Antibiotic consumption in Shandong Province, China

J Antimicrob Chemother doi:10.1093/jac/dkx469

Antibiotic consumption in Shandong Province, China: an analysis of provincial pharmaceutical centralized bidding procurement data at public healthcare institutions, 2012–16 Jia Yin1–3, Qinwei Li4 and Qiang Sun1–3* 1

School of Health Care Management, Shandong University, Jinan, China; 2Key Laboratory of Health Economics and Policy Research, NHFPC, Shandong University, Jinan, China; 3Center for Health Management and Policy Research, Shandong University, Jinan, China; 4 Division of Pharmaceutical Procurement, Shandong Public Resources Trading Center, Jinan, China *Corresponding author. Tel: 86-531-88382376; Fax: 86-531-88382693; E-mail: [email protected]

Received 27 July 2017; returned 14 September 2017; revised 23 October 2017; accepted 10 November 2017 Objectives: To explore the trends of antibiotic consumption in public healthcare institutions through analysing the provincial centralized bidding procurement (CBP) data in Shandong, China. Methods: The Shandong CBP system has been established since 2011, covering public healthcare institutions of 500 secondary and tertiary hospitals, 600 urban primary healthcare centres (PHCs) and 1600 rural PHCs. We collected all the antibiotic procurement records from the CBP system between 2012 and 2016. Antibiotic consumption data were calculated using Anatomical Therapeutic Chemical (ATC)/DDD methodology and normalized using DDD per 1000 inhabitants per day (DID). Results: Overall antibiotic consumption increased from 12.859 DID in 2012 to 15.802 DID in 2014, then decreased to 13.802 DID in 2016. The top three antibiotics consumed in 2016 were penicillins (4.251 DID), quinolones (2.957 DID) and macrolides (2.057 DID). PHCs consumed 80% of the total antibiotics, of which rural PHCs accounted for 88%. Antibiotic consumption peaked in 2014 for rural PHCs and in 2015 for hospitals, and declined thereafter. In urban PHCs, the consumption steadily increased from 2012 to 2016. Conclusions: Zero mark-up drug policies and national policies to improve rational use of antibiotic were associated with the reduction of antibiotic consumption in public healthcare institutions in Shandong Province. Regulations for antibiotic use in PHCs should be strengthened.

Introduction Overuse of antibiotics is the major driver of resistance as more and more studies have reported a positive relationship between antibiotic consumption and antimicrobial resistance (AMR).1,2 At the beginning of the 21st century, WHO developed global strategies to reduce antibiotic use.3 However, antibiotic consumption is still on the rise globally, particularly in low- and middle-income countries.4 China is the second largest human antibiotic consumer in the world.4 In 2013, a mean of 57 g of antibiotics was used by each Chinese inhabitant.5 As recommended by WHO, the antibiotic prescribing rate should be no more than 30% for patients with common colds, but this rate was .80% in China.6 Owing to the irrational use of antibiotics, China experiences a high rate of AMR. The 2015 national AMR surveillance, which covered 1427 secondary and tertiary hospitals, reported that the proportion of MRSA was 36% and the proportions of Escherichia coli resistant to third-

generation cephalosporins and quinolones were 59% and 54%, respectively.7 The Chinese government had made great efforts to combat AMR, issuing a series of strategies and guidelines on rational antibiotic use in the last decade. Since the 1950s, drug revenue was one of the main ways to compensate public hospitals in China. The government allowed these hospitals to add a 15% mark-up on medicines, which induced the increase of expenditures on medicines. To improve rational use of medicines, a zero mark-up policy (which removes profit from medicines) was first implemented in the primary healthcare system in 2009.8 In the same year, the essential medicines scheme was issued with the purpose of guaranteeing supplies of essential medicines. Meanwhile, the drug centralized bidding procurement and supply chain system (referred to hereafter as ‘CBP system’) was established at provincial level for supporting the implementation of essential medicine policy.9 All medicines (except for narcotic drugs, psychoactive drugs, radioactive drugs, toxic drugs for medical use and Chinese medicinal

C The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. V

For Permissions, please email: [email protected].

