Comparing furazolidone and tetracycline in quadruple therapy for eradication helicobacter pylori in dyspepsia patients

Helicobacter pylori (H. pylori) infection is by far the most common chronic bacterial infection among humans (1). In developing countries, it is more frequent and occurs earlier (1). Approximately, 80% of adults residing in developing countries are affected (1,2). Chronic gastritis is usually detected during endoscopy, however, H. pylori infection is strongly associated with peptic ulcer, adenocarcinoma of stomach and gastric MALToma (3-8). Therefore, prompt diagnosis and appropriate management is of utmost importance.

H. pylori infection is diagnosed by either invasive (endoscopy and biopsy) or non-invasive (urease breath test (UBT), serology, and stool antigen testing) techniques. Nevertheless, non-invasive techniques including serology and stool antigen are usually applied for early diagnosis while UBT is used for eradication follow up (9,10).

Various regimens have been proposed for H. pylori eradication, among which triple therapy with a proton pump inhibitor (PPI)(i.e., omeprazole) in combination with amoxicillin and clarithromycin or quadruple therapy with a pump inhibitor, bismuth, metronidazole and tetracycline are more commonly appreciated. However, proposed regimens have limitations including expenses, availability, drug side effects, patient’s tolerance, and microorganism resistance, thus, investigations are still continuing to find more tolerable appropriate regimens. Furazolidone has been studied in scanty researches (11-17), however, with respect to H. pylori resistance to metronidazole among Iranian patients (18-20) and availability of furazolidone, the present study was conducted to compare furazolidone and tetracycline in quadruple therapy for eradication of H. pylori in Iranian dyspepsia patients.    

PATIENTS and METHODS

This double-blinded randomized clinical trial was conducted during a 6-month period in Khatam hospital in Zahedan. Patients with gastrointestinal manifestations including heart burn, flatulence, and post-prandial nausea were visited by an expert gastroenterologist. The following exclusion criteria were applied at baseline: age >50 years, weight loss >10% during the past 6 months, severe anorexia, dysphagia, odynophagia, anemia, jaundice, abdominal mass, lymphadenopathy, family history of gastric or esophageal cancer, past history of gastric surgery, recurrent vomiting, hematemesis, prior history of H. pylori treatment, antibiotic treatment during the 4 weeks prior to the study or treatment with pump inhibitors during the week before the study.

Included patients were those who were positive for both serum IgG against H. pylori (Serum Anti-H.Pylori IgG, DIAPLUS, Germany) and stool antigen (ASTRA, Italy). Then, patients were randomly assigned in either group A or B. Group A (OAB-F) received omeprazole (20 mg/bid), bismuth subcitrate (200mg/qid), amoxicillin (1000mg/bid) and furazolidone (100mg/bid) for 14 days. Group B (OAB-T) received omeprazole (20 mg/bid), bismuth subcitrate (200mg/qid), amoxicillin (500mg/bid) and tetracycline (500mg/bid) for 14 days. Patients were explained about the protocol and probable side effects. In case of severe side effect, the patient was excluded. Patients were visited at weeks 1 and 4 and finally after the regimen completion, while stool antigen testing was applied. All tests were achieved by a single laboratory staff and an expert pathologist who was blind to the study group managed the protocol.   

All patients were requested to complete an informed consent. A checklist of demographic, laboratory, and pathologic features was completed prior to the commencement of therapy and during follow up. Data were analyzed by SPSS for Windows (version 10.5, USA).

RESULTS

Totally, 109 patients were enrolled, of whom 9 were excluded. Fortunately, none of the subjects developed life threatening side effects, however, minor tolerable complications including, pruritus, nausea, and vomiting occurred. Finally, 49 patients (26 males and 23 females) in group A versus 51 patients (32 males and 19 females) in group B completed the desired regimen. The mean age of the patients was 28.7±6.3 and 28.3±6.3 years in group A and B, respectively.

Table 1. Response to therapy based on stool antigen negativity after 1 and 4 weeks of therapy

OAB-F: Omeprazole/Amoxicillin/Bismuth/Furazolidone

OAB-T: Omeprazole/Amoxicillin/Bismuth/Tetracycline

DISCUSSION

Studies conducted in developing countries demonstrated the increasing frequency of H. pylori infection while they showed the necessity for microorganism eradication through a cheap, tolerable and effective regimen (11).

