Furazolidone-Based Quadruple Therapy for Eradication of Helicobacter pylori Infection in Peptic Ulcer Disease

There is a close relation between gastrointestinal diseases and Helicobacter pylori. This microorganism is the main pathogenic factor of chronic gastritis and peptic ulcer disease. In addition, the initiating factor in gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma is H. pylori (1). Finding this microorganism as a causative agent of peptic ulcer disease (PUD) has revolutionized the scientific understanding of the condition treatment (2). Because of the integral role of H. pylori in pathogenesis of PUD, its successful eradication is important in management of this disease (3-6), and substantially, the risk of ulcer recurrence and rebleeding could be reduced (3, 4). There has been a research focus to eradicate this microorganism for effective treatment of the above diseases (7). Multiple first-line treatments have been employed, and the eradication rates in the most successful regimens were from 75% to 92% (5).

There is a universal standard triple therapy with a proton pump inhibitor (PPI) or bismuth, amoxicillin and metronidazole or clarithromycin. Unfortunately, because of the widespread use of antibiotics, an increasing resistance to H. pylori, especially to metronidazole and clarithromycin has been resulted. “Legacy triple therapy”, recommended by the Maastricht Ⅲ consensus report, has disappointingly demonstrated low success rates (i.e. below 80%) worldwide (7). Primary bacterial resistance to antibiotics and patient compliance are two main cause of therapy failure. Moreover, there are some restrictions in the use of some expensive drugs such as clarithromycin and quinolones in developing countries, where a high prevalence of primary metronidazole resistance is present (8).

The high prevalence of H. pylori infection in adults over 35 years old (near 90%) has been shown in multiple seroepidemiological studies in different parts of Iran. There has been much lower eradication rate of H. pylori in this country than the rates reported from western and developed countries. Additionally, a high rate of metronidazole resistance (37%) and an increasing rate of resistance to clarithromycin have emerged (9). Therefore, it has been suggested to use furazolidone-based treatment by the World Gastroenterology Organization and Latin-America guidelines, to overcome these limitations in developing countries (10, 11). This drug is a synthetic nitrofuran with a broad spectrum of antimicrobial activities, widely used in treatment of bacterial and protozoal infections in both humans and animals (12). In spite of the low cost of the drug, some adverse effects, such as a molecule harboring a potential carcinogenetic effect, might influence the drug efficacy (13-19).

Increasing resistances of H. pylori to different antimicrobial drugs have encouraged scientists to find new effective therapeutic regimens. Using forgotten effective antimicrobial drugs in therapeutic regimens could be an effective solution for this problem. In this study, the efficacy of a therapeutic regimen containing furazolidone in comparison with a standard regimen against H. pylori was evaluated.

In this randomized clinical trial, each patient with persistent dispepsia, referred to Honari Clinic in Jahrom, Iran during a period of six mounts (from July to December 2012), swallowed a 14C-urea capsule for urease breath test (UBT) after a six-hour fasting period. Thereafter, patients laid down and changed sides every five minutes. Breath samples were collected from the subjects 15 minutes after the 14C-urea consumption. The samples were collected and counted using the Heliprobe method. In this method, patients exhaled into a special dry cartridge system (Heliprobe breath card) at the 15th minute. The activities of the cartridges were counted using a small designated GM (Geiger-Müller) counter system (Heliprobe analyzer); 110 patients with a positive UBT were selected. Neither of them had a history of using proton pump inhibitor (PPI) or H2 Blocker during the previous week nor using antibiotics during the previous mount. They were randomly divided into two equal groups. The first group received the standard regimen consisting of clarithromycin (500 mg Q12h), amoxicillin (1 g Q12) and a PPI (omeprazole 20 mg BID). The second group received bismuth subcitrate (120 mg Q6h), furazolidone (100 mg Q6h) and tetracycline (250 mg Q6h) and a PPI (omeprazole 20 mg BID). The treatment duration in both groups was two weeks. UBT was performed again for all the patients two months after completing the treatment to evaluate and compare the efficacy of these two regimens. Any patient with intolerance to these two regimens was excluded from the study. All the data was registered in special forms and analyzed with SPSS version 18 software using chi-square and Fisher tests and variance analysis.

