Eradication Rates of Helicobacter Pylori in Korea Over the Past 10 Years and Correlation Of

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Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12279 Eradication Rates of Helicobacter pylori in Korea Over the Past 10 years and Correlation of the Amount of Antibiotics Use: Nationwide Survey Woon Geon Shin,1 Sang Woo Lee,2 Gwang Ho Baik,1 Kyu Chan Huh,3 Sang In Lee,4 Jun-Won Chung,5 Woon Tae Jung,6 Moo In Park,7 Hye-kyung Jung,8 Heung Up Kim,9 Jeong Hwan Kim,10 Sang Young Seol,11 Soon Man Yoon,12 Seong Woo Jeon,13 Su Jin Hong,14 Gwang Ha Kim,15 Dong Ho Lee,16 Hyun Soo Kim,17 Suck Chei Choi,18 Hee Mo Kang,19 Joongyub Lee,20,21 Jae Gyu Kim22 and Jae J. Kim23

1Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea, 2Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea, 3Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea, 4Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, 5Department of Internal Medicine, Gachon University College of Medicine, Incheon, Korea, 6Department of Internal Medicine and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea, 7Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea, 8Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea, 9Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea, 10Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea, 11Department of Internal Medicine, Inje University College of Medicine, Busan, Korea, 12Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea, 13Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea, 14Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea, 15Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea, 16Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, 17Department of Internal Medicine, Chonnam National University School of Medicine, Gwangju, Korea, 18Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Korea, 19Department of Finance and Information Statistics, Hallym University College of Natural Science, Chuncheon, Korea, 20Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea, 21Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea, 22Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea, 23Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea

Keywords Abstract Helicobacter pylori, treatment failure, trends, Background: The efficacy of proton-pump inhibitor–amoxicillin– antibiotics. clarithromycin therapy for H. pylori eradication has decreased over time. Reprint requests to: Jae J. Kim, Division of Objective: We assessed the trend of H. pylori eradication rates over the last Gastroenterology, Samsung Medical Center, 10 years and the relationship between the eradication rates and the amount of Sungkyunkwan University School of Medicine, macrolide antibiotic use in a country with a high prevalence of H. pylori infection. 50 Ilwon-dong Gangnam-gu, Seoul 135-710, Methods: This vast nationwide multicenter study was conducted with Korea. E-mail: [email protected] 34,139 adults treated for H. pylori infection from January 2001 to December and Jae Gyu Kim, Division of Gastroenterology, 2010. The defined daily dose per km2 (DSD) of macrolide antibiotics was cal- Department of Internal Medicine, Chung-Ang = University Hospital, 224-1, Heukseok-dong, culated (n 141,019) using the Health Insurance Review & Assessment data Dongjak-gu, Seoul 156-755, Korea. base from 2008 to 2010 in the two cities which had the lowest (Jeju city) or E-mail: [email protected] highest (Chuncheon city) eradication rate. Results: The eradication rates of proton-pump inhibitor–amoxicillin–clarithromycin therapy ranged 84.9–87.5% from 2001 to 2007, and those of 2008 to 2010 ranged 80.0–81.4% with a decreasing trend (p < 0.0001). The decreasing trend of eradication rates for the overall first-line therapy was observed only in three of the seven geographic areas in Korea (p < 0.0001). The DSD of macrolide antibiotics was significantly higher in Jeju than Che- unchon city (0.85 vs 0.52, p < 0.0001). Conclusions: H. pylori eradication rates with clarithromycin-containing triple therapy in Korea showed a decreasing trend over the past 10 years, although the trend varied among geographic areas. This difference may be associated with the amount of macrolide antibiotic use.

Clarithromycin-containing triple therapy, which is com- commonly recommended as one of the ﬁrst-line Heli- bination treatment using a proton-pump inhibitor cobacter pylori (H. pylori) eradication therapies, now (PPI)–amoxicillin–clarithromycin (PAC) and is most shows unacceptably low treatment success rates. The

