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Widespread illegal sales of antibiotics in Chinese pharmacies – a nationwide cross-sectional study

Widespread illegal sales of antibiotics in Chinese pharmacies – a nationwide cross-sectional study Background: Access to antibiotics without a prescription from retail pharmacies has been described as a major contributor to anti-microbial resistance (AMR) globally. In the context of high rates of AMR, the Chinese government has recently introduced strict policies regarding hospital antibiotic use, but the existing ban on antibiotic sales without prescription in retail pharmacies has not been strongly enforced. In 2016, a goal of prescription-only antibiotics by 2020 was announced. The objective of the study was to determine progress towards the 2020 goal, through estimating the proportion of retail pharmacies selling antibiotics without prescription across the three regions of mainland China. Methods: Using the Simulated Patient method, we conducted a cross-sectional survey across purposively-sampled retail pharmacies in urban and rural areas of 13 provinces in eastern, central and western China. Medical students presented a scenario of a mild upper respiratory tract infection, following a strict three-step protocol. They recorded the pharmacy characteristics, and details of their experience, including at which step antibiotics were offered. Results: Complete data were obtained from 1106 pharmacies. Antibiotics were obtained in 925 (83.6, 95% CI: 81.5, 85.8%) pharmacies without a prescription, 279 (25.2%) at Stage 1 (symptoms only described), 576 (52.1%) at stage 2 (asked for antibiotics), and 70 (6.3%) at Stage 3 (asked for penicillin or cephalosporins). There were significant differences between provinces, with antibiotic access (at any stage) ranging from 57.0% (57/100) in Zhejiang (81/82) to 98.8% in Guizhou. However, there were no significant differences in access to antibiotics by level of city, county, township or village (P = 0.25), whether the pharmacy was part of a chain or independent (P = 0.23), whether a licensed pharmacist was attending (P = 0.82) or whether there was a sign saying that prescriptions were required for antibiotics (P = 0.19). Conclusions: It is easy to obtain antibiotics without a prescription in retail pharmacies in China, despite the fact it is against the law. This must be addressed as part of the wider anti-microbial stewardship effort which could include intense enforcement of the existing law, supported by a public education campaign. Keywords: Anti-microbial resistance, Antibiotic, Anti-microbial stewardship, Pharmacy, China * Correspondence: t.hesketh@zju.edu.cn; t.hesketh@ucl.ac.uk Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, People’s Republic of China Institute for Global Health, University College London, 30 Guilford St, London WC1N1EH, UK Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 2 of 8 Background of access to antibiotics without prescription: the first in Anti-microbial resistance (AMR) is acknowledged as one pharmacies in three Chinese cities [17], and the second of the greatest threats to global health this century, as well among university students, frequently self-medicating as a major contributor to rising healthcare costs world- with over-the-counter antibiotics [18]. At the G20 Sum- wide [1]. It is now a problem in all regions of the world mit in China in 2016, a comprehensive plan to address [2]. Mortality attributable to AMR is predicted to rise AMR was announced, and this included a prominent from 700,000 in 2015, to as high as 10 million by 2050, goal of prescription-only antibiotics at pharmacies in all unless effective control measures are introduced [3]. provinces by 2020 [19]. However, guidance about mech- Misuse of antibiotics, both in medicine and agricul- anisms for achieving the goal was notably absent. ture, is well-established as the major driver of AMR [4]. The main objective of this study, therefore, was to deter- In medicine, despite awareness by doctors that antibi- mine the degree of progress which has been made towards otics should be used with care, defensive medicine and the 2020 goal. We aimed to quantify the proportion of profit motives are driving the increase in antibiotic use pharmacies where antibiotics could be purchased without in many countries [5]. A recent study across 76 coun- a prescription, across the three regions of China. Second- tries reported a 65% increase in antibiotic use between ary objectives were to determine the impact of the phar- 2000 and 2015. Most of this increase was in low- and macies’ geographical location and characteristics, as well middle-income countries (LMICs), where it was corre- as the standard of pharmacy services during the sale of lated with growth in per capita gross domestic product. antibiotics. Based on this trajectory, global antibiotic consumption will double between 2015 and 2030 [6]. Reducing global Methods consumption is thus crucial to reducing the threat of We conducted a cross-sectional survey in 13 provinces, AMR [6, 7]. representing all three regions of China: four in the east Antibiotic stewardship programmes to reduce prescrib- (Jiangsu, Zhejiang, Fujian and Guangdong), five in the ing of antibiotics by doctors, have been introduced in central region (Anhui, Jiangxi, Henan, Hubei and Hunan) many countries, especially in hospital settings, with some and four in the west (Sichuan, Guizhou, Shaanxi and success in reducing antibiotic misuse [8]. But it is esti- Chongqing). The 13 provinces also represent the range of mated that more than 50% of antibiotics worldwide are socio-economic development in China. Sampling of phar- purchased without a prescription, from pharmacies, mar- macies was purposive, based on the need for broad repre- ket stalls or street vendors, especially in LMICs [9]. This sentation of different pharmacy characteristics: occurs because of the absence of prescription-only regula- tions, or lack of enforcement where such regulations do 1) administrative level, that is, at city, county and exist. This leads to large quantities of antibiotics in circu- township/village level representing the continuum lation which contribute considerably to AMR [10]. between urban and rural: city is urban, township Rising levels of AMR in China are contributing to over- and village are rural, and the county level, while all global increases of AMR [11]. In a national survey, 60% defined as rural, has mainly urban characteristics. of isolates of some species were drug-resistant, including The hypothesis was that access to antibiotics would methicillin-resistant Staphylococcus aureus, β-lactamase- be easier in rural areas, where enforcement is more producing Escherichia coli, quinolone-resistant E coli, and difficult. carbapenem-resistant Pseudomonas aeruginosa [10, 12]In 2) part of a pharmacy chain or independent. We 2016 colistin resistance was reported for the first time in hypothesised that chain pharmacies, some with China [13]. branches across the country, would be more likely This has led to action by the Chinese government. to comply with prescription-only regulations. AMR-targeted policies included the banning of antibi- 3) at a range of distance from a hospital, defined as otics sales without prescription as early as 2004 [14]. In closer or further than 2 km. Our hypothesis was 2011, the Ministry of Health set up a special task force that pharmacies close to hospitals (which provide on antibiotic stewardship, resulting in strict rulings cov- most of the primary care in China) would receive ering all aspects of antibiotic use in hospitals [15]. As a more prescriptions for antibiotics and would result, the use of antibiotics in many hospitals, especially therefore be more likely to refuse requests without in tertiary settings, has reduced. However, the use of prescription. antibiotics in primary care remains high [16]. Sale of antibiotic in retail pharmacies were not addressed in the The sampling process of pharmacies was multi-stage. 