Since the first antibiotic was discovered over 100 years ago, antibiotics have saved thousands of lives suffered from infectious diseases (Hutchings et al., 2019). However, inappropriate- or over-prescription of antibiotics were widely reported all over the world and has been proved to be associated with the increasing prevalence of antimicrobial-resistance (AMR) strains (Goossens et al., 2005; Mendelson and Matsoso, 2015). AMR has gradually become a global public health crisis that affects human health, increases medical expenditures, and even hinders social and economic development (Bloom et al., 2017; World Bank, 2017). In 2017, to support antibiotic surveillance and stewardship at local, national and global levels, WHO developed the Access, Watch, and Reserve (AWaRe) Classification of antibiotics and updated it in 2019 (World Health Organization, 2019). The access group contains 48 antibiotics that are recommended as the first- or second-choice for treating common infectious syndromes, while the watch group includes 110 antibiotics that have higher resistance potential and are suggested to be used for specific infectious syndromes. There are 22 antibiotics in the reserve group, which are considered as the last resort of treatment. In the not recommended group, 103 fixed-dose combinations of multiple broad-spectrum antibiotics are listed and not recommended for use in clinical practice.

China has a huge pharmaceutical market. In 2020, the total terminal sales of pharmaceutical products reached 1708 billion RMB in China, with 69.4 and 30.6% sold in health care institutions [including public and private hospitals, and primary healthcare centres (PHCs)] and retail private pharmacies, respectively (Ministry of Commerce, 2021). China is also one of the countries that consumed the most antibiotics in the world, and has attracted more and more global attention on the overuse of antibiotics and AMR during the last decade (Heddini et al., 2009; Yezli and Li, 2012; Van Boeckel et al., 2014). Studies published before 2014 showed an overall antibiotic prescribing rate of 83.7% among outpatients with upper respiratory tract infections (URTI) in China (Li et al., 2016). To improve antibiotic stewardship and combat AMR, China began to explore strategies in 2011 in the context of the new health system reform (Yip et al., 2019). In 2012, the ministry of health released a mandatory regulation which was recognized as the strictest regulation for antibiotic use in China (Xiao and Li, 2013). It required the provinces to develop their own Antibiotic Classifications List (ACL) due to various antibiotic-use behaviors and bacterial resistance. Antibiotics are classified into non-restricted, restricted or special-grade in the ACL according to their effectiveness, safety, bacterial resistance and price. Physicians with junior professional titles who often work at the community level could only prescribe non-restricted antibiotics. For physicians with intermediate or senior professional titles who usually work in secondary or tertiary hospitals, they could prescribe all classes of antibiotics and non-restricted or restricted antibiotics, respectively. During 2011 and 2013, a special national campaign was implemented with the aim of promoting clinical use of antibiotics mainly in secondary and tertiary hospitals (Xiao, 2018). In 2014, a guiding policy was issued that emphasized the rational use of antibiotics in PHCs (National Health and Family Planning Commission, 2014). After 2015, more actions were taken at the national level. In 2016, 14 ministries joint-issued the “National Action Plan on antimicrobial resistance (2016–2020)” in response to WHO’s call (NHFPC and other 13 ministries, 2016). This action plan set out targets for AMR control during 2016 and 2020 and provided guidance on specific measures. From 2017 to 2020, guidance documents on improving clinical use of antibiotics and AMR surveillance in children were released (Children’s National Medical Center, 2018; National Health Commission, 2020a).

The current published studies conducted in China often focus on the patterns of clinical use of antibiotics in selected tertiary hospitals with findings that indicate a decline in antibiotic prescribing rates (Bao et al., 2015; Wushouer et al., 2017; Chen et al., 2018). Few studies analyzed the changes of antibiotic consumption using data collected from all the health care institutions in a provincial area (Lin et al., 2016; Yin et al., 2018; Xu et al., 2020). In context of China’s 10-years national antibiotic stewardship program, this study analyzed the changes in trends and patterns of antibiotic consumption in health care institutions in the second-largest population province of China, by WHO AWaRe Classification.

The total antibiotic consumption rate increased by 22.9%, from 12.859 DID in 2012 to 15.802 DID in 2014, then continuously reduced at a CAGR of −9.2% between 2014 and 2019 (9.771 DID in 2019). The consumptions of the access, watch and reserve antibiotics also reached their peaks in 2014 (7.468, 7.059 and 0.077 DID), then all kept decreasing during 2014 and 2019 with a GACR of -10.1%, −9.0% and −8.1%, respectively (4.384, 4.409. and 0.050 DID in 2019) (Figure 1). The consumption of the access group accounted for less than 50% of the total and this proportion continuously decreased from 50.0 to 44.9% over the study period. However, the proportion of watch antibiotic consumption kept increasing and exceeded the proportion of the access group in 2016, then slightly reduced from 47.1% in 2016 to 45.2% in 2019. The consumption of reserve antibiotics accounted for around 0.5% of the total during the study period (Figure 2).

