Arab Journal of Gastroenterology

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1 Arab Journal of Gastroenterology 14 (2013) 1 5 Contents lists available at SciVerse ScienceDirect Arab Journal of Gastroenterology journal homepage: Original Article Penbactam for Helicobacter pylori eradication: A randomised comparison of quadruple and triple treatment schedules in an Iranian population Seyedali Seyedmajidi a, Dariush Mirsattari b, Homayoun Zojaji b, Elahe Zanganeh c, Mohammadreza Seyyedmajidi a,, Shohreh Almasi b, Mohammadreza Zali b a Golestan Research Center of Gastroenterology & Hepatology, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Iran b Research Center for Gastroenterology and Liver Disease, Department of Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran c Department of IT Engineering, Khajenasir Toosi University of Technology, Tehran, Iran article info abstract Article history: Received 19 December 2011 Accepted 9 December 2012 Keywords: Helicobacter pylori Treatment Penbactam Background & study aims: Selection of the best drug regimens for eradication of Helicobacter pylori infection especially in patients at risk of peptic ulcer relapses and the development of complications is challenging. This study assessed and compared the efficacy of the two common PPI based triple therapies to a quadruple therapy including PPI, metronidazole, amoxicillin and a bismuth compound in Iranian population. Patients & Methods: Three hundred and thirty patients with peptic ulcer and H. pylori infection were included in the study. Patients were randomly assigned to one of the three treatment protocols all given twice daily: (a) A 14-day quadruple therapy (OMAB group) comprising omeprazole 20 mg, metronicazole 500 mg, amoxicillin 1 g, and bismuth subcitrate 240 mg; (b) A 14-day triple regimen (OCP group) comprising omeprazole 20 mg plus clarithromycine 500 mg and penbactam 750 mg and (c) A 14-day triple regimen (OCA group) comprising omeprazole 20 mg plus clarithromycine 500 mg and amoxicillin 1 g. Cure was defined as a negative urea breath test at least six weeks after treatment. Results: The per-protocol eradication rates achieved with both OCP regimen (87.0%) and OCA treatment (90.8%) were significantly higher than the OMAB treatment protocol (56.0%); however, no significant difference emerged in eradication rates between the two triple treatment schedules. No significant differences between the groups were found in most side-effects. Conclusion: Two-week quadruple therapy showed a lower eradication rate compared to common triple treatment schedules when used as first-line eradication treatment for H. pylori infection in Iranian population. Ó 2012 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved. Introduction Selection of the best drug regimens for effective eradication of Helicobacter pylori (H. pylori) infection especially in patients at risk of peptic ulcer relapses and the development of complications of peptic ulcer disease is already challenging. Nowadays, quadruple therapy including classical triple therapy plus a proton pump inhibitor (PPI) has been produced as an effective drug regimen and even an alternative first-line treatment for eradicating H. pylori infection especially in areas of high prevalence of antibiotic resistance. Some recent studies suggested that the effectiveness, compliance and side effects of quadruple regimen including a gastric acid inhibitor, a bismuth compound and amoxicillin might be comparable with PPI-based triple therapy when administered as first-line treatment for H. pylori infection [1 4]. However, some Corresponding author. Tel./fax: address: mrsmajidi55@yahoo.com (M. Seyyedmajidi). others could show slight differences in effectiveness, usually in favour of quadruple therapy [5,6]. Besides, the eradication rates of different treatment schedules for H. pylori infection are potentially dependent on the duration of drug administration. It has been suggested that 1-week triple and quadruple therapy can lead to similar efficacy when used as a first-line eradication treatment [7]. Furthermore, although some studies showed that the eradication rates of quadruple therapy could be significantly increased when it was given for days [8], it has been also indicated that 1-week quadruple therapy may not be different from a 2-week regimen as an option for H. pylori eradication [9]. Therefore, the advantages of quadruple therapy at present do not seem clear enough to change current policies for H. pylori treatment. Further, the effect of prolonging the length of quadruple therapy on treatment efficacy is already questioned. The aim of the study was to assess and compare the efficacy of the two PPI-based triple therapies to a quadruple therapy including /$ - see front matter Ó 2012 Arab Journal of Gastroenterology. Published by Elsevier B.V. All rights reserved.

