Helicobacter pylori infection: several studies on epidemiology, eradication and gastric epithelial cell turnover Liu, W.

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1 UvA-DARE (Digital Academic Repository) Helicobacter pylori infection: several studies on epidemiology, eradication and gastric epithelial cell turnover Liu, W. Link to publication Citation for published version (APA): Liu, W. (1999). Helicobacter pylori infection: several studies on epidemiology, eradication and gastric epithelial cell turnover General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 02 Dec 2018

2 CHAPTER 4 Furazolidone-Containing Short-Term Triple Therapies Are Effective in the Treatment of Helicobacter pylori Infection Wen-Zhong Liu 1, Shu-Dong Xiao 1, Yao Shi 1, Shu-Ming Wu 1, De-Zhong Zhang 1, Wei-Wen Xu! and Guido NJ Tytgat 2 Shanghai Institute of Digestive Disease, Shanghai Second Medical University, Shanghai, People's Republic of China Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands Aliment Pharmacol Ther 1999;13:

3 Abstract Background/Aim: A furazolidone-containing therapeutic regimen for H. pylori infection has attracted special interest in the face of a world-wide rising resistance of H. pylori to metronidazole and the expense of currently used anti-microbial regimens. The aim of this study was to evaluate the efficacy of furazolidone-containing regimens in eradicating H. pylori. Methods: One hundred and forty H. pylori positive patients with endoscopically confirmed duodenal ulcer or functional dyspepsia received one of four different regimens to eradicate H. pylori. In the first trial, the patients were randomly assigned to receive a one-week course of furazolidone loomg bd and clarithromycin 250mg bd, with either tripotassium dicitrato bismuthate (TDB) 240mg bd (FCB group) or lansoprazole 30mg daily (FCL group). In the second trial, the patients were randomly assigned to receive a one-week course of clarithromycin 250mg bd and omeprazole 20mg daily, with either furazolidone loomg bd (FCO group) or metronidazole 400mg bd (MCO group). Endoscopy was repeated four weeks following completion of therapy with re-assessment of H. pylori status on gastric biopsies by histology and culture. Results: Four patients (1 in FCB, 1 in FCO and 2 in MCO groups) dropped out because they refused follow-up endoscopy. Eradication rates of H. pylori on intention-to-treat basis in FCB, FCL, FCO and MCO groups were 91.4% (32/35, 95% CI= %), 91.4% (32/35, CI = %), 85.7% (30/35, CI= %) and 74.3% (26/35, CI= %) (all P>0.05), respectively. Mild side effects occurred in 15.0% of the 140 patients. In MCO group, the eradication rate in the patients infected with metronidazole-sensitive isolates of H. pylori was 85.7%, but dropped to 66.6% in those with metronidazole-resistance strains (P=0.198). Conclusion: One-week regimens containing furazolidone and clarithromycin in combination with TDB or a proton pump inhibitor fulfill the criteria for successful H. pylori therapy. 60

4 Introduction Several indications to eradicate H. pylori are now well established(l,2). However, the ideal regimens for treatment of H. pylori infection have not yet been defined. The combination of metronidazole / tetracycline / bismuth or metronidazole/ clarithromycin/ proton pump inhibitor (PPI) are currently considered standard regimens for the treatment of H. pylori infection (3-5). The eradication rates are higher than 80% if the H. pylori strains are sensitive to metronidazole (MET). However, MET resistance is a rising problem world-wide, particularly in developing countries, which limits the usefulness of this drug (6-9). Furazolidone(FUR), a nitrofuran in clinical use for over 30 years, has a favorable safety profile and is relatively inexpensive. It was used in China for the treatment of peptic ulcer disease long before H. pylori was discovered as an etiological agent in this disease(10,ll). In the last decade, FUR has been found to be effective for eradication of H. pylori(\2-\a), and furthermore, serial passage of H. pylori culture containing FUR did not result in development of FUR-resistance, suggesting that resistance will not easily emerge(15). However, efficacious FUR-containing regimens have not yet been established. In the present study we used FUR and clarithromycin (CLA) in combination with either tripotassium dicitrato bismuthate (TDB) or a PPI to evaluate the efficacy of FUR as a replacement for MET in standard " triple therapy " regimens currently advocated to eradicate H. pylori. Materials and Methods Study Design The study consisted of two trials. In trial one, we used FUR and CLA in combination with either lansoprazole (LAN), or TDB to compare the efficacy of PPIbased triple versus bismuth-based triple therapy. In trial two, we used omeprazole (OME), an alternative PPI and CLA in combination with either FUR or MET to 61