The PHC was the leading antibiotic consumer. In 2012, the PHCs consumed 7.4 times as much volume of antibiotics as hospitals (388.4 million DDDs vs. 52.3 million DDDs). From 2014 to 2019, the PHCs saw a sharp fall, from 461.5 to 232.3 million DDDs, at a CAGR of −12.8%. Alternatively, the volume of antibiotics consumed by hospitals, although slightly declined in 2016, has doubled in 2019 (117.2 million DDDs) compared with that in 2012 (52.3 million DDDs). Health service utilization showed similar trends as antibiotic consumption in both the hospitals and PHCs. Outpatient visits and admissions increased at a GACR of 7.3 and 6.3% in hospitals but decreased with a GACR of 0.58 and 3.15% in the PHCs between 2012 and 2019. The consumption of the other group fluctuated during the study period, and it only accounted for 0.8% of the total on average (Figure 3).

In hospitals, access antibiotic consumption accounted for about one-third of the total antibiotic consumption. The proportion of access antibiotic consumption decreased yearly since 2015, while the proportion of watch antibiotic consumption maintained at 50–60%. In 2019, the volume of access antibiotics was only about one-half of the volume of the watch antibiotics in hospitals. In the PHCs, the proportions of the access and watch antibiotic consumptions were about 50 and 40%, respectively. The proportion of access antibiotic consumption has been increasing since 2015. By contrast, the proportion of the watch antibiotics consumed in the PHCs tended to decline between 2015 and 2019 (Figure 4).

People living in the UMIAs consumed twice as much antibiotics as people living in the HIAs between 2012 and 2014 (UMIAs: 14.74–17.94 DID; HIAs: 7.38–9.96 DID). The antibiotic consumption rate in the UMIAs having sharply declined at a CAGR of −10.9% since 2014 (17.94 DID) and reached a rate (10.05 DID) close to that in the HIAs (9.12 DID) in 2019. In the HIAs, the antibiotic consumption rate fluctuated slowly from 9.96 DID in 2014 to 9.12 DID in 2019. In both economic-level areas, the volume of antibiotic consumption showed a decreasing trend in the PHCs, while an increasing trend in hospitals. In the HIAs, the volume of antibiotics consumed by hospitals grew at a faster rate (CAGR: 14.7%) than that in the UMIA (CAGR: 10.6%) during the last 8 years and surpassed the volume of antibiotics consumed by the PHCs in 2019 (Figure 5).

In terms of access antibiotic consumption, the proportion maintained at approximately 50% in the UMIAs (2012: 52.0%; 2019: 49.5%), while decreasing yearly from 41.9 to 33.3% in the HIAs during the study period. The proportion of watch antibiotic consumption showed a trend of growth between 2012 and 2016 (HIAs: 51.7–57.7%; UMIAs: 39.9–44.4%) and then declined between 2016 and 2019 (HIAs: 57.7–55.3%; UMIAs: 44.4–41.2%) in both economic-level groups. With quite a small proportion (<1%) in both groups, the reserve antibiotics started to grow in 2015 and doubled in 2019 compared with 2015 (0.69 vs. 0.33%) in the HIAs (Figure 6).

In terms of the total consumption, the top three consumed access antibiotics were all penicillins, including amoxicillin (J01CA04), amoxicillin and beta-lactamase inhibitor (J01CR02), and benzylpenicillin (J01CE01). Amoxicillin was also the most consumed antibiotic among all, the consumption of which accounted for 27.2% of the total volume in 2019. Only amoxicillin and beta-lactamase inhibitor showed an increasing trend, while all the other access antibiotics declined over the past four or 5 years. The most commonly consumed watch antibiotic was levofloxacin (J01MA12), followed by cefuroxime (J01DC02) and roxithromycin (J01FA06). All the watch antibiotics showed a downward trend. In the reserve antibiotic group, fosfomycin (J01XX01), minocycline (J01AA08), and linezolid (J01XX08) were the most commonly consumed. Three of the top five consumed reserve antibiotics, which were minocycline (J01AA08), linezolid (J01XX08), and tigecycline (J01AA12) had growth trends in recent years (Table 1).

This study used antibiotic procurement data of almost all the health care institutions in a large-population province of China from 2012 to 2019. China has taken special actions to reduce antibiotic use and to combat AMR since 2011. After a decade of national antibiotic stewardship, the consumption of access, watch, and reserve antibiotics in health care institutions in Shandong Province have all showed decreasing trends since 2015. However, the access antibiotics had a greater reduction than the watch antibiotics. This resulted in a lower proportion of access antibiotics. The reduction in total consumption was mainly attributed to the remarkable decrease in antibiotic consumption at the PHCs and the UMIAs.

