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World J Gastroenterol. Feb 21, 2009; 15(7): 860-864
Published online Feb 21, 2009. doi: 10.3748/wjg.15.860
Furazolidone, amoxicillin, bismuth and rabeprazole quadruple rescue therapy for the eradication of Helicobacter pylori
Hong Cheng, Fu-Lian Hu
Hong Cheng, Fu-Lian Hu, Department of Gastroenterology, Peking University First Hospital, Beijing 100034, China
Author contributions: Cheng H designed and performed this work; Hu FL directed the design and writing of this work.
Correspondence to: Hong Cheng, Department of Gastroenterology, Peking University First Hospital, Beijing 100034, China. chenghong@medmial.com.cn
Telephone: +86-10-66551122-2581
Fax: +86-10-66518105
Received: December 2, 2008
Revised: January 4, 2009
Accepted: January 11, 2009
Published online: February 21, 2009

Abstract

AIM: To compare the efficacy and side effect profiles of three furazolidone and amoxicillin-based quadruple rescue therapies for the eradication of Helicobacter pylori (H pylori).

METHODS: Patients who failed in the H pylori eradication therapy for at least one course were randomly allocated into three groups. Group A received rebaprazole 10 mg + amoxicillin 1 g + furazolidone 100 mg, and bismuth subcitrate 220 mg, twice daily for 1 wk; group B received the same regimen of group A but for 2 wk; and group C received the same regimen of group B, but furazolidone was replaced by furazolidone 100 mg three times daily. To record the side effect profiles at the end of the treatment, H pylori eradication was assessed with 13C-urea breath test 4 wk after therapy.

RESULTS: Sixty patients were enrolled including 28 males, and 20 patients in each group. The average age of the patients was 49.2 years, ranging from 18 to 84 years. H pylori eradication rates with per-protocol analysis were 82%, 89% and 90% in the three groups, respectively. Side effects were found in 11 patients, including mild dizziness, nausea, diarrhea and increased bowel movement. None of the 11 patients needed treatment for their side effects.

CONCLUSION: One- or two-week furazolidone and amoxicillin-based quadruple rescue therapy with a low dose furazolidone (100 mg bid) for the eradication of H pylori is effective. Extending the antibiotic course to 14 d could improve the eradication rates.

Key Words: Helicobacter pylori, Rescue therapy, Quadruple therapy, Furazolidone, Low dose



INTRODUCTION

Helicobacter pylori (H pylori) infection is associated with many upper gastrointestinal diseases, such as chronic gastritis, peptic ulcer, gastric carcinoma and mild malignant mucosa-associated lymphoid tissue lymphoma (MALToma). During recent years, the efficacy of the first-line therapy including proton pump inhibitors plus two antibiotics seems to have decreased, and several studies have reported intention-to-treat eradication rates lower than 75%[13] and even lower than 50%[45]. The resistance to antibiotics is the main cause of H pylori treatment failure. A multicenter study conducted in China in 2005 showed that the resistant rates of H pylori were 27.4% for clarithromycin, 75.6% for metronidazole and 2.7% for amoxicillin[6]. Many patients needed to receive rescue therapy for the eradication of H pylori after first- or second-line therapies. The combination of metronidazole, tetracycline, bismuth, and proton pump inhibitor are currently considered standard rescue regimens for the treatment of H pylori infection[7]. However, metronidazole resistance is a rising problem worldwide, particularly in developing countries, such as China, which limits the usefulness of this drug.