5 compare the efficacy of FUR with MET in the eradication of H. pylori, particularly for MET-resistant isolates of H. pylori. Patients and Endoscopy The patients were recruited from those visiting the endoscopy unit at Shanghai Institute of Digestive Disease. H. pylori infected patients diagnosed with duodenal ulcer (DU) or functional dyspepsia (FD) were eligible to enter the study. Informed consent was obtained from the patients entered into the study. All patients had no history of previous anti-i/. pylori therapy. Pregnancy, major organic or systemic diseases, previous gastric surgery, or use of either antibiotics or PPI in the preceding 4 weeks precluded entry into the study. Endoscopy was performed within 3 days prior to treatment and again 4 weeks after the cessation of treatment. Assessment of H. Pylori Status At endoscopy, two biopsy specimens were taken from the antrum as well as the gastric corpus for histology (Hematoxylin & Eosin and Warthin-Starry stains). Two additional biopsy specimens were obtained from the antrum, one for culture and one for rapid urease testing. H. pylori sensitivity to CLA, MET, and FUR were performed on culture isolates using the in vitro disk diffusion method. The diagnosis of H. pylori infection was based upon positive culture and/or positive histology. Rapid urease testing served only as a screening test to facilitate the initiation of therapy immediately after endoscopy. H. pylori eradication was defined as absence of H. pylori by culture and histology from gastric biopsies obtained 4 weeks after completion of triple therapy. Treatment Patients included in this study were randomly assigned to receive one of the oneweek regimens listed in Table 1. All medicines were taken after meals. 62

6 Table 1. One-week znti-h. pylori treatment regimens Study phase Regimen Drugs combination Dosage loomg bd FCB 250mg bd Trial One 240mg bd loomg bd Trial Two FCL FCO MCO Furazolidone Clarithromycin TDB Furazolidone Clarithromycin Lansoprazole Furazolidone Clarithromycin Omeprazole Metronidazole Clarithromycin Omeprazole 250mg bd 30mg bd loomg bd 250mg bd 20mg qd 400mg bd 250mg bd 20mg qd The specific treatment regimen was known to the patient and the physician in charge, but the microbiologist and pathologist were blinded with regard to the treatment arm. During the treatment period of 7 days the patients were required to keep a diary documenting symptoms and compliance with the medication. Antimicrobials, bismuth-containing drugs, acid pump inhibitors and H 2 -receptor antagonists were not allowed during the four weeks preceding the second endoscopy. Statistical Analysis Intention-to-treat (ITT) analysis was used to assess the eradication rates of H. pylori in all groups. Eradication rates, DU healing rates and frequencies of side effects were compared using the chi-square test. The significance level was set at P O.05. Results One hundred and forty patients were included in this study with 35 patients in each group. Four patients (one in FCB group, one in FCO group and two in MCO 63

7 Table 2. Demographic and endoscopic data of patients in the treatment groups at entrance FCB FCL FCO MCO No.of patients Sex female/male 9/26 10/25 8/28 12/22 Age (S.D) 44.2 ± ± 13.6 Diagnosis DU Active stage in remission FD group) were excluded from analysis regarding eradication and ulcer healing because they refused a follow-up endoscopy. One hundred and thirty-six patients completed a course of treatment and underwent follow-up endoscopy. Relevant demographic and endoscopic data at entrance are provided in Table 2. Eradication Rates of H. Pylori H. pylori eradication rates are provided in Table 3. There were no significant differences in the eradication rate between FCB and FCL groups (P>0.05 ), or between FCO and MCO groups (P>0.05) on the basis of ITT analysis. Table3. H. pylori eradication rates in the treatment groups (ITT analysis) Group Eradication ~95%CÎ FCB 91.4% (32/35) % FCL 91.4% (32/35) % FCO 85.7% (30/35) % MCO 74.3% (26/35) % Healing Rates of Duodenal Ulcer 64