The antibiotic consumption rate in Shandong is at a lower level among the 34 provincial administrative districts in China and is also lower than the global median (17.2 DID in 2015) (Wushouer et al., 2020; Klein et al., 2021). The group of access antibiotics, as the first choice of treatment for common infections, was higher in Shandong than the national average in terms of the consumption rate and the proportion of the total, but lower than in most of the other countries (Wushouer et al., 2020). The national antibiotic stewardship strategies appear to play a role in reducing antibiotic use at health care institutions in Shandong Province, as well as in Hubei Province and Shanghai Municipality (Lin et al., 2016; Zhang et al., 2019). However, other studies indicate that China’s national antibiotic stewardship strategies have had no significant effect on antibiotic consumption in Shanxi Province where the volumes of antibiotic consumption kept increasing between 2016 and 2018 (Xu et al., 2020).

Although China’s antibiotic stewardship policies was mainly targeted at hospitals, the volume of antibiotic consumption still showed an increasing trend in secondary and tertiary hospitals. On the contrary, the consumption of antibiotics at PHCs in Shandong dramatically declined in the last few years. In addition to the policy effect, this may be because China’s PHCs are shrinking while hospitals are expanding. According to the China Health Statistics Yearbook 2020 (National Health Commission, 2020b), the number of health care workers in township hospitals has reduced by 23%, and the health care utilization at PHCs continuously decreased from 2012 to 2019. However, the numbers of health care workers and beds in hospitals have increased by 60 and 65% during the same period. For one reason, the number of rural PHCs accounted for 80% of the total PHCs (National Health Commission, 2020b). Rural-to-urban migration in China has contributed to the reduction in the scale of rural PHCs. Another reason is that China has implemented the Hierarchical Medical System in 2015 to divert patients with common diseases to the PHCs, but patients could freely choose which health care institutions to visit, and they still prefer to visit hospitals due to the higher quality of health care (Zhou et al., 2021). Moreover, PHCs mainly provide outpatient services, which are typically not covered by the basic medical insurance schemes. Thus, residents are more likely to visit hospitals for inpatient services that could be reimbursed.

Overall, there was no obvious change in the proportions of watch antibiotics. The proportion of watch antibiotics was much higher than that of the access antibiotics in the hospitals. However, this proportion decreased and was much lower than that of access antibiotics in the PHCs. This decrease may more likely be related to the effects of regulation which limited the prescription of antibiotics in watch and reserve groups by junior physicians. Therefore, some patients may visit hospitals instead of PHCs for restricted antibiotics. It should be noticed that the classifications of antibiotics in the ACL of Shandong, as well as the other provinces in China is different from those in the AWaRe Classification. All the top five watch antibiotics are grouped into non-restricted antibiotics in the Shandong ACL (2021 version), which may result in a lower policy impact on the watch group than the access one.

Globally, the high-income economies consumed more antibiotics per person than the low-or middle-income economies and consumed much more volume of access antibiotics than the watch antibiotics during 2011 and 2015 (Jackson et al., 2019). However, our study showed opposite results. The antibiotic consumption rate was lower in the HIAs than in the UMIAs. In the HIAs of Shandong, the watch group accounted for a higher proportion than the access group. Given that the two economic-level areas have the same political and cultural circumstances, it may reflect the importance of knowledge and attitudes of patients and health providers towards the rational use of antibiotics. In China, inappropriate use of antibiotics was more serious in less developed areas, especially in the rural areas (Shen et al., 2021). Thus, there was a greater improvement in the antibiotic consumption rate in the UMIAs, driven by antibiotic stewardship policies. Moreover, the HIAs have well-known hospitals that attract patients with serious diseases. This may cause a higher proportion of watch antibiotic consumption in these areas.

Although the consumption rate of reserve antibiotics also decreased in Shandong, it has the lowest reduction rate among all three categories. Linezolid (J01XX08) and tigecycline (J01AA12), two relatively new antibiotics that are often used to treat severe infections caused by multi-drug resistant bacteria (Kemung et al., 2018), had increasing consumption rates in Shandong. This may indicate that antibiotic-resistant infections are on the rise in hospitals.

The antibiotic consumption rate in health care institutions has indicated a downward trend in China’s Shandong Province after nearly a decade of antibiotic stewardship. However, the pattern of antibiotic consumption is still inappropriate in terms of the watch group of antibiotics consumed. In addition, the trends for antibiotic consumption were found to vary across areas with different economic levels. Indicating that further investigation is needed to understand the reasons for this variability in policy effects.