Furazolidone, a monoamine oxidase inhibitor, has broad antibacterial activity based on interference with bacterial enzymes. It has already been used to treat peptic ulcer disease for many years in China, before H pylori was discovered[89]. Furazolidone emerged as an agent for H pylori eradication regimens due to its low cost and prevalence of resistant strains in China. The consensus of reports of China in 2005[10] and 2007[11] all recommended that furazolidone should be used for H pylori eradication treatment. A large multicentrer study in China showed that a combination of omeprazole plus furazolidone and amoxicillin as the first-line regimen had an intention-to-treat H pylori eradication rate of 86%, compared to 69% for omeprazole plus clarithromycin and metronidazole[12]. However, in another study in China, the intention-to-treat eradication rate of omeprazole-furazolidone-amoxicillin regimen as the rescue regimen was only 52%[13]. The aim of this pilot study was to compare the efficacy and side effect profiles of three different furazolidone and amoxicillin-based quadruple rescue therapies for the eradication of H pylori.

MATERIALS AND METHODS
Subjects

This prospective clinical trial was conducted in Peking University First Hospital. Patients who failed in the eradication of H pylori for at least one course were invited to participate in this open-label pilot study. Informed written consent was obtained from all patients participating in the trial.

Patients younger than 18 years of age, and who presented with severe comorbidity, who were pregnant or lactating, with a known history of allergy to the study drugs, and patients who had used proton pump inhibitors, H2 receptor blockers, antibiotics, or bismuth salts up to 4 wk before the study were all excluded.

Treatment regimen

Patients were randomly allocated into three groups. Group A received rebaprazole 10 mg, amoxicillin 1 g, furazolidone 100 mg, and bismuth subcitrate 220 mg, twice daily each, for 1 wk; group B received the same regimen as group A but for 2 wk; and group C received the same regimen of group B but furazolidone was replaced by furazolidone 100 mg three times daily. Antibiotics were prescribed after meals whereas rabeprazole and bismuth were adminstered before meals. Patients were advised to maintain the treatment even with minor adverse effects. No other medication was allowed until the end of the treatment.

Assessment

Patients were evaluated using the 13C-urea breath test at least 4 wk after H pylori eradication treatment. Antimicrobials, bismuth-containing drugs and acid-reducing agents were not allowed during the 4 wk preceding the 13C-urea breath test. The eradication of H pylori was defined as a negative urea breath test.

The patient compliance and treatment-related side effects were assessed at the end of the treatment. Side effects were graded as mild if they did not interfere with daily activities of the patients, moderate if they interfered with daily activities to some extent and severe if daily activities became impossible.

Statistical analysis

Continuous variables were expressed by calculation of the mean and standard deviation. The H pylori eradication rate was assessed based on intention-to-treat and per-protocol analysis. The 95% confidence intervals (95% CI) were also calculated for both intention-to-treat and per protocol analysis and the eradication rate. The patients, who were lost to follow-up or could not complete the treatment course because of severe side effects, were considered as treatment failures and excluded in the per-protocol analysis. The Chi-square test and Fisher’s exact test were used to compare the differences between the three study groups in terms of baseline data, eradication rate and side effects. P < 0.05 was considered significant.

RESULTS

Sixty patients were enrolled in this study including 28 males, with 20 patients in each group. All of the patients had undergone endoscopy examination before they received H pylori eradication at the first time. The average age of the patients was 49.1 years, ranging from 18 to 84 years. Two patients had already undergone three treatments, 42 and 16 had undergone one and two, respectively. There was no predominance regarding the baseline characteristics of the patients (Table 1).

Table 1 Baseline characteristics of patients (mean ± SD).
GroupNo. of patientsAge (yr)MaleGastritisUlcer (DU/GU)SmokingDrinking
A2049.3 ± 15.28118 (7/1)63
B2049.9 ± 21.512139 (8/1)65
C2048.1 ± 9.38127 (7/0)63
Total6049.1 ± 15.8283624189
χ2 value--2.140.420.420.000.89
P value--> 0.05> 0.05> 0.05> 0.05> 0.05

All the patients finished the treatment, but four of them did not receive the 13C-urea breath test examination. H pylori eradication rates with per-protocol analyses were 82%, 89% and 90% in the three groups, respectively (P > 0.05) and the intention-to-treat eradication rates were 70% (14/20), 85% (17/20) and 90% (18/20) in the three groups (P > 0.05) (Table 2). No significant difference was found between the eradication rates of the patients who failed H pylori eradication for one, two or three courses (Table 3).