2011 regulations, despite the fact that ease of access to We selected the capital city, one small city and one antibiotics without a prescription had been documented county in each province, and selected a nodal point in [15]. Two studies conducted in 2015 illustrated the ease each location from which to sample the pharmacies. The Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 3 of 8 aim was to include at least 80 pharmacies in each of the including to determine access to prescription-only drugs 13 provinces, with an equal number of pharmacies in pharmacies [21, 22]. across the three characteristic categories listed above. To Our simulated patients were undergraduate medical stu- achieve this we used the Chinese equivalent of Google dents, from Zhejiang and Xiamen Universities. A notice maps, Baidu maps, which includes detail of the locations explaining the study was disseminated on campus via social of pharmacies and hospitals, together with the names of media, and 40 students were selected at interview, allowing the pharmacies, thus identifying whether they were for the allocation of three in each province. The case sce- chain or independent. We then selected 35 pharmacies nario, showninFig. 1, was deliberately chosen to represent within a 10 km radius of each of the three nodal points a situation where there could be no justification for the use in each province. The over-sampling was to allow for of antibiotics: a description of mild upper respiratory tract possible errors in Baidu maps, and for closures at the symptoms, without visible symptoms, in a healthy young time the pharmacies were visited. The distance of 10 km adult. The staged approach, is well-established within the allowed for inclusion of rural pharmacies. simulated patient methodology, and the exact steps were adapted from research by others [17, 22–24]. All students Procedures underwent training in the steps of the protocol. They ini- We used the Simulated Patient method to conduct the tially practised with each other, under the observation of the survey. A simulated patient is an individual trained to act investigators. When they were ready, they were required to as a real patient in order to simulate a set of symptoms or conduct a pilot in at least two local pharmacies, to ensure problems [ 20]. This method has been widely used for re- competence with the process and with the reporting re- search into health care provision in a number of countries, quirements, before leaving for their respective provinces. Fig. 1 Flowchart of protocol for simulated patient visits Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 4 of 8 The data collection was carried out from July to Sep- submitted forms had to be discarded, because of incom- tember 2017. Students worked in pairs, taking it in turns plete data and/or unacceptable variation from the proto- to act as simulated patients or to observe and ensure ad- col. Complete information was collected from 1106 herence to the protocol. Both independently recorded pharmacies, 364 (32.9%) from the eastern region, 416 the findings. All the simulated patients were told they (37.6%) the central region and 326 (29.5%) the west; 367 should not act any symptoms, should give no impression (33.2%) were at city level 433 (39.2%) at county level, of appearing unwell, and that they should not be too in- and 306 (27.6%) in townships. There were 702 (63.5%) sistent about obtaining antibiotics, that is they should chain pharmacies, and 588 (53.2%) were located within only ask once for antibiotics. They were instructed how 2 km of hospitals; 1011 (91.4%) of pharmacies displayed to respond to likely questions from the pharmacist, that prescription-only drug sales notices, and 922 (83.4%) is, they had no other symptoms, except a slight runny had antibiotic counters. Just over two-thirds 760 (68.8%) nose, and they had no fever. If offered medications, sim- employed a licensed pharmacist. At the time of the sim- ulated patients were told to say they had left their wallet ulated patients’ visit 485 (43.9%) were on duty. or purse at home. Therefore, no medications were actu- ally purchased. Antibiotics sales The simulated patient pairs were required to enter the Antibiotics were obtained in 925 (83.6, 95% CI: 81.5, following data into a standard form on their Smart- 85.8%) pharmacies without a prescription, 279 (25.2%) at phones, as soon as they left the pharmacy, and to send Stage 1 (symptoms only described), 576 (52.1%) at stage 2 to the principle investigator(PI) immediately: (asked for antibiotics), and 70 (6.3%) at Stage 3 (asked for penicillin or cephalosporin). This total excluded 15 (1.4%), 1) Details of the pharmacy included: who said they were willing to provide prescriptions via an a. the location; on-line consultation and e-prescription to patients who b. a chain or independent; had no prescriptions. Nearly all of these were in the prov- c. distance from nearest hospital; inces of Sichuan (n =7) and Hubei (n =5). d. whether there was a special counter for Of the 181 (16.4%) pharmacies where antibiotics were antibiotics. This is partly a marketing ploy, a not offered, the reasons given were: that a prescription place where antibiotics are displayed separately; was necessary in 113 (10.2%), that antibiotics were not e. whether there was a prescription drug sales logo. indicated in 58 (5.2%), or that there were no antibiotics This is required under legislation, and is a in stock in 6 (0.5%). declaration that “prescription-only” drugs, including The antibiotics offered were mainly of three types: antibiotics, will not be sold without a prescription; penicillins (333/925, 36.0%), cephalosporins (274/925, f. whether the pharmacy had a licensed pharmacist 29.6%) and macrolides (250/925, 27.0%). The remainder and whether present at the time. This were quinolones, metronidazole and clindamycin. In six information was obtained from the required cases two antibiotics were offered. licensed pharmacist certificate on the wall and Table 1 shows the “success” rates of acquiring antibi- the identification badges worn by the staff. otics by province and region, as well as by the stage at 2) If antibiotics were offered and at which stage (1,2 or 3). which they were offered. In total, in seven provinces over 3) Which antibiotics were offered. 90% of the simulated patients were offered antibiotics, in 4) Whether the pharmacist asked about a) the four 70–90%, and less than 70% in just two. The range symptoms, b) whether a doctor had been consulted, was from 57.0% in Zhejiang to 98.8% in Guizhou, where and c) allergies, before offering antibiotics. there was just one refusal. There were significant re- 5) Any other observations of note, especially in gional differences with access easiest in the central re- relation to the pharmacist’s communication. gion, and hardest in the east (P < 0.0001). In the west it was significantly easier to get antibiotics at the first stage Analysis (P = 0.004), but it was easier to get antibiotics at the sec- Descriptive statistics were reported as frequencies with ond stage in the central region (P = 0.07). In total 92.4% 95% confidence intervals. Chi-Squared tests were used of all antibiotics were offered at Stage 1 or 2. to compare categorical variables. Analysis was carried- Table 2 shows the success of acquiring antibiotics by out using SPSS 24.0. pharmacy characteristics. There were no significant dif- ferences in access to antibiotics by urban/rural location Results (city, county, township/village) (P = 0.25), or pharmacy Characteristics of the pharmacies ownership, independent or part of a chain (P = 0.23). It Pharmacy characteristics are shown in Tables 1 and 2.A was easier to get antibiotics in pharmacies more than 2 total of 1345 pharmacies were visited; 239 (17.7%) of the km from hospitals (P = 0.02). Having a special counter Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 5 of 8 Table 1 Antibiotics given without prescription at Stages 1, 2 & 3 by province & region n(%) Overall Success Success at Stage 1 Success at Stage 2 n Success at Stage 3 n(%) with 95% CI n (%) with 95% CI n(%) 95% CI n (%) 95% CI Total 1106(100.0) 83.6 (81.5,85.8). 