Secular trend analysis of antibiotic consumption in China’s hospitals 2011-2018, a retrospective analysis of sales data

Background: This study was aimed to explore the secular trends of antibiotic consumption over an 8-year period. Methods: We retrospectively analysed aggregated monthly surveillance data on antibiotic sales to 586 hospitals from 28 provinces in China from January 2011 to December 2018. Information including generic name, sales amount, dosage form, strength, the route of administration, and geographical data were collected. Population weighted Antibiotic consumption was expressed in DDD per 1,000 inhabitants per day (DID). WHO’s ‘Access, Watch, Reserve’ categorization was also adopted to analyse antibiotic consumption. Results: Between 2011 and 2018, total antibiotic consumption in China’s hospitals increased by 38.2% (from 4.8 DID in 2010 to 6.7 DID in 2018). Antibiotic consumption was stable or had moderately decreased in 13 provinces, while the other 15 provinces had substantially increased. Cephalosporins were the most consumed antibiotics, accounted for 26.9% of the total antibiotic consumption. In 2018, antibiotics in the Access category comprised 20.0% of total consumption, where antibiotics in the Watch category consumed the most with 72.2%. Population-weighted antibiotic consumption was larger in secondary hospitals than tertiary hospitals (7.3 DID VS 6.6 DID). The antibiotics consumption of oral form was almost two times the consumption of parenteral forms in secondary hospitals, whereas the proportion of tertiary hospitals was about the same. Conclusions: Although efforts were made towards restricting antibiotics in the past decade by Chinese government, antibiotic consumption demonstrated an upward trend during the study period. More efforts are needed to explore the quality of antibiotic usage in terms of rationality.

According to selective pressure theory, excessive antimicrobial consumption has caused an increased risk of antimicrobial resistance (AMR), which is a growing public health threat of broad concern to the world [1]. At the G20 Hangzhou Summit in 2016, AMR was one of the main topics and was included in the final communiqué. At the 71st UN General Assembly, AMR was the fourth health-related topic that was discussed in UN General Assembly in the history. It has been estimated that more than two million lives would be at risk, and up to 3.5 billion US dollars will be spent annually on average due to AMR in Europe, North America and Australia by 2050 if no action is taken [2].According to the theory of choice, the existence of an expected net benefit at individual level is one prerequisite for collective action [3], which means that protecting the efficacy of antibacterial agents and confining AMR as a common goal needs the collective efforts of every country instead of separating oneself from the problem. Given its largest population, China is estimated to be the second largest consumer of antibiotics in the world [4]. This gives China an important role in the process of constraining the use and misuse of antibiotics.
To address this issue, China has taken many measures to strengthen antimicrobials management such as the designation of antibiotic as prescription drugs in 2003, and the introduction of guidance for clinical use of antibiotics in 2004 [5,6].National surveillance networks for both antibiotic use and resistance were established in 2005, along with the introduction of a national formulary in 2008 [7,8].However, due to inefficient implementation and absence of supervision and inspection these policies and strategies did not fully achieve the expectation [4]. The overuse of antimicrobials has remained a serious public health challenge. Since the 2009 health system reform, the Chinese government has been committed to tackling the irrational use of antibiotics by enhancing antimicrobial stewardship. World Health Organization (WHO) called for a combat towards drug resistance with the slogan "no action today, no cure tomorrow" in 2011. Echoing the global governance endeavors of the WHO, the National Health and Family Planning Commission (NHFPC) launched a three-year Special Antimicrobial Stewardship Campaign (SAC) nationwide to strengthen the management of clinical use antimicrobials in healthcare settings [9]. The SAC was legislated then as a ministerial decree in 2012 [10].
In addition, structured antimicrobial formulary restriction management has been established, which categorized antimicrobials into three classes (non-restricted, restricted and highly-restricted), with different prescription privileges to different level of physicians. In 2016, a national action plan to confine AMR was released responding to WHO's call for "Global Action Plan on Antimicrobial Resistance" [11]. Moreover, to respond to the increasing carbapenem-resistant bacteria, the NHFPC made specific and more restrict requirement for the clinical use of carbapenems and tigecycline in 2018 [12].
Studies have centered around the impact of SAC and short-term trends of antibiotic consumption in China [13,14]. However, the long-term change of antibiotic consumption, especially after a decade since health system reform, was yet to explore. Hence, this study was designed to explore the secular trends of antibiotic consumption over 8-year period.