Table 2 H pylori eradication rates among three treatment groups.
GroupEradicationNon-eradicationLostTotalEradication ratea (PP, %) (95% CI, %)Eradication rateb (ITT, %) (95% CI, %)
A14332082 (57-96)70 (46-88)
B17212089 (67-99)85 (62-97)
C18202090 (68-99)90 (68-99)
Total48746087 (78-96)80 (70-90)
Table 3 H pylori eradication rates in relation to course of previous treatment.
Times of failureEradicationNon-eradicationLostTotalEradication ratea (PP,%) (95% CI, %)Eradication rateb (ITT, %) (95% CI, %)
135524288 (73-96)83 (74-96)
213121693 (66-100)81 (54-96)
3110250 (1-99)50 (1-99)
Total48746087 (78-96)80 (70-90)

Side effects were found in 11 patients, including mild dizziness, nausea, diarrhea and bowel movement increase (Table 4). None of the 11 patients needed treatment or stopped the therapy for their side effects.

Table 4 Side-effect profile of patients n (%).
Side effectsGroup AGroup BGroup CTotal
Nausea2125 (8.3)
Diarrhea1113 (5.0)
Bowel movement increasing0112 (3.3)
Dizziness0022 (3.3)
Headache0011 (1.7)
Asthenia1001 (1.7)
Total episodes43714 (23.3)
Total patients12 (10)3 (15)6 (30)11 (18.3)
DISCUSSION

The eradication of H pylori is the main objective in the treatment of peptic ulcer[1415]. The Masstricht III consensus report concluded that eradication of H pylori has the potential to reduce the risk of gastric cancer development; moreover, the optimal time to eradicate H pylori is before pre-neoplastic lesions (atrophy and intestinal metaplasia) are present[7]. Gastric carcinoma is common in China. So H pylori infection is a major public health problem, for which treatment should be provided when patients are diagnosed. The ideal therapy for H pylori infection should achieve a high cure rate of > 90% on per protocol analysis and > 80% on intention-to-treat analysis, should be simple and well tolerated, and should be easy to comply with and cost- effective[16]. The combination of proton pump inhibitor plus bismuth, tetracycline and metronidazole has been recommended as optimal second-line therapy by several guidelines on the management of H pylori infection[7]. However, metronidazole resistance is largely responsible for treatment failure. The prevalence of metronidazole resistance for H pylori is about 80% in China[6]. The best rescue treatment remains to be defined.

Furazolidone is a broad-spectrum nitrofuran, active against Gram-negative and positive bacteria and protozoa by inhibiting bacterial enzymes, and it has poor oral absorption[17]. Strains resistant to furazolidone are rare and have no cross-resistance to metronidazole[18]. Furthermore, its potential to develop resistance is low[19]. Several studies have shown the efficacy of regimens containing a high-dose furazolidone (200 mg, b.i.d.) as the therapy in patients with H pylori infection[2022]. The study of Fakheri et al showed that low-dose furazolidone (100 mg, b.i.d.) based triple and quadruple rescue regimens do not yield acceptable success rates[23]. We have reported that a pilot study of rabeprazole, bismuth, furazolidone and amoxicillin as rescue treatment of H pylori infection after failure for at least one course of eradication has intention-to-treat and per-protocol eradication rates of 70% and 82% for 1 wk in the group treated with furazolidone (100 mg, b.i.d.), 85% and 89% for 2 wk in the group with furazolidone (100 mg, b.i.d.), and 90% and 90% for 2 wk in the group with furozolidone (100 mg, t.i.d.), respectively. Our study is different from Fakheri et al, as a regimen which is useful in one area may not be effective in another area.