© 2015 John Wiley & Sons Ltd, Helicobacter 1 Eradication Rates of Helicobacter pylori and Correlation of Antibiotic Use Density Shin et al. efficacy of this triple therapy has decreased over time use per square kilometer (km2) between the geographic [1,2], largely due to the increase of clarithromycin areas with the lowest and highest eradication rates to resistance, which has had an enormous influence on identify the relationship between antibiotic use and eradication rates [2]. Most worldwide studies have eradication rate. showed unacceptably low eradication success rates for PAC, with about 60% of studies failing to reach 80% eradication rate in intention-to-treat (ITT) analysis [2]. Methods Therefore, the Maastricht IV/Florence consensus report recommends bismuth-containing quadruple therapy Eradication rates over the past 10 years (BCQT) for first-line empirical treatment to avoid clarithromycin use in areas with more than 20% clar- Study population. This multicenter study was conducted ≥ ithromycin resistance [3]. nationwide for adult subjects aged 20 treated for Although the seroprevalence of H. pylori infection in H. pylori infection in secondary or tertiary medical cen- asymptomatic adult subjects has decreased from 66.9% ters from January 2001 to December 2010. The search in 1998 to 59.6% in 2005 [4,5], the high prevalence of of these patients was performed based on the generic H. pylori infection in Korea remains a challenge for the names and doses of H. pylori eradication regimens using medical community. Since 1998, the Korean College of each hospital’s electronic medical chart systems. We Helicobacter and Upper Gastrointestinal Research had excluded patients who did not undergo tests to confirm recommended only 7–14 days PAC treatment as a first- H. pylori eradication within 3 months after the end of line therapy for H. pylori infection in their first and sec- H. pylori eradication therapy. ond edition guidelines [6,7] because of the high For balanced collection of the data from the national metronidazole resistance rate in Korea [8,9]. geographic areas, we recruited one medical center per Although several retrospective Korean studies 2.5 million resident population in a province or city. In reported that the eradication rates of PAC from 2000 to total, 20 medical centers located in either Seoul or in – 2010 surpassed 80% [10 12], the time trend of eradica- six different provinces (Chungcheong, Gangwon, tion rates showed discrepancies among these studies Gyeonggi, Gyeongsang, Jeolla, and Jeju) were included. because of the small sample sizes enrolled in individual centers. However, considering the increase in clarithromycin resistance for H. pylori in Korea [13,14], the Cases report form. First, a one-paged CRF, which could eradication rate of PAC for H. pylori has likely decreased be completed by selecting icons on a computer screen over the past 10 years, at least in some areas [10], with a mouse, was designed using Microsoft Office and new strategies are urgently needed to improve the Access to enhance accuracy and ease of data entry. The H. pylori eradication rate. It has been unclear which form was distributed to the authors along with the data areas in Korea require a different first-line regimen, entry guidelines. This CRF included questions on demo- although the BCQT can be used as a first-line therapy graphic data (e.g., age, sex, and residence), detection according to the 2013 revised Korean guideline of H. py- methods of H. pylori infection, reasons, regimens, dura- lori treatment [15]. Thus, we conducted this nationwide tions, and results of H. pylori eradication. Next, we con- and large-scale study to (1) elucidate the time trend of ducted a preliminary study from January to June 2011 H. pylori eradication rates over the last 10 years accord- to test interinvestigator agreement using the CRF. We ing to age, eradication regimens, and geographic area compared the agreement of the preliminary data for and (2) provide evidence of application of different erad- the same 20 patients between two data entry physicians ication regimens depending on geographic area in a in each hospital. Because the introductory data country with a high prevalence of H. pylori infection. punched in by two physicians coincided with each Antibiotic use is generally accepted as one of the other for all the variables included in the CRF, the form major factors determining the prevalence of antibiotic was used consistently throughout the main data entry resistance in a community [16]. Some studies reported period of September 2011 to December 2012 without a positive relation between antibiotic use and antibiotic any corrections. – resistance [16 18]. And population density is an impor- The Institutional Review Board of each hospital tant factor for the occurrence of antibiotic resistance approved the study protocol. because dissemination of resistant bacteria and genes among persons further increase the prevalence of antibiotic resistance in a population [16,18]. Therefore, Main outcome. The main outcome was the drift of erad- we assessed the difference in the amount of antibiotic ication rates of first- and second-line therapy in rela-

2 © 2015 John Wiley & Sons Ltd, Helicobacter Shin et al. Eradication Rates of Helicobacter pylori and Correlation of Antibiotic Use Density tion to geographic areas and age over the past Study population. Patients who were 20 years of age 10 years. The second-line outcomes were the difference and older with prescriptions of macrolide antibiotics in in eradication rates according to eradication regimens Chuncheon and Jeju city from January 2008 to Decem- and durations, geographic areas, and gastroduodenal ber 2010 were included. All commercially available diseases. The definition of H. pylori eradication success macrolide antibiotics in Korea were included, such as was as follows: (1) negative result in urea breath test azithromycin, clarithromycin, erythromycin, rox- (UBT) or (2) negative result in both rapid urease test ithromycin, and telithromycin. and histology with hematoxylin–eosin and/or Giemsa stain in the 1- to 3-month follow-up after eradication therapy. Main outcome. The main outcome was the difference in the amount of macrolide antibiotics consumption between Jeju and Chuncheon city. Macrolides antibi- Population standardization. In this report, eradication otic use was estimated as the number of DSD. rates were standardized to the mid-year Population of 2010 as a Korean standard population. The standard population provides age distributions to be used in the Statistical analyses estimation of age-standardized rates. The mid-year pop- Univariate analysis was performed to compare the dif- ulation of 2010 used denominator of the eradication ferences in eradication rates using chi-squared test. rate was generated using the resident registration popu- The continuous variables were analyzed by indepen- lation published annually by the Ministry of Govern- dent sample t-test. Multivariate logistic regression ment Administration and Home Affairs. analysis was performed for evaluating independent factors of H. pylori eradication success. Trend P was performed to assess the time trend of eradication rates Measurement of the amount of macrolide for the past 10 years. Statistical analyses were per- antibiotics use formed with IBM SPSS Statistics 19 Doctor’s Pack for windows. Study design. The lowest eradication rate of PAC used Paired t-test was used to compare the macrolide use as a first-line therapy for H. pylori was 67.3% in Jeju between Jeju and Chuncheon city. All statistical analy- province according to the results of this study. We ses were performed with SAS software, version 9.3. p hypothesized that the possible cause of this high eradi- values <.05 were regarded as significant differences. cation failure rate in Jeju province may be related to high clarithromycin resistance due to antibiotics con- Results sumption. Therefore, we proceeded to the next cross- sectional study from June 2013 to June 2014 to com- Baseline characteristics and H. pylori eradication pare the amount of antibiotic use from January 2008 to rates of first-line, second-line, and third-line December 2010 between the highest and lowest eradi- therapies cation areas. A total of 34,139 patients (31,886, 2108, and 145 The defined daily dose (DDD) is the assumed aver- patients in the first-, second-, and third-line therapy age maintenance dose per day for a drug used for its group, respectively) were included in this analyses. We main indication in adults. It is used to standardize the described detailed baseline characteristics and H. pylori comparison of drug usage between different drugs or eradication rates of first-line, second-line, and third-line between different healthcare environments. Thus, we therapies according to the reasons for eradication, acid assessed the 3 years’ DDD of macrolide antibiotics con- suppressive agent, treatment duration, and regimens in sumed per km2 per day (DSD) using the Health Insur- Tables 1 and 2. ance Review & Assessment (HIRA) database, which are accessible in the last 5 years, from January 2008 to December 2010 in Jeju city and Chuncheon city, where First-line therapy. In total, 31,886 patients were evalu- our eradication data had been collected in Jeju ated for the first-line therapy of H. pylori infection province and Gangwon province, respectively. Chun- (mean age, 52.9 years; male, 63.7%). The mean age of cheon city is a city located in Gangwon province and the eradication success group was younger than the had the highest eradication rate (86.2%) in this study eradication failure group (52.68 vs 54.46 years, (Table S1). p < .0001). Males had higher eradication rates than