1 of 7 Downloaded from https://academic.oup.com/jac/advance-article-abstract/doi/10.1093/jac/dkx469/4759195 by Shandong University user on 20 December 2017

Yin et al.

materials) procured by government-run healthcare institutions should be traded and registered in this online non-commercial system. In 2012, a fierce regulation for clinical use of antibiotics was announced, which classified antibiotics into non-restricted, restricted and special antibiotics based on their effectiveness, safety, bacterial resistance and price.10 Physicians with senior and intermediate professional titles were respectively permitted to prescribe all antibiotics, and all but special antibiotics. Junior physicians, which included general practitioners in primary healthcare institutions, could only prescribe non-restricted antibiotics. Then in 2014, the National Health and Family Planning Commission issued the policy to improve the rational use of antibiotics in primary healthcare centres (PHCs) for the first time.11 Starting from 2012, the zero mark-up policy has been introduced to secondary public hospitals and covered all county-level public hospitals by the end of 2015.12 In the same year, the National Health and Family Planning Commission updated the national guideline for antibiotic use in clinical practice and set prescription targets for secondary and tertiary public hospitals; meanwhile, these hospitals were required to regularly review and evaluate their prescriptions.13,14 Based on these strategies, antibiotic prescribing rates have significantly declined in secondary and higher level hospitals, as reported by a previous study.15 Currently, the limited published articles on antibiotic consumption were mainly based on data from pharmaceutical manufacturers or market sales.4,5 Studies on antibiotic use in different levels of healthcare institutions based on national or provincial data are rare in China. The aim of this study was to evaluate antibiotic consumption patterns in public hospitals and PHCs from 2012 to 2016 through analysing the provincial centralized bidding antibiotic procurement data in Shandong Province, China. This study will help to establish a national platform for surveillance of antibiotic use at different levels of public healthcare institutions, and link this platform with the existing national surveillance platform on AMR.

Methods Study setting The east of China where Shandong Province is located consumed the largest amount of antibiotics among all regions in China.5 Shandong Province has a population of 98.5 million, ranking second among 31 provinces in China. The rural population accounted for 52% of the total population in 2015. Shandong implemented the zero mark-up policy at all county-level

public hospitals in 2015 and at secondary and tertiary public hospitals throughout urban areas in mid-2016.

Data collection The CBP system was established in 2009 and was used across the whole province by the end of 2011. There were 500 secondary and tertiary hospitals, 600 urban PHCs and 1600 rural PHCs procured from this provincewide CBP system (Table 1). The ratio of total outpatient visits and total numbers of admissions were both 10:1 public hospitals to private hospitals;16 thus, data collected from the CBP system represented .90% of the total antibiotic use data in public healthcare institutions of Shandong. The platform collects each procurement record of different healthcare institutions, including name of region, name of buyer, procurement date, receiving date, drug name, strength, dosage and package, request quantity and unit price. We collected all the procurement records for antibiotics (except for first-line anti-TB antibiotics and topical antibiotics) between 2012 and 2016 from the CBP system.

Data analysis Public healthcare institutions are healthcare institutions run by the government. They were grouped into secondary and tertiary hospitals, urban PHCs and rural PHCs. Secondary and tertiary hospitals included general, specialized and Chinese traditional hospitals. Urban PHCs were healthcare centres in urban areas, while rural PHCs were township hospitals. Healthcare centres and township hospitals were also responsible for procuring medicines of healthcare stations and village clinics, respectively. Antibiotic utilization data were standardized using Anatomical Therapeutic Chemical (ATC)/DDD methodology developed by WHO.17 In the ATC classification system, medicinal products were classified into different groups based on the organ or system they act, and their therapeutic, pharmacological and chemical characteristics. All the antibiotics were classified at the ATC-4 level. DDD is a standardized unit of measurement, representing the average maintenance dose per day of a drug used for its major indication in adults. The intensity of antibiotic use was normalized according to DDD per 1000 inhabitants per day (DID). The number of inhabitants was counted according to the year-end population reported by the Statistical Year Reports of Shandong (2012–16) (http://www.stats-sd.gov.cn/col/col211/index.html). We used DDD to compare antibiotic consumption in different categories of healthcare institutions, as the number of patients using antibiotics in each healthcare institution was not available in the CBP system. DDD was calculated as number of boxes (vials) % number of pills (or other drug forms) % strength (g) of each pill (other drug forms)/DDD of the antibiotic (g).