30.2(27.2,33.1) 62.3(59.1,65.4) 7.6(5.9,9.3) Eastern Zhejiang 100(9.0) 57.0(47.1,66.9) 33.3(20.7,46.0) 59.6(46.5,72.8) 7.0(0.2,13.9) Jiangsu 92(8.3) 92.4(86.9,97.9) 42.4(31.6,53.1) 52.9(42.1,63.8) 4.7(0.1,9.3) Fujian 92(8.3) 91.3(85.4,97.2) 31.0(20.9,41.0) 61.9(51.3,72.5) 7.1(1.5,12.8) Guangdong 80(7.2) 58.8(47.7,69.8) 23.4(10.8,36.0) 68.1(54.3,81.9) 8.5(0.2,16.8) Central Anhui 92(8.3) 95.7(91.4,99.9) 36.4(26.1,46.6) 55.7(45.1,66.3) 8.0(2.2,13.7) Jiangxi 81(7.3) 97.5(91.4,99.3) 30.4(20.0,40.7) 65.8(55.1,76.5) 3.9(1.4,11.0) Hunan 83(7.5) 86.7(79.3,94.2) 29.2(18.4,39.9) 63.9(52.5,75.3) 6.9(0.9,13.0) Henan 80(7.2) 95.0(90.1,99.9) 6.6 (0.9,12.3) 81.6(72.7,90.5) 11.8(4.4,19.3) Hubei 80(7.2) 72.5(62.5,82.5) 13.8(4.6,22.9) 69.0(56.7,81.2) 17.2(7.2,27.3) Western Sichuan 81(7.3) 72.8(62.9,82.7) 15.3(5.8,24.7) 71.2(59.3,83.1) 13.6(4.6,22.6) Guizhou 82(7.4) 98.8(93.4,99.8) 34.6(24.0,45.1) 65.4(54.9,76.0) 0 Shanxi 83(7.5) 75.9(66.5,85.3) 38.1(25.8,50.4) 58.7(46.2,71.2) 3.3(0.9,11.2) Chongqing 80(7.2) 95.0(90.1,99.9) 47.4(35.9,58.9) 42.1(30.7,53.5) 10.5(3.5,17.6) Region Eastern 364(32.9) 75.0(70.5,79.5) 33.7(28.1,39.3) 59.7(53.9,65.6) 6.6(3.6,9.6) Middle 416(37.6) 89.7(86.7,92.6) 24.1(19.8,28.5) 66.8(62.0,71.6) 9.1(6.2,12.0) Western 326(29.5) 85.6(81.7,89.4) 34.8(29.1,40.4) 58.8(53.0,64.6) 6.5(3.6,9.4) p-value 0.00 0.004 0.07 0.34 for antibiotics increased the offer of antibiotics (P = Discussion 0.02), but having a prescription-only sign made no dif- While ease of access to antibiotics in retail pharmacies ference (P = 0.19). The employment of a licensed has been previously documented in China [17, 18], our pharmacist reduced the offer of antibiotics from 89.6 to results show that despite the prominently announced 80.9% (P = 0.0003), but whether the licensed pharmacist goal of prescription-only antibiotics by 2020, there has was actually attending at the time of the visit made no probably been no progress towards the goal. Indeed difference (P = 0.93). the situation may have deteriorated, with our results suggesting greater ease of access to antibiotics than re- ported in Chang et al’s 2015 urban study which also Pharmacy services used an simulated patient design [17]. This naturally Theseare showninTable 3. Overall 65.4%(723/1106) asked raises concerns about the role of pharmacies in overall about symptoms, 11.9%(132/1106) asked the simulated pa- antibiotic misuse and hence anti-microbial resistance. tient if they had a prescription, 24.4%(270/1106) asked Our findings are strengthened by the fact that they are about the history of drug allergy before giving antibiotics, consistent in urban and rural areas in all Chinese and only 1.0%(11/1106) asked if the simulated patient had regions, irrespective of ownership (chain or independ- seen a doctor. Most (785/1106, 71.0%) offered general ent), presence of a licensed pharmacist, a special coun- health and nutrition advice, including promoting the sale of ter for antibiotics, or a sign for prescription-only dietary supplements. The attending licensed pharmacists drugs. This shows clear failure to enforce the law. Our performed significantly worse on all the above. All the own search of media reports found only 12 convic- pharmacists offered some form of medication apart from tions for selling antibiotics between 2008 and 2011, the antibiotics: 628 (56.8%) offered Traditional Chinese with just minor penalties imposed. This lack of en- Medicine (183 different proprietary brands) most com- forcement has led to what appears to be the virtual monly Pudilan (11.3%), and Ganmaoling (8.2%). normalisation of illegal sales of antibiotics. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 6 of 8 Table 2 Antibiotics given without prescription at Stages 1, 2 and 3 by pharmacy characteristics n(%) Overall Success n(%) Success at Stage 1 n (%) Success at Stage 2 n Success at Stage 3 n with 95% CI with 95% CI (%) 95% CI (%) 95% CI Level City 367(33.2) 82.3(78.4,86.2) 23.2(18.8,27.5) 51.2(46.1,56.4) 7.9(5.1,10.7) County 433(39.2) 82.7(79.1,86.3) 22.6(18.7,26.6) 53.8(49.1,58.5) 6.2(3.9,8.5) Township 306(27.7) 86.6(82.8,90.4) 31.4(26.1,36.6) 50.7(45.0,56.3) 4.6(2.2,6.9) Chain 702(63.5) 82.6(79.8,85.4) 23.6(20.5,26.8) 52.0(48.3,55.7) 7.0(5.1,8.9) Independent 404(36.5) 85.4(81.9,88.9) 28.0(23.6,32.4) 52.2(47.3,57.1) 5.2(3.0,7.4) p-value 0.23 0.11 0.94 0.24 < 2 km from hospital 588(53.2) 81.3(78.1,84.5) 23.6(20.2,27.1) 51.0(47.0,55.1) 6.6(4.6,8.6) > 2 km from 518(46.8) 86.3(83.3,89.3) 27.0(23.2,30.9) 53.3(49.0,57.6) 6.0(3.9,8.0) hospital p-value 0.02 0.20 0.45 0.66 Special counter for antibiotics 922(83.4) 84.8(82.5,87.1) 24.3(21.5,27.1) 53.9(50.7,57.1) 6.6(5.0,8.2) No counter for antibiotics 184(16.6) 77.7(71.6,83.8) 29.9(23.2,36.6) 42.9(35.7,50.2) 4.9(1.7,8.0) p-value 0.02 0.22 0.01 0.38 Sign for prescription drugs 1011(91.4) 83.2(80.9,85.5) 24.9(22.3,27.6) 52.3(49.2,55.4) 5.9(4.5,7.4) No sign for prescription drugs 95(8.6) 88.4(81.9,95.0) 28.4(19.2,37.7) 49.5(39.2,59.7) 10.5(4.2,16.8) p-value 0.19 0.57 0.59 0.08 Licensed pharmacist employed 485(43.9) 80.8(77.3,84.3) 21.9(18.2,25.5) 50.9(46.5,55.4) 8.0(5.6,10.5) in pharmacy Licensed pharmacist employed, 275(24.9) 81.1(76.4,85.7) 24.0(18.9,29.1) 51.6(45.7,57.6) 5.5(2.8,8.2) not in pharmacy No licensed pharmacist 346(31.3) 89.6(86.4,92.8) 30.9(26.0,35.8) 54.0(48.8,59.3) 4.6(2.4,6.8) employed p-value 0.001 0.01 0.67 0.11 Our results are perhaps more concerning, given the approach, and elicited offers of antibiotics in 56% of way that we used the simulated patient methodology. paediatric diarrhoea scenarios, and 78% in young adult Similar studies, mainly from Europe and the Middle East respiratory infection scenarios, which included fever and [21–24], have used actors, or third-party approaches, cough, symptoms, explicitly excluded in our study. Our that is representing someone else, typically a relative, un- simulated patients described very minor symptoms and able to come to the pharmacy because of the illness. were told not to be insistent or aggressive. This direct Chang et al’s three-city Chinese study, used the latter approach is recognised as stronger in Simulated Patient Table 3 Characteristics of pharmacies and pharmacy services Ask about symptoms Ask about prescription Ask about allergies General advice City 59.7(54.6,64.7) 16.3(12.5,20.2) 24.3(19.8,28.7) 70.8(66.2,75.5) County 70.4(66.1,74.8) 10.9(7.9,13.8) 22.4(18.5,26.3) 70.4(66.1,74.8) Township 65.0(59.7,70.4) 8.2(5.1,11.3) 27.5(22.4,32.5) 71.9(66.8,77.0) p-value 0.01 0.003 0.29 0.91 Chain 66.5(63.0,70.0) 13.2(10.7,15.8) 24.2(21.0,27.4) 71.1(67.2,74.9) Independent 63.4(58.6,68.1) 9.7(6.8,12.5) 24.8(20.5,29.0) 68.8(64.3,73.3) p-value 0.29 0.08 0.84 0.23 No licensed pharmacist employed 63.9(59.6,68.2) 13.8(10.7,16.9) 25.6(21.7,29.5) 71.3(67.3,75.4) Licensed pharmacist employed not present 70.9(65.5,76.3) 14.2(10.0,18.3) 25.5(20.3,30.6) 74.5(69.4,79.7) Licensed pharmacist attending 63.0(57.9,68.1) 7.5(4.7,10.3) 22.0(17.6,26.3) 67.6(62.7,72.6) p-value 0.08 0.01 0.44 0.16 Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 7 of 8 methodology than using the third party approach [21, 22]. and inspections must be implemented before the scope of Our findings raise a number of issues: work of pharmacists can be increased [17]. First, we show the importance of the demand side of There are limitations to our study. First, we conducted the consultation. The majority of pharmacists gave anti- the study across 13 provinces, in the three regions, but biotics at Stage 2, “Could you just give me some antibi- the far north and far west were not included, raising otics?”, showing that pharmacy staff respond to the questions about national generalisability. Second, we in- specific demands of patients. It is well-documented that cluded only 80 to 100 pharmacies per