Abstract
Background:
To explore the risk factors for multi-drug–resistant organism (MDRO) infection in patients with Stanford acute type A aortic dissection (ATAAD). We conducted a retrospective cohort study using the data of post-operative patients with ATAAD in our hospital.
Patients and Methods:
This study included 82 post-operative patients with ATAAD in the past decade. They were divided into a MDRO group (n = 31) and a non-MDRO group (n = 51) according to whether they had acquired multi-drug–resistant (MDR) bacterial infection. Multivariable logistic regression was used to analyze the risk factors for MDR infections in patients with ATAAD.
Results:
The incidence of multi-drug–resistant bacterial infection was 37.80%. Seventeen factors, including hospital stay (p = 0.007), utilization of third-generation cephalosporins (p = 0.0068), antibiotic species of exposure (p = 0.0002), leukocyte-depleted red blood cell suspension dosage (p < 0.0001), fresh frozen plasma dosage (p < 0.0001), application of blood purification (p = 0.0493), and the total antibiotic days of exposure (p = 0.0001) diverged between the two groups (all p < 0.05). The logistic regression analysis revealed that the utilization of third-generation cephalosporins (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.01–5.33; p = 0.0478), antibiotic species of exposure (OR, 5.76; 95% CI, 1.45–22.83; p = 0.0128), leukocyte-depleted red blood cell suspension dosage (OR, 12.43; 95% CI, 2.71–57.07; p = 0.0012), and fresh frozen plasma dosage (OR, 5.05; 95% CI, 1.18–21.56; p = 0.0286) were independent variables for MDRO infections. Among the 23 drug-resistant bacteria detected, Acinetobacter baumannii was the main pathogen.
Conclusions:
Our study shows that the utilization of third-generation cephalosporins, antibiotic species of exposure, leukocyte-depleted red blood cell suspension dosage, and fresh frozen plasma dosage were independent risk factors for post-operative multi-drug–resistant infection in patients with ATAAD. Acinetobacter baumannii occupied the largest share of resistant bacteria that induce infection in post-operative patients with ATAAD.
Acute Stanford type A aortic dissection (ATAAD) has a rapid onset, rapid progression, and poor prognosis. With advancements in surgical technology, the overall survival rate of patients with ATAAD has increased, but the post-operative death rate remains high. 1 The mortality rate after ATAAD has been reported to reach 9% to 30%. 2 Multi-drug–resistant bacterial infection is a significant prognostic factor for patients with ATAAD. 3 Because of the complex and refractory characteristics of post-operative multi-drug–resistant organism (MDRO) infection, post-operative recovery is delayed or difficult. In severe cases, patients might suffer from multiple organ failures or even death. 4
Antibiotic agents are the dominant and most effective treatment for ATAAD infections. In long-term confrontation with selective pressure from antimicrobial drugs, infectious pathogens change their metabolic types or gene mutations, leading to a form of self-protection. 5 The risk factors and related mechanisms that may lead to MDR pathogen infection have rarely been reported in patients with ATAAD. Therefore, we retrospectively analyzed the relevant data on patients undergoing ATAAD surgery in our hospital from January 2011 to June 2021. We expected to search for the risk factors that may lead to the infection of patients with MDR to provide preventive measures, improve the treatment of ATAAD, and reduce severe post-operative complications from the disease.
Patients and Methods
Patients
Our inclusion criteria were as follows: patients diagnosed with ATAAD who underwent thoracotomy from January 2011 to June 2021. Our exclusion criteria were as follows: patients who did not undergo surgical treatment or only underwent endovascular exclusion; patients with Stanford type B aortic dissection; patients who died or were discharged automatically within 48 hours after surgery; and patients with incomplete data.
Data collection
The study subjects included 82 patients. They were subdivided into the MDRO group (31 cases) and the non-MDRO (51 cases) group according to whether they had acquired MDR bacterial infection based on the diagnostic criteria of MDR bacterial infection.
Six pre-operative factors were collected, including age, gender, hospital stay, clinical diagnosis, time from onset to admission, and past medical history. Three intra-operative factors were collected, including surgical duration, intra-operative bleeding volume, and intra-operative urine volume. Twenty-six post-operative indicators, including aspartate aminotransferase/alanine aminotransferase (AST/ALT), ALT, alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), creatinine, total protein, albumin, methylprednisolone, imipenem and cilastatin, third-generation cephalosporin use, tigecycline, vancomycin, olanzapine, the total days of antibiotic exposure, ventilator use duration, sputum suction times, ordinary frozen plasma dosage, leukocyte-depleted platelets dosage, leukocyte-depleted red blood cell suspension dosage, cryoprecipitate coagulation factor dosage, fresh frozen plasma dosage, extracorporeal circulation duration, endotracheal intubation duration, endotracheal intubation times, blood purification, and antibiotic species of exposure were collected. The Ethics Committee of The Fourth Affiliated Hospital of Harbin Medical University approved the retrospective study.