A total of 110 patients, 20-70 years old, with mean age of 36.18 ±9.43 years old were studied. They were divided into five age groups (Table 1). Most of the patients belonged to the 30-40-year-old group (40%); 50 patients (45.5%) were male and 60 (55.5%) were female; 55 patients were treated with standard regimen for two weeks, among which, the UBT results were negative for 46 (83.6%), while it was still positive in 9 (5.5%), two months after the end of the treatment. There was no statistically significant relationship between age and eradication of H. pylori in the standard regimen group (P = 0.41). In the second group in which 55 patients were treated with our experimental regimen, only 3 (5.5%) had positive UBT results two months after the end of the treatment and eradication of H. pylori was reported in 52 (94.5%) patients based on negative UBT results. In this group, the highest eradication rate of H. pylori was reported in 30-40-year-old patients. However, there was no significant relationship between age and eradication of H. pylori in our experimental regimen group, too (P = 0.21).

Nausea and vomiting was reported in 3 (5.45%) patients treated with our experimental regimen. These symptoms were tolerable and the treatment was completely continued. No adverse effect was recorded in the standard group. Moreover, no relationship was observed between gender and eradication of H. pylori in both groups (P = 0.5 in the standard group and P = 0.44 in the experimental group). Finally, despite a better therapeutic response to our experimental group in comparison with the standard group, no statistically significant difference was observed (P = 0.067).

Different types of drugs such as antibiotics, antacids and metal preparations have been effective against H. pylori infection in multiple clinical trials. The usefulness of many antibiotics such as tetracycline, clarithromycin, amoxicillin, metronidazole and furazolidone on this bacterium with bactericidal or bacteriostatic effects has been proven (20). Reduction in the eradication rate with the standard triple therapy (PPI-clarithromycin-amoxicillin or metronidazole) (21) to unacceptable levels (i.e. 80% or less) has been observed in several recent clinical trials and meta-analyses (22, 23). This drug resistance could be the result of overuse and inappropriate consumption of these drugs as well as frequent anti-H. pylori treatment failures (24) Therefore, using less frequently used antibiotics which may be less likely to induce antibiotic resistance, which could be a logical strategy.

Despite the lack of routine use of furazolidone in the standard regimen against H. pylori, its high sensitivity rate (100%) (25) and significant effect on H. pylori conducted our team to include this drug in therapeutic regimen of our patients. It was shown in various studies that an eradication rate around 80% was achievable by a furazolidone-based combination therapy (26-28). In our study, the eradication rate of our experimental regimen containing furazolidone was 94.5%, which was more successful than some other recent similar studies in Iran (29, 30). Our results were similar to another study in Shiraz, Iran, in which a therapeutic regimen containing furazolidone and clarithromycin achieved the most eradication rate against H. pylori and it was advised to use these medications to treat Iranian people with gastritis (31).

There are some other studies confirming the effectiveness of this drug against H. pylori. In Bahari’s study in Zahedan, Iran, a regimen containing furazolidone was more effective (85%) than another regimen without it (80%) (32). Moreover, in Babol, Iran, a regimen containing furazolidone achieved a higher rate (60%) than the other one (54.3%) (33). In Talebi’s study in Iran, H. pylori resistance to different antibiotics was evaluated. In this survey, the least resistance was reported against furazolidone, tetracycline and clarithromycin, and the bacteria showed the highest resistance against metronidazole and amoxicillin (34). This high resistance rate against metronidazole was confirmed by Tirgar’s study on 101 patients (35). An acceptable reason for the high rate in both groups of our study might be due to not using metronidazole in both regimens. Therefore, it could be advised not to use metronidazole as an ingredient of therapeutic regimen against H. pylori for Iranian people.

Unfortunately, adverse effects of furazolidone may lead to interruption of treatment. This could be the main cause limiting the usage of this medication (27-30, 36). In our study, nausea and vomiting were reported in 3 (5.45%) patients who received furazolidone. This finding was similar to Ghadir’s study results from Iran, who reported some adverse effects in six of 86 patients (7%) treated with a therapeutic regimen contain furazolidone. Their symptoms were weakness, nausea, anorexia, and dizziness (30). Additionally, Ma in China reported dizziness, nausea and vomiting as the most common adverse effects in the furazolidone group. These reactions were mild and well tolerated and all the patients in that study were able to complete the entire therapy duration (20). Similarly, in Fakheri’s study, the number of patients who discontinued treatment with a furazolidone-containing regimen was not significant (29). Therefore, it could be concluded that side effects of this drug are not significant and could often be well tolerated by patients.

Based on our findings in this study and similar studies in different parts of the world, furazolidone could be prescribed as an effective antibiotic against H. pylori in patients with gastritis. However, adverse effect should be mentioned and monitored by physicians. Therefore, it could be recommended to use different antibiotics against H. pylori infection alternatively to decrease the chance of antibiotic resistance against this bacterium.