Results The total antibiotic consumption in all public healthcare institutions in Shandong Province increased from 12.859 DID in 2012 to a

Table 1. Number of public healthcare institutions in Shandong, 2012–16

Year

General hospitalsa

Traditional Chinese hospitalsa

Specialized hospitalsa

Urban PHCs

Rural PHCs

Others (e.g. TB dispensaries)

Total

2012 2013 2014 2015 2016

294 294 342 341 346

101 101 117 112 111

31 31 41 46 50

560 559 598 537 578

1596 1597 1691 1597 1574

116 116 135 134 106

2698 2698 2924 2767 2765

a

Secondary and tertiary hospitals.


JAC

Antibiotic consumption in China

peak of 15.802 DID in 2014, and thereafter decreased to 13.802 DID in 2016. Though the consumption of oral antibiotics was about two times the consumption of parenteral forms, they shared a similar varying trend with that in the whole province. The increasing rates for both oral (24%) and parenteral agents’ consumption (22%) were .20% from 2012 to 2014, while the reduction rate for the parenteral antibiotics from 2014 to 2016 was much higher than that for oral antibiotics (22% versus 8%) (Figure 1). In 2016, penicillins was the most commonly used class of antibiotics (4.251 DID), followed by quinolones (2.957 DID) and macrolides (2.057 DID). Quinolones was the only class of antibiotics that appeared to have a stepwise increase from 2012 (1.894 DID) to 2016 (2.957 DID). The most widely used quinolones were levofloxacin and ofloxacin. Although first- and second-generation cephalosporin consumption declined from 2014 to 2016, the DID of the

Total Oral antibiotics Parenteral antibiotics

18 16 14

DID

12 10 8 6 4 2 0

2012

2013

2014

2015

2016

Figure 1. Total antibiotic consumption in Shandong, 2012–16.

third-generation cephalosporins remained constant at 1.4 DID over the same period (Figure 2). As shown in Figure 3, the most frequently used penicillins were extended-spectrum penicillins. After reaching a peak in 2014, consumption of narrow-spectrum penicillins reduced by 42% from 2014 to 2016, whereas extended-spectrum penicillins decreased by just 12%. Combinations of penicillins (mainly piperacillin and enzyme inhibitor) continued to increase from 2012 to 2016. More detailed information regarding the consumption of different classes of antibiotics is listed in Table S1 (available as Supplementary data at JAC Online). In 2016, 80% of antibiotics were consumed in the PHCs with the majority (88%) being used in rural PHCs. In the rural PHCs, antibiotic consumption rose by 18% from 2012 to 2014 then fell by 19% from 2014 to 2016. In the urban PHCs, antibiotic use increased each year, and the 2016 consumption was 1.6 times that of the 2012 consumption. In hospitals, the overall antibiotic consumption in 2015 had more than doubled from 2012, but then it fell by 25% in 2016. In hospitals, the consumption of both oral and parenteral forms reached a peak in 2014, with oral forms falling more quickly than parenteral forms from 2014 to 2016. In urban PHCs, both oral and parenteral antibiotic use steadily increased. Compared with 2012, the consumption of oral and parenteral agents increased 86% and 19%, respectively, in the urban PHCs in 2016. In the rural PHCs, oral and parenteral antibiotic consumption declined 12% and 33% from 2014 to 2016, after 3 years of growth (Figure 4). The three most commonly consumed antibiotics in both the rural and urban PHCs were penicillins, quinolones and macrolides, whereas the third-generation cephalosporins replaced quinolones as one of the top three in hospitals in 2016. In hospitals, the consumption for almost all the antibiotics fell in 2015 after a substantial increase between 2013 and 2015. In rural PHCs, a turning point appeared in 2014 for most classes of antibiotics. Quinolones was the only class of antibiotics that had a higher consumption in 2016 than that in 2015. In the urban PHCs, the trend of antibiotic consumption was the opposite of that in the hospitals. The consumption slightly dropped in 2015 then remarkably grew in the following year (Figure 5).

