Since the discovery of the etiological role of Helicobacter pylori (H pylori) in peptic ulcer disease[1], its eradication became the main objective of therapy, and several treatment regimens were developed. Currently, triple therapy with omeprazole, amoxicillin, and clarithromycin remains the best therapeutic option[2]. Despite its efficacy, 10% to 20% of the patients present with treatment failure, demanding alternative therapeutic regimes with variable success rates[3,4]. The reasons for this considerable rate of failure are several, including low patient compliance with treatment[5], and bacterial resistance to antimicrobial agents[6,7]. The development of effective salvage treatments is of paramount importance in this situation.

Furazolidone is a synthetic nitrofuran derivative with bactericidal or bacteriostatic activity against Gram-positive and Gram-negative bacteria, and it is well absorbed in the intestine with no tissue accumulation[8]. It has anti-H pylori activity and resistant strains appear to be rare or non-existent in many areas[9], characteristics that make it a potential option for retreatment of peptic ulcer disease caused by H pylori. One of the main limitations for its widespread use is the relatively high incidence of significant adverse effects, reported mainly in European studies[10]. In a country such as Brazil, which has large populations with low socioeconomic levels and a high bacterial resistance to metronidazole[11], furazolidone emerges as an interesting option.

This study aimed to establish the efficacy and safety of a 7-d therapeutic regimen for H pylori eradication (omeprazole, bismuth subcitrate, furazolidone, and amoxicillin) in patients with peptic ulcer disease who had been previously treated with other therapeutic regimens without success.

  MATERIALS AND METHODS

The study was performed in accordance with the declaration of Helsinki, and was approved by the institutional Ethics Review Board for clinical research, and all patients signed an informed written consent form.

Sample size calculation was determined for a descriptive study of a dichotomous variable, considering the prevalence of peptic ulcer with resistant H pylori in 2% of the general population.

Patients were selected from the Outpatient Gastroenterology Clinic of Hospital das Cli’nicas, Faculty of Medicine, University of Sao Paulo. Fifty-one patients with peptic ulcer who had previously been treated unsuccessfully with one or more eradication regimens for H pylori were included in the study. Bacterial persistence after treatment was confirmed by positive rapid urease test and histological examination through a modified Giemsa staining method. Gastric mucosa samples were obtained from the antrum and corpus during upper digestive endoscopy.

Patients younger than 18 years of age were excluded, as were those who presented with severe comorbidity, pregnant patients, infants, patients who had previously undergone gastrectomy, patients with a known history of allergy to the therapeutic regimen drugs, and patients who had used non-steroidal anti-inflammatory drugs, antibiotic therapy, or bismuth salts up to 4 wk before study inclusion.

In an open, cohort study, the patients were invited to use a therapeutic regimen for 7 d that consisted of 20 mg omeprazole, 240 mg colloidal bismuth subcitrate, 1000 mg amoxicillin, and 200 mg furazolidone, taken twice a day. Patients were advised not to ingest alcoholic beverages and to avoid foods related to potential side effects determined for drugs similar to monoamine oxidase (MAO) inhibitors. They were also encouraged to take the full medication regularly and were informed about the importance of adequate use of the medication for successful treatment. No other medication was allowed until the end of the treatment, when patients were evaluated regarding compliance by counting the remaining tablets. Adverse effects were recorded in a questionnaire, and each adverse effect was specifically investigated.

Treatment efficacy was determined by bacterial negativity at the rapid urease test and histological examination of gastric antrum and corpus mucosa samples taken during digestive endoscopy performed 12 wk after the end of treatment.

A confidence interval of 95% was calculated for the eradication rate percentiles. The c2 method with Pearson coefficient was used for the comparison among the variables, eradication rate for previous treatment, gender, and age, with significance value of P

< 0.05. Statistical analysis was performed with the statistics software, version 10.0 (SPSS Inc., USA).

  RESULTS

Among the 51 patients enrolled in the study, there was no predominance regarding gender, and the median age was 48 years. Duodenal ulcer was most commonly observed. Five (10%) patients had already undergone three or more previous treatments (32 and 14 had undergone one and two, respectively). Six patients were excluded from the analysis, three for not undergoing follow-up evaluation, and three for early interruption of the treatment due to adverse effects.

The eradication rate was 68.8% (31/45). Eradication rates were similar regardless of the number of previous treatments (one treatment- 21/32, 65.6%; two treatments- 8/14, 57.1%; three or more treatments- 2/5, 40%). Age and gender did not correlate with eradication rates (P > 0.05). Adverse effects were reported by 31.4% of the patients, most of which were considered to be slight or moderate. Three patients had to withdraw from the treatment due to the severe adverse effects (one with nausea, one with diarrhea, and one with dizziness).

