Proton pump inhibitor (proton pump inhibitor)-based triple therapies using clarithromycin in combination SUMMARY INTRODUCTION

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1 Aliment Pharmacol Ther 2003; 18: doi: /j x Esomeprazole-based one-week triple therapy with clarithromycin and metronidazole is effective in eradicating Helicobacter pylori in the absence of antimicrobial resistance S. MIEHLKE, W. SCHNEIDER-BRACHERT*, E. BÄSTLEIN, S.EBERT,C.KIRSCH,C.HAFERLANDà, M. BUCHNER, M. NEUMEYER, M. VIETH**, M. STOLTE, N. LEHN* & E. BAYERDÖRFFERàà Medical Department I, Technical University Hospital, Dresden, Germany; *Institute for Medical Microbiology, University Hospital Regensburg, Germany; Gastroenterologist in private practice, Cologne, Germany; àgastroenterologist in private practice, Görlitz, Germany; Gastroenterologist in private practice, Ribnitz-Damgarten, Germany; Gastroenterologist in private practice, Oldenburg, Germany; **Institute for Pathology, University Hospital, Magdeburg, Germany; Institute for Pathology, Academic Teaching Hospital, Bayreuth, Germany; and ààcentre for Internal Medicine, University Hospital, Marburg, Germany Accepted for publication 1 August 2003 SUMMARY Aim: This study aimed to investigate the effectiveness of a one-week triple therapy with esomeprazole, clarithromycin and metronidazole for eradication of Helicobacter pylori infection in the absence of antimicrobial resistance. Methods: Patients testing positive for H. pylori susceptible to metronidazole and clarithromycin (E-test) were randomized to receive a one-week regimen with either esomeprazole 2 20 mg or omeprazole 2 20 mg in combination with clarithromycin mg and metronidazole mg. Follow-up endoscopy with histology and culture and/or rapid urease test was performed 4 8 weeks after the end of treatment. Results: Eighty patients were randomized. Helicobacter pylori infection was cured in 38/39 patients of the esomeprazole group and 31/33 patients of the omeprazole group (per protocol 97.4% (95% confidence interval [CI], ), 93.7% (95% CI, ), P ¼ 0.59); intention-to-treat 90.4% (95% CI: ), 81.6% (95% CI: ), respectively. No major side effects occurred. Minor side effects occurred in eight (20%) and six (23%) patients during esomeprazole and omeprazole therapy, respectively. Post-treatment susceptibility testing revealed resistance to both metronidazole and clarithromycin in two of the three patients who failed. Conclusion: We conclude that esomeprazole, clarithromycin and metronidazole as one-week triple therapy is effective for eradication of H. pylori in the absence of antimicrobial resistance. INTRODUCTION Proton pump inhibitor (proton pump inhibitor)-based triple therapies using clarithromycin in combination Correspondence to: Dr Stephan Miehlke, Medical Department I, Technical University Hospital, Fetscherstr. 74, Dresden, Germany. miehlke@mk1.med.tu-dresden.de with either amoxicillin or metronidazole are at present the most commonly used first line therapies for Helicobacter pylori infection, with pooled eradication rates of approximately 90%. 1 3 The largest experience has been gained with regimens using omeprazole. 4 6 Recent European Consensus authorities recommended that proton pump inhibitor-based triple therapy containing clarithromycin and amoxicillin should be Ó 2003 Blackwell Publishing Ltd 799

2 800 S. MIEHLKE et al. preferred to clarithromycin combined with metronidazole. 7 However, the latter combination is still clinically useful, for example, in the case of known intolerance to amoxicillin. Pre-treatment metronidazole resistance of H. pylori can be expected in the range of 26% to 37% of patients in Europe and in the United States, respectively. 6, 8, 9 Pretreatment metronidazole resistance is clearly an important risk factor for failure of metronidazole containing triple therapy. 10, 11 However, in patients with known pre-treatment susceptibility to metronidazole, metronidazole containing proton pump inhibitor-based triple therapy has been shown to be an effective first line 5, 10 therapy. Esomeprazole, the S isomer of omeprazole, is the first proton pump inhibitor to be developed as an optical isomer for the treatment of acid related disorders. It provides a greater inhibition of acid secretion than 12, 13 omeprazole and all other proton pump inhibitors, and has recently also been introduced in the treatment of H. pylori infection. Several multicentre trials have shown that esomeprazole in combination with clarithromycin and amoxicillin is effective as first line treatment of H. pylori infection. 