Our studied population had functional dyspepsia and underwent noninvasive diagnostic approach for early diagnosis of H. pylori infection, while diagnostic endoscopy was not advised based on age of <50 years and lack of alerting symptoms (21). Serum IgG anti H.pylori is a cheap suitable approach for early diagnosis of H. pylori. In a metanalysis, sensitivity and specificity of IgG anti H.pylori-ELISA kit was 85% and 79%, respectively (22). Meanwhile, Stevens et al have reported an accuracy of 78% for anti H.Pylori ELISA kit in 558 samples (23). Nevertheless, diagnostic value of serology approaches depends mainly on H.Pylori prevalence and the underlying etiology (dyspepsia, peptic ulcer, etc.). However, stool antigen testing and urease breath test (UBT) are preferable to serology for early diagnosis and follow up (24-26). Therefore, we used serology and stool antigen testing for early diagnosis and stool antigen testing for follow up. Vaira et al reported stool antigen test to have sensitivity and specificity of 94% and 86%, respectively (25,26). These figures were 94% and 92% in Trevisani et al study (27). On the other hand, stool antigen testing was showed to be a valuable test for eradication follow up, however, the exact timing is a matter of controversy. Some investigators have proposed the 4^th week after the therapy to be a suitable point (25-28) while Vaira et al reported a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 91% if the test had been offered 1 week following the therapy (26). We advised our subjects to perform the test at weeks 1 and 4.

Antibiotics, bismuth and PPIs may be associated with false negative stool antigen testing results (29), however, Makristathis et al reported 32% false positive results among 41 patients after the 5^th week (30).

Prior investigators have proposed different eradication regimens. Suitable regimens may be advised based on the following criteria: expenses, side effects, availability, easy to use, and drug resistance pattern. A combination of omeprazole, bismuth, metronidazole and tetracycline is usually prescribed, however, combination of a PPI, clarithromycin, amoxicillin, and metronidazole is quite common in USA. Resistance to metronidazole is becoming a worldwide health concern. In a well designed study in USA, resistance was reported 22-39% (31), however, in another study 36.9% of strains were resistant to metronidazole (32). In Iran, Safaralizadeh et al showed 33% of H. Pylori specimens to be metronidazole-resistant (33). Unfortunately, scanty reports have addressed furazolidone as an alternative. Some studies have suggested furazolidone as a second choice of treatment (34). Malekzadeh et al compared furazolidone versus metronidazole in quadruple therapy for eradication of H. pylori in duodenal ulcer disease. After the 4^th week, 75% of patients became H.pylori-free in furazolidone-based regimen in comparison with 55% of metronidazole-based regimen (p<0.05)(35). Furthermore, Fakheri et al compared clarithromycin vs. furazolidone in quadruple therapy regimens for the treatment of H.pylori in a population with a high metronidazole resistance rate and reported an eradication rate of 85% and 84%, respectively (36). In another study, they compared the following 3 regimens: (A): omeprazole-amoxicillin-furazolidone (100mg/bid), (B): omeprazole-amoxicillin-bismuth-furazolidone (100mg/bid), and (C): omeprazole-amoxicillin-bismuth-furazolidone (200mg/bid) and reported 54%, 72%, and 92% eradication rate, respectively (37). Therefore, furazolidone with a higher dose (200mg/bid) is more effective, however, we have found an eradication rate of 85% with 100mg/bid. On the other hand, Daghaghzadeh et al have compared one-week versus two-week furazolidone-based quadruple therapy as the first-line treatment for Helicobacter pylori infection and reported an eradication rate of 84.8% and 82.6%, respectively (17). In Buzas study furazolidone-based regimen with PPI revealed an eradication rate of 76.3%, whereas, furazolidone-based quadruple therapy had eradicated H.Pylori in 83.4% of cases (24).

REFERENCES

1.     Pounder RE. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol Ther 1995; 9(Suppl 2):33-39.

2.     Torres J, Leal-Herrera Y, Perez-Perez G, et al. A community-based seroepidemiologic study of Helicobacter pylori infection in Mexico. J Infect Dis 1998;178:1089-94.

3.     Dunn BE, Cohen H, Blaser MJ. Helicobacter pylori. Clin Microbiol Rev 1997;10:720–41.

4.     The EUROGAST Study Group, An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993;341:1359.

5.     Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991;325:1127-31.

6.     Nomura A, Stemmermann GN, Chyou PH, et al. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 1991; 325:1132-36.

7.     Wotherspoon AC, Ortiz-Hidalgo C, Falzon M, et al. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 1991; 338:1175-76.

8.     Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 1994; 330:1267-71.

9.     Malfertheiner P, Megraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection. The Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther 2002; 16:167-80.

10.  Perri F, Manes G, Neri M, et al. Helicobacter pylori antigen stool test and 13C-urea breath test in patients after eradication treatments. Am J Gastroenterol 2002; 97:2756.

11.  Fakheri H, Malekzadeh R, Merat S, et al. 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;15:411-16.

12.  Eisig JN, Silva FM, Rodriguez TN, et al. A furazolidone-based quadruple therapy for Helicobacter pylori retreatment in patients with peptic ulcer disease. Clinics 2005 ;60(6):485-8. 

