First-line therapy in Helicobacter pylori eradication therapy: experience of a surgical clinic
Gökhan Selçuk Özbalcı1, Saim Savaş Yürüker1, İsmail Alper Tarım1, Hamza Çınar2, Ayfer Kamalı Polat1, Aysu Başak Özbalcı3, Kağan Karabulut1, Kenan Erzurumlu1
1Department of General Surgery, Ondokuz Mayıs University Faculty of Medicine, Samsun, Turkey
2Clinic of General Surgery, Kurtalan State Hospital, Siirt, Turkey
3Clinic of Radiology, Mehmet Aydın Training and Research Hospital, Samsun, Turkey
Objective: Helicobacter pylori (HP) is the world’s most common infectious agent. Despite conventional therapy consisting of proton pump inhibitor (PPI), amoxicillin (AMO) and clarithromycin (CLA), approximately half of the patients remain infected. We compared the PPI-based triple therapy with quadruple treatment (BPMT) including bismuth citrate (BS), PPI, metronidazole (MET) and tetracycline (TET).
Material and Methods: Forty-three patients who used triple therapy (LAC) consisting of lansoprazole (L), AMO and CLA and 42 patients who used quadruple therapy (BPMT) for 14 days between May 2008 and November 2013 were included in the study. The LAC group included patients who received 30 mg L 2x1, 1000 mg AMO 2x1, and 500 mg CLA 2x1 for 14 days, whereas the BPMT group was designed from patients who received 600 mg BS 2x1, 40 mg omeprazole (O) 2x1 or 30 mg L 2x1, 500 mg MET 3x1 and 500 mg TET 4x1.
Results: Demographic characteristics and endoscopic findings were similar in both groups. The eradication rate was 53.4% in the LAC group and 78.5% in the BPMT group (p<0.05). Compliance problems and side effects were significantly higher in the BPMT group as compared to the LAC group (p<0.05).
Conclusion: Due to high antibiotic resistance in Turkey, the efficacy of LAC treatment has reduced. The BPMT protocol should be kept in mind in the first line of treatment, since it provides a higher eradication rate.
Keywords: Helicobacter pylori, eradication, triple therapy, quadruple therapy
Helicobacter pylori (HP) is the world’s most common infectious agent (1). It is an important cause of many gastric pathologies including gastric adenocarcinoma, and has been recently reported to be associated with various hematological, neurological, and cardiovascular diseases (2-6).
Triple therapies, which consist of two antibiotics and a proton pump inhibitor (PPI), have been used as standard eradication treatment for more than 10 years after the discovery of Helicobacter pylori. Amoxicillin (AMO) and clarithromycin (CLA) are the most commonly used antibiotics as part of this treatment (1, 4, 6-28). However, in subsequent years different treatment options have been investigated (29, 30). Especially as it became clear that there was a worldwide increase in CLA resistance, an inclination for different treatments emerged and quadruple protocols containing bismuth citrate (BS) gained acceptance (1, 3, 4, 6-14, 16, 18, 20-24, 26, 31-40). In our country, relevant studies have been conducted and it has been demonstrated that CLA resistance was above 50%, and accordingly the classic triple treatment success rates decreased to unacceptable levels (2, 15, 19, 25, 27, 41).
Despite all these studies, practice treatment alternatives other than the standard protocol have not gained acceptance in daily surgical practice. In our clinic, the quadruple treatment (BPMT) that consists of BS 2 × 600 mg, PPI 2 x 1 (omeprazole (O) 20 mg or lansoprazole (L) 30 mg), metronidazole (MET) 3 × 500 mg, and tetracycline (TET) 4 x 500 mg, all in their oral forms, is being used for 14 days for eradication, for the last 2 years. However, in previous years, all patients received the conventional therapy (LAC) consisting of 2 x 30 mg of lansoprazole, AMO 2 x 1000 mg and 2 x 500 mg CLA. This study was designed to compare these two most preferred treatment protocols in first line HP eradication.