Management of first- or second-line H pylori eradication failures has become a challenge. In one study, a H pylori eradication rate of 69% was obtained after treatment with a 7-d association of bismuth, high-dose furazolidone (200 mg, b.i.d.), amoxicillin and a proton-pump inhibitor for patients with peptic ulcer who failed to respond to other eradication regimens[24]. In another study, a similar eradication rate (63%, intention-to-treat) was achieved with a rescue treatment of a 7-d quadruple regimen with omeprazole, bismuth, tetracycline, and high-dose furazolidone (200 mg, b.i.d.)[25]. Currently, a standard third-line therapy is lacking, and several guidelines recommend a culture to select proper treatment according to microbial sensitivity to antibiotics for these patients[711]. However, cultures are often carried out only in research centers. It is a common practice to select a rescue therapy according to experience, especially in China. In this study, the intention-to-treat eradication rates were 73%, 81% and 50% for the patients who failed in H pylori eradication for one, two or three courses, respectively. Although, without information of microbial sensitivity to antibiotics, it has been shown that furazolidone-(100 mg, b.i.d. or t.i.d.) and amoxicillin-based quadruple rescue therapy was highly effective in the population of this region. H pylori eradication can be achieved in most patients, even when antibiotic susceptibility is not tested.

Furazolidone presents some side effects, especially gastrointestinal ones[17]. Several studies showed that side effects were very common (more than 20%) in the patients who received treatment with furazolidone-based regimens[13], especially with high-dose furazolidone of 200 mg b.i.d.[2426]. A major problem with furazolidone at high doses is the high rate of severe side effects. Most of these effects are related to its role as a monoamino-oxidase inhibitor and include fever, rash and severe abdominal pain. Such side effects may lead to the discontinuation of treatment in some patients[21]. In this study, the occurrence of side events was 18.3%, and no intolerable side effects leading to early discontinuation of treatment were found. The most common side effects were nausea and diarrhea. Although the side effects were more frequent after extending the treatment course and adding furazolidone, this difference was not significant among different treatment groups.

The weakness of this study is that although set up as a controlled trial, the number of patients in each arm was small. Further studies should be done to conclude whether the increased dose of furazolidone or the longer period of treatment is helpful.

In conclusion, our study shows that the association of rabeprazole, bismuth, amoxicillin, and low-dose furazolidone is a valuable rescue treatment for patients who failed to respond to the first- or second-line H pylori eradication in China. Lower doses of furazolidone could decrease the incidence of side effects, but this strategy can also lead to a lower eradication rate. However, extending the antibiotic course to 14 d could improve eradication rates, despite a greater likelihood of side effects. The regimens are well tolerated by most patients. These are effective, cheap and safe options for salvage therapy of H pylori positive patients, and may be recommended as good alternative choice regimens in the eradication of H pylori in the population with high metronidazole resistance.

COMMENTS
Background

Helicobacter pylori (H pylori) infection is associated with many upper gastrointestinal diseases. The prevalence of H pylori resistant to antibiotics was increased with the spreading of H pylori eradication. Many patients needed to receive rescue therapy for the eradication of H pylori after first- or second-line therapies.

Research frontiers

Furazolidone-based regimens for the eradication of H pylori are low in cost. Lower doses of furazolidone could decrease the incidence of side effects. Not many studies have been performed to evaluate the efficacy of low-dose furazolidone-based quadruple regimens for treatment of H pylori infection.

Innovations and breakthroughs

This study provides further evidence of the efficacy and tolerability of low-dose furazolidone-based quadruple regimens in China.

Applications

Low-dose furazolidone-based quadruple regimens may be useful rescue therapies for H pylori eradication due to their low cost, low resistance rate and relatively minor side effects, especially in developing countries such as China.

Peer review

Furazolidone has been used for the eradication of H pylori for many years, but here it has been used as a component of quadruple rescue therapy. This has been reported less frequently. In this series of three groups of 20 patients, in which H pylori eradication therapy had failed to respond to at least one previous treatment regimen, each group was treated with one of three regimens of quadruple therapy containing furazolidone (either in different doses or for a different time), and the results were highly successful. Side effects from furazolidone are the main disadvantage of this drug, but when used in small doses as in this study, side effects were relatively minor. For the above reasons this is a useful publication.