2 2 S. Seyedmajidi et al. / Arab Journal of Gastroenterology 14 (2013) 1 5 PPI, metronidazole, amoxicillin and a bismuth compound in the Iranian population. Patients and methods A prospective double-blinded randomised clinical trial study was conducted on 330 patients referred to Taleghani Hospital in Tehran from March 2007 to September All patients signed an informed consent form. This research was approved by the Ethics Committee of the Research Center for Gastroenterology and Liver Disease in the Shahid Beheshti University of Medical Sciences. Patients had not been previously treated for H. pylori infection. Subjects were excluded if they had been taking non-steroidal antiinflammatory drugs (NSAIDs), PPI, bismuth preparations or antibiotics during the previous 4 weeks. Pregnant women and patients with a history of gastric surgery, renal and hepatic impairment were not enrolled. Dyspepsia was defined as epigastric pain or discomfort lasting for at least 3 months. All patients were diagnosed to be H. pylori positive by histopathological examination. Gastroscopy was done using a videoscope (Olympus GIF-XQ260, Japan). Two specimens were obtained from the antrum. Patients were randomly assigned (110 patients in each group) using a computer-generated list to one of the three treatment protocols: (a) a 14-day quadruple therapy (OMAB group) comprising omeprazole 20 mg, metronidazole 500 mg, amoxicillin 1 g and bismuth subcitrate 240 mg, all given twice daily; (b) a 14-day triple regimen (OCP group) comprising omeprazole 20 mg plus clarithromycin 500 mg and penbactam 750 mg, all given twice daily and (c) a 14-day triple regimen (OCA group) comprising omeprazole 20 mg plus clarithromycin 500 mg and amoxicillin 1 g, all given twice daily. Patients were asked to return at the end of the treatment to assess compliance with therapy that was defined as consumption of greater than 90% of the prescribed drugs. Medications were discontinued if any intolerable adverse events such as fever, urticarial rash or generalised body pain occurred. A 13 C-urea breath test was performed for eradication assessment 6 weeks after completion of the treatment. The results of treatment were evaluated with per-protocol analysis (which included only patients who completed the study). Statistical analysis was performed with the chi-squared test as well as Fisher s exact test, and the one-way analysis of variance (ANOVA) test. P values of 0.05 or less were considered statistically significant. All the data were analysed using Statistical Package for Social Sciences (SPSS) 16 for Windows (SPSS Inc., Chicago, IL, USA) and the values were expressed as mean ± standard deviation (SD) for continuous variables and percentages for categorical variables. Results Among 110 patients in each group, 100 patients in the OMAB group (90.9%), 100 patients in the OCP group (90.9%) and 98 patients in the OCA group (89.1%) would continued treatment protocols and underwent 13 C-urea breath testing. All patients included into the study were ranged between 18 and 81 years and 48.7% of them were male. The three studied groups were matched for sex, age and general risk factors such as hypertension, diabetes mellitus, current cigarette smoking and alcohol use (Table 1). The most common endoscopic finding in the three groups was gastroduodenitis, whereas gastroduodenal ulcer was rarely reported in each group. Regarding pathological findings, all patients suffered from gastritis and other findings such as intestinal metaplasia and dysplasia were less common in patients. Three treatment groups were similar in terms of reported endoscopic and pathological findings (Table 2). The per-protocol eradication rates achieved with both the OCP regimen (87.0%) and the OCA treatment (90.8%) were significantly higher than the OMAB treatment protocol (56.0%); however, no significant difference emerged in eradication rates between the two triple treatment schedules (Fig. 1). Totally, per-protocol eradication rate of H. pylori in all studied men and women was 76.6% and 79.1%, respectively. No significant differences were found in eradication rates between the two genders in each treatment group (Table 3). However, in both genders, Table 1 Demographic characteristics and clinical data of studied patients. Characteristics OMAB group (n = 100) OCP group (n = 100) OCA group (n = 98) p-value Male gender 40 (40.0) 50 (50.0) 55 (56.1) Age (years) 44.0 ± ± ± Hypertension 17 (17.0) 19 (19.0) 17 (17.3) Diabetes mellitus 10 (10.0) 11 (11.0) 10 (10.2) Cigarette smoking 11 (11.0) 12 (12.0) 10 (10.2) Alcohol use 2 (2.0) 2 (2.0) 0 (0.0) Data are presented as mean ± SD or n (%). p-value as significant. Table 2 Endoscopy report and pathological findings in studied patients. Characteristics OMAB group (n = 100) OCP group (n = 100) OCA group (n = 98) p-value Endoscopy report Gastroduodenitis 98 (98.0) 97 (97.0) 94 (95.9) Gastric ulcer 16 (16.0) 20 (20.0) 20 (20.4) Gastroduodenal ulcer 2 (2.0) 1 (1.0) 1 (1.0) Duodenal ulcer 20 (20.0) 21 (21.0) 21 (21.4) Pathological findings Gastritis 100 (100) 100 (100) 98 (100) Intestinal metaplasia 9 (9.0) 7 (7.0) 6 (6.1) Dysplasia 2 (2.0) 2 (2.0) 1 (1.0) Data are presented as n (%). p-value as significant.