8 The healing rates of active DU in each of the treatment groups are provided in Table 4. There were no significant differences in healing rate between the treatment groups (P>0.05). Table 4. Healing rates of active duodenal ulcers Group Healing rates of DU FCB 94.4% (17/18) FCL 100% (18/18) FCO 93.3% (14/15) MCO 85.7% (12/14) Resistance of H. pylori to Antimicrobials and Its Impact on Efficacy of Treatment One hundred and thirty strains of H. pylori were successfully isolated, and analysed for sensitivity to CLA, MET and FUR. The primary resistance rates of H. pylori strains to the antibiotics used in this study are shown in Table 5. No isolates were resistant to FUR. Primary resistance to CLA was 6.2% (8/130). Of the 8 patients with H. pylori strains resistant to CLA, only one (in group FCB) responded to therapy. Among the 16 patients who failed eradication, 7 were infected with H. pylori strains primarily resistant to CLA. Of the remaining 9 patients, 3 (one from each of FCL, FCO, and MCO groups ) had H. pylori strains which demonstrated resistance to CLA only after treatment. The primary resistance rate of H. pylori strains to MET was 38.5% (50/130). In MCO group, H. pylori eradication was achieved in 66.6% (8/12) of patients with isolates resistant to MET compared with 85.7% (18/21) of patients with isolates sensitive to MET (P=0.198). Side Effects Medication side effects are listed in Table 6. Twenty-one of 140 (15.0%) patients reported probable medication-related side effects, which were mild and disappeared after the medication was discontinued. None of these side effects resulted in cessation of treatment. There were no significant differences in the rate of side effects between 65

9 the treatment groups (P>0.05). Table 5. Primary resistance of H. pylori to antibiotics used in this study. No.of Primary resistance of H. pylori to the antibiotics Group Isolates CLA-R MET-R FUR-R LA+MET-R FCB FCL FCO MCO Total (6.2%) 50 (38.5%) 0(0) 6 (4.6% ) Table 6. Side effects occurred in the patients of tl lis study FCB FCL FCO MCO Taste disturbance Nausea Fatigue 1 Dizziness 1 Total 6(17.1%) 6(17.1%) 7 (20.0%) 8 (22.9%) Discussion A rapid increase in H. pylori resistance to metronidazole (MET), an important component of most H. pylori eradication regimens, warrants careful consideration of alternative agents. Because of demonstrated anti-i/. pylori activity as well as an anticipated lower rate of H. pylori resistance to furazolidone (FUR), this agent has attracted the attention of H. pylori researchers, and new FUR-containing regimens have been proposed and tested [16-18]. Using a combination of FUR, amoxycillin and bismuth for two weeks, eradication was achieved in 86% of patients treated (17). Dual therapies, using either a combination of FUR plus TDB or FUR plus OME appear to be somewhat less effective(16,18). In the first trial, we showed that eradication rates of these two FUR-containing triple regimens were both higher than 90% based on the ITT analysis, suggesting that 66

10 TDB and PPI are similar in efficacy with FUR and CLA even though their mechanisms of action differ. The side effects of these regimens were mild and well-tolerated, the dosages low, and the course of therapy relatively short. These two regimens, therefore, fulfill the criteria for successful H. pylori therapy (2, 5). In the second trial, the eradication rate of H. pylori in FCO group was 85.7% (30/35), vs. 74.3% (26/35) in MCO group (P=0.232). Similarly, eradication rate in MCO group was 66.6% in patients with MET-resistant isolates of//, pylori compared with 85.7% in patients with MET-sensitive isolates (P=0.198). The existence of METresistant strains may account for a relatively lower eradication rate in the MCO groups compared to the FCO group regimen although the difference did not reach statistical significance. Among five patients (2 in FCB group, 3 in FCL group) who failed to be eradicated in the first trial, four patients were infected with H. pylori strains resistant to CLA. Primary CLA-resistance of H. pylori appeared to be the explanation for treatment failure as reported by others (19). FCB, FCL or MCO regimens are each effective one-week regimens for eradicating H. pylori and healing of duodenal ulcer, confirming the observation of others that H. pylori eradication is effective treatment for duodenal ulcer disease (20,21). Furazolidone is an attractive, efficacious and relatively cheap alternative to metronidazole in one-week regimens to eradicate H. pylori. References 1. NIH Consensus Development Panel. H. pylori in peptic ulcer disease. JAMA 1994;272: The European H. pylori Study Group. Current European concepts in management of// pylori infection. The maastricht Consensus Report. Gut 1997; 41: Van der Hulst RWM, Keller JJ, Rauws EA, Tytgat GNJ. treatment of//, pylori 67