Footnotes

Peer reviewers: Frank I Tovey, OBE, ChM, FRCS, Honorary Research Fellow, Department of Surgery, University College London, London, United Kingdom; Anthony TR Axon, Professor, Department of Gastroenterology, Infirmary At Leeds, Room 190a, Clarendon Wing, the General Infirmary at Leeds Great George Street, Leeds Ls1 3ex, United Kingdom

References
1.  Paoluzi P, Iacopini F, Crispino P, Nardi F, Bella A, Rivera M, Rossi P, Gurnari M, Caracciolo F, Zippi M. 2-week triple therapy for Helicobacter pylori infection is better than 1-week in clinical practice: a large prospective single-center randomized study. Helicobacter. 2006;11:562-568.  [PubMed]  [DOI]
2.  Calvet X, Ducons J, Bujanda L, Bory F, Montserrat A, Gisbert JP. Seven versus ten days of rabeprazole triple therapy for Helicobacter pylori eradication: a multicenter randomized trial. Am J Gastroenterol. 2005;100:1696-1701.  [PubMed]  [DOI]
3.  Rokkas T, Sechopoulos P, Robotis I, Margantinis G, Pistiolas D. Cumulative H. pylori eradication rates in clinical practice by adopting first and second-line regimens proposed by the Maastricht III consensus and a third-line empirical regimen. Am J Gastroenterol. 2009;104:21-25.  [PubMed]  [DOI]
4.  Altintas E, Sezgin O, Ulu O, Aydin O, Camdeviren H. Maastricht II treatment scheme and efficacy of different proton pump inhibitors in eradicating Helicobacter pylori. World J Gastroenterol. 2004;10:1656-1658.  [PubMed]  [DOI]
5.  Gumurdulu Y, Serin E, Ozer B, Kayaselcuk F, Ozsahin K, Cosar AM, Gursoy M, Gur G, Yilmaz U, Boyacioglu S. Low eradication rate of Helicobacter pylori with triple 7-14 days and quadriple therapy in Turkey. World J Gastroenterol. 2004;10:668-671.  [PubMed]  [DOI]
6.  Chinese Helicobacter pylori Research Group, Chinese Society of Gastroenterology. Prevalence of Helicobacter pylori resistance to antibiotics and its influence on the treatment outcome in China: A mulficenter clinical study. Weichang Bingxue. 2007;12:525-530.  [PubMed]  [DOI]
7.  Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772-781.  [PubMed]  [DOI]
8.  Zheng ZT, Wang ZY, Chu YX, Li YN, Li QF, Lin SR, Xu ZM. Double-blind short-term trial of furazolidone in peptic ulcer. Lancet. 1985;1:1048-1049.  [PubMed]  [DOI]
9.  Zhao HY, Li GZ, Guo JD, Yan Z, Sun SW, Li LS, Duan YM, Yue FZ. Furazolidone in peptic ulcer. Lancet. 1985;2:276-277.  [PubMed]  [DOI]
10.  Chinese Society of Gastroenterology, Chinese Medical Association. Consensus Report on the management of Helicobacter pylori infection (2003, Tongcheng, Anhui province). Weichang Bingxue. 2004;9:46-47.  [PubMed]  [DOI]
11.  Hu FL, Hu PJ, Liu WZ, De Wang J, Lv NH, Xiao SD, Zhang WD, Cheng H, Xie Y. Third Chinese National Consensus Report on the management of Helicobacter pylori infection. J Dig Dis. 2008;9:178-184.  [PubMed]  [DOI]
12.  Xiao SD, Liu WZ, Hu PJ, Ouyang Q, Wang JL, Zhou LY, Cheng NN. A multicentre study on eradication of Helicobacter pylori using four 1-week triple therapies in China. Aliment Pharmacol Ther. 2001;15:81-86.  [PubMed]  [DOI]