14, 15 At present, there are no data regarding the efficacy of esomeprazole in combination with clarithromycin and metronidazole. In this randomized multicentre trial we tested the hypothesis that a one-week triple therapy with esomeprazole, clarithromycin and metronidazole is effective for eradication of H. pylori infection in the absence of antimicrobial resistance. PATIENTS AND METHODS Study design and recruitment of patients The study was designed as a prospective, randomized trial involving university hospitals, community hospitals and gastroenterologists in private practice in Germany. Participating centres were asked to obtain biopsies for H. pylori culture from consecutive patients who presented for endoscopy for evaluation of dyspeptic symptoms. Antimicrobial susceptibility testing had to be performed at the collaborating Department of Medical Microbiology. To be eligible for inclusion into the study, patients had to be H. pylori positive by both culture and histology, and antimicrobial susceptibility testing had to be available showing susceptibility to both metronidazole and clarithromycin. Further inclusion criteria were age, between 18 and 80 years, and a recommended or advisable indication for H. pylori eradication therapy according to the Maastricht-2 Consensus Report. 7 Patients were not eligible for the study if one of the following criteria was present: more than one previous attempt of H. pylori therapy, known or suspected intolerance against one of the study drugs, contraindication against biopsy taking, present complicated peptic ulcer (bleeding, perforation, stenosis), regular use of nonsteroidal anti-inflammatory drugs, antibiotics or bismuth compounds within the 4 weeks prior to randomization, history of partial gastrectomy or proximal selective vagotomy, known malignant disease or other severe concomitant diseases (Karnofsky index <60). The study was approved by the Ethics Committee of the Technical University Hospital Carl Gustav Carus in Dresden and was conducted according to the principles of the Second Declaration of Helsinki. All participants provided written informed consent. Randomization and therapy Eligible patients were randomized by groups of four patients according to a central computer generated randomization list to: (1) esomeprazole 20 mg (Nexium MUPS, AstraZeneca, Wedel, Germany), clarithromycin 250 mg, metronidazole 400 mg (ECM); (2) omeprazole 20 mg (Antra MUPS, AstraZeneca), clarithromycin 250 mg and metronidazole 400 mg (OCM). All tablets were given twice daily for 7 days. Patients were instructed to take the study medication in the morning before breakfast and then 12 h later in the evening. Compliance and adverse events were assessed by standardized interview at the end of treatment. Patients who used less than 80% of the study medication were considered as noncompliant and excluded from the analysis. A follow-up endoscopy was scheduled at 4 8 weeks after the end of treatment. Endoscopy and biopsies Upper endoscopy was performed prior to inclusion into the study, and 4 8 weeks after completion of treatment. At each endoscopy, two biopsies from antrum and two biopsies from corpus were obtained for H. pylori culture and antimicrobial susceptibility testing. The biopsy specimens were immediately placed into Portagerm pylori transport medium (BioMerieux, Marcy l Etoile, France) and sent within 24 h to the participating Department of

3 ESOMEPRAZOLE-BASED ANTI H. PYLORI THERAPY 801 Microbiology. In addition, there were two biopsies from antrum and corpus for histology. Additional biopsies for rapid urease testing were recommended. H. pylori culture and susceptibility testing Primary H. pylori culture and antimicrobial susceptibility testing was performed in anaerobic jars, containing an atmosphere of 9% CO 2, 11% O 2, and 80% N 2, incubated at 36 C. Susceptibility testing was performed using the E-test (AB Biodisk, Solna, Sweden), as previously described. 16 Briefly, a dense suspension (approximately McFarland 4) was streaked out with sterile cotton swabs on Wilkins-Chalgren agar with 8% horse blood (Oxoid, Wesel, Germany). E-test strips were placed on the dried plate for h. Quality control strains were always included. The occurrence of any colony within an inhibition zone was regarded as resistance, and the respective minimal inhibitory concentration value of the resistant subpopulation was used for the evaluation. Minimal inhibitory concentration breakpoints for resistance were defined as follows: metronidazole, 6 lg/ml; clarithromycin, 0.5 lg/ml; amoxicillin, 0.5 lg/ml. Helicobacter pylori cure rates were calculated by intention-to-treat and per protocol analyses. For intention-totreat analysis, all randomized patients were included. For per protocol analysis, all protocol violators (use of less than 80% of study medication, patients lost to follow-up) were excluded. For statistical analysis, 95% confidence interval (CI), Student s t-test, one way analysis of variance and Fisher s exact test were used. P-values of less than 0.05 were considered to indicate statistical significance. The statistical software package SPSS 10.0 for Windows was used. RESULTS Patient population Between April 2001 and November 2002, a total of 80 patients were randomized, 42 patients to the ECM group and 38 patients to the OCM group. There were no significant differences with respect to major demographic data between the two groups (Table 1). The prevalence of peptic ulcer disease was comparable in both groups. At least one quarter of patients had experienced one previous treatment failure. At least 12 patients had been previously exposed to metronidazole or clarithromycin, but none of them had developed antimicrobial resistance. Histology The formalin fixed biopsies were embedded in paraffin and cut into 4 lm sections. Each slide was stained with Warthin-Starry or Giemsa for detection of H. pylori, and with haematoxylin & eosin for classification and grading of gastritis according to the updated Sydney System. 