province, but we doctors often balance appropriate treatment against pa- did sample purposively to include the range of locations tient demands [16, 25]. With reports indicating that and types of pharmacy, and this is a very large study around two-thirds of Chinese believe that colds and flu compared with other simulated patient studies in phar- should be treated with antibiotics [18], we show that macy settings. Third, we used only one clinical scenario pharmacists readily respond to demands for antibiotics. which was of a very minor nature, but it rather served to The relatively high profit margin on many antibiotics emphasise how consistently easy it was to get unneces- provides considerable supply-side incentive [26]. sary antibiotics illegally. Second, while we found some significant differences in access to antibiotics according to characteristics of the Policy implications pharmacies, these differences were small. Enforcement The anti-microbial stewardship programme is creating a was virtually non-existent at all levels in all regions. Hav- new prescribing paradigm in many hospitals across the ing a prescription-only sign, it appears, was for display country. The pharmacy sector is able to follow its own only, and usually ignored by pharmacists and customers anti-microbial stewardship programme. China with its alike. The antibiotic counter just served to reinforce the top-down approaches, is one of the few countries which concept of antibiotics as a commodity. The only major can actually address this by combining enforcement of differences we found were between provinces, with lower the law, with a campaign to educate the general public. offers of antibiotics in Zhejiang and Guangdong, both Pharmacists need to be trained to explain to customers wealthy, developed eastern provinces. However, this is why antibiotics are refused, and this needs to be rein- not the full explanation since in Jiangsu and Fujian (both forced with a public education campaign. developed eastern provinces) antibiotics were relatively China has achieved very rapid behaviour change in re- easy to purchase. Subsequent enquiries among pharma- lation to public health measures in the past. For ex- cists (who were not in the original study) suggested that ample, in May 2011 punitive measures were introduced the lower offers in Zhejiang may be due to the effect of for driving under the influence of alcohol, backed-up by the G20 Summit held in Hangzhou, the capital of Zhejiang, a short period of strict enforcement. Within three in 2016. The general crackdown that surrounded this months behaviour had changed dramatically, with driv- event included warnings to pharmacies about all non- ing under the influence of alcohol reduced by an average prescription sales of antibiotics, ahead of the announce- of over 50%, gradually introducing a widespread accept- ment that antibiotic sales without prescription would ance of zero tolerance of alcohol for driving across much cease by 2020. We speculate that some of this G20 ef- of China [29]. fect has been sustained. Third, we raise questions about the role of the pharmacy Conclusion profession. Nearly a third of our pharmacies did not employ The very easy access to antibiotics in retail pharmacies in a licensed pharmacist. In 2007 the government announced China needs to be addressed as a matter of urgency. This that all pharmacies must employ a licensed pharmacist. But should be part of the wider anti-microbial stewardship ef- by the end of 2015 only half did, reflecting the national fort. This may require a new approach to policy. More shortage of pharmacists [26]. But there is also a problem of work needs be done to meet the goal of prescription-only quality. The stated role of pharmacists is to “ensure the antibiotics in pharmacies in China. rational and legal sale of drugs” [27]. In our study 81.0% of Abbreviations licensed pharmacists sold antibiotics irrationally and il- AMR: Anti-microbial resistance; LMIC: Low- and middle-income country legally, and their services were of a lower standard than Acknowledgements unlicensed pharmacy staff. This is not unique to China. A We thank all the medical students who gave up time in their summer systematic review of 30 studies from LMICs, identified a vacation to act as simulated patients in this project. range of deficiencies in the quality of licensed pharmacists’ practice, including sales of prescription-only drugs [28]. But Authors’ contributions The research idea came from all authors. The study was designed by JC and in China the government is currently seeking to increase TH. JC and YMW supervised the implementation of the research and the role of pharmacists to reduce pressures on primary analysed the data. All authors contributed to the drafting of the paper. All care. Clearly, improved training, quality control measures have read and approved the final manuscript. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 8 of 8 Funding 16. Wei X, Zhang Z, Walley JD, et al. Effect of a training and educational This work was supported by Zhejiang University Explorative Research intervention for physicians and caregivers on antibiotic prescribing for Programme No. GW-17-04. upper respiratory tract infections in children at primary care facilities in rural China: a cluster-randomised controlled trial. Lancet Glob Health. 2017;5:e1258–e67. Availability of data and materials 17. Chang J, Ye D, Lv B, et al. Sale of antibiotics without a prescription at The datasets used and/or analysed during the current study are available community pharmacies in urban China: a multicentre cross-sectional survey. from the corresponding author on reasonable request. J Antimicrob Chemoth. 2017;72:1235–42. 18. Wang XM, Peng DD, Wang WY, et al. Massive misuse of antibiotics by Ethics approval and consent to participate university students in all regions of China: implications for national policy. Ethical approval was obtained from Zhejiang University School of Public Int J Antimicrob Ag. 2017;50:441–6. Health Ethics Committee. (Approval number ZGL201706–5). 19. Xiao Y. National action plan to contain Antimicrobial Resistance in China: 2016–2020. http://en.nhfpc.gov.cn/2016-08/26/c_70276.htm. Consent for publication 20. Nestel D, Bearman M. Simulated patient methodology: theory, evidence and Not applicable. practice; Wiley on-line; 2015. 21. Xu T, Neto ACDA, Moles RJ. A systematic review of simulated-patient Competing interests methods used in community pharmacy to assess the provision of non- The authors declare that they have no competing interests. prescription medicines. Int J Pharm Pract. 2012;20:307–19. 22. Watson MC, Norris P, Granas AG. A systematic review of the use of Author details simulated patients and pharmacy practice research. Int J Pharm Pract. Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 2006;14:83–93. 310058, People’s Republic of China. Department of Gastroenterology, Third 23. Llor C, Cots JM. The Sale of antibiotics without prescription in pharmacies in Xiangya Hospital, Central South University, Changsha 410013, Hunan Catalonia, Spain. Clin Infect Dis. 2009;48:1345–9. Province, People’s Republic of China. Centre for Global Health, Zhejiang 24. Ibrahim MI, Palaian S, Alsulaiti F, et al. Evaluating community pharmacy University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, practice in Qatar using simulated patient method: acute gastroenteritis People’s Republic of China. Institute for Global Health, University College management. Pharm Pract. 2016;14:800. London, 30 Guilford St, London WC1N1EH, UK. 25. Group MDN. Antibiotic overuse: the influence of social norms. J Am Coll Surg. 2008;207:265–75. Received: 15 December 2018 Accepted: 15 November 2019 26. Certification Center for Licensed Pharmacist of China Food and Drug Administration. Report on National Licensed Pharmacist Registration of November 2015. http://www.cqlp.org/info/link.aspx?id=2662&page=1. References Accessed 6 Dec 2018. 