S t u d y d e s i g n
We retrospectively analyzed aggregated monthly surveillance data on antibiotic sales to 586 hospitals from 28 provinces in China from January 2011 to December 2018 (Table 1).  Hongkong, Macau, and Taiwan excluded). The details of the data source were described elsewhere [14]. Hospitals were selected on the basis that they each had full records of antibiotic consumption during the study period of 8 years, among which 452 tertiary hospitals accounts for 21.9% of the total tertiary hospitals and 134 secondary hospitals accounts for 2.3% of the total secondary hospitals in study regions.
D a t a c o l l e c t i o n a n d m a n a g e m e n t We extracted monthly antibiotic sales records data from the CMEI electronic database.
Information including the generic name, sales amount, dosage form, strength, the route of administration, and geographical data were collected. Hospital names were concealed to protect confidentiality.
Sales data were categorized according to Anatomical Therapeutic and Chemical (ATC) classification J01 (i.e. antibacterial for systemic use) expressed in defined daily dose (DDD) as measurement unit, following the recommendation of the WHO Collaborating Center for Drug Statistic Methodology [15]. The DDD of the drugs which could not be coded in the ATC system were calculated as the recommended daily amounts for each study medication based on dosage regimen recommended in the manufacturers' D a t a a n a l y s i s To make the antibiotic sales data available to provide internationally comparable information, the data were converted into DDD per 1,000 inhabitants per day (DID) at the level of the active substance. Based on the following two assumptions, equation1 was adopted to calculate the weighted population as a proxy for the population our sample hospitals had covered. First, there was no significant difference in the distribution of the sample hospitals across the provinces; second, there was no significant difference in the distribution of the population which was covered by the sample hospitals across the provinces. To avoid bias in calculating inhabitants, the inhabitants of outpatients and inpatients were calculated altogether instead of separately calculated as we did before [14]. Coverage inhabitants for secondary hospitals and tertiary hospitals were calculated separately.
( In addition to ATC classification, we adopted 'Access, Watch, Reserve' (AWaRe) categorization established by WHO as part of the update of the WHO Model List of Essential Medicines in 2017 to analyze the antibiotic consumption [16].
To derive a comparable metric of antibiotic consumption across time, we calculated the compound annual growth rate (CAGR) of antibiotic consumption.     internationally, which would be informing for healthcare providers, decision-makers, as well as the public.
In the nearly past two decades, Chinese government has endeavor to contribute for confining AMR by a series of policies and measures including confining antibiotic use. The evolution of the policy management has been well documented [10]. According to the National Health Commission, the outpatient antibiotic prescription proportion in Chinese hospitals (secondary and tertiary hospitals) has continuously declined from 16 When comparing with European countries, our result showed that antibiotic consumption in China's hospitals was more than three times than the average level of antibiotic consumption in hospital setting in 24 EU/EEA countries (2.0 DID in 2017, ranged from 0.9 to 3.1 DID) [25]. One more worrying fact was that, the antibiotic consumption in China's hospitals increased by a CAGR of 4.3% while the average annual hospital setting in EU/EEA countries was 1.0% [25]. Despite the growth was significant, these results still need to be interpreted with caution, because outpatient antibiotic use accounted for 90%-94% of the total use for the countries that provided separate data in ESAC [25,26],meaning most of the antibiotics were consumed in community setting, whilst more antibiotics were identified as a target for antibiotic stewardship interventions) and assessment of trends over time (to evaluate the impact of interventions) [2].
When looking at the pattern of antibiotic consumption, we found that cephalosporin was the most consumed antibiotics in China's hospitals, followed by combinations of penicillins, which were often defined as extended-spectrum antibiotics, and quinolones.
This pattern was similar to the previous studies conducted in other regions of China [19,20],as well as national surveillance data [18], whilst more penicillins were prescribed in Europe and United States [28][29][30].This might partly attribute to the different setting that antibiotics were consumed with more consumption was made to inpatient setting in China, whereas ambulatory care setting consumed more antibiotics as mentioned. Cephalosporin were recommended by national guidance for majority of the perioperative prophylaxis in China [31]. Although quinolones were noted by US FDA that should be only used for those have no other treatment options [32], physicians may prefer quinolones and cephalosporins more than penicillins due to the time-consuming skin testing requirement for penicillins prior to administration for allergy assessment in China [33],Although the consumption of carbapenems, a class of last-resort antibiotics, was similar to EU/EEA countries (0.10DID VS 0.06 DID in 2017, country range: 0.02-0.17), the significant increase of carbapenems consumption still cannot be ignored (0.03 DID in 2011 to 0.10 DID in 2018) [25]. Because carbapenems are categorized as highly restricted antibiotics by National Health Commission and requires pre-authorization before use in China, this increase could be partly due to the rise in extended-spectrum β-lactamase-producing Gram-negative bacteria, which has been identified in epidemiological surveillance studies [18,34]. As the increase of carbapenems consumption, the resistance rate of carbapenemresistant Enterobacteriaceae is also reported [35].
Population-weighted antibiotic consumption was larger in secondary hospitals than tertiary hospitals. As tertiary hospitals receive more severe patients than secondary hospitals, this might indicate that some increases in antibiotic consumptions, especially in secondary hospitals, are very likely caused by inappropriate use. Studies found that diseases, such as diarrheal illness, colds, pharyngitis, acute bronchitis, were likely to be prescribed antibiotics in rural and underdeveloped regions [36][37][38], although most of these illnesses are viral instead of bacterial. Besides, the high proportion of oral form of antibiotics consumed in secondary hospitals, though more less severe patients were received, would also support the inference that more irrational antibiotic use might took place in lower level of hospitals. This phenomenon may be severe in primary healthcare setting, especially in rural areas, not only because regulations towards primary healthcare setting in terms of antibiotic use has not been developed, but also the knowledge level of the physicians in primary healthcare setting are lower than the physicians in hospital setting [37].
The findings of this study are subject to several limitations. First, the hospital in the database was on a voluntarily basis instead of mandatory participation, especially the proportion of secondary hospitals in the study was relatively low, therefore could bring selected bias. Second, primary healthcare setting was not included which may cause bias on the pattern of antibiotic consumption since a number of antimicrobial agents was used in primary care setting. Third, the population denominator used in the study was determined under certain condition which may underestimate antibiotic consumption as it cannot include cross-provincial patient flow. Finally, as the study analyzed sales data rather than clinical usage of antibiotics, we were unable to determine the appropriateness of antibiotic use at the individual level.

Conclusions
The increase of antibiotic consumption and the increase in use of last-resort antibiotics raises serious concern for public health. The study adopted aggregated sales data to analyze the antibiotic consumption in China's hospitals over an eight-year period.
Although efforts have been made towards restricting antibiotic use in the past decade by