Multicenter Clinical Investigation of Vancomycin-resistant Enterococcus Infection


 Background: To understand the clinical characteristics of vancomycin-resistant Enterococcus (VRE) infection.Methods: The clinical characteristics of patients with VRE infection, members of CHINET Bacterial Drug Resistance Monitoring Network, in 2016, were analyzed and compared to patients with vancomycin-susceptible Enterococcus (VSE) infection patients.Results: Urinary tract infection was the main type, followed by bloodstream infection and intraabdominal infection. Compared to VSE infection, VRE infection is observed in more patients who have intravenous catheterization and undergo dialysis. In addition, the proportion of patients complicated with shock, multiple organ failure, and other bacterial and fungal infections is high, the clinical outcome is poor, the hospitalization expenses are high, and the hospitalization duration is prolonged. Multivariate logistic regression analysis showed that intravenous catheterization was an independent risk factor for VRE infection.Conclusions: Intravenous catheterization is an independent risk factor for VRE infection. Thus, clinical measures should be strengthened to prevent VRE infection.


Background
Enterococcus is an opportunistic pathogen that is widely distributed in the human intestinal tract and genitourinary tract and it is a crucial pathogen of bloodstream infection, intraabdominal infection, and genitourinary tract infection. Among these, Vancomycin-resistant Enterococcus (VRE) is one of the Gram-positive bacteria that has attracted much attention at present due to its high drug resistance and poor prognosis (1). The isolated rate of VRE varies greatly worldwide: 2% in Finland, 34% in Ireland and 33% in USA intensive care unit (2). Despite the rapid rise in bacterial resistance in China, the resistance rate of Enterococcus to vancomycin is still low. From 2005 to 2017, the resistance rate of Enterococcus faecalis to vancomycin uctuated from 0-0.6% and that of Enterococcus faecium from 0.4-4.2%; however, the isolation rate uctuated greatly in different regions (3,4). Therefore, timely detection of such infection and adoption of treatment and control measures are critical to avoid the spread of such bacteria. In order to understand the current situation of VRE infection in China, the characteristics of VRE infection should be identi ed, and the current situation of VRE drug resistance should be mastered. This study, for the rst time, carried out a multicenter prospective study on the characteristics of VRE infection in China based on the national bacterial drug resistance monitoring network to provide a reference for the general situation of VRE infection.

Methods
This study was based on a VRE clinical survey conducted by China Antimicrobial Surveillance Network (CHINET). Herein, hospitalized or outpatient and emergency patients with positive culture results from various hospitals between January 1 and December 31, 2016, were enrolled. According to the diagnostic criteria of infection, patients featuring contaminated or colonized bacteria, as well as incomplete or missing medical history data were eliminated, while those suffering from VRE infection were recruited as research subjects for clinical investigation. Clinical data, including patient demographic information, location of onset, predisposing factors, infection condition, anti-infection treatment, and outcome, were collected from the medical history information system of each research center. The distribution of pathogenic bacteria collected from various research centers were concentrated in CHINET Central Laboratory for the determination of bacterial drug sensitivity. Subsequently, the sensitivity and drug resistance of pathogenic bacteria from bloodstream infection to various therapeutic drugs were analyzed.

Source of Cases
Clinical and laboratory data of VRE infection of clinical specimens from CHINET research hospitals were collected according to Centers for Disease Control and Prevention/National Healthcare Safety Network (CDC/HNSN) standard for diagnostic criteria (5). According to the uni ed investigation plan, non-infectious bacteria were excluded from obtaining characteristic clinical data of VRE infection.
Inclusion criteria: Patients positive for VRE culture in 2016 were selected regardless of age and gender and were diagnosed as VRE infection.
Exclusion criteria: All cases that cannot be clearly diagnosed as VRE infection and whose clinical data are incomplete.
A reference is made to the following criteria for judging the acquisition of infection: Hospital-acquired infection: Infection with speci c appearances in different parts and bacteriological-positive, occurring 48 h after admission or related to the previous hospitalization.
Community-acquired infection: Conformed to clinical signs, VRE infection is excluded from a hospital-acquired infection.
Carrier status: VRE was isolated from different types of specimens from patients, but no clinical manifestation of infection was observed.