Multi-drug–resistant organism definition
The definition of MDR bacteria refers to bacteria resistant to three or more classes of antibiotic agents commonly used in clinical practice at the same time, including cephalosporins, penicillins, quinolones, aminoglycosides, β-lactams, etc. Refer to the diagnostic criteria for nosocomial infections issued by the Ministry of Health of the People's Republic of China in 2001. The sputum, drainage fluid, urine, bronchoalveolar lavage fluid, blood, secretions, and other specimens of post-operative patients are sent to the pathogenic bacteria culture plus drug susceptibility test. When MDR bacterial strains are cultured, the patient can be diagnosed with MDR bacterial infection.
Statistical analyses
The measurement data were expressed as the mean ± standard deviation, and χ 2 tests were used for comparisons between groups if the conditions met χ 2 tests; otherwise, Fisher's exact probabilistic approach was used. The occurrence of post-operative MDR in the patients with ATAAD was regarded as a dependent variable (0 = MDRO; 1 = non-MDRO). Variables with a single factor <0.05 were included in the binary logistic regression analysis model. To avoid collinearity between variables, stepwise regression was used to filter variants. Statistical significance was defined as p < 0.05. All statistical analyses were performed using SAS 9.4 (SAS Institute, College Station, TX) international standard statistical programming software.
Results
Risk factor analysis
There were no differences in age, gender, clinical outcomes, hospital stay, or past medical history between the two groups (all p > 0.05). However, there was a difference in the length of hospital stay (p < 0.05) because patients who developed MDR bacterial infections required more extended treatment and incurred higher medical costs (Table 1). No differences were found between the two groups regarding their surgical duration, surgical modality, intra-operative bleeding volume, and intra-operative urine volume (all p > 0.05). This result suggested that these intra-operative factors had a negligible effect on MDR bacterial infections (Table 2).
Pre-Operative Factor Analysis
p value of <0.05 was considered to be statistically significant.
MDRO = multi-drug–resistant organism; non-MDRO = non-multi-drug–resistant organism.
Intra-Operative Factor Analysis
p value of <0.05 was considered to be statistically significant.
MDRO = multi-drug–resistant organism; non-MDRO = non-multi-drug– resistant organism.
Among post-operative factors, there was no evidence for a statistically significant difference in hepatic insufficiency, total protein, methylprednisolone, imipenem and cilastatin, olanzapine, extracorporeal circulation duration, endotracheal intubation duration, or endotracheal intubation times (all p > 0.05). Other post-operative factors, including creatinine, albumin, utilization of third-generation cephalosporins, linezolid or vancomycin, tigecycline, antibiotic species of exposure, ventilator use duration, sputum suction times, ordinary frozen plasma dosage, leukocyte-depleted platelet dosage, leukocyte-depleted red blood cell suspension dosage, cryoprecipitate coagulation factor dosage, fresh frozen plasma dosage, application of blood purification, and the total antibiotic days of exposure had differences between the two groups (all p < 0.05; Table 3).
Post-Operative Factors Analysis
p value of <0.05 was considered to be statistically significant.
MDRO = multi-drug–resistant organism; non-MDRO = non-multi-drug–resistant organism; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; GGT = γ-glutamyl transferase.
To identify the independent risk factors for MDRO infection further, a logistic analysis was performed. The multivariable analysis revealed that the utilization of third-generation cephalosporins (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.01–5.33; p = 0.0478), antibiotic species of exposure (OR, 5.76; 95% CI, 1.45–22.83; p = 0.0128), leukocyte-depleted red blood cell suspension dosage (OR, 12.43; 95% CI, 2.71–57.07; p = 0.0012), and fresh frozen plasma dosage (OR, 5.05; 95% CI, 1.18–21.56; p = 0.0286) were independent risk factors for post-operative MDR bacterial infection (Table 4).
Multivariable Analyses of Explanatory Variables for MDRO Pathogen Infection
SE = standard error; OR = odds ratio; CI = confidence interval.
Multi-drug–resistant pathogen infection
In total, we detected 151 bacterial pathogens in 82 patients. The micro-organisms are summarized in Table 5. We found that gram-negative isolates (72.9%) accounted for the major proportion of bacterial pathogens in patients with ATAAD. Acinetobacter baumannii (45.7%) and Streptococcus pneumoniae species (7.9%) were mainly identified, followed by Pseudomonas aeruginosa (5.3%). A total of 134 cases of MDR pathogens were detected, of which 95 (70.9%) were gram-negative bacteria and 39 (29.1%) were gram-positive bacteria. The top two MDR pathogens were Acinetobacter baumannii (n = 69) and Streptococcus pneumoniae (n = 12). A total of 134 MDR pathogens were derived from six biologic samples, 56 from sputum, 15 from drainage, 10 from percutaneous ascites, 37 from blood specimens, 12 from catheter terminals, and four from secretions.
Total Micro-Organisms and Multi-Drug–Resistant Micro-Organisms in Body Fluid Samples of Eighty-Two Patients
MDRO = multi-drug–resistant organism; non-MDRO = non-multi-drug–resistant organism.