In our country, many hospitals have general surgery clinics with endoscopy units and they are actively working. Since it is the most common infectious agent in the world and it is especially closely associated with gastric cancer, recent evidence-based information on HP eradication should be followed up not only by gastroenterologists but also by general surgeons.
Material and Methods
This study was approved by the Ondokuz Mayıs University Faculty of Medicine ethics committee on 26.12.2013, with the approval number of 2013/460.
All patients admitted to our clinic’s endoscopy unit between May 2008 and November 2013 were retrospectively reviewed. Eighty-five patients who were diagnosed with HP by endoscopic biopsy, completed the 14-day treatment period, and who have been tested for eradication by control endoscopy, urea breath test (Heliprob to, Noster AB, Sweden) or HP stool antigen test (Antigen card test, Dialab, Austria) were included in the study. Patients were divided into 2 groups as Group I (LAC) and Group II (BPMT), and they were contacted over the telephone to inform them about the study and to address several questions. Eradication rates, treatment compliance and drug side effects were questioned, and smoking, alcohol, drug history and co-morbidities were evaluated. In addition, pathology reports were examined in detail to assess the presence of precancerous lesions concomitant with HP and the results were recorded.
Statistical Package for the Social Sciences (SPSS® Inc., Chicago, IL, USA) version 15.0 statistical software was used for analysis. Chi-square test was used for statistical comparison. P<0.05 was accepted as statistically significant.
There were 43 patients in the classical triple therapy (LAC) group, and 42 patients in the BPMT group. Demographic characteristics, co-morbidities, smoking, alcohol and drug history were similar in both groups (p>0.05) (Table 1). A significant difference was not detected between the two groups in terms of endoscopic biopsy findings (p>0.05) (Table 2).
Eleven patients in Group 1, and 22 in Group 2 stated difficulty in treatment compliance (p=0.021). Regarding side effects, 6 patients in LAC group and 18 patients in BPMT group gave a positive response (p=0.007). Dry mouth and metallic taste were the most commonly complained side effects. The rate of eradication success was identified as 53.4% in the LAC group, and 78.5% in the BPMT group, and this group showed significantly higher treatment success (p=0.027) (Table 3).
Helicobacter pylori is a gram-negative, spiral bacteria and is the world’s most common infectious agent. It is thought to affect about 50% of the world’s population. It is an important factor in the etiology of gastritis, gastric and duodenal ulcer, gastric mucosa-associated lymphoma (MALT lymphoma), and gastric adenocarcinoma (1-5). In addition, it has been recently reported that HP infection is associated with non-gastrointestinal diseases such as hematologic (persistent iron deficiency anemia, idiopathic thrombocytopenic purpura), neurologic (stroke, Parkinson’s disease, Alzheimer’s disease) and cardiovascular (ischemic heart disease) disorders (6).
There have been major changes in the diagnosis and treatment of diseases such as gastritis and ulcer after the discovery of Helicobacter pylori in 1983 (28). In 1994, the World Health Organization International Agency for Research on Cancer (IARC / WHO) concluded that HP showed a causal relationship with gastric carcinogenesis and was considered as a definite carcinogen in humans, drew all attention on this bacteria (42). The Mongolian gerbil model showed that HP infection stimulates gastric cancer, independent of low-dose chemical carcinogen exposure (43). Especially in observational studies at the beginning of the 2000s in Japan, HP infection has been shown to increase the risk of both intestinal and diffuse types of gastric cancer (28, 44). The estimated risk factor rates attributed to HP for the development of cancer ranged from 50 to 73% (45). In a randomized trial from Colombia that evaluated high-risk patients with precancerous lesions, a significant decrease was detected in gastric cancer in the HP eradication group (45). In another randomized trial conducted in China, it has been shown that HP eradication significantly reduced the risk of gastric cancer among individuals without gastric atrophy, intestinal metaplasia or dysplasia (46). The effects of HP eradication on gastric cancer have been the focus of many interesting studies. In Japan, it has been shown that HP eradication reduced the risk of gastric cancer in the remnant stomach, in patients who underwent distal gastrectomy and Billroth II anastomosis for early gastric cancer (47).