3 S. Seyedmajidi et al. / Arab Journal of Gastroenterology 14 (2013) Fig. 1. Rate of H. pylori eradication in studied patients. Table 3 Positive eradication rates in the three schedules in men and women. Treatment group Men with PER (n = 111) Women with PER (n = 121) p-value OMAB therapy (n = 100) 20/40 (50.0) 36/60 (60.0) OCP therapy (n = 100) 41/50 (82.0) 46/50 (92.0) OCA therapy (n = 98) 50/55 (90.9) 39/43 (90.7) p-value PER: positive eradication rate. Data are presented as number (percentage). Table 4 Drug side effects in studied patients. Characteristics OMAB group (n = 100) OCP group (n = 100) OCA group (n = 98) p-value Dyspepsia 13 (13.0) 10 (10.0) 12 (12.2) Diarrhoea 8 (8.0) 6 (6.0) 14 (14.3) Nausea 14 (14.0) 10 (10.0) 11 (11.2) Abdominal pain 9 (9.0) 6 (6.0) 11 (11.2) Stool abnormality 14 (14.0) 8 (8.0) 7 (7.1) Dizziness 4 (4.0) 2 (2.0) 2 (2.0) Headache 6 (6.0) 3 (3.0) 8 (8.2) Cough 2 (2.0) 1 (1.0) 2 (2.0) Bad taste 3 (3.0) 35 (35.0) 37 (37.8) <0.001 Metallic taste 15 (15.0) 2 (2.0) 5 (5.1) Data are presented as n (%). p-value as significant. eradication rates in cases that underwent OMAB treatment were significantly lower than in groups with triple therapies. Common side effects are shown in Table 4. No significant differences were found in drug side effects in the three groups except for bad taste and metallic taste that were more common in OCA and OMAB groups, respectively.