Discussion
In our study, Acinetobacter baumannii was the most frequently occurring pathogen. Acinetobacter baumannii infection risk factors include prolonged hospital stay, admission to the intensive care unit, mechanical ventilation, invasive procedures, exposure to antibiotics, and serious underlying diseases.6,7. Patients with ATAAD need timely surgical treatment, and mechanical ventilation and invasive procedures are unavoidable. Nineteen of 82 patients were admitted to the intensive care unit, which contributed to the multiplication of Acinetobacter baumannii. Previous antibiotic exposure: carbapenems, third-generation cephalosporins, and/or fluoroquinolones are independent risk factors for acquiring MDR Acinetobacter baumannii.8-10 In our study, all patients applied the drugs mentioned above to varying degrees.
Our study shows that the application of third-generation cephalosporins was also closely related to the generation of MDR bacteria. Broad application of third-generation cephalosporins will induce the emergence and spread of extended-spectrum β-lactamase (ESBL) strains, resulting in MDR bacterial infections. Kerry et al. found that reducing the use of third-generation cephalosporins reduced the incidence of ceftazidime-resistant Klebsiella pneumoniae and piperacillin-resistant and ceftazidime-resistant Pseudomonas aeruginosa infections, of which the incidence of ceftazidime-resistant Klebsiella pneumoniae infection decreased from 13% in the same period of the previous year to 3%. 11 Liang Zhuozheng et al. found that utilization of third-generation cephalosporins can cause changes in the drug resistance of Pseudomonas aeruginosa and induce multi-β-lactam antibiotic resistance and even carbapenem resistance in Pseudomonas aeruginosa. 12 Therefore, clinicians should be more cautious when choosing third-generation cephalosporins.
In addition to third-generation cephalosporins, the application of more than three types of antimicrobials was an independent risk factor for MDR. The selective pressure of antibacterial drugs is considered an essential reason for the induction of bacterial resistance, which plays a role in screening dominant drug-resistant bacteria. Bacterial acquired resistance includes chromosomal and plasmid-mediated resistance, the latter being the most common. Drug-resistant plasmids are widely present in various pathogenic bacteria and can spread laterally among strains, causing outbreaks of nosocomial infections.13,14 Therefore, types of antimicrobial drug applications should be more streamlined and targeted. Surgeons should strictly adhere to aseptic techniques, avoid contamination, and reduce the risk of infection. In terms of hospital management, multidisciplinary teams (MDTs) have been shown to improve the situation of MDR.
In recent years, many studies have shown that post-operative blood transfusions are related to increasing peri-operative complications and negatively affect the patient's short-term survival.15,16 In this study, transfusion of fresh frozen plasma and leukocyte-depleted erythrocyte suspension was found to be an independent risk factor for MDR bacterial infection after surgery in patients with ATAAD. Patients with aortic dissection require large doses of blood products during and after surgery because of long cardiopulmonary bypass and long turnaround time during surgery, disorder of coagulation mechanism, and destruction of blood components. 17 Blood transfusion causes the formation of various microemboli, which directly affect lung function. Entry of large amounts of cellular debris and foreign proteins from banked blood into the body can lead to the same result.
It has been reported that intra-operative transfusion of a small amount of packed red blood cells can still increase in-hospital mortality and pulmonary infection complications. 18 This is consistent with our findings. Therefore, intra-operative and post-operative transfusion of fresh frozen plasma and leukocyte-depleted erythrocyte suspension increases the chance of post-operative MDR bacterial infection through immunosuppression, endangering the patient's life. We suggest that clinicians should consider reducing the use of blood products as an important measure to prevent MDR infections. Clinicians should improve surgical cooperation and operation ability, shorten the time of surgery and cardiopulmonary bypass, achieve strict intra-operative hemostasis, reduce active bleeding and hidden blood loss, reduce intra-operative and post-operative blood transfusion, and reduce the incidence of post-operative complications.
Conclusions
Multi-drug–resistant organism infections were common in patients with ATAAD and gram-negative bacteria were the primary pathogen. The top two MDRO pathogens were Acinetobacter baumannii and Streptococcus pneumoniae species. The single factor analysis showed that 16 factors, which included hospital stay, creatinine, albumin, utilization of third-generation cephalosporins, tigecycline, vancomycin, linezolid, the total antibiotic days of exposure, ventilator use duration, sputum suction times, ordinary frozen plasma dosage, leukocyte-depleted platelet dosage, leukocyte-depleted red blood cell suspension dosage, cryoprecipitate coagulation factor dosage, fresh frozen plasma dosage, and application of blood purification, were risk factors for MDR pathogen infections in ATAAD. Furthermore, the utilization of third-generation cephalosporins, antibiotic species of exposure, leukocyte-depleted red blood cell suspension dosage, and fresh frozen plasma dosage were independent risk factors for MDRO infections.
Footnotes
Authors' Contributions
Design of experiments: Liang. Acquisition and analysis of data: Chen, Shao. Drafting the manuscript: Wang. Funding acquisition and supervision: Yang. All authors approved the final version of the paper.
Funding Information
This work was supported by the grants from the Funds for Project of Qiqihar Academy of Medical Sciences (QMSI2020B-04) and Innovation and Entrepreneurship Training Program for College Students in Heilongjiang Province (202111230007).
Author Disclosure Statement
The authors declare that they have no conflict of interest.