5 4.5 J01C Penicillins J01DB Cephalosporins I J01DC Cephalosporins II J01DD Cephalosporins III J01FA Macrolides J01M Quinolones J01FF Lincosamides J01GB Other aminoglycosides

4 3.5 DID

3 2.5 2 1.5 1 0.5 0

2012

2013

2014

2015

2016

Figure 2. Major classes of antibiotics consumed in Shandong, 2012–16. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.


Yin et al.

200 180 160

J01CR Combinations of penicillins

DDD (million)

140

J01CF Beta-lactamase resistant penicillins

120

J01CE Penicillins with narrow spectrum

100

J01CA Penicillins with extended spectrum

80 60 40 20 0

2012

2013

2014

2015

2016

Figure 3. Different types of penicillin consumed in Shandong, 2012–16. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

(a)

(b)

(c)

400

400

600

350

350 500

300

300

250

250

200

200

150

150

100

100

50

50

DDD (million)

400

300

200

100

0

0 2012

2013

2014

2015

2016

0 2012

Secondary and tertiary hospitals

2013

2014

2015

Urban PHCs

2016 Rural PHCs

2012

2013

2014

2015

2016

Others

Figure 4. (a) Oral antibiotic consumption in public healthcare institutions in Shandong, 2012–16. (b) Parenteral antibiotic consumption in public healthcare institutions in Shandong, 2012–16. (c) Overall antibiotic consumption in public healthcare institutions in Shandong, 2012–16. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Discussion The CBP system provides a unique data source for monitoring the use of medicines, including antibiotics, in all public healthcare institutions from tertiary hospitals to village clinics in China. To the best of our knowledge, this study is the first to attempt to describe and compare antibiotic consumption trends in public healthcare institutions using reliable data from the CBP system in China. We found that antibiotic consumption increased first then decreased in the

healthcare institutions run by the government in Shandong from 2012 to 2016. The turning point appeared in 2014 for rural PHCs, and in 2015 for hospitals. However, antibiotic consumption in urban PHCs has continuously increased in the past 5 years. Broadspectrum antibiotics were used more than narrow-spectrum antibiotics. Unexpectedly, this study reported a similar or even lower antibiotic consumption in Shandong compared with that reported by some high-income countries (10–32 DID).1,18 In these developed


JAC


(a) 160

(b)

(c)

30

16

27

140

14

24 12

120

DDD (million)

21 100

10

18 15

80

8

12

60

6

9 4

40 6 20

2

3

0

0

0 2012

2013

2014

2015

2016

2012

2013

2014

2015

2016

2012

2013

2014

2015

2016

J01C Penicillins

J01DB Cephalosporins I

J01DC Cephalosporins II

J01DD Cephalosporins III

J01FA Macrolides

J01M Quinolones

Figure 5. Major classes of antibiotics consumed in Shandong, 2012–16 in: (a) rural PHCs; (b) secondary and tertiary hospitals; and (c) urban PHCs. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

countries, antibiotics were mostly only available in healthcare institutions with prescriptions; however, oral antibiotics are easier to access without prescriptions in China, e.g. through drugstores and markets.19,20 Although the China FDA forbade retail pharmacies to sell antibiotics without prescriptions from 2004, few pharmacies have complied with this regulation. A recent study conducted in three cities using the simulated client method, which respectively on behalf of eastern, centre and western areas of China, revealed that people can get antibiotics without prescriptions from more than half of the retail pharmacies.21 Meanwhile, basic medical insurances in China enabled residents to purchase medicines in private pharmacies conveniently. The insurance premiums were made up of personnel payment, employer’s payment or government subsidy in China. Personnel payment was stored in the individual or household account, which could be used to pay for medicines at appointed retail pharmacies. This indicates that a considerable part of the antibiotic needs was covered by private pharmacies instead of PHCs. The easy availability of antibiotics by this route has caused a high rate of self-medication and irrational use of antibiotics among Chinese residents.22,23 The 5 year national action plan to fight against AMR issued in 2016 reproposed to restrict antibiotic selling in the market and to ensure that antibiotics are prescription-only products in all retail pharmacies by 2020.24 The long-term effects of this policy need to be estimated further. The Chinese government has continuously put forward antimicrobial stewardship policies, but not until mid-2014 was the need for improving antibiotic use in primary healthcare institutions stressed. This strategy may help to reduce antibiotic consumption

