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

Transcription

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: 12 Jan 2018

2 CHAPTER 5 High Cure Rate of H. pylori Infection Using Tripotassium Dicitrato Bismuthate, Furazolidone and Clarithromycin Triple Therapy for One Week Shu-Dong Xiao 1, Wen-Zhong Liu 1, Pin-Jin Hu 2, De-Huang Xia 3 and Guido NJ Tytgat 4 1 Shanghai Institute of Digestive Disease, Shanghai Second Medical University, Shanghai, P. R. China 1 First Affiliated Hospital, Sun Yat Sen University of Medical Science J,P. R. China Shanghai First Textile Bureau Worker's Hospital, P. R. China Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands Aliment Pharmacol Ther 1999:13:

3 Abstract Background/Aim: When metronidazole is used in bismuth-based or proton pump inhibitor-based triple therapy, the cure rate of H. pylori is usually high. However, metronidazole-resistance H. pylori strains, which are increasing in frequency, are the main cause of failed H. pylori eradication. The aim of this study was to evaluate the efficacy of non-metronidazole containing bismuth-based triple therapy for H. pylori infection. Methods: One hundred and eighty H. pylori positive patients with endoscopically documented peptic ulcer disease or functional dyspepsia were randomly assigned to one of three one-week regimens containing tripotassium dicitrato bismuthate 240mg bid and two antibiotics: furazolidone loomg bid and clarithromycin 250mg bid (Group A); clarithromycin 250mg bid and amoxycillin looomg bid (Group B); or furazolidone 100mg bid and josamycin looomg bid (Group C). H. pylori status was assessed by rapid urease test, histology and culture of gastric biopsy specimens taken from both the antrum and corpus before and at least 4 weeks after completion of therapy. Results; Thirteen patients dropped out (3 in group A, 5 in group B and 5 in group C). Based on intention-to-treat analysis, the eradication rates achieved in group A, B and C were 88.3% (53/60), 58.3% (35/60) and 76.7% (46/60) respectively. These differences were significant between group A and group B (po.001), as well as between group B and group C (p<0.05). Side effects occurred in 7 (11.7%) patients in group A, 3 (5.0%) in group B and 8 (13.3%) in group C, and were mild with the exception of vomiting in one patient (group C) resulting in withdrawal from the study. Conclusion: One week triple therapy consisting of tripotassium dicitrato bismuthate, low dose furazolidone and low dose clarithromycin achieves a high cure rate of//, pylori. 72

4 Introduction H. pylori infection is associated with a spectrum of gastroduodenal diseases. The eradication of H. pylori has been recommended for most of H. pylori associated diseases, particularly for peptic ulcer disease(l-3). However, the ideal regimen for treatment of H. pylori infection has not yet been established. Because no single agent provides acceptable rates of cure, combination regimens are presently required for treatment of H. pylori infection. The classical bismuth-based triple therapy with a combination of tripotassium dicitrato bismuthate (TDB), tetracycline (or amoxycillin) and metronidazole are considered standard regimens for treatment of H. pylori infection (3, 4-5). The eradication rates are high if H. pylori strains are sensitive to metronidazole. However metronidazole resistance is becoming an increasing problem world-wide, which will limit the usefulness of metronidazole-containing regimens(6-9). This concern has prompted the search for effective, inexpensive, non-metronidazole therapies(lo). Furazolidone has been found to be highly effective for eradication of H. pylori (11-14) with in-vitro studies suggesting a relatively low risk of developing resistance(15). Clarithromycin is an important component of successful triple therapies for treatment of H. pylori infection. Josamycine, another macrolide in clinical use for many years, has not been extensively evaluated so far. In the present study we used TDB containing triple therapy regimens and furazolidone, clarithromycin, amoxycillin or josamycin to evaluate the efficacy of these non-metronidazole regimens. Materials and Methods Patients and Endoscopy The patients were recruited from the endoscopy suites at Shanghai Institute of Digestive Disease, First Affiliated Hospital of Sun Yat Sen University of Medical 73

5 Science, Shanghai First Textile Bureau Worker's Hospital in P. R. China, where they were undergoing evaluation for clinical symptoms and subsequently diagnosed with either duodenal ulcer (DU) or functional dyspepsia (FD). Only patients with H. pylori infection were candidates to enter the study. Informed consent was obtained from patients entered into the study. Patients with pregnancy, major organic or systemic diseases, previous gastric surgery, or who had received antibiotic therapy or proton pump inhibitor (PPI) in the preceding 4 weeks were excluded. Endoscopy was performed within 3 days prior to treatment and again 4 weeks following the completion of treatment. Assessment of H. pylori Status A total of eight biopsy specimens were taken from the antrum (4)and corpus (4) during each endoscopy. From each region, one biopsy was used for rapid urease testing, one for culture and 2 for histology (by hematoxylin & eosin stain). The diagnosis of H. pylori infection was based upon positive culture and/or positive histology in addition to positive rapid urease test. Eradication of H. pylori was defined as all tests were negative at least 4 weeks after completion of triple therapy. Treatment Patients included in this study randomly received one of the one-week triple therapy regimens (listed in Table 1). All medicines were taken after meals. The treatment was open, but the microbiologists and pathologists were blinded with regard to treatment arms. During the treatment period of 7 days, the patients kept a diary to monitor compliance and symptoms. Statistical Analysis Both Intention-to-treat (ITT) and per protocol (PP) analyses were used to express the eradication rates oîh. pylori in all groups. Eradication rates, DU healing rates and frequencies of adverse events were compared using the chi-square test. The significance level was set at P <