17 Definition of H. pylori cure For documentation of successful treatment of H. pylori infection, at least two negative, biopsy-based tests were required (either histology and culture, or histology and rapid urease test). If one of the performed tests was positive for H. pylori, the patient was defined as treatment failure. For patients who refused follow-up endoscopy, a validated 13C-urea breath test (INFAI, Cologne, Germany) was accepted to confirm cure of H. pylori infection. Statistical analysis Compliance and side effects None of the patients withdrew prematurely due to side effects. All patients used the study medication as prescribed. Therefore, a total of 72 patients (90%) was available for per protocol analysis. The rate of minor side effects without need for discontinuation of treatment was low and comparable with the literature Table 1. Baseline characteristics of randomized patients Characteristics ECM group n ¼ 42 OCM group n ¼ 38 Sex (female/male) 19/23 14/24 Age (years) Median (range) 46 (18 83) 39 (19 76) Peptic ulcer disease n (%) 18 (42.8) 14 (36.8) 0.64 Dyspepsia 24 (57.2) 24 (63.2) Pre-treated patients, n (%) 12 (28.6) 9 (23.7) 0.58 Previous regimens, n Proton pump inhibitor-a-c 5 5 Proton pump inhibitor-mc 1 0 Proton pump inhibitor-a-m 3 1 Dual therapy 2 1 Other 1 2 P

4 802 S. MIEHLKE et al. Table 2. Side effects (Table 2). Predominant minor side effects were diarrhoea, taste disturbance and headache, all of which were self limiting after completion of treatment. H. pylori cure rates ECM group n ¼ 42 OCM group n ¼ 38 Patients with Adverse events, n (%) 9 (21.4) 6 (15.8) 0.77 Severe adverse events, n (%) 0 (0) 0 (0) Frequency of adverse events* Diarrhoea 5 3 Taste disturbance 3 1 Headache 4 1 Nausea 0 0 Skin reaction (erythema) 0 2 * Some patients reported more than one adverse event. Three patients from the ECM group (7.1%) and five patients from the OCM group (13.2%) were lost to follow-up (denial of follow-up examination, untraceable). Seventy patients returned to follow-up endoscopy (ECM: 38 patients; OCM: 32 patients). In all of them, both histology and H. pylori culture were available. Two patients, one from each group, denied follow-up endoscopy but agreed to 13C-urea breath test. Thirty-eight patients from the ECM group and 31 patients from the OCM group were cured of H. pylori infection. Thus, the per protocol H. pylori cure rates were high and not significantly different between the two groups (Table 3). There were no significant differences in H. pylori cure rates between patients with peptic ulcer disease and those with nonulcer dyspepsia (data not shown). Pre- and post-treatment antimicrobial susceptibility As predefined by the inclusion criteria, all H. pylori isolates were susceptible to clarithromycin and P metronidazole at baseline. In all three patients with documented treatment failure, post-treatment antimicrobial susceptibility testing was available, showing resistance to both metronidazole and clarithromycin in two patients (Table 4). The minimal inhibitory concentration values for resistance were generally high. None of the three patients was previously exposed to metronidazole or clarithromycin. Resistance of H. pylori to amoxicillin was not detected in any of the 80 patients. DISCUSSION This study suggests that one-week triple therapy with esomeprazole, clarithromycin and metronidazole is effective for eradication of H. pylori susceptible to both antibiotics. It further shows that either one of the treatment regimens used in this study following pretreatment susceptibility testing is an effective approach to cure H. pylori infection if patients colonized with H. pylori resistant to metronidazole and/or clarithromycin are excluded. A decision analysis by Breuer et al. has suggested that routine pre-treatment susceptibility testing of H. pylori, followed by tailored antibiotic treatment, may be a cost effective approach in a United States population. 18 Whether such a strategy as this may be useful in a European patient population is currently unknown, since comparable analyses are lacking. A clinical study from Italy recently suggested that primary H. pylori therapy based on antimicrobial susceptibility testing may yield significantly higher eradication rates than standard triple therapy without susceptibility testing. 19 An obvious drawback of this strategy is the still limited availability of experienced laboratories providing a high success rate of primary H. pylori culture, and the time consuming process of primary culture and susceptibility testing. Esomeprazole has been introduced in H. pylori therapy in combination with clarithromycin and amoxicillin. Various multicentre trials have proved this regimen to be efficacious as a first line treatment of H. pylori ECM group OCM group P Table 3. H. pylori cure rates Randomized patients (n) Per protocol analysis (n) Patients cured of the infection (n) H. pylori cure rates Per protocol,% (95% CI) 97.4 ( ) 93.9 ( ) 0.59 Intention-to-treat, % (95% CI) 90.4 ( ) 81.6 ( )