1. Marston HD, Dixon DM, Knisely JM, et al. Antimicrobial Resistance. JAMA. 27. The State Council of People’s Republic of China. The twelfth five year plan 2016;316:1193–204. of drug safety 2012. http://www.gov.cn/gongbao/content/2012/content_2 2. World Health Organization. Antimicrobial resistance: global report on 068275.htm. Accessed 6 Dec 2018. surveillance. http://apps.who.int/iris/bitstream/10665/112642/1/9789241564 28. Smith F. The quality of private pharmacy services in low and middle-income 748_eng.pdf?ua=1. Accessed 6 Dec 2018. countries: a systematic review. Pharm World Sci. 2009;31:351–61. 3. O’Neill J. The Review on Antimicrobial Resistance. Tackling drug resistance 29. Ministry of Public Security of People’s Republic of China 2017. http://www. globally- final report and recommendations. https://amr-review.org. mps.gov.cn/n2255040/n2255043/c3749988/content.htm. Accessed 6 Dec Accessed 6 Dec 2018. 4. Okeke IN, Klugman KP, Bhutta ZA, et al. Antimicrobial resistance in developing countries. Part II: strategies for containment. Lancet Infect Dis. 2005;5:568–80. Publisher’sNote 5. Laxminarayan R, Duse A, Wattal C. Antibiotic resistance-the need for global Springer Nature remains neutral with regard to jurisdictional claims in solutions. Lancet Infect Dis. 2013;13:1057–98. published maps and institutional affiliations. 6. Klein EY, Van Boeckel TP, Martinez EM, et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. P Natl Acad Sci. 2018. https://doi.org/10.1073/pnas.1717295115. 7. Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of cross mark 742 national pharmaceutical sales data. Lancet Infect Dis. 2014;14:742–50. 8. Huttner B, Harbarth S, Nathwani D. Success stories of implementation of antimicrobial stewardship: a narrative review. Clin Microbiol Infec. 2014;20:954–62. 9. Morgan DJ, Okeke IN, Laxminarayan R, et al. Non-prescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis. 2011;11:692–701. 10. Xiao YH, Giske CG, Wei ZQ, et al. Epidemiology and characteristics of antimicrobial resistance in China. Drug Resist Update. 2011;14:236–50. 11. Xiao YH, Zhang J, Zheng BW, et al. Changes in Chinese policies to promote the rational use of antibiotics. PLoS Med. 2013;10:e1001556. 12. Ding C, Yang Z, Wang J, et al. Prevalence of Pseudomonas aeruginosa and antimicrobial-resistant Pseudomonas aeruginosa in patients with pneumonia in mainland China: a systematic review and meta-analysis. Int J Infect Dis. 2016;49:119–28. 13. Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016;16:161–8. 14. State Food and Drug Administration. The five prescription sales only antibacterial released by SFDA. http://eng.sfda.gov.cn/WS03/CL0757/61674. html. 15. Xiao YH, Li LJ. Legislation of clinical antibiotic use in China. Lancet Infect Dis. 2013;13:189–91. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance & Infection Control Springer Journals

Widespread illegal sales of antibiotics in Chinese pharmacies – a nationwide cross-sectional study

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10.1186/s13756-019-0655-7
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Abstract

Background: Access to antibiotics without a prescription from retail pharmacies has been described as a major contributor to anti-microbial resistance (AMR) globally. In the context of high rates of AMR, the Chinese government has recently introduced strict policies regarding hospital antibiotic use, but the existing ban on antibiotic sales without prescription in retail pharmacies has not been strongly enforced. In 2016, a goal of prescription-only antibiotics by 2020 was announced. The objective of the study was to determine progress towards the 2020 goal, through estimating the proportion of retail pharmacies selling antibiotics without prescription across the three regions of mainland China. Methods: Using the Simulated Patient method, we conducted a cross-sectional survey across purposively-sampled retail pharmacies in urban and rural areas of 13 provinces in eastern, central and western China. Medical students presented a scenario of a mild upper respiratory tract infection, following a strict three-step protocol. They recorded the pharmacy characteristics, and details of their experience, including at which step antibiotics were offered. Results: Complete data were obtained from 1106 pharmacies. Antibiotics were obtained in 925 (83.6, 95% CI: 81.5, 85.8%) pharmacies without a prescription, 279 (25.2%) at Stage 1 (symptoms only described), 576 (52.1%) at stage 2 (asked for antibiotics), and 70 (6.3%) at Stage 3 (asked for penicillin or cephalosporins). There were significant differences between provinces, with antibiotic access (at any stage) ranging from 57.0% (57/100) in Zhejiang (81/82) to 98.8% in Guizhou. However, there were no significant differences in access to antibiotics by level of city, county, township or village (P = 0.25), whether the pharmacy was part of a chain or independent (P = 0.23), whether a licensed pharmacist was attending (P = 0.82) or whether there was a sign saying that prescriptions were required for antibiotics (P = 0.19). Conclusions: It is easy to obtain antibiotics without a prescription in retail pharmacies in China, despite the fact it is against the law. This must be addressed as part of the wider anti-microbial stewardship effort which could include intense enforcement of the existing law, supported by a public education campaign. Keywords: Anti-microbial resistance, Antibiotic, Anti-microbial stewardship, Pharmacy, China * Correspondence: t.hesketh@zju.edu.cn; t.hesketh@ucl.ac.uk Centre for Global Health, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, People’s Republic of China Institute for Global Health, University College London, 30 Guilford St, London WC1N1EH, UK Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 2 of 8 Background of access to antibiotics without prescription: the first in Anti-microbial resistance (AMR) is acknowledged as one pharmacies in three Chinese cities [17], and the second of the greatest threats to global health this century, as well among university students, frequently self-medicating as a major contributor to rising healthcare costs world- with over-the-counter antibiotics [18]. At the G20 Sum- wide [1]. It is now a problem in all regions of the world mit in China in 2016, a comprehensive plan to address [2]. Mortality attributable to AMR is predicted to rise AMR was announced, and this included a prominent from 700,000 in 2015, to as high as 10 million by 2050, goal of prescription-only antibiotics at pharmacies in all unless effective control measures are introduced [3]. provinces by 2020 [19]. However, guidance about mech- Misuse of antibiotics, both in medicine and agricul- anisms for achieving the goal was notably absent. ture, is well-established as the major driver of AMR [4]. The main objective of this study, therefore, was to deter- In medicine, despite awareness by doctors that antibi- mine the degree of progress which has been made towards otics should be used with care, defensive medicine and the 2020 goal. We aimed to quantify the proportion of profit motives are driving the increase in antibiotic use pharmacies where antibiotics could be purchased without in many countries [5]. A recent study across 76 coun- a prescription, across the three regions of China. Second- tries reported a 65% increase in antibiotic use between ary objectives were to determine the impact of the phar- 2000 and 2015. Most of this increase was in low- and macies’ geographical location and characteristics, as well middle-income countries (LMICs), where it was corre- as the standard of pharmacy services during the sale of lated with growth in per capita gross domestic product. antibiotics. Based on this trajectory, global antibiotic consumption will double between 2015 and 2030 [6]. Reducing global Methods consumption is thus crucial to reducing the threat of We conducted a cross-sectional survey in 13 provinces, AMR [6, 7]. representing all three regions of China: four in the east Antibiotic