A wide range of therapy protocols are being used for HP eradication. Before the 2000s, the standard triple treatments were said to have up to 95% of success rates (17). However, especially with the increasing resistance to CLA over time, this rate dropped to 55% (21). From there on, there has been an inclination for protocols that contain BS. BS has anti-HP and mucosal cytoprotective effect. Treatments containing BS are expected to be more effective in the treatment of peptic ulcer and HP infection (48). In fact, this activity has been shown by studies (4, 12).
In our study, the two most preferred treatment protocols in first line HP eradication were compared. The PPIs that were used in the BPMT group, O or L, varied according to the physician in charge. According to the literature, there is no difference between the effectiveness of PPIs used for HP eradication (49). Patients were evaluated at least eight weeks after the treatment to assess the success of treatment by control endoscopy, urea breath test or HP stool antigen test. Both of these tests have been reported to have similar results with sensitivity and specificity rates over 90% (50). Therefore, these differences did not influence our results.
There was no difference in the general characteristics or endoscopic biopsy findings of the study patients. When treatment compliance and side effects were evaluated, it was identified that patients in the BPMT group had significantly more complaints. The number of drugs (13 tablets per day) and high doses may explain this finding. The challenge in using the BPMT protocol has already been the subject of several studies (2). The patient should be told to take these antibiotics with plenty of water on a full stomach to reduce the side effects. In addition, the use of probiotics as an alternative approach is being discussed to reduce the side effects of antibiotics and to enhance eradication success (6, 14).
When eradication was evaluated in our study, the success rate was identified as 78.5% in the BPMT group, and 53.4% in the LAC group (Figure 1). This difference was statistically significant. The low rate in the LAC group is compatible with previous studies from our country, and the high rate of CLA resistance may be responsible for this situation (15, 19, 41). In a recent meta-analysis from our country, it was determined that the success rate achieved by triple treatment was 79.4% in 1996, whereas this rate decreased to 61.1% by 2005 (25). Currently, this rate was reported as 50-55% (19). The eradication rate of 78.5% in the BPMT group is far from meeting expectations, although it is quite higher than the LAC group. The increasing MET resistance both in the world and in our country in recent years can be proposed as the reason of this (2, 6, 21).
Different treatment schemes should be considered in resistant cases where eradication could not be achieved. Recently, many different treatment modalities are being used. Protocols called sequential, combined, hybrid treatments, or rescue therapies are being tested as well as levofloxacin, and rifabutin, an anti-tuberculosis agent, based treatments (6, 14).
The lack of access in some patients and not being able to obtain sufficient data from some patients who have been treated a certain period of time ago were limitations of our study that prevented our study volume to be higher.
In conclusion, the 14-day BPMT treatment is more successful than the classic LAC treatment for HP eradication. Compliance issues and the frequency of side effects may pose a problem for this protocol, in certain patients. In case of failure of eradication, it would be appropriate to consider different schemes in accordance with the literature.
Ethics committee approval was received for this study from the ethics committee of Ondokuz Mayıs University Faculty of Medicine (26.12.2013, No: 2013/460).
This is a retrospective study. We called the patients that can we reach and explained the reason of our call. Also we gived information about the study.
Concept - G.S.Ö.; Design - G.S.Ö., H.Ç.; Supervision - K.E., A.K.P.; Funding - G.S.Ö., S.S.Y.; Materials - G.S.Ö., S.S.Y., K.E.; Data Collection and/or Processing - İ.A.T., H.Ç., K.K.; Analysis and/or Interpretation - G.S.Ö., S.S.Y., K.K.; Literature Review - G.S.Ö., H.Ç., İ.A.T.; Writer - G.S.Ö., A.K.P., A.B.Ö.; Critical Review - K.E., A.K.P., A.B.Ö.; Other - İ.A.T., A.B.Ö., K.K.
No conflict of interest was declared by the authors.
The authors declared that this study has received no financial support
- Altintaş E, Ulu O, Sezgin O, Aydin O, Camdeviren H. Comparison of ranitidine, bismuth citrate, tetracycline and metronidazole with ranitidine, bismuth citrate and azithromycin for the eradication of Helicobacter pylori in patients resistant to PPI based triple therapy. Turk J Gastroenterol 2004; 15: 90-93.