  DISCUSSION

H pylori infection is highly prevalent in Brazil. Among blood donors without gastrointestinal complaints, positive serology for H pylori is found in 68%[12]. In a country with more than 200 million inhabitants, we may estimate that 140 millions individuals are currently infected. If we consider a 10% incidence of peptic ulcer disease or gastric cancer, we will find 14 million people in whom eradication of H pylori is mandatory. Despite the good eradication rates achieved with the combination of omeprazole, amoxicillin, and clarithromycin, 10% to 15% of the patients present with treatment failure[2]. In face of this reality, it is interesting to pursue the development of alternative therapeutic regimens with satisfactory eradication rates, low incidence of adverse effects, and low cost.

The efficacy of different regimens varies according to patient compliance and bacterial resistance to the antibiotics[13]. Clarithomycin, quinolones and metronidazole should not be used more than once, due to H pylori intrinsic or induced resistance[14,15]. For patients with primary treatment failure it would be ideal to test the H pylori antimicrobial sensitivity, but the high cost and the lack of laboratories capable of adequately performing sensitivity tests limit this strategy. Retreatment must be based on knowledge of the antimicrobial agents previously used.

In our country, H pylori strains show an intrinsic resistance to metronidazole that reaches 50%, which decreases the efficacy of schemes containing this drug or other nitroimidazolics[16-19]. Furazolidone is widely available in public health care facilities in Brazil. Despite that no decrease in susceptibility has been observed[20], and bacterial resistance appears to be rare or non-existent in many areas[18,21,22], even among metronidazole-resistant isolates[23]. The main concern regarding its use is the adverse effects observed, especially among individuals who do not adhere to the dietary restrictions recommended, since this drug belongs to the group of the MAO inhibitors. Asian and European studies have reported a relatively high incidence of adverse effects (31.4%-35%)[10,24,25]. Conversely, two South American[26,27] studies have shown fewer undesirable symptoms when compared to the previously mentioned studies. In the present study, despite a comparable incidence of adverse effects during treatment, only three patients had severe symptoms demanding treatment discontinuation. Lower doses of furazolidone could decrease the incidence of undesirable symptoms, but this strategy can also lead to a lower eradication rate[22,28,29].

The prevalence of smokers was similar to that in the Brazilian population and no significant differences in the results were observed when analyzing the number of previous treatments, gender and age. Even though compliance was good, and the length of treatment was short, this regimen ought to be considered only as an alternative for patients with previous treatment failures. Extending the antibiotic course to 10 d or 14 d could improve eradication rates, despite a greater likelihood of adverse effects[30,31].

Furazolidone appears to be an excellent choice for combination therapy for H pylori infection, especially as a substitute for metronidazole in quadruple therapy regimens in areas with high prevalence of metronidazole-resistant strains[32]. In our study, the eradication rate was 68.8%, which was superior to that previously reported[33,34], and, considering the efficacy, safety and potential cost-effectiveness, it seems reasonable to introduce furazolidone-based regimens following the failure of initial eradication attempts[32]. The differences regarding the safety profile between South American and American and European studies may be attributed to the limited clinical experience with this drug in the former regions, where it is unavailable and expensive[33].

In conclusion, our study shows that the association of bismuth, furazolidone, amoxicillin and a proton-pump inhibitor is a valuable alternative for patients who failed to respond to an initial therapeutic regime in a country with high prevalence of H pylori metronidazole-resistant strains. This scheme is an effective, cheap and safe option for salvage therapy of H pylori positive patients.

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Guilherme Eduardo Gonc,alves Felga, Fernando Marcuz Silva, Ricardo Correa Barbuti, Toma’s Navarro-Rodriguez, Schlioma Zaterka, Jaime Natan Eisig,  Department of Gastroenterology, University of Sa~o Paulo, School of Medicine, Sa~o Paulo 054003-000, Brazil

Author contributions -  Eisig JN designed this work; Barbuti RC, Navarro-Rodriguez T and Zaterka S made substantial contributions to the conception of the study; Silva FM and Barbuti RC performed the acquisition of data and quality control; Silva FM, Felga GEG and Eisig JN performed the statistical analysis and interpretation of data; Felga GEG and Eisig JN prepared and submitted the manuscript; All authors read and approved the final manuscript.

Correspondence to -  Jaime Natan Eisig, MD, PhD, Department of Gastroenterology, University of Sa~o Paulo, Rua Dr. Ene’as de Carvalho Aguiar, 255-Sala 9159, Sa~o Paulo 054003-000, Brazil. .(JavaScript must be enabled to view this email address)

Telephone -  +55-11-30696447   Fax -  +55-11-30697830

Received -  February 2, 2008     Revised -  July 19, 2008

Accepted -  July 26, 2008

Published online -  October 28, 2008