6 Table 1. One week H. pylori eradication regimens used in this study Group Regimen Dosage X: B: C: TDB 240mg b.d. Clarithromycin 250mg b.d Furazolidone 100mg b.d. TDB 240mg b.d, Clarithromycin 250mg b.d, Amoxycillin 1000mg b.d, TDB 240mg b.d, Josamycin 1000mg b.d, Furazolidone 100mg b.d, Results One hundred and eighty patients were included in this study with 60 patients in each of the three groups. Thirteen patients (3 in group A, 5 in group B and 5 in group C) dropped out mainly because they refused a second endoscopy. One patient (group C) was withdrawn from the study because of vomiting. One hundred and sixty-six patients completed a course of treatment and follow-up endoscopy. Relevant demographic and endoscopic data at entrance are given in Table 2. Table2. Demographic and endoscopic data of patients in the treatment groups at entrance Group A B C No. of patients Female /male 36/24 41/19 38/22 Age (range) 44.1(18-70) 45.1(26-72) 43.8(23-69) Diagnosis DU Active stage In remission FD ^38 75

7 Eradication Rates of H. Pylori H. pylori eradication rates are provided in Table 3. There were significant differences in the eradication rates between group A and group B (po.001 ), and between group B and group C (p< 0.05) both on the basis of ITT and PP analysis. Table 3. H. pylori eradication rates in the treatment groups Eradication rate 95% CI Intention-to-treat Group A 88.3% (53/60) % Group B 58.3% (35/60) % Group C 76.7% (46/60) % Per protocol Group A 93.0%(53/57) % Group B 63.6%(35/55) % GroupC 85.2%(46/54) % Healing Rates of Duodenal Ulcer The healing rates of active duodenal ulcer in each treatment groups are provided in Table 4. There were no significantly differences in healing rates between the treatment groups (P>0.05). Side Effects Side effects associated with the treatment regimens are provided in Table 5. Eighteen of 180 patients (10.0%) reported mild side effects which were tolerable and promptly disappeared after cessation of medications. One patient was withdrawn from treatment because of excessive vomiting. There were no significant differences in the rates of side effects between all treatment groups (P>0.05). 76

8 Table 4. DU healing rates in treatment groups. Group A B C Healing rates 90.0% (18/20) 73.9% (17/23) 80.0% (12/15) Table 5. Treatment associated side effects Group A B C Taste disturbance Nausea 2 5 Vomiting 1 Dizziness 1 Diarrhea 2 2 Drowsiness 1 Total 7(11.7%) 3 (5.0%) 8 (13.3%) Discussion Classical bismuth-based triple therapy for H. pylori remains standard in many parts of world. This regimen typically requires a two-week treatment course which increases the risk of side effects as well as reduces patient compliance with regimen. Furthermore, a world-wide increase in H. pylori resistance to metronidazole, a key component of this triple therapy, limits the usefulness of this regimen(6-9). Therefore, evaluation of new non-metronidazole bismuth-based triple therapies are warranted. Furazolidone, a nitrofuran in clinical use for over 30 years, was used in China for the treatment of peptic ulcer disease long before H. pylori was discovered as an etiological agent in this disease(16-17). In the last decade, furazolidone has been found to be highly effective for eradication of H. pylori (11-14), H. pylori resistance to furazolidone has not been encountered, and serial passage of H. pylori did not result 77

