www.nature.com/scientificreports OPEN Changes of antibiotic prescribing pattern and its resistance to E. Coli in South Korea: a 12‑year retrospective observational study Geun Woo Lee1,4, Sukhyun Ryu2,4, Juhee Park1, Eun Jee Lee1, Kwang Jun Lee3, Jungyeon Tae2, Youngsik Hwang2 & Dong‑Sook Kim1* In the present study, we investigated the pattern of changes in antibiotic prescription and antimicrobial resistance (AMR) in Escherichia coli in South Korea between 2007 and 2018. We collected data related to antibiotic prescription and AMR in E. coli from the national surveillance system. We used the Mann–Kendall test and Spearman’s correlation to identify the trends of antibiotic prescription and AMR in E. coli and to examine the relationship between them, respectively. Although we noted a signifcant decreasing trend of ampicillin and gentamicin prescriptions in all medical institutions, we identifed a higher level of AMR in long‑term care facilities than in other medical institutions. We did not identify a signifcant positive correlation between ampicillin and gentamicin prescriptions and their resistance in E. coli. However, we found a signifcant positive correlation between cefotaxime prescription and its resistance in E. coli in hospitals, long‑term care facilities, and clinics. Our results strongly suggest that long‑term care facilities in South Korea have the potential to sustain AMR epidemics and that more eforts are needed to curb AMR in E. coli. Further epidemiological studies using enhanced AMR surveillance are warranted. Te development of antimicrobial resistance (AMR) is a normal evolutionary process in microorganisms. It is ofen accelerated by selective pressure exerted by the overuse or misuse of antimicrobial agents1. Te increasing use of antibiotics has led to the emergence of AMR, which limits the treatment of common bacterial infections. Gram-negative bacteria, such as Escherichia coli, which are resistant to third-generation cephalosporins, are par- ticularly of great concern. Tis resistance is conferred by the production of extended-spectrum beta-lactamases (ESBLs) and is transferred to other gram-negative bacteria; therefore, the surveillance of AMR in E. coli is ofen used as a proxy for the surveillance of ESBLs in humans, animals, and the environment2. South Korea is an East Asian country with a population of 51.4 million. In South Korea, broad-spectrum antibiotics, including quinolone, penicillin, and cephalosporin are frequently prescribed3,4. In the twenty-frst century, extensive eforts have been made in South Korea to reduce AMR. Tese include the Korean National Antimicrobial Resistance Safety Control Program led by the Korean Ministry of Food and Drug Safety from 2003 to 20135 and the Korean national action plan on AMR led by the Korean Ministry of Health and Welfare from 2016 to 20206. To identify the level of antibiotic consumption and AMR within a country, population-based stud- ies have mainly been conducted in countries in the UK and USA 7,8. Diferent healthcare settings and public health policies in each country would afect the changes in antibiotic prescription because these factors are very likely to afect the selection pressures exerted on microorganisms in the population. Terefore, surveillance and research on changes in antibiotic consumption and AMR with changes in related health policies in diferent countries are important in order to develop evidence-based strategies to overcome AMR6. However, there exists a knowledge gap regarding the level of antibiotic prescription and AMR in Asia, which is highly vulnerable to AMR threats 9. To the best of our knowledge, no long-term observational study has been conducted in South Korea to assess the frequency of antibiotic prescription and AMR considering the changes in healthcare regulation. In the present 1Pharmaceutical and Medical Technology Research Team, Department of Research, Health Insurance Review and Assessment Service, Wonju, South Korea. 2Department of Preventive Medicine, Konyang University College of Medicine, Daejeon, South Korea. 3National Institute of Health, Korean Centers for Disease Control and Prevention, Osong, South Korea. 