4 4 S. Seyedmajidi et al. / Arab Journal of Gastroenterology 14 (2013) 1 5 Discussion H. pylori infection is usually eradicated by using multi-drug regimens. Recently, quadruple drug therapies using a PPI with bismuth triple therapy has been recommended to decrease failure rates of H. pylori eradication caused by resistance to some antibiotics such as metronidazole and clarithromycin [2]. However, the present study could show that the eradication rates achieved with both 2 weeks PPI-based triple regimens comprising penbactam or amoxicillin were higher than PPI-based quadruple therapy including metronidazole, amoxicillin and bismuth subcitrate. In our study, a per-protocol eradication rate in quadruple therapy was 56.0%. A review of similar studies showed an eradication rate ranging between 57.5% and 92% following 2-week triple therapies and between 70.0% and 96% following 2-week quadruple therapies that all were higher than our finding [7,9 13]. Further, regarding the low susceptibility of H. pylori infection to metronidazole, administration of quadruple therapy containing this antibiotic has been recommended as a second-line choice for H. pylori eradication [13]. It seems that low cure rates following quadruple therapy in our study group can be due to antimicrobial drug resistance, which is a main source of treatment failure following these regimens. Broad or inappropriate use of potent antibiotics in our hospitals results in low susceptibility of H. pylori to some common antibiotics such as amoxicillin and metronidazole in our population that can lead to development of antibiotic resistance. Therefore, other regimens such as tetracycline-containing quadruple rescue therapy are more recommended instead of treatment comprising amoxicillin. It has been shown that tetracycline-containing quadruple therapy is highly effective in treating H. pylori eradication failures of the amoxicillin-containing regimen [14]. Although the obtained eradication rates following both triple schedules were comparable with other previous studies, we found lower eradication rates of H. pylori infection following experienced quadruple drug therapy. In a similar study by Clavet et al., per-protocol cure rates were 86% for OCA triple therapy and 89% for quadruple therapy including PPI, tetracycline chloride, metronidazole and bismuth that was not significantly different between the two groups [5]. However, an eradication rate of 72.7% in the recent 2 years necessitates the development of a more efficient eradication regimen [15]. The results of the recent studies provided support for the equivalence of triple and quadruple therapies in terms of effectiveness and compliance when administered as first-line treatment for H. pylori infection. Moreover, the new protocol using ampicillin sulbactam instead of amoxicillin in the quadruple regimen is a suitable first-line alternative to be used in regions with amoxicillin-resistant H. pylori strains [16]. However, some research for comparing PPI-based triple and quadruple therapies found similar eradication rates following 1-week and 2-week drug administrations [4,7] and by some others, quadruple therapy using a PPI was well tolerated and significantly superior to an alternative PPI-based triple therapy especially in patients with older ages [12,17,18]. Although we used a 2-week drug regimen for bacteria eradication, some studies suggested no differences in the eradication rate and tolerance between 1-week and 2-week regimens [9]. However, relation between treatment efficacy and duration of drug administration was also found in some other studies. Fischbach et al. showed similar treatment success for quadruple schedule given for 4 or 7 days; however, these were 6% less effective than those given for days [8]. Prolonging therapy to 14 days increases the eradication to some degree; per-protocol eradication rates approach 90% [19]. Besides, the disadvantages of prolonged quadruple therapies were also discussed. A major disadvantage of quadruple therapy is its complicated dosage. Reduced quadruple therapy regimens administered thrice daily for 7 days, or even twice daily for 14 days, have been shown to be highly effective in pilot studies, and may improve treatment compliance [20,21]. Moreover, it seems that prolonging therapy is not a cost-effective strategy because the increase in effectiveness is modest, and does not outweigh the marked increase in drug expenses. We also found that most of the drug-induced side effects were comparable in triple and quadruple anti-h. pylori regimens and only the bad taste-related side effect was different between the two regimens. Findings of other surveys in terms of treatment side effects were varied. In some of them, a similarity of side effects in the two regimens was shown [7,10,12]. Besides, in some others, the side effects tended to be more frequent in triple therapy than in quadruple therapy [1]. It seems that the occurrence of side effects is directly dependent on the type and duration of drug consumption. An increased rate of side effects with quadruple therapy using higher metronidazole doses was reported [22,23]. The combination of bismuth subsalicylate or subcitrate with metronidazole and tetracycline or amoxicillin also accompanied by the complexity and relatively a high rate of side effects, but these effects can be surpassed by PPI-based regimens [24 26]. Further, no significant differences were found in eradication rates between the two genders in each treatment protocol. In conclusion, we found that PPI-based quadruple therapy had no higher eradication rate in comparison with PPI-based triple therapies. The superiority of 2-week triple therapy to 2-week quadruple protocol can be due to the low susceptibility of H. pylori to administered drugs such as metronidazole or amoxicillin in the second regimen and also low resistance of used antibiotics such as clarithromycin or penbactam in triple therapy among our population. Furthermore, similar side effects following triple and quadruple therapies can emphasise the administration of triple treatment because of its less complexity and more cost effectiveness. Conflict of interest The authors declared that there was no conflict of interest. References [1] Gené E, Calvet X, Azagra R, et al. Triple vs. quadruple therapy for treating Helicobacter pylori infection: a meta-analysis. 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