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World J Gastroenterol. Jul 28, 2006; 12(28): 4553-4556
Published online Jul 28, 2006. doi: 10.3748/wjg.v12.i28.4553
Azithromycin in one week quadruple therapy for H pylori eradication in Iran
Shahrokh Mousavi, Jafar Toussy, Siamak Yaghmaie, Mehrdad Zahmatkesh
Shahrokh Mousavi, Jafar Toussy, Siamak Yaghmaie, Mehrdad Zahmatkesh, Semnan Gastrointestinal and Liver diseases Research Center, Semnan University of Medical Sciences, Semnan, Iran
Co-correspondence: Mehrdad Zahmatkesh
Correspondence to: Dr. Shahrokh Mousavi, Department of gastroenterology, Fatemieh hospital, Semnan university of medical sciences, PO Box 35195-16, Semnan, Iran. shahrokhmousavi@yahoo.com
Telephone: +98-231-3341449 Fax: +98-231-3328302
Received: January 31, 2006
Revised: February 12, 2006
Accepted: February 28, 2006
Published online: July 28, 2006

Abstract

AIM: To investigate eradication rates, patient compliance and tolerability of a 1-wk Azithromycin-based quadruple therapy versus the 2-wk conventional therapy.

METHODS: A total of 129 H pylori-positive patients were randomized to either omeprazole 20 mg, bismuth subcitrate 240 mg, azithromycin 250 mg, and metronidazole 500 mg, all twice daily for 1-wk (B-OAzM) or omeprazole 20 mg, bismuth subcitrate 240 mg, amoxicillin 1g, and metronidazole 500 mg all twice daily for 2-wk (B-OAM). H pylori infection was defined at entry by histology and rapid urease test and cure of infection was determined by negative urea breath test.

RESULTS: H pylori eradication rates produced by B-OAzM and B-OAM were 74.1% and 70.4% respectively based on an intention to treat analysis, and 78.1% versus 75.7% respectively based on a per-protocol analysis. The incidence of poor compliance was lower, although not significantly so, in patients randomized to B-OAzM than for B-OAM (3.5% versus 4.3%) but intolerability was similar in the two groups ( 35% versus 33.3%).

CONCLUSION: 1-wk azithromycin based quadruple regimen achieves an H pylori eradication rate comparable to that of standard 2-wk quadruple therapy, and is associated with comparable patient compliance and complications.

Key Words: Peptic ulcer, Treatment, Azithromycin, H pylori, Non-ulcer dyspepsia



INTRODUCTION

H pylori is a common human pathogen that has been shown to be a major factor in peptic ulcer disease. It has also been linked to gastric adenocarcinoma and gastric lymphoma[1].

A number of antimicrobial agents have been used in various regimens to eradicate H pylori. Clinical trails are regularly undertaken to search for simpler but equally effective regimens[2-4]. Azithromycin, a new generation macrolide, has some special attributes that suggest it would be a promising compound to be used in regimens for H pylori eradication. It is acid-stable, has a long half-life and achieves remarkably high concentration in the gastric tissue[3,5]. There have been several clinical trials of azithromycin for the therapy of H pylori infection[3,4,6,7]. As the pharmacological properties of azithromycin make it possible to use shorter courses, the problem has been to define an optimal dose and duration of azithromycin treatment in the course of therapy[3,4]. On the other hand, in developed countries, regimens of one week’s duration are recommended for H pylori eradication[1,2] but in developing countries 1-wk regimens failed to eradicate the microbe. A minimum of 10 to 14 d of treatment were needed for eradication of the microbe, even in the presence of a favorable sensitivity profile[8-10]. The aim of this study was to assess the efficacy of azithromycin in a 1-wk regimen compared with a conventional 2-wk regimen in Iran, so we compared two quadruple regimens; bismuth subcitrate, omeprazole, azithromycin, and metronidazole, for 1-wk (B-OAzM) and bismuth subcitrate, omeprazole, amoxicillin and metronidazole, for 2-wk (B-OAM) in

H pylori eradication. The safety and tolerability of the two drugs combinations were also evaluated and compared.