Table 1 Baseline characteristics and Helicobacter pylori eradication rates of ﬁrst-, second-, and third-line therapies

First-line therapies Second-line therapies Third-line therapies

Eradication Eradication Eradication success success success Total rates p Value Total rates p Value Total rates p Value

Total, n (%) 31,886 (100.0) (83.7) 2108 (100.0) (83.5) 145 (100.0) (68.9) Sex, n (%) 31,886 (100.0) (83.7) <.0001 2108 (100.0) (83.5) .906 145 (100.0) (68.9) .850 Male 20,296 (63.7) (84.6) 1205 (57.2) (81.0) 83 (57.2) (70.0) Female 11,590 (36.3) (81.8) 903 (42.8) (86.5) 62 (42.8) (81.6) Reasons for eradication, n (%) 31,886 (100.0) (83.7) <.0001 2108 (100.0) (83.5) .145 145 (100.0) (68.9) .793 BGU 10,862 (34.1) (84.1) 663 (31.5) (85.0) 45 (31.0) (76.5) BDU 9796 (30.7) (84.2) 552 (26.2) (80.1) 29 (20.0) (76.5) Gastritis 6977 (21.9) (82.9) 554 (26.3) (88.0) 33 (22.8) (77.2) BGU +BDU 1729 (5.4) (86.3) 85 (4.0) (83.2) 9 (6.2) (100.0) Gastric cancer 1009 (3.2) (84.5) 94 (4.5) (71.3) 14 (9.7) (67.9) Benign gastric neoplasm 354 (1.1) (84.3) 60 (2.8) (77.2) 8 (5.5) (100.0) MALToma 315 (1.0) (85.3) 15 (0.7) (100.0) 1 (0.7) (100.0) Others 844 (2.6) (78.3) 85 (4.0) (85.5) 6 (4.1) (100.0) Acid suppression agent, n (%) 31,784 (100.0) (83.7) <.0001 2048 (100.0) (83.4) .038 139 (100.0) (68.5) .061 Pantoprazole 7948 (25.0) (81.3) 596 (29.1) (84.7) 32 (23.0) (82.9) Lansoprazole 6607 (20.8) (82.6) 470 (22.9) (85.4) 37 (26.6) (83.7) Rabeprazole 6173 (19.4) (84.0) 486 (23.7) (77.2) 35 (25.2) (84.6) Omeprazole 5438 (17.1) (85.7) 156 (7.6) (84.2) 8 (5.8) (100.0) Esomeprazole 5618 (17.7) (86.4) 340 (16.6) (87.9) 27 (19.4) (68.3) Duration of treatment, n (%) 31,886 (100.0) (83.7) <.0001 2108 (100.0) (83.5) .895 139 (100.0) (73.9) .442 <7 344 (1.1) (91.7) 41 (1.9) (92.3) 55 (39.6) (79.9) 7 23,441 (73.5) (82.5) 1434 (68.0) (81.8) 84 (60.4) (84.2) 8–13 586 (1.8) (85.1) 36 (1.7) (82.4) 14 7468 (23.4) (86.4) 594 (28.2) (86.0) >14 47 (0.1) (91.5) 3 (0.1) (100.0) Mean age, years Æ SD Total 52.98 Æ 12.86 <.0001 55.24 Æ 12.78 .122 57.55 Æ 12.69 .401 Eradication success 52.68 Æ 12.77 55.05 Æ 12.71 58.13 Æ 11.87 Eradication failure 54.46 Æ 13.17 56.22 Æ 13.11 55.81 Æ 14.96