Antimicrobial Susceptibility Test
An in vitro drug sensitivity culture of Enterococcus was carried out in the clinical microorganism laboratories of each participating unit, and the strain was identi ed out according to the national clinical examination operation procedures. On the other hand, the drug sensitivity test was carried out using the automatic tester combined with Kirby-Bauer disk agar diffusion method. Source of the disc: The drug was purchased from the National Institute for the Control of Pharmaceutical and Biological Products, and the sensitivity results were judged according to the 2016 Clinical and Laboratory Standards Institute (CLSI) drug susceptibility standard.

Statistical analysis
The baseline situation, infection type, inducing factors, diagnosis and treatment process, and outcome (calculated according to the effective rate). This indicates that the clinical symptoms and signs of the patients are improved, and no further use of antibacterial drugs is required for the bacteriological examination results; also, other information of eligible VRE infection patients was analyzed. After collecting a VRE case, the clinical information of the patient infected with VSE of the same type was collected as the control group. In the statistical process, the continuity index was described by median (25th percentile and 75th percentile), and Wilcoxon rank-sum test was used for intergroup comparison. The classi cation index described the number and percentage of cases in each category, and the chisquare test or Fisher's accurate probability test was adopted. Multivariate logistic regression was used to analyze the in uencing factors of drug resistance with VRE infection as the outcome. All the data were analyzed using SAS 9.4 statistical software, and P < 0.05 was statistically signi cant.

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This research plan has been reviewed and approved by the Ethics Committee of Huashan Hospital of Fudan University in Shanghai (KY-2016-336). All methods were performed in accordance with the Declaration of Helsinki and relevant guidelines and regulations.

Participating sites
In 2016, a total of 20 hospitals, including 16 tertiary and 4 secondary, participated in CHINET drug resistance monitoring network. These hospitals were distributed in 9 provinces and cities, including Shanghai, Beijing, Henan, Liaoning, Sichuan, Shanxi, Guangdong, Hubei, and Hunan. Next, 97 cases of VRE infection and 95 cases of VSE infection were collected, and the information of the two groups compared to the diagnostic criteria of infection, excluding colonized bacteria.

Demographic Characteris
The clinical characteristics of patients with VRE and VSE infections are primarily observed in males. Also, hospitalacquired infection is common. However, the age of patients with VRE infection is higher than that of those with VSE infection (75-years-old vs. 65-years-old). The VRE infection was distributed in all departments, while the number of patients who had been admitted to ICU was more than that of VSE infection (44.79% vs. 23.08%, P = 0.0018) ( Table 1).

Discussion
Enterococcus faecalis is intrinsic resistance to many drugs. Enterococcus faecalis is usually susceptible to ampicillin and high concentration gentamicin, but combined therapy should be used to achieve curative effect. However, Enterococcus faecium has higher drug resistance and limited treatment options, especially the VRE group. Therefore, monitoring the changes in Enterococcus drug resistance, discovering VRE in time, and achieving an infection control is crucial (6).
This study carried out a multicenter survey of VRE infection nationwide based on CHINET, and the results provide a reference for a comprehensive understanding of the current situation of VRE infection in China.
CHINET was initiated and established by the Institute of Antibiotics of Huashan Hospital a liated to Fudan University and has been operational for 15 years. A myriad of data on the distribution and drug sensitivity of common bacteria in China released every year provide reference material for the diagnosis and treatment of bacterial infections and the prevention and control of bacterial drug resistance. However, since the data were obtained from all clinical isolates with positive specimens from various hospitals, and some colonized bacteria that were not infected were mixed, the monitoring quality of bacterial drug resistance was affected. According to the case investigation of the host of the isolated strain, distinguishing infection from colonization elucidates the exact situation of Enterococcus infection.
Thus, secondary and tertiary hospitals participated in the survey for the above purpose. Hospitals of different regions and grades in China were selected to explore and analyze the clinical isolates of vancomycin-resistant Enterococcus, and the data on the distribution and drug resistance of VRE pathogenic bacteria were obtained. This information elaborated the current situation of VRE infection in China and provided a crucial basis for the prevention and treatment of VRE infection.
The survey found that the majority of adult patients infected with VRE were men of average old age. Urinary tract infection is the most common type of VRE infection, which is similar to the Enterococcus infection. However, the proportion of severe patients is higher, and the prognosis is poor, which is consistent with that of previous reports (7).
Literature shows that the risk factors of VRE infection include serious primary diseases, long-term hospitalization, admission to ICU, intravenous indwelling catheter, major surgery, and application of broad-spectrum antibacterial drugs (7,8