- Köksal AS, Onder FO, Torun S, Parlak E, Sayilir A, Tayfur O, et al. Twice a day quadruple therapy for the first-line treatment of Helicobacter pylori in an area with a high prevalence of background antibiotic resistance. Acta Gastroenterol Belg 2013; 76: 34-37.
- Wong WM, Gu Q, Lam SK, Fung FM, Lai KC, Hu WH, et al. Randomized controlled study of rabeprazole, levofloxacin and rifabutin triple therapy vs. quadruple therapy as second-line treatment for Helicobacter pylori infection. Aliment Pharmacol Ther 2003; 17: 553-560.
- Zheng Q, Chen WJ, Lu H, Sun QJ, Xiao SD. Comparison of the efficacy of triple versus quadruple therapy on the eradication of Helicobacter pylori and antibiotic resistance. J Dig Dis 2010; 11: 313-318.
- Frenck RW Jr, Clemens J. Helicobacter in the developing world. Microbes Infect 2003; 5: 705-713.
- Georgopoulos SD, Papastergiou V, Karatapanis S. Current options for the treatment of Helicobacter pylori. Expert Opin Pharmacother 2013; 14: 211-223.
- Suzuki H, Matsuzaki J, Hibi T. Metronidazole-based quadruple versus standard triple therapy: which is better as first-line therapy for Helicobacter pylori eradication? Expert Rev Clin Pharmacol 2011; 4: 579-582.
- Marko D, Calvet X, Ducons J, Guardiola J, Tito L, Bory F. Comparison of two management strategies for Helicobacter pylori treatment: clinical study and cost-effectiveness analysis. Helicobacter 2005; 10: 22-32.
- Buzás GM. First-line eradication of Helicobacter pylori: are the standard triple therapies obsolete? A different perspective. World J Gastroenterol 2010; 16: 3865-3870.
- Tsukanov VV, Amelchugova OS, Butorin NN, Tretiakova OV, Vasiutin AV. Helicobacter pylori eradication: current status. Ter Arkh 2013; 85: 73-75.
- Gené E, Calvet X, Azagra R, Gisbert JP. Triple vs quadruple therapy for treating Helicobacter pylori infection: an updated meta-analysis. Aliment Pharmacol Ther 2003; 18: 543-544.
- Dore MP, Farina V, Cuccu M, Mameli L, Massarelli G, Graham DY. Twice-a-day bismuth-containing quadruple therapy for Helicobacter pylori eradication: a randomized trial of 10 and 14 days. Helicobacter 2011; 16: 295-300.
- Xu MH, Zhang GY, Li CJ. Efficacy of bismuth-based quadruple therapy as first-line treatment for Helicobacter pylori infection. Zhejiang Da Xue Xue Bao Yi Xue Ban 2011; 40: 327-331.
- O’Connor A, Molina-Infante J, Gisbert JP, O’Morain C. Treatment of Helicobacter pylori infection 2013. Helicobacter 2013; 18: 58-65.
- Uygun A, Ozel AM, Yildiz O, Aslan M, Yesilova Z, Erdil A, et al. Comparison of three different second-line quadruple therapies including bismuth subcitrate in Turkish patients with non-ulcer dyspepsia who failed to eradicate Helicobacter pylori with a 14-day standard first-line therapy. J Gastroenterol Hepatol 2008; 23: 42-45.
- Seyedmajidi S, Mirsattari D, Zojaji H, Zanganeh E, Seyyedmajidi M, Almasi S, et al. Penbactam for Helicobacter pylori eradication: a randomised comparison of quadruple and triple treatment schedules in an Iranian population. Arab J Gastroenterol 2013; 14: 1-5.
- Ching CK, Chan YK, Ng WC. The combination of omeprazole, amoxycillin, and clarithromycin eradicates Helicobacter pylori in 95% of patients-7 days of therapy is as good as 10 days. Hong Kong Med J 1998; 4: 7-10.