9 in development of resistance to furazolidone, suggesting that it is very unlikely that resistance will emerge easily(15). Clarithromycin, a new generation macrolide, is highly effective for eradication ofh. pylori, when included as a component of standard triple therapy (3, 18-20). A combination of clarithromycin with amoxycillin in PPIbased triple therapies is effective, but insufficiently tested in a bismuth-based triple therapies. Josamycin, a earlier generation macrolide, has rarely been examined for H. pylori infection. For these reasons, we tested these antibiotics with TDB to determine the efficacy of these non-metronidazole bismuth-based regimens at eradicating H. pylori. In this study, we demonstrated that the combination of TDB, clarithromycin and furazolidone achieved the highest eradication rate ( 88.3% on intention-to-treat analysis and 93.0% on per protocol analysis) of the three bismuth-based triple therapies tested. The dosages of clarithromycin and furazolidone used in this regimen were relatively low, and the one week treatment course was relatively short. Moreover the patients tolerated the regimen quite well. Therefore, this combination fulfills the criteria for successful H. pylori therapy. In a previous pilot study of furazolidonecontaining therapy for H. pylori infection, we demonstrated that primary resistance to clarithromycin is the key factor of treatment failure while using this regimen (21). Compared to cure rates of 90% or more achieved by the triple therapies containing PPI, clarithromycin and amoxycillin, the cure rate obtained by the replacement of PPI with TDB in our present study is relatively low (58.3% on intention-to treat analysis and 63.6% on per protocol analysis). Although clarithromycin is less dependent on acid suppression for its efficacy, amoxycillin is largely dependent upon acid suppression(22-23). We speculate that the reduced efficacy of amoxycillin due to reduced acid suppression in our study may explain the relatively low cure rate observed with this regimen. 78

10 Josamycin-combined therapy for H. pylori infection has rarely been reported. Although the combination of TDB, josamycin and furazolidone in this study achieved sub-optimal results (76.7% on intention-to-treat analysis and 85.2% on per-protocol analysis), it is inexpensive, widely available and may be used as an alternative when clarithromycin is not available. We conclude that the one-week low-dose triple therapy consisting of TDB, clarithromycin and furazolidone provides a satisfactory result for the cure of H. pylori infection, and may become an important alternative in light of a worldwide increase in H. pylori resistance to metronidazole. Acknowledgements The study was supported by DUTCHIGAS Project from Dutch Ministry of Education and Science and the Ministry of Public Health of People's Republic of China. References 1. NIH Consensus Development Panel. H. pylori in peptic ulcer disease. JAMA 1994;272: The European Helicobacter pylori Study Group. Current European concepts in management of Helicobacter pylori infection. The maastricht Consensus Report. Gut 1997;41: Lam SK, Talley NJ. Report of the 1997 Asia pacific consensus conference on the management of Helicobacter pylori infection. J Gastroenterol. Hepatol. 1998;13: Van der Hulst RWM, Keller JJ, Rauws EA, Tytgat GNJ. treatment of Helicobacter pylori infection: A review the world literature. Helicobacter 1996;1: Walsh JH, Peterson WL. The treatment of Helicobacter pylori infection in the 79

11 management of peptic ulcer disease. N Engl J Med 1995; 333: Xia HX, Buckley M, Hyde D, keane CT, O'Morain CA. Effects of antibioticresistance on clarithromycin-combined triple therapy for Helicobacter pylori. Gut 1995;37 (suppl): A Noach LA, Langenberg WL, Bertola MA, Dankert J, Tytgat GNJ. Impact of metronidazole resistance on the eradication of Helicobacter 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 Helicobacter pylori infection: Should efficacy or side - effect profile determine our choice. Scand J Gastroenterol 1995;30: 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: 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 Kleim PD, Opekum AR, et al. In vivo susceptibility of Campylobacter pylori. Am J Gastroenterol 1989; 84: Xiao SD, Liu WZ, Xia DH, et al. The efficacy of furazolidone and metronidazole in the treatment of chronic gastritis associated with Helicobacter pylori - a randomized double-blind placebo-controlled clinic trial. Hepat-Gastroenterology 1990;37: Xiao SD, Liu WZ, Lin GJ, et al. TDB combined therapy for eradication of 80

12 Helicobacter pylori. Chinese Journal of Digestion 1995;15(suppl): Haas CE, Nix DE, Schentag JJ. In vitro selection of resistant Helicobacter pylori. Antimicrob Agents Chemother 1990;34: 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: Peterson WL, Graham DY, Marshall B, et al. Clarithromycin as monotherapy for eradication of Helicobacter pylori: a randomized double-blind trial. Am J Gastroenterol 1993;88: Pipkin GA, Dixon JS, Williamson R, and Wood JR. Clarithromycin dual therapy regimens for eradication of Helicobacter pylori: A review. Helicobacter 1997;2: de Boer WA, Tytgat GNJ. 90% cure: which anü-helicobacter pylori therapy can achieve this treatment goal? Am J Gastroenterol 1995;90: Liu WZ, Li BM, Xiao SD, et al. Clarithromycin combined short-term triple therapies for eradication of H pylori. Chinese Journal of Internal Medicine 1966;35: Labenz J, Stolte M, Blum AL, et al. Intragastric acidity as a predictor of the success of Helicobacter pylori eradication: a study in peptic ulcer patients with omeprazole and amoxycillin. Gut 1995;37: Miehlke S, Mannes GA, Lehn N, et al. An increasing dose of omeprazole combined with amoxycillin cures Helicobacter pylori infection more effectively. Aliment Pharmacol Ther 1997;11:

13