BGU, benign gastric ulcer; BDU, benign duodenal ulcer; SD, standard deviation. females (84.6 vs 81.8%, p < .0001). The most common therapy (CT) (92.3%), BCQT (89.4%), sequential ther- reason for H. pylori eradication was benign gastric ulcer apy (ST) (91.9%), and others (82.6%) (p < .0001) (BGU) (10,862/31,886, 34.1%). The eradication rates (Table 2). ranged from 78.3% to 86.3% according to gastroduodenal diseases such as gastritis, peptic ulcer, benign gastric neoplasm, gastric cancer, and MALToma and were sig- Second-line therapy. In total, 2108 patients were evalu- nificantly different among the gastroduodenal diseases ated for the second-line therapy of H. pylori infection (p < .0001). Acid suppression agents such as pantopra- (mean age, 55.24 years; male, 57.2%). The mean age zole, lansoprazole, rabeprazole, omeprazole, and showed no differences between the eradication success esomeprazole had significantly different H. pylori eradi- and failure groups (55.05 vs 56.22 years, respectively, cation rates (p < .0001). The eradication rates were p = .122). The eradication rate did not differ according 82.5–91.7% for treatment durations such as <7, 7, 8– to sex (male, 81.0% vs female, 86.5%, p = 1.000). The 13, 14, and more than 14 days. (p < .0001) (Table 1). most common reason for H. pylori eradication was BGU The most commonly prescribed regimen for first-line (663/2108, 31.5%). The eradication rates were 71.3% therapy was PAC (30,534/31,886, 95.8%). The eradica- to 100% according to gastroduodenal diseases and did tion rates were significantly different according to the not differ among the gastroduodenal diseases treatment regimens such as PAC (83.6%), concomitant (p = .145). Acid suppression agents had significantly

Table 2 Helicobacter pylori eradication rates according to treatment there was no significant difference (p = .061). The erad- regimens ication rates were 79.9% and 84.2% according to treatment durations of <7 and 7 days, respectively Eradication (p = .442) (Table 1). The regimen most commonly pre- success scribed as a third-line therapy was BCQT (62/139, Total rates p Value 44.6%). The eradication rates were 70.5% to 86.0% First-line therapy 31,886 (100.0) (83.7) <.0001 according to treatment regimens and were significantly regimens, n (%) different among the third-line treatment regimens PAC 30,534 (95.8) (83.6) (p = .001) (Table 2). CT 303 (1.0) (92.3) BCQT 186 (0.6) (89.4) ST 126 (0.4) (91.9) Multivariate logistic regression analysis for Others 917 (2.9) (82.6) H. pylori Second-line therapy 2040 (100.0) (83.3) <.0001 assessing independent factors of regimens, n (%) eradication success BCQT 1612 (79.0) (88.3) Multivariate logistic regression analysis was performed PAC 160 (7.8) (49.5) PTM 70 (3.4) (90.6) including various valuables that could influence on PLM 44 (2.2) (74.8) H. pylori eradication rates such as age, sex, gastroduode- PAM 1 (0.0) (100) nal diseases, acid suppression agents, treatment duration, Others 153 (7.5) (67.8) and regimens. Male sex (adjusted odds ratio (AOR), 1.28; Third-line therapy 139 (100.0) (81.3) .001 95% confidence interval (CI), 1.20–1.36; p < .0001), regimens, n (%) BGU (AOR, 1.29; 95% CI, 1.09–1.53; p = .004), BDU BCQT 62 (44.6) (86.0) (AOR, 1.52; 95% CI, 1.27–1.80; p < .0001), gastritis PAL 23 (16.5) (70.6) – = + PAC 12 (8.6) (70.5) (AOR, 1.28; 95% CI, 1.07 1.52; p .007), BGU BDU – < Others 42 (30.2) (82.5) (AOR, 1.61; 95% CI, 1.30 1.99; p .0001), gastric cancer (AOR, 1.31; 95% CI, 1.04–1.65; p = .022), esomepra- P, proton-pump inhibitor; A, amoxicillin; C, clarithromycin; M, metron- zole (AOR, 1.26; 95% CI, 1.16–1.36; p < .0001), CT idazole; T, tetracycline; L, levofloxacin; CT, concomitant therapy; (AOR, 2.01; 95% CI, 1.34–3.02; p = .001), BCQT (AOR, BCQT, bismuth-containing quadruple therapy; ST, sequential therapy. 2.02; 95% CI, 1.22–3.33; p = .006), and ST (AOR, 2.40; 95% CI, 1.26–4.55; p = .007) were independent factors different H. pylori eradication rates (p = .038). The erad- of H. pylori eradication success in the first-line therapies. ication rates ranged from 81.8% to 100% according to In the second-line therapies, independent factors were treatment durations (p = .895) (Table 1). The most BCQT (AOR, 5.36; 95% CI, 3.73–7.70; p < .0001) and common regimen prescribed as a second-line therapy PTM (PPI-tetracycline-metronidazole) (AOR, 4.86; 95% was BCQT (1612/2040, 79.0%). The eradication rates CI, 2.18–10.88; p < .0001). Only BCQT (AOR, 5.19; 95% ranged from 49.5% to 100% according to treatment CI, 1.81–14.85; p = .002) was independent factor in regimens and were significantly different among the third-line therapies (Table 3). second-line treatment regimens (p < .0001) (Table 2).