MATERIALS AND METHODS

Patients considered for the study included individuals 18-80 years old with upper GI symptoms that were referred to our gastroenterology clinic for upper endoscopy. Patients with H pylori infection were included in the study. Other inclusion criteria included indication for treatment as per the National Institutes of Health (NIH) Consensus Conference including: peptic ulcer disease, history of peptic ulcer, chronic gastritis, gastric mocusa associated lymphoid tissue, or intestinal metaplasia[1,7]. Between October 2003 and October 2004, a total of 129 patients were enrolled in the study. All patients gave written informed consent before entering the study and the protocol was reviewed and approved by the Semnan Gastrointestinal and Liver diseases Research Center. The criteria for exclusion were: intake of proton pump inhibitors, antibiotic or bismuth salts within 4 wk prior to the study, stomach surgery, known hypersensitivity to one of the study medications, patients with liver cirrhosis, renal failure or other serious severe concomitant illness, pregnant women, and patients who had previously undergone eradication therapy. These criteria were ascertained by taking a complete history, physical examination, and appropriate hematological and biochemical tests. The demographic and endoscopic data of these patients are reported in Table 1.

Table 1 Clinical and demographic data of patients in the treatment groups.
DataB-OAM-2 wk regimen n (%)B-OAzM-1 wk regimen n (%)P value¹
ITT analysis7158
Age: yr, Mean (SD)48.3 (7.4)46.7 (5.4)0.17
Male45 (63.3)33 (56.8)0.45
NSAID users21 (29.5)15 (25.8)0.63
Cigarette smokers11 (15.4)8 (13.7)0.78
Abdominal pain47 (66.1)31 (53.4)0.14
Heartburn14 (19.7)18 (31)0.13
Dyspepsia57 (80.2)40 (68.9)0.13
PU37 (52.1)25 (43.1)0.3
Non-ulcer dyspepsia34 (47.8)33 (56.8)0.3
Loss to follow up21
Poor compliance32
Drop-outs53
PP analysis6655

On initial endoscopy, H pylori infection was deter-mined by rapid urease test and histological assessment. Rapid urease test was performed using two biopsy specimens; one from the antrum and the other from the corpus[11]. Histological assessment of H pylori status was performed using one further biopsy specimen from the antrum; within 3 cm of the pylorus (hematoxylin-eosin and Giemsa stains)[12]. The patients were considered to be infected if both the urease test and histology were positive on initial testing. The patients that satisfied the inclusion criteria were randomly assigned to one of the following regimes; one group received a regimen of bismuth subcitrate 240 mg, omeprazole 20 mg, azithromycin (Azithromycin TC®, Tehran shimi, Iran) 250 mg and metronidazole 500 mg, all bid, for 1-wk (B-OAzM) and the second group received a regimen of bismuth subcitrate 240 mg, omeprazole 20 mg, amoxicillin 1 g and metronidazole 500 mg, all bid, for 2-wk (B-OAM). Patients with duodenal or gastric ulcers continued on omeprazole (20 mg/d) for a total of 1 mo. Repeat examination was performed 1 wk and 4-8 wk after the cessation of therapy. Subjects recorded any side effects and change in symptoms, and performed an exit interview and pill count to evaluate compliance and side effects. Hematological and biochemical analyses were performed at the last visit. H pylori infection was determined by urea breath test (UBT) at the second examination. All patients were instructed to discontinue all proton pump inhibitors, H2 blockers, and bismuth for at least 4 wk before UBT. Eradication was defined on the basis of a negative UBT (carbon 13-Isomax 2000 TM device); results under the 5 cut off were considered negative[13].

Analysis of the two groups was conducted in the form of both per protocol (PP) and intention to treat (ITT). The ITT analysis for eradication was defined before the study to include all subjects who were randomized and received at least one dose of medication. The PP analysis for eradication included all subjects who took at least 80% of each study medication as prescribed.

The comparison of efficacy was evaluated using the χ2 test. The analysis was performed using the SPSS 11.5 statistical package (SPSS, Chicago, IL).

RESULTS

The two groups were comparable in terms of common clinical variables that are summarized in Table 1. Three patients were lost to follow up (two from the B-OAM regimen and one subject from the B-OAzM regimen); also five patients discontinued the drugs because of severe side effects (three from the B-OAM regimen and two subject from the B-OAzM regimen). The remaining 121 patients completed the study as planned.

PP analysis: H pylori infection was eradicated in 43 of 55 patients in the B-OAzM group (78.18%, CI0.95: 64.98%-88.18%) and in 50 of 66 patients in the B-OAM group (75.75%, CI0.95: 63.63%-85.46%); the difference was not statistically significant (χ2 = 0.1, P = 0.75).