- Wang Z, Wu S. Doxycycline-based quadruple regimen versus routine quadruple regimen for rescue eradication of Helicobacter pylori: an open-label control study in Chinese patients. Singapore Med J 2012; 53: 273-276.
- Nadir I, Yonem O, Ozin Y, Kilic ZM, Sezgin O. Comparison of two different treatment protocols in Helicobacter pylori eradication. South Med J 2011; 104: 102-105.
- Marin AC, McNicholl AG, Gisbert JP. A review of rescue regimens after clarithromycin-containing triple therapy failure (for Helicobacter pylori eradication). Expert Opin Pharmacother 2013; 14: 843-861.
- Wong WM, Gu Q, Wang WH, Fung FM, Berg DE, Lai KC, et al. Effects of primary metronidazole and clarithromycin resistance to Helicobacter pylori on omeprazole, metronidazole, and clarithromycin triple-therapy regimen in a region with high rates of metronidazole resistance. Clin Infect Dis 2003; 37: 882-889.
- Wong WM, Xiao SD, Hu PJ, Wang WH, Gu Q, Huang JQ, et al. Standard treatment for Helicobacter pylori infection is suboptimal in non-ulcer dyspepsia compared with duodenal ulcer in Chinese. Aliment Pharmacol Ther 2005; 21: 73-81.
- Gisbert JP, Perez-Aisa A, Rodrigo L, Molina-Infante J, Modolell I, Bermejo F, et al. Third-line rescue therapy with bismuth-containing quadruple regimen after failure of two treatments (with clarithromycin and levofloxacin) for H. pylori infection. Dig Dis Sci. Published online: 2013 Oct 15.
- Chung JW, Lee GH, Han JH, Jeong JY, Choi KS, Kim do H, et al. The trends of one-week first-line and second-line eradication therapy for Helicobacter pylori infection in Korea. Hepatogastroenterology 2011; 58: 246-250.
- Kadayifci A, Buyukhatipoglu H, Cemil Savas M, Simsek I. Eradication of Helicobacter pylori with triple therapy: an epidemiologic analysis of trends in Turkey over 10 years. Clin Ther 2006; 28: 1960-1966.
- Venerito M, Krieger T, Ecker T, Leandro G, Malfertheiner P. Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. Digestion 2013; 88: 33-45.
- Gumurdulu Y, Serin E, Ozer B, Kayaselcuk F, Ozsahin K, Cosar AM, et al. Low eradication rate of Helicobacter pylori with triple 7-14 days and quadruple therapy in Turkey. World J Gastroenterol 2004; 10: 668-671.
- Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345: 784-789.
- de Boer WA, Driessen WM, Jansz AR, Tytgat GN. Quadruple therapy compared with dual therapy for eradication of Helicobacter pylori in ulcer patients: results of a randomized prospective single-centre study. Eur J Gastroenterol Hepatol 1995; 7: 1189-1194.
- de Boer WA, Driessen WM, Tytgat GN. Only four days of quadruple therapy can effectively cure Helicobacter pylori infection. Aliment Pharmacol Ther 1995; 9: 633-638.
- Salazar CO, Cardenas VM, Reddy RK, Dominguez DC, Snyder LK, Graham DY. Greater than 95% success with 14-day bismuth quadruple anti- Helicobacter pylori therapy: a pilot study in US Hispanics. Helicobacter 2012; 17: 382-390.
- Moon JY, Kim GH, You HS, Lee BE, Ryu DY, Cheong JH. Levofloxacin, metronidazole, and lansoprazole triple therapy compared to quadruple therapy as a second-line treatment of Helicobacter pylori infection in Korea. Gut Liver 2013; 7: 406-410.
- de Boer SY, v d Meeberg PC, Siem H, de Boer WA. Comparison of four-day and seven-day pantoprazole-based quadruple therapy as a routine treatment for Helicobacter pylori infection. Neth J Med 2003; 61: 218-222.
- Vekens K, Vandebosch S, De Bel A, Urbain D, Mana F. Primary antimicrobial resistance of Helicobacter pylori in Belgium. Acta Clin Belg 2013; 68: 183-187.