Time trend of H. pylori eradication rates over the last 10 years according to eradication regimens, Third-line therapy. In total, 145 patients were evaluated age, and geographic areas for the third-line therapy of H. pylori infection (mean age, 57.55 years; male, 57.2%). The mean age was no We depicted the detailed time trend of H. pylori eradica- different between the eradication success and failure tion rates over 10 years in relation to the overall first- groups (58.13 vs 55.81 years, respectively, p = .401). line therapy, second-line therapy, PAC, BCQT, age, and The eradication rate did not differ according to sex geographic areas in Figs 1 and 2. The eradication rates of (male, 70.0% vs female, 81.6%, p = .850). The most PAC as a first-line therapy ranged from 84.9% to 87.5% common reason for H. pylori eradication was BGU (45/ from 2001 to 2007, and those of 2008, 2009, and 2010, 145, 31.0%). The eradication rates ranged from 67.9% ranged from 80.0% to 81.4% with a decreasing trend to 100% according to gastroduodenal diseases and did (p < .0001) (Fig. 1A). This decreasing trend was not differ among the gastroduodenal diseases observed in both the ≥60 and <60 years old groups (p = .793). Omeprazole had the highest eradication rate (p < .0001), although the eradication rates from 2004 to (100%) among the various PPIs investigated, although 2010 were significantly lower in the ≥60 years group

Table 3 Multivariate logistic regression analysis for independent fac- CI, 0.89–1.27; p = .526). The eradication rates of BCQT tors of Helicobacter pylori eradication success were also not statistically different between gastric cancer and gastritis patients (92.2% vs 94.6%; OR, 1.85; Independent Adjusted 95% conﬁdence 95% CI, 0.81–4.28; p = .145). PAC used as a ﬁrst-line p factors odds ratio interval Value therapy had higher eradication rates in patients with

First-line Male 1.28 1.20–1.36 <.0001 benign duodenal ulcer (BDU) than in those with gastric – therapies BGU 1.29 1.09–1.53 .004 ulcer (84.5% vs 82.5%; OR, 1.14; 95% CI, 1.06 1.23; BDU 1.52 1.27–1.80 <.0001 p < .0001), whereas the eradication rates of BCQT used Gastritis 1.28 1.07–1.52 .007 as a second-line therapy were not significantly different BGU + BDU 1.61 1.30–1.99 <.0001 between patients with benign duodenal and gastric – Gastric cancer 1.31 1.04 1.65 .022 ulcer (87.5% vs 85.4%; OR, 1.15; 95% CI, 0.78–1.69; Esomeprazole 1.26 1.16–1.36 <.0001 p = .488) (Table 4). CT 2.01 1.34–3.02 .001 BCQT 2.02 1.22–3.33 .006 Gangwon province had the highest eradication rate ST 2.40 1.26–4.55 .007 for PAC used as a first-line therapy, whereas Jeju pro- Second-line BCQT 5.36 3.73–7.70 <.0001 vince the lowest (86.2% vs 67.3%). The eradication therapies PTM 4.86 2.18–10.88 <.0001 rate for PAC in Jeju province was significantly lower Third-line BCQT 5.19 1.81–14.85 .002 than in other geographic areas. Chungcheong province therapies had the highest eradication rate for BCQT used as a second-line therapy, whereas Jeju province had the lowest BGU, benign gastric ulcer; BDU, benign duodenal ulcer; CT, concomitant therapy; BCQT, bismuth-containing quadruple therapy; ST, (92.3% vs 77.3%). The eradication rates for BCQT were sequential therapy; P, proton-pump inhibitor; T, tetracycline; M, significantly higher than those of PAC in Chungcheong metronidazole. province (92.3% vs 84.6%, p = .023), Seoul (88.7% vs 83.2%, p = .001), Gyeongsang (90.8% vs 80.2%, p = .001), and Jeju province (77.3% vs 67.3%, p = .002) (Fig. 1A). The eradication rates of BCQT as a second-line (Fig. 3). therapy were 91.8%, 83.2%, 92.1%, 85.5%, 93.2%, 91.4%, 93.4%, 93.7%, 88.2%, and 85.7% for each year DDD per km2 per day (DSD) of macrolide from 2001 to 2010 without significant changes antibiotics by generic name in Chuncheon and (p = .352) (Fig. 1B). There was no change in the eradi- Jeju city cation rates in both the ≥60 (p = .431) and <60 years old groups (p = .577) over those 10 years (Fig. 1B). The ages and genders of patients who were prescribed The decreasing trend of eradication rates of overall macrolide antibiotics in Chuncheon (n = 49,155) and first-line and second-line therapy was observed in three Jeju city (n = 91,864) from January 2008 to December of seven geographic areas in Korea, specifically, Chung- 2010 are shown in Table S2. The number of prescrip- cheong province, Seoul, and Gyeongsang province tions of macrolide antibiotics in the two cities under (p < .0001) (Fig. 2). generic names including azithromycin, clarithromycin, erythromycin, roxithromycin, and telithromycin is shown in Table S3. The most commonly prescribed H. pylori eradication rates according to treatment macrolide was roxithromycin in both Chuncheon (56/ durations, gastroduodenal diseases, and 9%) and Jeju city (62.1%). The mean DSD of macro- geographic areas lide antibiotics was significantly higher in Jeju than in We described and depicted detailed H. pylori eradication Chuncheon city (0.85 vs 0.52, p < .0001). The mean rates according to treatment durations, gastroduodenal DSD of clarithromycin was significantly higher in Jeju diseases, and geographic areas in Table 4 and Fig. 3. than in Chuncheon city (0.29 vs 0.27, p = .006) The eradication rate of 14-day PAC used as a first- (Table 5). The fluctuating monthly DSD of overall line therapy was significantly higher than that of 7-day macrolide antibiotics and clarithromycin is depicted in PAC (86.9% vs 82.4%; OR, 1.43; 95% CI, 1.32–1.55; Fig. 4. The DSD had the lowest value from July to p < .0001). However, there was no difference in eradi- September each year in both Chuncheon and Jeju city. cation rates between 14-day and 7-day BCQT used as a second-line therapy (86.6% vs 92.0%; OR, 1.07; 95% Discussion CI, 0.75–1.54; p = .696). The eradication rates of PAC were not statistically different between gastric cancer The time trend of overall first-line and second-line and gastritis patients (87.9% vs 82.7%; OR, 1.05; 95% eradication rates for H. pylori have decreased over the