In patients with peptic ulcer, H pylori infection was eradicated in 19 of 25 patients in the B-OAzM group (76%, CI0.95: 54.87%-90.64%) and in 28 of 37 in the B-OAM group (75.67%, CI0.95: 58.8%-88.22%); the difference was not statistically significant (χ2 < 0.001, P = 0.97).

ITT analysis: H pylori infection was eradicated in 74.13% (CI0.95: 60.95%-84.74%) in the B-OAzM group and 70.42% (CI0.95: 58.4%-80.67%) in the B-OAM group; the difference was not statistically significant (χ2 = 0.3, P = 0.58).

Complications: the overall results for side effects are summarized in Table 2. Complications were noted in 14 patients in the B-OAzM group (25.45%) and 17 patients in the B-OAM group (25.75%) with no statistically significant differences between the groups (χ2 < 0.001, P = 0.96). The symptoms were mild and did not necessitate any additional treatment except in the five patients that discontinued the drugs for severe complications.

Table 2 Complications of drugs in H pylori treatment.
ComplicationB-OAM-2 wk regimenB-OAzM-1 wk regimenP value²
n69³57³
Diarrhea (%)4 (5.7)4 (7)
Vomiting (%)5 (7.2)¹4 (7)¹
Abdominal pain (%)7 (10.1)5 (8.7)
Bad taste (%)7 (10.1)5 (8.7)
Anal pain (%)02 (3.5)
Total (%)23 (33.3%)20 (35%)0.83
DISCUSSION

Although various regimens have been recommended for H pylori eradication, all of them include at least 2 antibi-otics and one acid inhibitory drug[1]. In western countries, the most effective and usual regimens for preliminary treatment include; triple regimens for at least 1 wk, and use of clarithromycin as the antibiotic of choice against H pylori. Metronidazole, on the other hand, has largely been eliminated from first-line H pylori therapy because of its intolerability and high drug resistance[14]. However, in developing countries, effective treatments for H pylori vary from those used in developed countries. For example in middle east countries it has been shown that one week regimens fail to eradicate the microbe and the course of treatment should be continued for at least 10-14 d to provide for eradication[8-10]. Further, clarithromycin is not appropriate use because of its high price, drug resistance and unavailability[15,16], and so metronidazole is a common and effective drug in H pylori treatment in this setting.

Although the prevalence of H pylori strains that are resistant to metronidazole varies from 46%-51% in Iran[15-17], it has been shown that this drug in high doses (> 1 g) and in combination with other drugs remains effective against H pylori[18-21]. Therefore, in Iran as also done in some Asian countries[14,18] metronidazole is a very common drug used in H pylori eradication regimens[22]. In Iran, the most common regimens for first-line treatment are 2-wk quadruple regimens that include; metronidazole, omeprazole, bismuth and tetracycline or amoxicillin[22]. This conventional regimen introduced initially by Hosking, Deboer, Borody, and Laine as an effective regimen in

H pylori treatment has confirmed efficiency of a 63%-93% eradication rate[7,23-25]. On other hand, due to high rates of resistance to metronidazole, furazolidine was used instead of it, as first or particularly second line treatment[26].

Although 2 wk regimens have been effective in H pylori eradication, some patients withdraw from their treatment because of the long duration and large number of tablets. Thus, in this study we showed that a quadruple regimen, where azithromycin replaced amoxicillin, the duration of the treatment can be decreased without any change in its effectiveness.

Azithromycin is a new macrolide related to clarithro-mycin with an effective role in H pylori eradication and it was reported that azithromycin has a synergic effect with esomeprazole, even in presence of drug resistance[27]. In various studies the effectiveness of azithromycin has been evaluated in different doses from 500 mg to 3 g[2,27-29], although in most studies this drug was used for 3 d (1.5 g) as in respiratory tract infection but at this dose it has less effect than clarithromycin[3,5]. However, by increasing the total dose to 3 g, it has been shown that the effectiveness of azithromycin can be restored[3,4,6,7].

This is the first study in which azithromycin was used at a prescribed amount of 3.5 g (250 mg bid for 7d) in the treatment of H pylori infection. Fortunately; the patients’ tolerance was excellent. There were a few side effects based on biochemical tests, but most side effects were mild and disappeared with conservative therapy without the need to terminate the treatment.