- Kamberoglou D, Polymeros D, Sanidas I, Doulgeroglou V, Savva S, Patra E, et al. Comparison of 1-week vs. 2- or 4-week therapy regimens with ranitidine bismuth citrate plus two antibiotics for Helicobacter pylori eradication. Aliment Pharmacol Ther 2001; 15: 1493-1497.
- Wong WM, Huang J, Xia HH, Fung FM, Tong TS, Cheung KL, et al. Low-dose rabeprazole, amoxicillin and metronidazole triple therapy for the treatment of Helicobacter pylori infection in Chinese patients. J Gastroenterol Hepatol 2005; 20: 935-940.
- Mégraud F. Current recommendations for Helicobacter pylori therapies in a world of evolving resistance. Gut Microbes 2013; 4: 541-548.
- Buzás GM. Helicobacter pylori-2010. Orv Hetil 2010; 151: 2003-2010.
- Castro-Fernández M, Lamas E, Pérez-Pastor A, Pabón M, Aparcero R, Vargas-Romero J, et al. Efficacy of triple therapy with a proton pump inhibitor, levofloxacin, and amoxicillin as first-line treatment to eradicate Helicobacter pylori. Rev Esp Enferm Dig 2009; 101: 395-402.
- Shiota S, Yamaoka Y. Strategy for the treatment of Helicobacter pylori infection. Curr Pharm Des 2013 Oct 14 [Epub ahead of print].
- Ergül B, Doğan Z, Sarikaya M, Filik L. The efficacy of two-week quadruple first-line therapy with bismuth, lansoprazole, amoxicillin, clarithromycin on Helicobacter pylori eradication: a prospective study. Helicobacter 2013; 18: 454-458.
- IARC Working Group on the evaluation of carcinogenic risks to humans schistosomes, liver flukes and Helicobacter pylori . Lyon, 7–14 Ju ne 1994. IARC Monogr Eval Carcinog Risks Hum 1994; 61: 1-241.
- Sugiyama A, Maruta F, Ikeno T, Ishida K, Kawasaki S, Katsuyama T, et al. Helicobacter pylori infection enhances N-methyl-N-nitrosourea-induced stomach carcinogenesis in the Mongolian gerbil. Cancer Res 1998; 58: 2067-2069.
- Yamagata H, Kiyohara Y, Aoyagi K, Kato I, Iwamoto H, Nakayama K, et al. Impact of Helicobacter pylori infection on gastric cancer incidence in a general Japanese population: the Hisayama study. Arch Intern Med 2000; 160: 1962-1968.
- Correa P, Fontham ET, Bravo JC, Bravo LE, Ruiz B, Zarama G, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst 2000; 92: 1881-1888.
- Wong BC, Lam SK, Wong WM, Chen JS, Zheng TT, Feng RE, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291: 187-194.
- Hamaguchi K, Ogawa K, Katsube T, Konno S, Aiba M. Does eradication of Helicobacter pylori reduce the risk of carcinogenesis in the residual stomach after gastrectomy for early gastric cancer? Comparison of mucosal lesions in the residual stomach before and after Helicobacter pylori eradication. Langenbecks Arch Surg 2004; 389: 83-91.
- Aydın A, Günşar F, Yılmaz M, Karasu Z, Özütemiz Ö, İlter T, et al. Ranitidine bismuth citrate based dual and triple therapies in Helicobacter pylori eradication. Turk J Gastroenterol 1999; 10: 202-206.
- Keum B, Lee SW, Kim SY, Kim JM, Choung RS, Yim HJ, et al. Comparison of Helicobacter pylori eradication rate according to different PPI-based triple therapy--omeprazole, rabeprazole, esomeprazole and lansoprazole. Korean J Gastroenterol 2005; 46: 433-439.
- Monteiro L, de Mascarel A, Sarrasqueta AM, Bergey B, Barberis C, Talby P, et al. Diagnosis of Helicobacter pylori infection: noninvasive methods compared to invasive methods and evaluation of two new tests. Am J Gastroenterol 2001; 96: 353-358.