrobials On The Infection Caused By Acinetobacter Baumannii

Objective:Acinetobacter baumannii is an important pathogen of nosocomial infections,and carbapenem-resistant Acinetobacter baumannii has been listed by the World Health Organization?WHO?in the list of first-class"critical"key pathogens urgently needing new antibiotics.Before obtaining clear clinical microbiological results,the current empirical treatment was usually taken by experience or the severity of the infection,without any theorecal basis for early identification of special resistant bacteria.Because of high drug resistance,early and rational use of antibiotics based on risk identification is also extremely important for clinical efficacy and avoidance of induced drug resistance.Therefore,based on the comprehensive exploration of the risk factors of imipenem-resistant Acinetobacter baumannii infection in our area,we intend to pre-determine the potential"infection group"of imipenem-resistant Acinetobacter baumannii;to further determine the difference and hysteresis effect for the various types of antibiotics exposure on Acinetobacter baumannii infection;finally,the Monte Carlo simulation was used to evaluate the effect of the common drugs for Acinetobacter baumannii to optimize the dosing regimen and prolong the service life of existing antimicrobial agents.Methods:1.Retrospective investigation was conducted for the hospitalized patients in the First Hospital of China Medical University from January 2013 to December 2015.All patients with Acinetobacter baumannii infection who met the inclusion criteria were divided into two groups,the imipenem-resistant group and the non-imipenem-resistant group.2.All data were statistically analyzed by SPSS 22.0?SPSS,Inc,Chicago,IL?and SAS 9.4?SAS Institute Inc.,Cary,NC?.The characteristics of the subjects were assessed using the t-test for continuous variables and the chi-square test for categorical variables.P<0.05 was considered statistically significant.All included patients were divided into two groups according to the admission date:the training set and the testing set.In the training set,10-fold cross-validation and binary logistic regression were used to establish the risk scoring system for the infection of imipenem-resistant Acinetobacter baumannii.After performing ROC curve,it is necessary to comprehensively consider the sensitivity,specificity,positive predictive value,negative predictive value and Youden index.By comprehensive comparison of the higher accuracy and the optimal cut-off,the risk scoring systemr of imipenem-resistant Acinetobacter baumannii infection was established.The external performance of the risk scoring tool was evaluated and validated in the testing set.3.The results of drug-resistant monitoring for patients with Acinetobacter baumannii infection from January 2013 to June 2016 were extracted.Data analysis was performed by WHONET software,which was summarized for each quarter,and the resistant rate was expressed as a percentage.The antibiotics used in each case of imipenem-resistant Acinetobacter baumannii infection?including the name,specification,dosage,quantity,etc.?were surveyed through the medical records in the HIS information system?including long-term and temporary medical advice?.4.The Cox-Staurt trend test was used to study the trends of Acinetobacter baumannii resistance.The use of various antibiotics before 72h of infection were analyzed by binary logistic regression.The transfer function model was used to analyze the hysteresis effect of various antibiotics against Acinetobacter baumannii.5.The minimum inhibitory concentration?MICs?of Acinetobacter baumannii for four commonly used antibiotics was detected by agar dilution method.Then Monte Carlo simulation was used to obtain PTA and CFR for various dosing regimens based the pharmacokinetic and pharmacodynamic?PK/PD?parameters of each drug.Results:1.A total of 746 patients met the inclusion criteria.For 746 patients infected with Acinetobacter baumannii,their mean age was 61.37±17.04?years?,of which 494?66.2%?were male and 252?33.8%?were female.According to the results of the clinical drug susceptibility test,all patients were divided into two groups:imipenem-resistant group?593,79.5%?and non imipenem-resistant group?153,20.5%?.Univariate analysis showed that among all 36 variables,a total of 23 univariate variables were significantly associated with imipenem-resistant Acinetobacter baumannii infection?P<0.05?.2.Based on the date of admission,571 patients were included in the training set and 175 in the testing set.According to the results of 10-fold cross-validation in the training set and multivariate logistic regression,there are eight important risk factors associated with imipenem-resistant Acinetobacter baumannii infection,which are gender?male?,prior ICU stay,pneumonia before admission,respiratory failure,urinary catheter,indwelling gastric tube,prior use of a single antibiotic within 72h and