Finally, in areas where clarithromycin cannot be used because of drug resistance or unavailability, azithromycin with a total dose of 3.5 g is an appropriate and safe drug for H pylori eradication regimen.

The effectiveness of furazolidone based triple or quadruple regimens has been evaluated in Iran[15,22,25,26], but because of resistance to metronidazole, it seems possible that a combination of azithromycin and furazolidone instead of azithromycin and metronidazole will achieve more favorable eradication rates, although further evaluation is needed.

Footnotes

S- Editor Wang J L- Editor Barrett KE E- Editor Bi L

References
1.  Malfertheiner P, Megraud F, O'Morain C, Hungin AP, Jones R, Axon A, Graham DY, Tytgat G. Current concepts in the management of Helicobacter pylori infection--the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther. 2002;16:167-180.  [PubMed]  [DOI]
2.  Sullivan B, Coyle W, Nemec R, Dunteman T. Comparison of azithromycin and clarithromycin in triple therapy regimens for the eradication of Helicobacter pylori. Am J Gastroenterol. 2002;97:2536-2539.  [PubMed]  [DOI]
3.  Blandizzi C, Malizia T, Gherardi G, Costa F, Marchi S, Marveggio C, Natale G, Senesi S, Bellini M, Maltinti G. Gastric mucosal distribution and clinical efficacy of azithromycin in patients with Helicobacter pylori related gastritis. J Antimicrob Chemother. 1998;42:75-82.  [PubMed]  [DOI]
4.  Ivashkin VT, Lapina TL, Bondarenko OY, Sklanskaya OA, Grigoriev PY, Vasiliev YV, Yakovenko EP, Gulyaev PV, Fedchenko VI. Azithromycin in a triple therapy for H.pylori eradication in active duodenal ulcer. World J Gastroenterol. 2002;8:879-882.  [PubMed]  [DOI]
5.  Silva FM, Eisig JN, Chehter EZ, da Silva JJ, Laudanna AA. Low efficacy of an ultra-short term, once-daily dose triple therapy with omeprazole, azithromycin, and secnidazole for Helicobacter pylori eradication in peptic ulcer. Rev Hosp Clin Fac Med Sao Paulo. 2002;57:9-14.  [PubMed]  [DOI]
6.  Krichhoff RM, Laufen H, Schäcke G, Kirchhoff G, Gallo E. Determination of azithromycin in gastric biopsy samples. Int J Clin Pharmacol Ther. 1999;37:361-364.  [PubMed]  [DOI]
7.  Peitz U, Menegatti M, Vaira D, Malfertheiner P. The European meeting on Helicobacter pylori: therapeutic news from Lisbon. Gut. 1998;43 Suppl 1:S66-S69.  [PubMed]  [DOI]
8.  Malekzadeh R, Merat S, Derakhshan MH, Siavoshi F, Yazdanbod A, Mikaeli J, Sotoudemanesh R, Sotoudeh M, Farahvash MJ, Nasseri-Moghaddam S. Low Helicobacter pylori eradication rates with 4- and 7-day regimens in an Iranian population. J Gastroenterol Hepatol. 2003;18:13-17.  [PubMed]  [DOI]
9.  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]
10.  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]
11.  Nishikawa K, Sugiyama T, Kato M, Ishizuka J, Kagaya H, Hokari K, Asaka M. A prospective evaluation of new rapid urease tests before and after eradication treatment of Helicobacter pylori, in comparison with histology, culture and 13C-urea breath test. Gastrointest Endosc. 2000;51:164-168.  [PubMed]  [DOI]
12.  Min K, Hong SM, Kim KR, Ro JY, Park MJ, Kim JS, Kim JM, Jung HC, Yu E. Intramucosal Helicobacter pylori in the human and murine stomach: its relationship to the inflammatory reaction in human Helicobacter pylori gastritis. Pathol Res Pract. 2003;199:1-8.  [PubMed]  [DOI]
13.  Lahner E, Vaira D, Figura N, Pilozzi E, Pasquali A, Severi C, Perna F, Delle Fave G, Annibale B. Role of noninvasive tests (C-urea breath test and stool antigen test) as additional tools in diagnosis of Helicobacter pylori infection in patients with atrophic body gastritis. Helicobacter. 2004;9:436-442.  [PubMed]  [DOI]