stewardship programmes to reduce prescrib- (Jiangsu, Zhejiang, Fujian and Guangdong), five in the ing of antibiotics by doctors, have been introduced in central region (Anhui, Jiangxi, Henan, Hubei and Hunan) many countries, especially in hospital settings, with some and four in the west (Sichuan, Guizhou, Shaanxi and success in reducing antibiotic misuse [8]. But it is esti- Chongqing). The 13 provinces also represent the range of mated that more than 50% of antibiotics worldwide are socio-economic development in China. Sampling of phar- purchased without a prescription, from pharmacies, mar- macies was purposive, based on the need for broad repre- ket stalls or street vendors, especially in LMICs [9]. This sentation of different pharmacy characteristics: occurs because of the absence of prescription-only regula- tions, or lack of enforcement where such regulations do 1) administrative level, that is, at city, county and exist. This leads to large quantities of antibiotics in circu- township/village level representing the continuum lation which contribute considerably to AMR [10]. between urban and rural: city is urban, township Rising levels of AMR in China are contributing to over- and village are rural, and the county level, while all global increases of AMR [11]. In a national survey, 60% defined as rural, has mainly urban characteristics. of isolates of some species were drug-resistant, including The hypothesis was that access to antibiotics would methicillin-resistant Staphylococcus aureus, β-lactamase- be easier in rural areas, where enforcement is more producing Escherichia coli, quinolone-resistant E coli, and difficult. carbapenem-resistant Pseudomonas aeruginosa [10, 12]In 2) part of a pharmacy chain or independent. We 2016 colistin resistance was reported for the first time in hypothesised that chain pharmacies, some with China [13]. branches across the country, would be more likely This has led to action by the Chinese government. to comply with prescription-only regulations. AMR-targeted policies included the banning of antibi- 3) at a range of distance from a hospital, defined as otics sales without prescription as early as 2004 [14]. In closer or further than 2 km. Our hypothesis was 2011, the Ministry of Health set up a special task force that pharmacies close to hospitals (which provide on antibiotic stewardship, resulting in strict rulings cov- most of the primary care in China) would receive ering all aspects of antibiotic use in hospitals [15]. As a more prescriptions for antibiotics and would result, the use of antibiotics in many hospitals, especially therefore be more likely to refuse requests without in tertiary settings, has reduced. However, the use of prescription. antibiotics in primary care remains high [16]. Sale of antibiotic in retail pharmacies were not addressed in the The sampling process of pharmacies was multi-stage. 2011 regulations, despite the fact that ease of access to We selected the capital city, one small city and one antibiotics without a prescription had been documented county in each province, and selected a nodal point in [15]. Two studies conducted in 2015 illustrated the ease each location from which to sample the pharmacies. The Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 3 of 8 aim was to include at least 80 pharmacies in each of the including to determine access to prescription-only drugs 13 provinces, with an equal number of pharmacies in pharmacies [21, 22]. across the three characteristic categories listed above. To Our simulated patients were undergraduate medical stu- achieve this we used the Chinese equivalent of Google dents, from Zhejiang and Xiamen Universities. A notice maps, Baidu maps, which includes detail of the locations explaining the study was disseminated on campus via social of pharmacies and hospitals, together with the names of media, and 40 students were selected at interview, allowing the pharmacies, thus identifying whether they were for the allocation of three in each province. The case sce- chain or independent. We then selected 35 pharmacies nario, showninFig. 1, was deliberately chosen to represent within a 10 km radius of each of the three nodal points a situation where there could be no justification for the use in each province. The over-sampling was to allow for of antibiotics: a description of mild upper respiratory tract possible errors in Baidu maps, and for closures at the symptoms, without visible symptoms, in a healthy young time the pharmacies were visited. The distance of 10 km adult. The staged approach, is well-established within the allowed for inclusion of rural pharmacies. simulated patient methodology, and the exact steps were adapted from research by others [17, 22–24]. All students Procedures underwent training in the steps of the protocol. They ini- We used the Simulated Patient method to conduct the tially practised with each other, under the observation of the survey. A simulated patient is an individual trained to act investigators. When they were ready, they were required to as a real patient in order to simulate a set of symptoms or conduct a pilot in at least two local pharmacies, to ensure problems [ 20]. This method has been widely used for re- competence with the process and with the reporting re- search into health care provision in a number of countries, quirements, before leaving for their respective provinces. Fig. 1 Flowchart of protocol for simulated patient visits Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 4 of 8 The data collection was carried out from July to Sep- submitted forms had to be discarded, because of incom- tember 2017. Students worked in pairs, taking it in turns plete data and/or unacceptable variation from the proto- to act as simulated patients or to observe and ensure ad- col. Complete information was collected from 1106 herence to the protocol. Both independently recorded pharmacies, 364 (32.9%) from the eastern region, 416 the findings. All the simulated patients were told they (37.6%) the central region and 326 (29.5%) the west; 367 should not act any symptoms, should give no impression (33.2%) were at city level 433 (39.2%) at county level, of appearing unwell, and that they should not be too in- and 306 (27.6%) in townships. There were 702 (63.5%) sistent about obtaining antibiotics, that is they should chain pharmacies, and 588 (53.2%) were located within only ask once for antibiotics. They were instructed how 2 km of hospitals; 1011 (91.4%) of pharmacies displayed to respond to likely questions from the pharmacist, that prescription-only drug sales notices, and 922 (83.4%) is, they had no other symptoms, except a slight runny had antibiotic counters. Just over two-thirds 760 (68.8%) nose, and they had no fever. If offered medications, sim- employed a licensed pharmacist. At the time of the sim- ulated patients were told to say they had left their wallet ulated patients’ visit 485 (43.9%) were on duty. or purse at home. Therefore, no medications were actu- ally purchased. Antibiotics sales The simulated patient pairs were required to enter the Antibiotics were obtained in 925 (83.6, 95% CI: 81.5, following data into a standard form on their Smart- 85.8%) pharmacies without a prescription, 279 (25.2%) at phones, as soon as they left the pharmacy, and to send Stage 1 (symptoms only described), 576 (52.1%) at stage 2 to the principle investigator(PI) immediately: (asked for antibiotics), and 70 (6.3%) at Stage 3 (asked for penicillin or cephalosporin). This total excluded 15 (1.4%), 1) Details of the pharmacy included: who said they were willing to provide prescriptions via an a. the location; on-line consultation and e-prescription to patients who b. a chain or independent; had no prescriptions. Nearly all of these were in the prov- c. distance from nearest hospital; inces of Sichuan (n =7) and Hubei (n =5). d. whether there was a special counter for Of the 181 (16.4%) pharmacies where antibiotics were antibiotics. This is partly