prior use of combined antibiotics within 90 days?P<0.05?,and then the average regression coefficients of each risk factor were used to develop a risk scoring system,with a score ranging from 0 to 25.The higher the score,the higher risk of imipenem-resistant Acinetobacter baumannii infection.For the 571 patients in the training set,the mean risk score for imipenem-resistant Acinetobacter baumannii infection was 15.14±4.46.Taking into account the higher accuracy?82.29%?and Youden's Index?57.01%?,11 was set as the optimal cut-off value to determine the high risk of imipenem-resistant Acinetobacter baumannii infection.At the same time,according to the risk score and diagnostic efficacy,175 patients?score range 0 to 25?in the validation group were divided into three groups:low risk group,moderate risk grou and high risk groups.In the high-risk group,116?66.3%?patients were correctly classified,and only 14?8%?patients were misclassified?risk was overestimated?.Finally,using this scoring tool,a total of 78.3%of patients were correctly classified as with or without imipenem-resistant Acinetobacter baumannii infection.3.For the investigation of prior antibiotic therapy within 72h,second-generation cephalosporin,third-generation cephalosporin,carbapenems,enzyme inhibitor compound preparations and quinolones were all included.And the DDDs of enzyme inhibitor compound preparations ranked first.Logistic regression analysis of various antibacterial DDDs against imipenem-resistant Acinetobacter baumannii infection showed that exposure of enzyme inhibitor complex preparations,carbapenems,quinolones and anti-positive cocci were all independent risk factors for imipenem-resistant Acinetobacter baumannii infection.4.The cumulative DDDs for the enzyme inhibitor complex preparations of the 746 patients with Acinetobacter baumannii infection during three years was the biggest,followed by carbapenems,quinolones and anti-positive cocci.The Cox-Staurt trend test showed a significant downward trend in the resistant rate of piperacillin and ceftazidime.5.The transfer function model showed that the correlation between the DDDs of enzyme inhibitor complex and the resistance rates of piperacillin,ceftazidime,ceftriaxone,imipenem and ciprofloxacin,0.867 and 0.861,respectively.0.580,0.613 and 0.613,and the lag was 1,1,0,0 and 0 quarter respectively;the correlation between DDDs of antibiotics for Gram-positive cocci and piperacillin and ceftazid resistance was 0.823 and 0.846,respectively.The numbers were 1 lag and 0 lag,respectively.6.In the Monte Carlo simulation of the common dosing regimen of Acinetobacter baumannii,for the combination of the four dose levels of imipenem and the two infusion times,when the MIC value was?8?g/ml,90%of PTA was obtained except for the 0.5 g q8h dosing regimen.The four imipenem dosing regimens showed almost no difference in PTA at 2h and 0.5h infusion conditions,and none of the regimens can achieve meaningful 90%CRF.Cefoperazone/Sulbactam?2:1?can improve the bactericidal effect of the drug by increasing the dosing regimen under 0.5h infusion.When MICs of cefoperazone/sulbactam?2:1?for Acinetobacter baumannii increased to64?g/ml,two high-dose dosing regimens?4.5 g q6h and 6 g q6h?could reach 90%PTA,and when the regimen increased from 1.5g q8h to 6g q6h,CFR increased only from26.97%to 67.34%.When tigecycline was administered at a dose of 50 mg q12h,the ideal PTA could be obtained within MICs 1?g/ml,but even for dose of 100 mg q12h,CFR can only increase to 66.22%.The three regimens of polymyxin showed that the change of PTA was positively correlated with dose,and negatively correlated with the renal function of the patient.As the CL_Crr increases,the effective PTA decreases.Only the dosing regimen of 3MU q8h could achieve effective CFR??86.94%?.Conclusions:Based on the risk factors of imipenem-resistant Acinetobacter baumannii infection,this study realized the possibility of pre-judging patients with imipenem-resistant Acinetobacter baumannii infection through the construction of risk assessment system.Exposure of carbapenems,enzyme inhibitor complex,quinolones and antibiotics for Gram-positive cocci before 72 hours of infection are independent risk factors for drug-resistant infections;there was one quarter lag effect on the resistance of piperacillin and ceftazidime caused by enzyme inhibitor complex,and the antibiotics for Gram-positive cocci had a one quarter lag effect on piperacillin resistance.Finally,four common antibacterials were simulated by Monte Carlo.The results suggests that the initial empirical drug selection,therapeutic effect and targeted treatment should be combined with the regional PK/PD parameters.Based on observation and evaluation,the optimal drug exposure will be achieved.And patients with high-level resistance should be treated by a combination regimens that may be effective for early empirical antibacterial therapy and reducing the development of induced resistance.