5 ESOMEPRAZOLE-BASED ANTI H. PYLORI THERAPY 803 Table 4. Post-treatment resistance to metronidazole (MET) and clarithromycin (CLA) Per protocol ECM group n ¼ 38 OCM group n ¼ 32 Treatment failure (PP*), n 1 2 MET + CLA resistance, n 1 1 MIC (lg/ml) MET: > 256, CLA: > 256 MET: > 256, CLA: 64 * Per protocol analysis. 14, 15 infection. At present, no fully published studies exist which have investigated the efficacy of esomeprazole in combination with clarithromycin and metronidazole for H. pylori eradication. Although the number of patients in our study was too low to prove equivalence, the data clearly suggest that the efficacy of triple therapy with esomeprazole, metronidazole and clarithromycin is certainly in the range of the omeprazole containing regimen. A recent Canadian multicentre trial published in abstract form has also compared esomeprazole and omeprazole in combination with clarithromycin and metronidazole in a large patient population. 20 However, the study is flawed by the fact that no pre-treatment susceptibility testing was performed and a small proportion of patients with a history of previous attempts to eradicate H. pylori was included. This study produced per protocol eradication rates of 80% (ECM) vs. 75% (OCM), suggesting equivalence between the esomeprazole and omeprazole based regimen. These somewhat lower eradication rates compared with our results may have been caused by the unknown background metronidazole resistance rate and the unknown proportion of patients with previously acquired post-treatment metronidazole resistance. Approximately 26% of H. pylori infected individuals within the general population in Germany appear to be infected with metronidazole resistant strains. 8 According to the recent recommendation of the Masstricht-2 Consensus Report, 7 a clarithromycin/metronidazole containing triple therapy should not be used as first line therapy, particularly if the antimicrobial susceptibility pattern is unknown. The major threat is treatment failure and a high rate of post-treatment resistance to metronidazole and even clarithromycin. A recent multicentre study from Germany including 550 H. pylori isolates has shown that double antimicrobial resistance against both metronidazole and clarithromycin may occur in up to 65% of patients after at least one failure of H. pylori therapy. 16 A recent antimicrobial susceptibility survey from Hong Kong produced similar results. 21 In our present study, combined resistance of H. pylori to metronidazole and clarithromycin occurred in two of the three patients who failed treatment, supporting the contention of a high potential to develop this unfavourable condition. Patients with combined resistance to metronidazole and clarithromycin present a particular clinical problem. We recently found that these difficult to treat patients infected with metronidazole + clarithromycin resistant H. pylori may be successfully treated with an esomeprazole-based triple therapy using rifabutin and amoxcillin, reaching an H. pylori eradication rate of 80%. 22 A further therapeutic option in this situation may be quadruple therapy or high-dose omeprazole/amoxicillin therapy. 23 In conclusion, our study suggests that one-week triple therapy with esomeprazole, clarithromycin and metronidazole is well tolerated and is effective for eradication of H. pylori infection in the absence of antimicrobial resistance. Whether the approach of antimicrobial susceptibility guided treatment is useful or cost effective in a European patient population is currently unknown. ACKNOWLEDGEMENTS The study was supported by AstraZeneca. We thank R. Beckmann for her assistance in the data management. REFERENCES 1 Laheij RJ, Rossum LG, Jansen JB, Straatman H, Verbeek AL. Evaluation of treatment regimens to cure Helicobacter pylori infection a meta-analysis. Aliment Pharmacol Ther 1999; 13: Schmid CH, Whiting G, Cory D, Ross SD, Chalmers TC. Omeprazole plus antibiotics in the eradication of Helicobacter pylori infection: a meta-regression analysis of randomized, controlled trials. Am J Ther 1999; 6: Miehlke S, Bayerdörffer E, Graham DY. Treatment of Helicobacter pylori infection. Sem Gastrointest Dis 2001; 12: Lind T, Veldhuyzen van Zanten SJO, Unge P, et al. The MACH 1 study: Optimal one-week treatment for H. pylori defined? Helicobacter 1996; 1: Lind T, Megraud F, Unge P, et al. The MACH 2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology 1999; 116: Megraud F, Lehn N, Lind T, et al. Antimicrobial susceptibility testing of Helicobacter pylori in a large multicenter trial: the MACH 2 study. Antimicrob Agents Chemother 1999; 43:

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