in PHCs. However, specific requirements such as antibiotic prescribing targets set in secondary and tertiary hospitals were not available for PHCs. Since 2015, the comprehensive reform of public hospitals has been implemented throughout China. As a core element of the public hospital reform, a zero mark-up policy was implemented to help lower the antibiotic prescribing rate in county-level hospitals.25 Similarly, the implementation of zero mark-up policy in secondary and tertiary hospitals in Shandong may also contribute to the downward trend of antibiotic consumption in hospitals. In contrast, the consumption in urban PHCs displayed an increased trend during the same period. In urban areas of China, both urban PHCs and hospitals are easy to access by walk-in patients, so people prefer to visit big hospitals with a higher level of medical technologies even though they suffered from minor illnesses.26 However, our findings revealed a possibility that patients flowed to urban PHCs due to the stricter constraints on antibiotic use in hospitals. The reduction of parenteral agents also reflected the efficacy of government policies. Since 2015, the intravenous injection rate has been used as an index of performance assessment in PHCs in Shandong. This could explain the rapid decline of parenteral antibiotic consumption in rural PHCs. Extended-spectrum antibiotics were widely used in Shandong as well as numerous countries.1,27 In this study, penicillins with extended spectrums were consumed far more than the other subgroups in Shandong, similar to that in other countries or regions.1,18 In addition, combinations of penicillins, which are often defined as extended-spectrum antibiotics, grew year by year. Quinolone consumption also had an increasing trend, as 5 of 7

Downloaded from https://academic.oup.com/jac/advance-article-abstract/doi/10.1093/jac/dkx469/4759195 by Shandong University user on 20 December 2017

Yin et al.

discovered in this study. In 2016, the US FDA stated that quinolones should be only used for those who have no other treatment options.28 However, this class of antibiotics is commonly prescribed to patients with uncomplicated infections such as diarrhoea or bronchitis in China.29 Unfortunately, the use of quinolones does not only cause serious adverse drug effects, but also largely increases the risk of bacterial resistance to this class of antibiotics and leads to environmental contamination.30,31 The pattern of antibiotic use in Shandong greatly depended on antibiotic use in PHCs as .80% of the total antibiotics were consumed there. Therefore, PHCs should be the focus of antimicrobial stewardship. Irrational use of antibiotics in rural and urban PHCs has been extensively reported.32–34 However, there is no regulation that guides antibiotic use in primary medical care. Some trials demonstrated that the interventions of desk guides, public reporting, peer review or recording justifications for antibiotic use have been effective at improving antibiotic use in PHCs.35,36 Specific guidelines and regulations that could improve antibiotic use in PHCs should be developed. This study systematically analysed the trend of antibiotic consumption in different levels of public healthcare institutions in Shandong, China, which provides valuable evidence to national and provincial governments for further developing antibiotic stewardship policies with more clear targets. In addition, the findings and experiences from this study contribute to setting up a national antibiotic consumption monitoring platform based on the CBP system for improving the rational use of antibiotics. This would then make it possible to map the whole picture of antibiotic use in the public healthcare institutions, which would be an important contribution to global antibiotic control. The findings of this study are subject to several limitations. First, we only collected antibiotic consumption data from public healthcare institutions. However, a portion of consumption occurred at private pharmacies where such data were not available. Thus, the overall antibiotic consumption in Shandong Province will be under-estimated. Second, there were no consumption data before 2012 in Shandong, so the effects of earlier antibiotic-related policies could not be identified. Third, being limited to the natural experimental study design, the causal relationship between policies and changes cannot be proved in this study. Finally, we only used descriptive statistics; however, statistical significance would not add extra meaning to the results.