13.  Huo XH, Chu JK, Yang XF, et al. Efficacy of one-day quadruple therapy for H pylori infection in Chinese patients. World J Gastroenterol 2006;12(19):3105-7.

14.  Khatibian M, Ajvadi Y, Nasseri-Moghaddam S, et al. Furazolidone-based, metronidazole-based, or a combination regimen for eradication of Helicobacter pylori in peptic ulcer disease. Arch Iran Med 2007; 10(2):161-7.

15.  Kawakami E, Machado RS, Ogata SK,et al. Furazolidone-based triple therapy for H pylori gastritis in children. World J Gastroenterol 2006; 12(34):5544-9.

16.  Nijevitch AA, Shcherbakov PL, Sataev VU, et al. Helicobacter pylori eradication in childhood after failure of initial treatment: advantage of quadruple therapy with nifuratel to furazolidone. Aliment Pharmacol Ther 2005;22(9):881-7.

17.  Daghaghzadeh H, Emami MH, Karimi S, et al. One-week versus two-week furazolidone-based quadruple therapy as the first-line treatment for Helicobacter pylori infection in Iran. J Gastroenterol Hepatol 2007;22(9):1399-403. 

18.  Fallahi GH, Maleknejad S. Helicobacter pylori culture and antimicrobial resistance in Iran. Indian J Pediatr 2007;74(2):127-30.

19.  Rafeey M, Ghotaslou R, Nikvash S,et al. Primary resistance in Helicobacter pylori isolated in children from Iran. J Infect Chemother 2007; 13(5):291-5. 

20.  Siavoshi F, Safari F, Doratotaj D, et al. Antimicrobial resistance of Helicobacter pylori isolates from Iranian adults and children. Arch Iran Med 2006; 9(4):308-14.

21.  Talley N, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on evaluation of dyspepsia. Gastroenterology 2005; 129(5):1756-80

22.  Loy CT, Irwig LM, Katelaris PH, et al. Do commercial serological kits for Helicobacter pylori infection differ in accuracy? A meta-analysis. Am J Gastroenterol 1996; 91:1138

23.  Stevens M, Livsey S, Swann R, editors. Evaluation of sixteen EIAs for the detection of antibodies to Helicobacter pylori. London, England: Department of Health, 1997:1.

24.    Buzás GM, Józan J. Nitrofuran-based regimens for the eradication of Helicobacter pylori infection.  J Gastroenterol Hepatol 2007;22(10):1571-81

25.  Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. HpSA European study group. Lancet 1999;354:30-33. 

26.  Vaira D, Vakil N, Menegatti M, et al. The stool antigen test for detection of Helicobacter pylori after eradication therapy. Ann Intern Med 2002; 136:280-87.

27.  Trevisani L, Sartori S, Galvani F, et al. Evaluation of a new enzyme immunoassay for detecting Helicobacter pylori in feces: A prospective pilot study. Am J Gastroenterol 1999; 94:1830-33.

28.  Manes G, Balzano A, Iaquinto G, et al. Accuracy of stool antigen test in posteradication assessment of Helicobacter pylori infection. Dig Dis Sci 2001; 46:2440-44.

29.  Bravo LE, Realpe JL, Campo C, et al. Effects of acid suppression and bismuth medications on the performance of diagnostic tests for Helicobacter pylori infection. Am J Gastroenterol 1999; 94:2380-83.

30.  Makristathis A, Pasching E, Schutze K, et al. Detection of Helicobacter pylori in stool specimens by PCR and antigen enzyme immunoassay. J Clin Microbiol 1998; 36:2772-74.

31.  Osato MS, Reddy R, Reddy SG, et al. Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States. Arch Intern Med 2001; 161:1217-20.

32.  Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resitance in the United States: The surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 1993-1999. Ann Intern Med 2002; 136:13-24.

33.  Safaralizadeh R, Siavoshi F, Malekzadeh R, et al. Antimicrobial effectiveness of furazolidone against metronidazole-resistant strains of Helicobacter pylori. East Mediterr Health J 2006;12(3-4):286-93.

34.  Qasim A, Sebastian S, Thornton O, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication therapies after failure of standard first- and second-line eradication attempts in dyspepsia patients. Aliment Pharmacol Ther 2005;21:91-6.

35.  Malekzadeh R, Ansari R, Vahedi H, et al. Furazolidone versus metronidazole in quadruple therapy for eradication of Helicobacter pylori in duodenal ulcer disease. Aliment Pharmacol Ther 2000;14(3):299-303.

36.  Fakheri H, Malekzadeh R, Merat S, et al. 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;15:411-15.