Figure 1 The time trend of H. pylori eradication rates over the last 10 years. (A) The eradication rates of PAC as a first-line therapy showed a decreasing trend (p < .0001). This trend was observed in both the ≥60 and <60 years old groups (p < .0001). However, the eradication rates were significantly lower in the patients ≥60 years of age from 2004 to 2010. (B) The eradication rates of BCQT as a second-line therapy did not change (p = .352) regardless of age. PAC, proton-pump inhibitor-amoxicillin-clarithromycin; BCQT, bismuth-containing quadruple therapy. past 10 years in Korea. However, the trends were dif- different guidelines should be applied for H. pylori erad- ferent in subgroup analysis depending on geographic ication based on the data for antibiotics resistance for area. Only three of seven regions, Seoul, Chuncheong, regional areas within the same country or ethnic group and Gyeongsang province, showed a decreasing trend [3,15]. Fortunately, BCQT can be recommended as a in first-line and second-line eradication rates. We can- first-line regimen in these three regions (Seoul, Chun- not found the comparable regional characteristics cheong, and Gyeongsang province) because the eradica- among these three regions including demographic and tion rates of BCQT were about >90% and were geographic factors. However, this result can be partially significantly higher than PAC as shown in Fig. 3. explained by differences in antibiotics resistance accord- Surprisingly, the mean eradication rate of PAC used ing to geographic area, although drug compliance, bac- as a first-line therapy in Jeju province for 10 years was terial load, and type of strain of H. pylori can impact on only 67.3%, whereas that in Gangwon province was eradication rates [19]. One Korean study reported that 86.2%. This result is possibly associated with the the resistance rate of clarithromycin prepared by the amount of antibiotics usage and population density, agar dilution method was 42.1% in Busan city, Gyeon- which are closely related to antibiotics resistance [16– sang province, whereas that of Gangwon province, 18,21]. We postulated that population density might be which did not show any changes in eradication rate in a important factor for the development of antibiotics this study, was 12.5% [20]. This result indicates that resistance because the main route of H. pylori infection,

Figure 2 The time trend of H. pylori eradication rates over the last 10 years according to geographic area. The decreasing trend of eradication rates for overall ﬁrst- (A) and second-line (B) therapy was observed in three of seven geographic areas: Chungcheong province, Seoul, and Gyeongsang province (p < .0001).

Table 4 The differences in Helicobacter pylori eradication rates according to treatment durations and gastroduodenal diseases

PAC as a primary therapy BCQT as a secondary therapy

Success Odds (95% CI) p Value Success Odds (95% CI) p Value

Treatment duration, n/N (%) 24,786/29,792 (83.6) 1421/1585 (84.4) 7 days 18,968/23,102 (82.4) 1 1014/1133 (86.6) 1 14 days 5818/6690 (86.9) 1.43 (1.32, 1.55) <.0001 407/452 (92.0) 1.07 (0.75,1.54) .696 Gastric lesions, n/N (%) 5959/7215 (82.7) 427/462 (94.3) Gastric cancer 766/937 (87.9) 1 57/65 (92.2) 1 Gastritis 5193/6278 (82.7) 1.05 (0.89,1.27) .526 370/397 (94.6) 1.85 (0.81,4.28) .145 Peptic ulcer diseases, n/N (%) 16,670/19,973 (83.8) 848/962 (86.1) BGU 8688/10,526 (82.5) 1 468/527 (85.4) 1 BDU 7982/9447 (84.5) 1.14 (1.06,1,23) <.0001 380/435 (87.5) 1.15 (0.78,1.69) .488