Conclusions The reduction of antibiotic consumption in public healthcare institutions may be associated with national policies on improving antibiotic use. Rural PHCs have large amounts and small reductions in antibiotic consumption whereas urban PHCs increased their antibiotic consumption, thus specific regulations for antibiotic use in PHCs need to be formulated and strengthened.

Acknowledgements We would like to thank: Qiang Li from Shandong Public Resources Trading Center for technical support; Hongyu Li from Shandong University for data entry and cleaning; and Oliver James Dyar from Karolinska Institutet for providing critical comments and polishing the language.

Funding This study was conducted as part of our routine work.

Transparency declarations None to declare.

Supplementary data Table S1 is available as Supplementary data at JAC Online.

References 1 Goossens H, Ferech M, Vander Stichele R et al. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005; 365: 579–87. 2 Hsu LY, Tan TY, Tam VH et al. Surveillance and correlation of antibiotic prescription and resistance of Gram-negative bacteria in Singaporean hospitals. Antimicrob Agents Chemother 2010; 54: 1173–8. 3 WHO. WHO Global Strategy for Containment of Antimicrobial Resistance. Geneva, Switzerland, 2001. http://apps.who.int/iris/bitstream/10665/66860/ 1/WHO_CDS_CSR_DRS_2001.2.pdf? ua"1. 4 Van Boeckel TP, Gandra S, Ashok A et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14: 742–50. 5 Zhao QQ, Ying GG, Pan CG et al. Comprehensive evaluation of antibiotics emission and fate in the river basins of China: source analysis, multimedia modeling, and linkage to bacterial resistance. Environ Sci Technol 2015; 49: 6772–82. 6 Zou G, Wei X, Hicks JP et al. Protocol for a pragmatic cluster randomised controlled trial for reducing irrational antibiotic prescribing among children with upper respiratory infections in rural China. BMJ Open 2016; 6: e010544. 7 China Antimicrobial Resistance Surveilance System. National Antimicrobial Resistance Surveilance Report, 2015. Bejing, China, 2015. http://www.carss. cn/Sys/res/file/201512/20151220130134_7741_482f3b7ae95841998a3789 .pdf. 8e2ab2fa87_2015 8 National Health and Family Planning Commission. Plan on Recent Priorities in Carrying Out the Reform of Health Care System (2009-2011). Beijing, China, 2009. http://www.gov.cn/zwgk/2009-04/07/content_1279256.htm. 9 National Health and Family Planning Commission. Further Standardize the Drug Centralized Bidding Procurement in Hospitals. Beijing, China, 2009. http:// www.sda.gov.cn/WS01/CL0056/35597.html. 10 Xiao Y, Li L. Legislation of clinical antibiotic use in China. Lancet Infect Dis 2013; 13: 189–91. 11 National Health and Family Planning Commission. The Announcement of Administrative Measures for the Clinical Use of Antibiotics in 2014. Beijing, China, 2014. http://www.nhfpc.gov.cn/yzygj/s3593/201404/49973560ddde4 293a489b158081d777c.shtml. 12 The State Council. Opinion on Fully Implementing the Comprehensive Reform of County-Level Public Hospitals. 2015. http://www.gov.cn/zhengce/ content/2015-05/08/content_9710.html. 13 National Health and Family Planning Commission. Guideline on Antibiotic Use in Clinical Practice. Beijing, China, 2015. http://www.nhfpc.gov.cn/ewebedi tor/uploadfile/2015/09/20150928170007470.pdf. 14 National Health and Family Planning Commission. Improving Administrative Measures for the Clinical Use of Antibiotics. Beijing, China, 2015. http://www.nhfpc.gov.cn/yzygj/s3593/201508/f0fdf1f52df14b87aa97be538 19f1036.shtml.