4These authors contributed equally: Geun Woo Lee and Sukhyun Ryu. *email: [email protected] Scientifc Reports | (2021) 11:5658 | https://doi.org/10.1038/s41598-021-84450-z 1 Vol.:(0123456789) www.nature.com/scientificreports/ DID General hospitals Hospitals LTCFs Clinics Overall Fluoroquinolone 4.00 (3.60–4.32) 0.91 (0.78–0.99) 1.19 (0.75–2.47) 1.79 (1.33–2.15) 7.90 (6.46–9.93) Ampicillin 0.97 (0.64–1.12) 0.94 (0.65–1.16) 0.57(0.33–1.18) 2.12 (1.24–2.91) 4.60 (2.85–6.36) Cefotaxime 5.04 (5.34–4.58) 0.83 (0.49–1.15) 1.28 (0.86–1.73) 0.59 (0.29–0.97) 7.75 (6.21–9.19) Gentamicin 0.03 (0.02–0.06) 0.04 (0.03–0.07) 0.08 (0.06–0.22) 0.08 (0.06–0.10) 0.23 (0.15–0.44) Table 1. Antibiotic prescription in South Korea between 2007 and 2018. Each value in the cell indicates the mean DID and the range (min–max). DID defned daily dose/1000 inhabitants/day, LTCFs long-term care facilities. AB 5 LTCFsHospital 4 General hospital Primary clinics Ampicillin Fluoroquinolone G G G G G G G G G G 4 G G 3 G y G 3 G G G G G G G 2 G G G G G G G G G G 2 G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G G 1 G G G G G G G G G G G G G G 1 G G G G G G G G G G G G G G G 0 0 CD 6 CefotaximeG0.25 entamicin G G G G G G G G G G 5 G G G 0.20 4 0.15 3 G G 0.10 G G G G G G G G G 2 G G G G G G G G G G G G GG G G G G G G G G Defined daily dose/1,000 inhabitants/da G G G G G G G G G G G G G G G 0.05 G G G G G G G G G G G G 1 G G G G G G G G G G G G G G G G G GGG G G G 0 0.00 2007 2010 20132016 2007 2010 2013 2016 Years Figure 1. Prescription trend of antibiotics, including (A) fuoroquinolone, (B) ampicillin, (C) cefotaxime and (D) gentamicin, in South Korea between 2007 and 2018. Te red line indicates long-term care facilities (LTCFs), and the blue line indicates hospitals. Te white-blue line indicates general hospitals, and the black line indicates primary clinics. study, we used the South Korean national surveillance data of 12 years to focus on broad-spectrum antimicrobial agents and their resistance in E. coli. Results Te overall mean DID of fuoroquinolone and cefotaxime during the study period was 7.90 (range, 6.46–9.93) and 7.75 (6.21–9.19), respectively (Table 1). Tese antibiotics were prescribed more commonly in general hospitals than in other medical institutions. Te overall mean DID of ampicillin and gentamicin was 4.60 (2.85–6.36) and 0.23 (0.15–0.44), respectively. Ampicillin was mostly prescribed in clinics (DID, 0.59; range, 1.24–2.91), while gentamicin was mostly prescribed in LTCFs (DID, 0.08; range, 0.06–0.22). We observed a decreasing trend of fuoroquinolone prescription in hospitals (τ = − 0.52, p = 0.02) and clinics (τ = − 0.94, p < 0.01) (Fig. 1, Supple- mentary Table 1). Furthermore, we observed a decreasing trend of ampicillin and gentamicin prescriptions in Scientifc Reports | (2021) 11:5658 | https://doi.org/10.1038/s41598-021-84450-z 2 Vol:.(1234567890) www.nature.com/scientificreports/ Antibiotic to which E. coli was resistant General hospitals Hospitals LTCFs Clinics Fluoroquinolone 39.54 (32.00–47.80) 50.33 (44.80–58.40) 75.97 (66.80–85.60) 32.44 (23.20–41.40) Ampicillin 68.51 (65.20–71.20) 73.26 (71.20–74.60) 84.94 (82.40–88.80) 63.81 (62.50–66.10) Cefotaxime 27.98 (13.00–38.60) 31.94 (22.70–41.00) 54.24 (36.770–70.50) 15.13 (4.70–23.10) Gentamicin 28.19 (26.60–29.60) 32.82 (30.60–36.90) 43.36 (40.20–47.40) 25.08 (22.90–27.10) Table 2. Antibiotic resistance rate of Escherichia coli in South Korea between 2007 and 2018. Each value in the cell indicates the mean antimicrobial resistance rate and the range (min–max). LTCFs long-term care facilities. AB LTCFs Hospital Ampicillin 100 General hospital Primary clinics 100 ) Fluoroquinolone 80 80 60 60 40 40 esistance (% 20 20 0 0 CD 100 Cefotaxime 100 Gentamicin )R 80 80 60 60 40 40 Resistance (% 20 20 0 0 2007 2010 2013 2016 2007 2010 2013 2016 Ye ars Figure 2. Resistance rate of Escherichia coli to antibiotics, including (A) fuoroquinolone, (B) ampicillin, (C) cefotaxime and (D) gentamicin, in South Korea between 2007 and 2018. Te red line indicates long-term care facilities (LTCFs), and the blue line indicates hospitals. Te white-blue line indicates general hospitals, and the black line indicates primary clinics. all medical institutions (Fig. 1, Supplementary Table 1). However, we noted an increasing trend of cefotaxime prescription in hospitals (τ = 0.94, p < 0.01), LTCFs (τ = 0.55, p = 0.02) and clinics (τ = 1.0, p < 0.01).