Antimicrobial stewardship program in China’s tertiary hospitals in 2018: a nationwide cross-sectional online survey

Background The study aimed to assess the development of antimicrobial stewardship (AMS) program in China’s tertiary hospitals to identify the potential challenges for AMS program and provide references and benchmarks for strategic policymaking. A nationwide cross-sectional study was conducted online by sending questionnaires to tertiary hospitals under China Antimicrobial Resistance Surveillance System (CARSS) between November 1, 2018 and December 10, 2018. The questionnaire included 5 sections regarding structure, technical support, antimicrobial use management, antimicrobial use surveillance and education. Descriptive statistics were used for data analysis. a form to report the relevant information of patients who used carbapenems or tigecycline, including name, diagnose, generic name of the drugs, dosage, etc. Specific persons are assigned to collect the forms and analyze the data to propose effective ways of controlling carbapenems and tigecycline resistance [19].


Abstract Background
The study aimed to assess the development of antimicrobial stewardship (AMS) program in China's tertiary hospitals to identify the potential challenges for AMS program and provide references and benchmarks for strategic policymaking. Conclusions AMS in China's tertiary hospitals were primarily headed by hospital presidents and involved collaboration among various disciplines and administrative departments. More efforts should be put into further promoting and strengthening the development of hospital-specific guidelines and the establishment of progress and outcome evaluation system.

Background
Antimicrobial resistance (AMR) has been identified as a critical crisis to public health around the world [1,2,3]. Inappropriate antimicrobial use fosters the emergence and spread of new resistance organisms [4]. In an era of serious AMR and a diminishing pipeline of new antimicrobial development, antimicrobial stewardship (AMS) program has been introduced to hospitals as a way to optimize antimicrobial use [2,5,6]. AMS program has been defined as a comprehensive and coordinated interventions designed to improve and measure appropriate antimicrobial use through optimizing drug selection including dosing, therapy duration as well as administration route [7]. Guidelines for establishing and implementing AMS program have been developed, such as a checklist including core elements of hospital AMS programs by the US Centers for Disease Control and Prevention and a checklist on structure and process indicators for hospital AMS program by the Transatlantic Taskforce on Antimicrobial Resistance [8,9].
China is one of the largest consumers of antimicrobials [10,11,12]. To promote antimicrobial rational use and confine AMR, several administrative regulations and technical specifications, such as the Regulations for Antimicrobials Clinical Use, National Action Plan to Contain Antimicrobial Resistance (2016-2020), have been issued in the past decade [13]. However, the extent to which AMS program has been implemented in China's tertiary hospitals is a lack of study. The present study aimed to assess the development of AMS program in China's hospitals, as well as to identify the potential challenges for AMS program establishment, and to provide references and benchmarks for strategic policymaking.

Methods
The questionnaire was designed based on literature review of previous studies for AMS program, the published guidelines and checklists as well as relevant Chinese policies [6,8,11,13,14,15].
Potential survey questions were extracted and classified. After three rounds of face-to-face consensus meetings with professionals from governments, hospitals and academic institutions, the final survey questionnaire was determined by including 5 sections regarding structure, technical support, antimicrobial use management, antimicrobial use surveillance and education. The questionnaire was sent to the tertiary hospitals under China Antimicrobial Resistance Surveillance System (CARSS) [16].
The hospitals participated in the survey voluntarily. To ensure the accuracy of the information, only the staff involved in AMS program were eligible to complete the questionnaire. The completed questionnaire was required to affix the hospital's seal before being sent back. Only one questionnaire could be accepted for each hospital. The nationwide cross-sectional study was conducted between

Results
A total of 140 out of 1045 hospitals under CARSS were investigated, and the response rate was 13.4%. The hospitals participating accounted for 5.5% of all tertiary hospitals (140/2548) [17], and geographically covered all provinces and municipalities in mainland China except Fujian, Gansu, Ningxia, Qinghai, and Tibet. (Fig. 1  Prescription audit 133 (95.0) AMS, antimicrobial stewardship; AMR, antimicrobial resistance. a Structured antimicrobial formulary restriction management has been established in China, which categorized antimicrobials into three classes (non-restricted, restricted and highly-restricted), with different prescription privileges to different level of physicians. b Clean incision surgery means no inflammation is encountered in a surgical procedure, without a break in sterile technique, and during which the respiratory, alimentary and genitourinary that are not entered [18].