14.  Suzuki H, Masaoka T, Nomura S, Hoshino Y, Kurabayashi K, Minegishi Y, Suzuki M, Ishii H. Current consensus on the diagnosis and treatment of H. pylori-associated gastroduodenal disease. Keio J Med. 2003;52:163-173.  [PubMed]  [DOI]
15.  Ebrahimi-Dariani N, Mirmomen S, Mansour-Ghanaei F, Noormohammadpoor P, Sotodehmanesh R, Haghpanah B, Bahrami H. The efficacy of furazolidone-based quadruple therapy for eradication of Helicobacter pylori infection in Iranian patients resistant to metronidazole-based quadruple therapy. Med Sci Monit. 2003;9:PI105-PI108.  [PubMed]  [DOI]
16.  Mégraud F. Resistance of Helicobacter pylori to antibiotics and its impact on treatment options. Drug Resist Updat. 2001;4:178-186.  [PubMed]  [DOI]
17.  Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53:1374-1384.  [PubMed]  [DOI]
18.  Nagahara A, Miwa H, Kawabe M, Kurosawa A, Asaoka D, Hojo M, Iijima K, Terai T, Ohkusa T, Miyazaki A. Second-line treatment for Helicobacter pylori infection in Japan: proton pump inhibitor-based amoxicillin and metronidazole regimen. J Gastroenterol. 2004;39:1051-1055.  [PubMed]  [DOI]
19.  Fattahi E, Motamedi R, Nayebi AR, Rezazadeh H, Shakir A. Triple therapy using two dosages of metronidazole along with amoxicillin and omeprazole to eradicate Helicobacter pylori infection: a randomized, open study. Indian J Gastroenterol. 2004;23:154.  [PubMed]  [DOI]
20.  Roghani HS, Massarrat S, Pahlewanzadeh MR, Dashti M. Effect of two different doses of metronidazole and tetracycline in bismuth triple therapy on eradication of Helicobacter pylori and its resistant strains. Eur J Gastroenterol Hepatol. 1999;11:709-712.  [PubMed]  [DOI]
21.  Alarcon T, Domingo D, Lopez-Brea M. Antibiotic resistance problems with Helicobacter pylori. Int J Antimicrob Agents. 1999;12:19-26.  [PubMed]  [DOI]
22.  Sotoudehmanesh R, Malekzadeh R, Vahedi H, Dariani NE, Asgari AA, Massarrat S. Second-line Helicobacter pylori eradication with a furazolidone-based regimen in patients who have failed a metronidazole-based regimen. Digestion. 2001;64:222-225.  [PubMed]  [DOI]
23.  Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spenard J. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole, and tetracycline given with omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: a prospective, randomized, multicenter, North American trial. Am J Gastroenterol. 2003;98:562-567.  [PubMed]  [DOI]
24.  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.  [PubMed]  [DOI]
25.  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]
26.  Malekzadeh R, Ansari R, Vahedi H, Siavoshi F, Alizadeh BZ, Eshraghian MR, Vakili A, Saghari M, Massarrat S. Furazolidone versus metronidazole in quadruple therapy for eradication of Helicobacter pylori in duodenal ulcer disease. Aliment Pharmacol Ther. 2000;14:299-303.  [PubMed]  [DOI]
27.  Iacopini F, Crispino P, Paoluzi OA, Consolazio A, Pica R, Rivera M, Palladini D, Nardi F, Paoluzi P. One-week once-daily triple therapy with esomeprazole, levofloxacin and azithromycin compared to a standard therapy for Helicobacter pylori eradication. Dig Liver Dis. 2005;37:571-576.  [PubMed]  [DOI]
28.  Laine L, Estrada R, Trujillo M, Cheybani K, Yeramian P, Smith S, Neil G. Once-daily therapy for H. pylori infection: a randomized comparison of four regimens. Am J Gastroenterol. 1999;94:962-966.  [PubMed]  [DOI]
29.  Anagnostopoulos GK, Kostopoulos P, Margantinis G, Tsiakos S, Arvanitidis D. Omeprazole plus azithromycin and either amoxicillin or tinidazole for eradication of Helicobacter pylori infection. J Clin Gastroenterol. 2003;36:325-328.  [PubMed]  [DOI]