11 infection: A review of the world literature. Helicobacter 1996; 1: Walsh JH, Peterson WL. The treatment of H. pylori infection in the management of peptic ulcer disease. N Engl J Med 1995; 333: Lam SK, Talley NJ. Report of the 1997 Asia pacific consensus conference on the management of H. pylori infection. J Gastroenterol. Hepatol. 1998;13: Xia HX, Buckley M, Hyde D, keane CT, O'Morain CA. Effects of antibioticresistance on clarithromycin-combined triple therapy for H. pylori. Gut 1995;37 (suppl): A Noach LA, Langenberg WL, Bertola MA, Dankert J, Tytgat GNJ. Impact of metronidazole resistance on the eradication of H. pylori. Scand J Infect Dis 1994;26: Reddy R, Osato M, Gutierrez O, Kim JG, Graham DY. Metronidazole resistance is high in Korea and Colombia and appears to be rapidly increasing in the US. Gastroenterology 1996;110:A de Boer WAD, Tytgat GNJ. The best therapy for H. pylori infection: Should efficacy or side-effect profile determine our choice. Scand J Gastroenterol 1995;30: Zheng ZT, Wang ZY, Chu YX, et al. Double-blind short term trial of furazolidone in peptic ulcer. Lancet 1985; i: Zheng ZT, Wang YB. Treatment of peptic ulcer disease with furazolidone. J Gastroenterol. Hepatol. 1992;7: Morgan D, Kraft W, Bender M, Pearson A. Nitrofurans in the treatment of gastritis associated with Campylobacter pylori. The Gastrointestinal Physiology Working Group of Cayetano Heredia and The Johns Hopkins Universities. Gastroenterology 1988; 95: Graham DY Klein PD, Opekum AR, et al. In vivo susceptibility of Campylobacter pylori. Am J Gastroenterol 1989; 84:

12 14. Xiao SD, Liu WZ, Xia DH, et al. The efficacy of furazolidone and metronidazole in the treatment of chronic gastritis associated with Helicobacter(Campylobacter) pylori-a randomized double-blind placebo-controlled clinic trial. Hepato- Gastroenterology 1990;37: Haas CE, Nix DE, Schentag JJ. In vitro selection of resistant H. pylori. Antimicrob Agents Chemother 1990;34: Xiao SD, Liu WZ, Lin GJ, et al. TDB combined therapy for eradication of Helicobacter pylori. Chinese Journal of Digestion 1995;15(suppl): Segura AM, Gutierrez O, Otero W, Angel A, Genta RM, Graham DY. Furazolidone, amoxycillin, bismuth triple therapy for H. pylori infection. Aliment Pharmacol Ther 1997;11: Van Zwet AA, Thijs JC, Van der Wouden EJ, Kooy A. Low cure rate of Helicobacter infection with omeprazole and furazolidone dual therapy for one week. Aliment Pharmacol Ther 1997; 11: Cayla R, Zerbib F, Talbi P, et al. Pre- and post-treatment clarithromycin resistance of H. pylori strains: A key factor of treatment failure. Gut 1995;37(suppl2):A Forne, M, Viver JM, Espinos JC, et al. Impact of colloidal bismuth subcitrate in the eradication rates of H. pylori infection- associated duodenal ulcer using a short treatment regimen with omeprazole and clarithromycin: A randomized study. Am J Gastroenterol 1995;90: Hosking SW, Ling TKW, Chung SCS, et al. Duodenal ulcer healing by eradication of H. pylori without anti-acid treatment: randomized controlled trial. Lancet 1994;343:

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