a marketing ploy, a not offered, the reasons given were: that a prescription place where antibiotics are displayed separately; was necessary in 113 (10.2%), that antibiotics were not e. whether there was a prescription drug sales logo. indicated in 58 (5.2%), or that there were no antibiotics This is required under legislation, and is a in stock in 6 (0.5%). declaration that “prescription-only” drugs, including The antibiotics offered were mainly of three types: antibiotics, will not be sold without a prescription; penicillins (333/925, 36.0%), cephalosporins (274/925, f. whether the pharmacy had a licensed pharmacist 29.6%) and macrolides (250/925, 27.0%). The remainder and whether present at the time. This were quinolones, metronidazole and clindamycin. In six information was obtained from the required cases two antibiotics were offered. licensed pharmacist certificate on the wall and Table 1 shows the “success” rates of acquiring antibi- the identification badges worn by the staff. otics by province and region, as well as by the stage at 2) If antibiotics were offered and at which stage (1,2 or 3). which they were offered. In total, in seven provinces over 3) Which antibiotics were offered. 90% of the simulated patients were offered antibiotics, in 4) Whether the pharmacist asked about a) the four 70–90%, and less than 70% in just two. The range symptoms, b) whether a doctor had been consulted, was from 57.0% in Zhejiang to 98.8% in Guizhou, where and c) allergies, before offering antibiotics. there was just one refusal. There were significant re- 5) Any other observations of note, especially in gional differences with access easiest in the central re- relation to the pharmacist’s communication. gion, and hardest in the east (P < 0.0001). In the west it was significantly easier to get antibiotics at the first stage Analysis (P = 0.004), but it was easier to get antibiotics at the sec- Descriptive statistics were reported as frequencies with ond stage in the central region (P = 0.07). In total 92.4% 95% confidence intervals. Chi-Squared tests were used of all antibiotics were offered at Stage 1 or 2. to compare categorical variables. Analysis was carried- Table 2 shows the success of acquiring antibiotics by out using SPSS 24.0. pharmacy characteristics. There were no significant dif- ferences in access to antibiotics by urban/rural location Results (city, county, township/village) (P = 0.25), or pharmacy Characteristics of the pharmacies ownership, independent or part of a chain (P = 0.23). It Pharmacy characteristics are shown in Tables 1 and 2.A was easier to get antibiotics in pharmacies more than 2 total of 1345 pharmacies were visited; 239 (17.7%) of the km from hospitals (P = 0.02). Having a special counter Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 5 of 8 Table 1 Antibiotics given without prescription at Stages 1, 2 & 3 by province & region n(%) Overall Success Success at Stage 1 Success at Stage 2 n Success at Stage 3 n(%) with 95% CI n (%) with 95% CI n(%) 95% CI n (%) 95% CI Total 1106(100.0) 83.6 (81.5,85.8). 30.2(27.2,33.1) 62.3(59.1,65.4) 7.6(5.9,9.3) Eastern Zhejiang 100(9.0) 57.0(47.1,66.9) 33.3(20.7,46.0) 59.6(46.5,72.8) 7.0(0.2,13.9) Jiangsu 92(8.3) 92.4(86.9,97.9) 42.4(31.6,53.1) 52.9(42.1,63.8) 4.7(0.1,9.3) Fujian 92(8.3) 91.3(85.4,97.2) 31.0(20.9,41.0) 61.9(51.3,72.5) 7.1(1.5,12.8) Guangdong 80(7.2) 58.8(47.7,69.8) 23.4(10.8,36.0) 68.1(54.3,81.9) 8.5(0.2,16.8) Central Anhui 92(8.3) 95.7(91.4,99.9) 36.4(26.1,46.6) 55.7(45.1,66.3) 8.0(2.2,13.7) Jiangxi 81(7.3) 97.5(91.4,99.3) 30.4(20.0,40.7) 65.8(55.1,76.5) 3.9(1.4,11.0) Hunan 83(7.5) 86.7(79.3,94.2) 29.2(18.4,39.9) 63.9(52.5,75.3) 6.9(0.9,13.0) Henan 80(7.2) 95.0(90.1,99.9) 6.6 (0.9,12.3) 81.6(72.7,90.5) 11.8(4.4,19.3) Hubei 80(7.2) 72.5(62.5,82.5) 13.8(4.6,22.9) 69.0(56.7,81.2) 17.2(7.2,27.3) Western Sichuan 81(7.3) 72.8(62.9,82.7) 15.3(5.8,24.7) 71.2(59.3,83.1) 13.6(4.6,22.6) Guizhou 82(7.4) 98.8(93.4,99.8) 34.6(24.0,45.1) 65.4(54.9,76.0) 0 Shanxi 83(7.5) 75.9(66.5,85.3) 38.1(25.8,50.4) 58.7(46.2,71.2) 3.3(0.9,11.2) Chongqing 80(7.2) 95.0(90.1,99.9) 47.4(35.9,58.9) 42.1(30.7,53.5) 10.5(3.5,17.6) Region Eastern 364(32.9) 75.0(70.5,79.5) 33.7(28.1,39.3) 59.7(53.9,65.6) 6.6(3.6,9.6) Middle 416(37.6) 89.7(86.7,92.6) 24.1(19.8,28.5) 66.8(62.0,71.6) 9.1(6.2,12.0) Western 326(29.5) 85.6(81.7,89.4) 34.8(29.1,40.4) 58.8(53.0,64.6) 6.5(3.6,9.4) p-value 0.00 0.004 0.07 0.34 for antibiotics increased the offer of antibiotics (P = Discussion 0.02), but having a prescription-only sign made no dif- While ease of access to antibiotics in retail pharmacies ference (P = 0.19). The employment of a licensed has been previously documented in China [17, 18], our pharmacist reduced the offer of antibiotics from 89.6 to results show that despite the prominently announced 80.9% (P = 0.0003), but whether the licensed pharmacist goal of prescription-only antibiotics by 2020, there has was actually attending at the time of the visit made no probably been no progress towards the goal. Indeed difference (P = 0.93). the situation may have deteriorated, with our results suggesting greater ease of access to antibiotics than re- ported in Chang et al’s 2015 urban study which also Pharmacy services used an simulated patient design [17]. This naturally Theseare showninTable 3. Overall 65.4%(723/1106) asked raises concerns about the role of pharmacies in overall about symptoms, 11.9%(132/1106) asked the simulated pa- antibiotic misuse and hence anti-microbial resistance. tient if they had a prescription, 24.4%(270/1106) asked Our findings are strengthened by the fact that they are about the history of drug allergy before giving antibiotics, consistent in urban and rural areas in all Chinese and only 1.0%(11/1106) asked if the simulated patient had regions, irrespective of ownership (chain or independ- seen a doctor. Most (785/1106, 71.0%) offered general ent), presence of a licensed pharmacist, a special coun- health and nutrition advice, including promoting the sale of ter for antibiotics, or a sign for prescription-only dietary supplements. The attending licensed pharmacists drugs. This shows clear failure to enforce the law. Our performed significantly worse on all the above. All the own search of media reports found only 12 convic- pharmacists offered some form of medication apart from tions for selling antibiotics between 2008 and 2011, the antibiotics: 628 (56.8%) offered Traditional Chinese with just minor penalties imposed. This lack of en- Medicine (183 different proprietary brands) most com- forcement has led to what appears to be the virtual monly Pudilan (11.3%), and Ganmaoling (8.2%). normalisation of illegal sales of antibiotics. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 6 of 8 Table 2 Antibiotics given without prescription at Stages 1, 2 and 3 by pharmacy characteristics n(%) Overall Success n(%) Success at Stage 1 n (%) Success at Stage 2 n Success at Stage 3 n with 95% CI with 95% CI (%) 95% CI (%) 95% CI Level City 367(33.2) 82.3(78.4,86.2) 23.2(18.8,27.5) 51.2(46.1,56.4) 7.9(5.1,10.7) County 433(39.2) 82.7(79.1,86.3) 22.6(18.7,26.6) 53.8(49.1,58.5) 6.2(3.9,8.5) Township 306(27.7) 86.6(82.8,90.4) 31.4(26.1,36.6) 50.7(45.0,56.3) 4.6(2.2,6.9) Chain 702(63.5) 82.6(79.8,85.4) 23.6(20.5,26.8) 52.0(48.3,55.7) 7.0(5.1,8.9) Independent 404(36.5) 85.4(81.9,88.9) 28.0(23.6,32.4) 52.2(47.3,57.1) 5.2(3.0,7.4) p-value 0.23 0.11 0.94 0.24 < 2 km from hospital 588(53.2) 81.3(78.1,84.5) 23.6(20.2,27.1) 51.0(47.0,55.1) 6.6(4.6,8.6) > 2 km from 518(46.8) 86.3(83.3,89.3) 27.0(23.2,30.9) 53.3(49.0,57.6) 6.0(3.9,8.0) hospital p-value 0.02 0.20 0.45 0.66 Special counter for antibiotics 922(83.4) 84.8(82.5,87.1) 24.3(21.5,27.1) 53.9(50.7,57.1) 6.6(5.0,8.2) No counter for antibiotics 184(16.6) 77.7(71.6,83.8) 29.9(23.2,36.6) 42.9(35.7,50.2) 4.9(1.7,8.0) p-value 0.02 0.22 0.01 0.38 Sign for prescription drugs 1011(91.4) 83.2(80.9,85.5) 24.9(22.3,27.6) 52.3(49.2,55.4) 5.9(4.5,7.4) No sign for prescription drugs 95(8.6) 88.4(81.9,95.0) 