13.  Wong WM, Wong BC, Lu H, Gu Q, Yin Y, Wang WH, Fung FM, Lai KC, Xia HH, Xiao SD. One-week omeprazole, furazolidone and amoxicillin rescue therapy after failure of Helicobacter pylori eradication with standard triple therapies. Aliment Pharmacol Ther. 2002;16:793-798.  [PubMed]  [DOI]
14.  NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 1994;272:65-69.  [PubMed]  [DOI]
15.  Cheng H, Hu FL, Yuan SY, Pan GZ. Epidemiology of peptic ulcer in the Beijing area. Shijie Huaren Xiaohua Zazhi. 2007;15:3518-3523.  [PubMed]  [DOI]
16.  European Helicobacter Pylori Study Group. Current European concepts in the management of Helicobacter pylori infection. The Maastricht Consensus Report. Gut. 1997;41:8-13.  [PubMed]  [DOI]
17.  Altamirano A, Bondani A. Adverse reactions to furazolidone and other drugs. A comparative review. Scand J Gastroenterol Suppl. 1989;169:70-80.  [PubMed]  [DOI]
18.  Kwon DH, Lee M, Kim JJ, Kim JG, El-Zaatari FA, Osato MS, Graham DY. Furazolidone- and nitrofurantoin-resistant Helicobacter pylori: prevalence and role of genes involved in metronidazole resistance. Antimicrob Agents Chemother. 2001;45:306-308.  [PubMed]  [DOI]
19.  Treiber G, Wittig J, Ammon S, Walker S, van Doorn LJ, Klotz U. Clinical outcome and influencing factors of a new short-term quadruple therapy for Helicobacter pylori eradication: a randomized controlled trial (MACLOR study). Arch Intern Med. 2002;162:153-160.  [PubMed]  [DOI]
20.  Treiber G, Ammon S, Malfertheiner P, Klotz U. Impact of furazolidone-based quadruple therapy for eradication of Helicobacter pylori after previous treatment failures. Helicobacter. 2002;7:225-231.  [PubMed]  [DOI]
21.  Fakheri H, Malekzadeh R, Merat S, Khatibian M, Fazel A, Alizadeh BZ, Massarrat S. Clarithromycin vs. furazolidone in quadruple therapy regimens for the treatment of Helicobacter pylori in a population with a high metronidazole resistance rate. Aliment Pharmacol Ther. 2001;15:411-416.  [PubMed]  [DOI]
22.  Isakov V, Domareva I, Koudryavtseva L, Maev I, Ganskaya Z. Furazolidone-based triple 'rescue therapy' vs. quadruple 'rescue therapy' for the eradication of Helicobacter pylori resistant to metronidazole. Aliment Pharmacol Ther. 2002;16:1277-1282.  [PubMed]  [DOI]
23.  Fakheri H, Merat S, Hosseini V, Malekzadeh R. Low-dose furazolidone in triple and quadruple regimens for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2004;19:89-93.  [PubMed]  [DOI]
24.  Felga GE, Silva FM, Barbuti RC, Navarro-Rodriguez T, Zaterka S, Eisig JN. Quadruple therapy with furazolidone for retreatment in patients with peptic ulcer disease. World J Gastroenterol. 2008;14:6224-6227.  [PubMed]  [DOI]
25.  Eisig JN, Silva FM, Rodriguez TN, Hashimoto CL, Barbuti RC. A furazolidone-based quadruple therapy for Helicobacter pylori retreatment in patients with peptic ulcer disease. Clinics. 2005;60:485-488.  [PubMed]  [DOI]
26.  Isakov V, Domareva I, Koudryavtseva L, Maev I, Ganskaya Z. Furazolidone-based triple 'rescue therapy' vs. quadruple 'rescue therapy' for the eradication of Helicobacter pylori resistant to metronidazole. Aliment Pharmacol Ther. 2002;16:1277-1282.  [PubMed]  [DOI]