BCQT, Bismuth-containing quadruple therapy; P, proton-pump inhibitor; A, amoxicillin; C, clarithromycin; B, bismuth; M, metronidazole; T, tetracycline; CI, conﬁdence interval; BGU, benign gastric ulcer; BDU, benign duodenal ulcer. although still unclear, appears to be interpersonal trans- In fact, the DSD of macrolide of Jeju city in Jeju pro- mission via the fecal-to-oral route [22]. Therefore, we vince was statistically higher than that of Chuncheon calculated the DSD (DDD/km2) rather than DID (DDD/ city in Gangwon province in the present study 1000 inhabitants) in the two cities [16]. Furthermore, (p < .0001). Especially, there is no doubt that previous we included all kinds of macrolide antibiotics for calcu- exposure to clarithromycin is one of the major causes lating DSD because it is well known that macrolide of resistance development based on some studies antibiotics have cross-resistance with each other [14]. reporting that the second-line resistance of clar-

Figure 3 The mean H. pylori eradication rates for the last 10 years according to geographic area. The eradication rates of BCQT were signiﬁcantly higher than those of PAC in Chungcheong province (p = .023), Seoul (p = .001), Gyeongsang (p = .001), and Jeju province (p = .002). PAC, proton- pump inhibitor-amoxicillin-clarithromycin; BCQT, bismuth-containing quadruple therapy.

Table 5 Deﬁned daily doses per km2 per day p of macrolide and clarithromycin by generic DSD Chuncheon city Jeju city Difference Value name in Chuncheon and Jeju city from Jan- Æ Æ Æ À Æ < uary 2008 to December 2010 Macrolide Mean SD 0.52 0.08 0.85 0.16 0.33 0.10 .0001 Median 0.52 0.86 À0.34 Clarithromycin Mean Æ SD 0.27 Æ 0.04 0.29 Æ 0.05 À0.021 Æ 0.03 .006 Median 0.27 0.29 À0.02

DSD, deﬁned daily doses per km2 per day; SD, standard deviation.

ithromycin for H. pylori was significantly higher than exposure, lower compliance, or additional underlying the first-line resistance [14,23]. However, it is unclear chronic diseases including diabetes [29] in elderly at this point that why Jeju city has increased macrolide patients may also explain the result. However, taking use. In summation, as antibiotic use is generally into consideration of second-line resistance of clar- accepted as the main factor determining antibiotics ithromycin for H. pylori than that of metronidazole, resistance, macrolide-resistant H. pylori following previ- prior macrolide antibiotics exposure may be a possible ous macrolide exposure might be the main cause of the cause for reduced eradication rate in elderly patients low eradication rate in Jeju province, although there is only with PAC not BCQT. still no data on the resistance rate of clarithromycin Interestingly, BCQT was most commonly prescribed prepared by the agar dilution method in Jeju province. regimen as a third-line therapy, which was also the Thus, new strategies such as tailored therapy, a pre- most frequently prescribed as a second-line regimen in treatment antimicrobial susceptibility-guided method this study. There is a next therapeutic dilemma in [24], will be needed to improve the first-line eradica- patients with persistent H. pylori infection after second- tion rate in Jeju province after conducting well-de- line eradication therapy because no standard third-line signed epidemiologic, experimental, and clinical studies therapy has been established in Korea. Some studies on the prevalence of antibiotics resistance for H. pylori, reported success of immediate retreatment with the compliance, bacterial load, and type of strain. same regimen, although rescue therapies generally con- The time trend of the first-line eradication rate of sist of two or more antibiotics that were not used previ- H. pylori treating PAC decreased especially in the ous treatment without knowing the H. pylori resistance patients aged 60 and older, whereas the second-line status. [30,31] In fact, one Korean study reported that eradication rate of BCQT did not change over the the third-line eradication rate of immediately repeated 10 years studied. The eradication rates of PAC after the same treatment of second-line BCQT was 75.0% 2004 in the older patients (≥60 years) were significantly (95% CI 71.3–78.7%) in PP analysis after the failure of lower than in the patients <60 years of age. Some pre- second-line quadruple therapy. [31] This result can be vious studies provide evidence for this result [25,26]. partially explained by the fact that resistance to metron- However, the evidence is still debated because of con- idazole can frequently be overcome by increasing the flicting results [27,28]. A higher likelihood of antibiotics dose and duration of treatment. One meta-analysis

Figure 4 The ﬂuctuating monthly deﬁned daily doses per km2 per day (DSD) of (A) overall macrolide antibiotics and (B) clarithromycin in Chun- cheon and Jeju city from January 2008 to December 2010. The DSD had the lowest value from July to September each year in both Chuncheon and Jeju city.

reported that nitroimidazole resistance did not signifi- On the other hand, quinolone-containing therapy cantly influence H. pylori eradication rate when quadru- can be used as a third-line therapy. However, the H. py- ple regimens were used for 7 days [32]. lori eradication rates with levofloxacin-containing