28.4(19.2,37.7) 49.5(39.2,59.7) 10.5(4.2,16.8) p-value 0.19 0.57 0.59 0.08 Licensed pharmacist employed 485(43.9) 80.8(77.3,84.3) 21.9(18.2,25.5) 50.9(46.5,55.4) 8.0(5.6,10.5) in pharmacy Licensed pharmacist employed, 275(24.9) 81.1(76.4,85.7) 24.0(18.9,29.1) 51.6(45.7,57.6) 5.5(2.8,8.2) not in pharmacy No licensed pharmacist 346(31.3) 89.6(86.4,92.8) 30.9(26.0,35.8) 54.0(48.8,59.3) 4.6(2.4,6.8) employed p-value 0.001 0.01 0.67 0.11 Our results are perhaps more concerning, given the approach, and elicited offers of antibiotics in 56% of way that we used the simulated patient methodology. paediatric diarrhoea scenarios, and 78% in young adult Similar studies, mainly from Europe and the Middle East respiratory infection scenarios, which included fever and [21–24], have used actors, or third-party approaches, cough, symptoms, explicitly excluded in our study. Our that is representing someone else, typically a relative, un- simulated patients described very minor symptoms and able to come to the pharmacy because of the illness. were told not to be insistent or aggressive. This direct Chang et al’s three-city Chinese study, used the latter approach is recognised as stronger in Simulated Patient Table 3 Characteristics of pharmacies and pharmacy services Ask about symptoms Ask about prescription Ask about allergies General advice City 59.7(54.6,64.7) 16.3(12.5,20.2) 24.3(19.8,28.7) 70.8(66.2,75.5) County 70.4(66.1,74.8) 10.9(7.9,13.8) 22.4(18.5,26.3) 70.4(66.1,74.8) Township 65.0(59.7,70.4) 8.2(5.1,11.3) 27.5(22.4,32.5) 71.9(66.8,77.0) p-value 0.01 0.003 0.29 0.91 Chain 66.5(63.0,70.0) 13.2(10.7,15.8) 24.2(21.0,27.4) 71.1(67.2,74.9) Independent 63.4(58.6,68.1) 9.7(6.8,12.5) 24.8(20.5,29.0) 68.8(64.3,73.3) p-value 0.29 0.08 0.84 0.23 No licensed pharmacist employed 63.9(59.6,68.2) 13.8(10.7,16.9) 25.6(21.7,29.5) 71.3(67.3,75.4) Licensed pharmacist employed not present 70.9(65.5,76.3) 14.2(10.0,18.3) 25.5(20.3,30.6) 74.5(69.4,79.7) Licensed pharmacist attending 63.0(57.9,68.1) 7.5(4.7,10.3) 22.0(17.6,26.3) 67.6(62.7,72.6) p-value 0.08 0.01 0.44 0.16 Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 7 of 8 methodology than using the third party approach [21, 22]. and inspections must be implemented before the scope of Our findings raise a number of issues: work of pharmacists can be increased [17]. First, we show the importance of the demand side of There are limitations to our study. First, we conducted the consultation. The majority of pharmacists gave anti- the study across 13 provinces, in the three regions, but biotics at Stage 2, “Could you just give me some antibi- the far north and far west were not included, raising otics?”, showing that pharmacy staff respond to the questions about national generalisability. Second, we in- specific demands of patients. It is well-documented that cluded only 80 to 100 pharmacies per province, but we doctors often balance appropriate treatment against pa- did sample purposively to include the range of locations tient demands [16, 25]. With reports indicating that and types of pharmacy, and this is a very large study around two-thirds of Chinese believe that colds and flu compared with other simulated patient studies in phar- should be treated with antibiotics [18], we show that macy settings. Third, we used only one clinical scenario pharmacists readily respond to demands for antibiotics. which was of a very minor nature, but it rather served to The relatively high profit margin on many antibiotics emphasise how consistently easy it was to get unneces- provides considerable supply-side incentive [26]. sary antibiotics illegally. Second, while we found some significant differences in access to antibiotics according to characteristics of the Policy implications pharmacies, these differences were small. Enforcement The anti-microbial stewardship programme is creating a was virtually non-existent at all levels in all regions. Hav- new prescribing paradigm in many hospitals across the ing a prescription-only sign, it appears, was for display country. The pharmacy sector is able to follow its own only, and usually ignored by pharmacists and customers anti-microbial stewardship programme. China with its alike. The antibiotic counter just served to reinforce the top-down approaches, is one of the few countries which concept of antibiotics as a commodity. The only major can actually address this by combining enforcement of differences we found were between provinces, with lower the law, with a campaign to educate the general public. offers of antibiotics in Zhejiang and Guangdong, both Pharmacists need to be trained to explain to customers wealthy, developed eastern provinces. However, this is why antibiotics are refused, and this needs to be rein- not the full explanation since in Jiangsu and Fujian (both forced with a public education campaign. developed eastern provinces) antibiotics were relatively China has achieved very rapid behaviour change in re- easy to purchase. Subsequent enquiries among pharma- lation to public health measures in the past. For ex- cists (who were not in the original study) suggested that ample, in May 2011 punitive measures were introduced the lower offers in Zhejiang may be due to the effect of for driving under the influence of alcohol, backed-up by the G20 Summit held in Hangzhou, the capital of Zhejiang, a short period of strict enforcement. Within three in 2016. The general crackdown that surrounded this months behaviour had changed dramatically, with driv- event included warnings to pharmacies about all non- ing under the influence of alcohol reduced by an average prescription sales of antibiotics, ahead of the announce- of over 50%, gradually introducing a widespread accept- ment that antibiotic sales without prescription would ance of zero tolerance of alcohol for driving across much cease by 2020. We speculate that some of this G20 ef- of China [29]. fect has been sustained. Third, we raise questions about the role of the pharmacy Conclusion profession. Nearly a third of our pharmacies did not employ The very easy access to antibiotics in retail pharmacies in a licensed pharmacist. In 2007 the government announced China needs to be addressed as a matter of urgency. This that all pharmacies must employ a licensed pharmacist. But should be part of the wider anti-microbial stewardship ef- by the end of 2015 only half did, reflecting the national fort. This may require a new approach to policy. More shortage of pharmacists [26]. But there is also a problem of work needs be done to meet the goal of prescription-only quality. The stated role of pharmacists is to “ensure the antibiotics in pharmacies in China. rational and legal sale of drugs” [27]. In our study 81.0% of Abbreviations licensed pharmacists sold antibiotics irrationally and il- AMR: Anti-microbial resistance; LMIC: Low- and middle-income country legally, and their services were of a lower standard than Acknowledgements unlicensed pharmacy staff. This is not unique to China. A We thank all the medical students who gave up time in their summer systematic review of 30 studies from LMICs, identified a vacation to act as simulated patients in this project. range of deficiencies in the quality of licensed pharmacists’ practice, including sales of prescription-only drugs [28]. But Authors’ contributions The research idea came from all authors. The study was designed by JC and in China the government is currently seeking to increase TH. JC and YMW supervised the implementation of the research and the role of pharmacists to reduce pressures on primary analysed the data. All authors contributed to the drafting of the paper. All care. Clearly, improved training, quality control measures have read and approved the final manuscript. Chen et al. Antimicrobial Resistance and Infection Control (2020) 9:12 Page 8 of 8 Funding 16. Wei X, Zhang Z, Walley JD, et al. 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Published: Jan 15, 2020

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