Discussion
We systematically conducted a nationwide survey on the implementation and current status of AMS program in 140 tertiary hospitals, covering 26 provinces in China. In this survey, AMS program was implemented in 99.3% (139/140) of the responding hospitals, which was higher than that in the studies conducted in developed countries such as the US and Netherland [20,21]. AMS program has been required to be implemented in China since 2011. Furthermore, in the past decade, a relatively systematical management system and advanced technical support framework have been established by the Chinese government, contributing to setting up AMS program in the hospitals. The hospitals surveyed were all tertiary hospitals which were likely to be larger, urban and have better access to medical resource and financial support. As adequate manpower and funding are identified as main barriers to developing AMS program, tertiary hospitals surveyed were probably more capable of policy execution and AMS program implementation when comparing with other hospitals [22,23,24].
Leadership and teamwork are paramount prerequisites for successful and effective implementation of AMS program. The survey demonstrated that hospital presidents were heading AMS program in most hospitals. Different from our result, previous studies found that AMS team was more likely to be led by pharmacists or infectious disease physicians in the US [20,25]. According to the management regulations and technical specifications issued by the Chinese government, hospital presidents were appointed as the leaders of AMS program. It is emphasized that a wide range of health professionals could provide unique support in achieving the over-all goal of AMS [26,27,28]. Obviously, the hospital presidents possess the supreme power, and it is beneficial for ordering commanding and dedicating necessary human resources for the program when the hospital presidents take charge of AMS program. Under this circumstances, financial support could be also guaranteed, which greatly augments the capacity and influence of the program. Furthermore, the survey confirmed that pharmacy departments exerted a critical role in AMS implementation. It is recommended that along with infectious disease physicians, pharmacists are considered as the core members as drug expertise in AMS team [8].
In the survey, most infectious disease departments were still occupied by the management of common communicable diseases such as hepatitis and tuberculosis. Also, infectious disease physicians played a limited role in AMS program implementation in most hospitals. This finding was similar with the result in a prior study [29]. The tertiary hospitals in China has been required to establish infectious disease departments since the outbreak of severe acute respiratory syndrome in 2013. The main duties of the departments are to treat various infectious diseases, address AMR and deal with infectious disease emergence. However, when comparing with the developed countries, our finding revealed that the effectiveness of infectious disease department in antimicrobial rational use promotion and AMR confinement needs to be strengthened. The limited privilege of infectious disease physicians would undoubtedly restrict the impact of AMS on antimicrobial rational use and AMR confinement in China. This may be partly attributed to the shortage of adequately trained physicians interested in infectious diseases and the lack of consciousness of AMR control of the physicians.
Hence, it is imperative that the infectious disease department and the physicians should attach great importance to their commitment to AMS implementation. Society for Healthcare Epidemiology of America [6]. Previous studies showed that the implementation of hospital-specific guidelines was associated with optimal antimicrobial use by increasing the likelihood of sufficient initial therapy, narrower-spectrum antimicrobial use, shorter therapy duration and timely switch from intravenous to oral antimicrobials [32,33,34,35,36,37,38]. Hence, multidiscipline collaboration of AMS program in development of hospital-specific guidelines for infectious diseases should be emphasized.
Our findings highlighted the ongoing difficulties in antimicrobial usage measurement, which has long been considered as an essential opponent to promote AMS [39]. Although up to 138 hospitals surveyed reported antimicrobial usage on a regular basis, most of them tracked antimicrobial use using define daily dose (DDD) and ranked antimicrobials based on usage and expenditure. Neither indicator was appropriate and optimal for benchmarking [40,41]. Specifically, although DDD is a direct and widely adopted metric for antimicrobial usage measurement and comparison, the limitations of DDD are obvious. Unlike number of days of therapy which is recommended as the first option for antimicrobial usage measurement in the US, DDDs is not an applicable measuring tool in pediatric setting and is not an optimal metric for individuals with renal and/or liver impairment because of the dose reduction [8,42]. Previous study also showed that some hospitals in China might mechanically define DDDs by restricting the total dosage of antimicrobials during infectious disease treatment [29]. This would result in antimicrobial underuse and even possibly exacerbate AMR. The limited access to computerized pharmacy data may also narrow the options of tracking antimicrobial usage. We also found that there was a lack of evaluating AMS outcome from the clinical and the economic perspective. Of note, optimizing patient outcomes and confining AMR is the primary goal of AMS [6]. The outcome measurement would provide useful information on the effectiveness of strategies used and assist in adjusting AMS program. Moreover, cost savings could be achieved by optimized antimicrobial use, shorter duration and avoidance of unnecessary antimicrobials. This will in turn motivate the implementation of AMS program. Hence, there is a necessity to identify appropriate metrics for antimicrobial use, AMR outcome, patient outcome and expenditure and establish a comprehensive evaluation system for the program.
Our study has some limitations. Firstly, though up to 140 tertiary hospitals participated in the survey, they only accounted for 5.5% (140/2548) of all tertiary hospitals in China [17]. The relatively small sample size and low response rate may introduce non-response bias and affect generalizability given the extensive application of antibiotics and increasing emergence of AMR in tertiary hospitals in China. Secondly, the survey solely assessed tertiary hospitals on AMS implementation. In contrast to primary care setting, tertiary hospitals have better access to medical resource and more funding for AMS development, which may lead to over-estimation in our results. We aim to extend the survey to obtain information on this topic in primary care setting in the future. Furthermore, the hospitals participated in this survey voluntarily. Therefore, the respondents might be those most interested or active in AMS than non-respondents, which probably provided an optimistic view of the results.

Conclusions
In conclusion, this nationwide survey provided important information on the progress of AMS that was made in China's tertiary hospitals. AMS program in tertiary hospitals were mainly headed by hospital presidents and involved collaboration among a wide range of disciplines and administrative departments. More efforts are required to further promote and strengthen the development of hospital-specific guidelines. Furthermore, establishment of progress and outcome evaluation system should be strengthened to guarantee the feasibility or sustainability of AMS program.

Availability of data and materials
The datasets used during the current study are available from the corresponding author on reasonable request. the study and collection, analysis, and interpretation of data and in writing the manuscript.
Authors' contributions LWS conceived the study. YZ and HW designed the study. All authors acquired and analyzed the data. YZ, HW, and XZ interpreted the findings. YZ and HW wrote the first draft of the manuscript. LWS drafted subsequent versions. All authors critically reviewed this article and approved the final version. Figure 1 The distribution of sample hospitals. Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. This map has been provided by the authors.