10 © 2015 John Wiley & Sons Ltd, Helicobacter Shin et al. Eradication Rates of Helicobacter pylori and Correlation of Antibiotic Use Density rescue therapies were only 69.8% in PP analysis as a of this bias would be minimal because we selected the first-line and second-line treatment in Korea [33]. This hospitals in proportion to the population and tried to result can be explained by the increasing trend of resis- include all patients treated for H. pylori at the institu- tance to quinolone for H. pylori in Korea. Resistance tions from 2001 to 2010 in our search strategies, men- rate to levofloxacin has been reported to be increasing tioned above in the methods section. We also validated from 4.5% in 2003–2005 to 29.5% in 2007–2009. Simi- our CRF to minimize input error and interinvestigator larly, there was a significant increase in ciprofloxacin discrepancy by performing the preliminary study. 3) resistance from 16.7% during 2003–2005 to 34.6% in We investigated the DSD of macrolide only from 2008 2007–2009. In particular, the MIC patterns of ciproflox- to 2010 because HIRA data were accessible in the last acin and levofloxacin showed a bimodal distribution 5 years from 2013, even though reduced eradication representing typical resistance pattern in 2007–2009 rates can be a result of prior antibiotic exposure. How- [34]. Therefore, use of quinolone as a third-line therapy ever, the results of DSD had little bias because of com- has been limited in Korea. plete enumeration survey in the two cities. The 14-day PAC treatment regimen had a signifi- In conclusion, the H. pylori eradication rates of PAC cantly higher eradication rate than the 7-day regimen showed decreasing trends over the past 10 years, possi- (OR, 1.43; 95% CI, 1.32–1.55; p < .0001). Two meta- bly due to an increase of antibiotics usage in Korea. analyses provide evidence for our result [35,36]. A 14- Reasonable guidelines for H. pylori eradication should day treatment improved the eradication rate by 5–9% be applied based on the data for antibiotics resistance in and showed no difference in the side effects compared to each regional area because the decreasing trend of a 7-day treatment. Although the 2013 revised Korean H. pylori eradication rate was confined to only three guideline of H. pylori treatment recommends a 7– geographic areas. 14 days of treatment duration for PAC [15], extending the treatment duration to 14 days should be considered Acknowledgments and Disclosures in the regions with decreased trends in eradication rates. Benign duodenal ulcer was associated with Competing Interests: The authors have no competing inter- improved eradication using PAC compared to BGU in ests. this study. Higher eradication rates in patients with BDU have previously been reported [37]. However, this Author Contributions result is inconclusive because of previous contrasting results [25,38–42]. Jae Gyu Kim and Jae J. Kim are guarantors of article The strength of our study lies in its vast scale and and involved in final approval of the article. Woon use of nationwide data, unlike previous single center Geon Shin, Sang Woo Lee, Hye-kyung Jung, Hee Mo studies that reported discrepancies for the time trend of Kang, Joongyub Lee, Jae Gyu Kim, and Jae J. Kim eradication rates in Korea [10–12]. We found that involved in study design. Woon Geon Shin, Sang Woo BCQT can be used as a first-line regimen at three Lee, Gwang Ho Baik, Kyu Chan Huh, Sang In Lee, regions in Korea. Furthermore, we demonstrated that Jun-Won Chung, Woon Tae Jung, Moo In Park, Hye- the amount of macrolide antibiotics usage was linked to kyung Jung, Heung Up Kim, Jeong Hwan Kim, Sang the eradication rate of H. pylori in two geographic areas Young Seol, Soon Man Yoon, Seong Woo Jeon, Su Jin using the HIRA data for about 140,000 people. Based Hong, Gwang Ha Kim, Dong Ho Lee, Hyun Soo Kim, on this result and taking into account the fact that the Suck Chei Choi, and Jae Gyu Kim enrolled the subjects eradication rates of both PAC and BCQT in Jeju pro- and collected the data. AnWoon Geon Shin, Sang Woo vince were <80%, special recommendations such as tai- Lee, Hye-kyung Jung, Hee Mo Kang, Joongyub Lee, lored therapy may be needed in this region. Jae Gyu Kim, Jae J. Kim, Gwang Ho Baik, Kyu Chan There are some limitations in this paper: (1) We Huh, Sang In Lee, Jun-Won Chung, Woon Tae Jung, could not apply the same cut-off value for the UBT test and Moo In Park took part in analysis and interpreta- among the hospitals. This can be a confounding factor. tion of the data. Woon Geon Shin drafted the article. (2) This study has a chance of selection bias because of Critical revision of the article: Sang Woo Lee, Jae Gyu the retrospective manner for data collection and miss- Kim, and Jae J. Kim, Heung Up Kim, Jeong Hwan ing data in the selected secondary or tertiary hospitals. Kim, Sang Young Seol, Soon Man Yoon, Seong Woo Actually, institutional differences in the eradication rate Jeon, Su Jin Hong, Gwang Ha Kim, Dong Ho Lee, of H. pylori may be possible because of institutional dif- Hyun Soo Kim, and Suck Chei Choi involved in critical ferences in the antibiotic resistance of H. pylori within revision of the article. All authors approved the final the same region [43]. However, we think that the effect version of the article, including the authorship list.

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