JAC


15 Bao L, Peng R, Wang Y et al. Significant reduction of antibiotic consumption and patients’ costs after an action plan in China, 2010-2014. PLoS One 2015; 10: e0118868. 16 Li X, Liang Z, Yin A et al. Comparative analysis of the operation status of non-public hospitals and public hospitals in Shandong Province. Med Soc 2015; 28: 35–7.

26 Wang HH, Wang JJ, Wong SY et al. Epidemiology of multimorbidity in China and implications for the healthcare system: cross-sectional survey among 162, 464 community household residents in southern China. BMC Med 2014; 12: 188. 27 Stimac D, Vukusic I, Culig J. Outpatient use of systemic antibiotics in Croatia. Pharm World Sci 2005; 27: 230–5.

17 WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment 2013. Oslo, Norway, 2012. https:// www.whocc.no/filearchive/publications/1_2013guidelines.pdf.

28 McCarthy M. US warns against use of fluoroquinolones for uncomplicated infections. BMJ 2016; 353: i2755.

18 Yoon YK, Park GC, An H et al. Trends of antibiotic consumption in Korea according to national reimbursement data (2008-2012): a population-based epidemiologic study. Medicine (Baltimore) 2015; 94: e2100. 19 Kan QC, Wen JG, Liu XH et al. Inappropriate use of antibiotics in children in China. Lancet 2016; 387: 1273–4. 20 Morgan DJ, Okeke IN, Laxminarayan R et al. Non-prescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis 2011; 11: 692–701. 21 Chang J, Ye D, Lv B et al. Sale of antibiotics without a prescription at community pharmacies in urban China: a multicentre cross-sectional survey. J Antimicrob Chemother 2017; 72: 1235–42. 22 Fang Y. China should curb non-prescription use of antibiotics in the community. BMJ 2014; 348: g4233. 23 Li R, Xiao F, Zheng X et al. Antibiotic misuse among children with diarrhea in China: results from a national survey. PeerJ 2016; 4: e2668. 24 Fourteen Chinese Government Ministries and Administrations. A FiveYear National Action Plan to Contain Antimicrobial Resistance (2016-2020). Bejing, China, 2016. http://www.moh.gov.cn/yzygj/s3593/201608/f1ed26a0 c8774e1c8fc89dd481ec84d7.shtml. 25 Wei X, Yin J, Walley JD et al. Impact of China’s essential medicines scheme and zero-mark-up policy on antibiotic prescriptions in county hospitals: a mixed methods study. Trop Med Int Health 2017; 22: 1166–74.

29 Reynolds L, McKee M. Factors influencing antibiotic prescribing in China: an exploratory analysis. Health Policy 2009; 90: 32–6. 30 Committee on Infectious Diseases. The use of systemic fluoroquinolones. Pediatrics 2006; 118: 1287–92. 31 Hao X, Cao Y, Zhang L et al. Fluoroquinolones in the Wenyu River catchment, China: occurrence simulation and risk assessment. Environ Toxicol Chem 2015; 34: 2764–70. 32 Andrajati R, Tilaqza A, Supardi S. Factors related to rational antibiotic prescriptions in community health centers in Depok City, Indonesia. J Infect Public Health 2017; 10: 41–8. 33 Sun Q, Dyar OJ, Zhao L et al. Overuse of antibiotics for the common cold—attitudes and behaviors among doctors in rural areas of Shandong Province, China. BMC Pharmacol Toxicol 2015; 16: 6. 34 Dyar OJ, Beovic B, Vlahovic-Palcevski V et al. How can we improve antibiotic prescribing in primary care? Expert Rev Anti Infect Ther 2016; 14: 403–13. 35 Meeker D, Linder JA, Fox CR et al. Effect of behavioral interventions on inappropriate antibiotic prescribing among primary care practices: a randomized clinical trial. JAMA 2016; 315: 562–70. 36 Yang L, Liu C, Wang L et al. Public reporting improves antibiotic prescribing for upper respiratory tract infections in primary care: a matched-pair clusterrandomized trial in China. Health Res Policy Syst 2014; 12: 61.
