ACADEMIE ROYALE DES SCIENCES D OUTRE-MER BULLETIN DES SEANCES Vol. 4 No. 3 June 2015 pp. 177-182
ISSN: 0001-4176
Corresponding Author: Rahmatollah Rafiei
Is the prescription of azithromycin instead of clarithromycin more effective in the sequential therapy of helicobacter pylori eradication?
1Rahmatollah Rafiei,1Ahmadreza Hemmat,2Mahboobeh Bemanian,1Ahmad Sobhani,3Fereshteh Rafiei,
4Lotfollah Fouladi,5Alimohammad Rafatzand,3Farid Esmaeili
1Assistant Professor, Department of Internal Medicine, School of Medicine, Islamic Azad University, Najafabad Branch, Isfahan, Iran
2Department of Internal Medicine, School of Medicine, Islamic Azad University, Najafabad Branch, Isfahan,
3Student of Medicine, School of Medicine, Islamic Azad University, Najafabad Branch, Isfahan, IranIran
4Clinical Anatomical Pathologist, Dr Fouladi Laboratory, Isfahan, Iran
5B.S in chemistry, Sharif Institute of Technology
Abstract:
Introduction: Resistance to antibiotics of eradication regimens is the most important cause of failure in treatment of H. pylori in Iran. This study is aimed at comparison of treatment of H. pylori eradication with the two sequential regimen containing clarithromycin and the sequential regimen containing azithromycin. Method: This study is a randomized clinical trial. It was conducted during the period of March 2012 to March 2013 in Shariati Hospital in Isfahan [Iran] on patients with gastrointestinal problems who underwent endoscopy. 106 patients were randomly selected and equally divided into two treatment groups of 53. In sequential treatment regimens, Clarithromycin was administered to one group and azithromycin to the other group. At the end of treatment, urease breath test was performed on the patients. Results and findings: The overall H. pylori eradication rate of all the patients was 63.2%; it was 63.3% in the clarithromycin group and 64.2% in the azithromycin group. There was no statistically significant difference between the two groups [P=0.84]. Treatment compliance in both treatment groups was 100% and there was no significant difference between the two treatment groups [p value=1]. The incidence of adverse effects was 43.4% in the clarithromycin group and 33.4% in the azithromycin group and from among the adverse effects only the bad taste in the mouth was higher in the clarithromycin group [p=0.049]. Conclusion: Based on the results, it can be proposed that the two treatment methods used for H. pylori eradication are not appropriate; but these two treatments have an acceptable level of treatment compliance and also adverse effects
.Key words:
Helicobacter pylori
Clarithromycin
Azithromycin
Sequential therapy
INTRODUCTIONHelicobacter pylori [H. pylori] is a micro aerobic gram-negative bacterium and one of the most common human infections and this germ is the cause of three important diseases in the upper gastrointestinal tract including duodenal ulcers, gastric cancer and gastric lymphoma [1]. Infection eradication results in the long- term treatment of duodenal ulcers in more than 80% of the patients whose ulcers were not caused by the use of NSAID [2] and even H. pylori eradication helps to the
prevention of gastric cancer of the mucosa-associated lymphoid tissue [MALT] type and the other gastric cancers [3].
Several treatment regimens are used in Europe and the U.S. for treatment of H. pylori eradication [4 ,5]. Over the last ten years, a mild decrease in H. pylori eradication has been reported in the first step by regimens containing treatment with two antibiotics [6- 9]. Eradication level of less than 80% has been reported in many regimens [10-13]. The clinical studies performed in Iran and some other developing countries
have shown that the eradication rate of H. pylori is far less than this rate in developed countries. Moreover, the rate of relapse and re-infection in developing countries, with the same regimens used in the west, is very higher [14]. Resistance to antibiotics of eradication regimens is the most important cause of failure in treatment of H.
pylori eradication in Iran [15]. The common treatment regimens in western countries, for treatment of H.
pylori eradication, do not have much efficiency in Iran and therefore different double, triple or quadruple therapy regimens have been proposed for H. pylori eradication [15].
Over the recent years, an alternative treatment strategy known as “sequential therapy” has been proposed for H. pylori eradication. This treatment includes a proton pump inhibitor with amoxicillin for 5 days and then a proton pump inhibitor with clarithromycin and tinidazole for 5 other days. This treatment method is in fact a smart method; so, by using amoxicillin in the first five days it destroys the H. pylori cell membrane and leads to the higher effectiveness of the used antibiotics in the second five days [tinidazole and clarithromycin].
Clarithromycin is a macrolide and the most common adverse effect of this antibiotic was diarrhea and taste disorder which occurred in 6% of the patients. The other less common effects included nausea, indigestion, abdominal pain and headache. Clarithromycin is not a suitable drug for several reasons:
1- Based on the studies, over the last decade, H. pylori have shown resistance to antibiotics, particularly clarithromycin [3, 16].
2- Resistance to clarithromycin, which is the main component of H. pylori eradication regimen, is not only increasing in the eastern countries and South America but is also on the rise in European countries and North America and in a sense in the whole world and therefore, over the last years, the rate of H. pylori eradication has considerably decreased even in western countries [17].
3- Clarithromycin is very expensive and not affordable in developing countries [18, 19]. It can be thus concluded that in developing countries, in addition to antibiotic resistance, clarithromycin is an expensive medicine. As evident from the studies, antibiotic resistance to clarithromycin is on the rise in Iran as well and it is also a very expensive drug [20].
The choosing of a special regimen is affected by several factors including: efficiency, the patient’s tolerance, antibiotic resistance and the medical costs [21]. In this study also the main goal is the comparison of sequential treatment with clarithromycin and sequential treatment with azithromycin. In this regard, it is mainly intended to replace azithromycin with clarithromycin in order to avoid the recent adverse effects of antibiotics.
Furthermore, it is also intended to investigate the
effectiveness of this regimen in the epidemiologic conditions of the country of Iran and particularly Isfahan Province so that, based on the response rate to treatment and estimated costs, the best regimen in the patients can be finally determined. Undoubtedly, by means of more effective, less complicated and less costly regimens, the ability to recover can be increased in these patients.
METHODS AND MATERIALS
This research is an experimental study of clinical trial.
It was performed during the period of March 2012 to March 2013 in Shariati Hospital in Isfahan [Iran] after the ethics committee approval of the Medical School of Islamic Azad University of Najafabad on the patients with gastrointestinal problems who underwent endoscopy for various reasons such as gastrointestinal bleeding, weight loss, abdominal pain, etc. 106 patients were randomly selected and equally divided into two treatment groups of 53 individuals and underwent endoscopy by PENTAX video endoscopic device made in Japan by the gastroenterologist after obtaining informed consent and lack of contraindications for endoscopy including advanced heart and lung diseases.
The patients with H. pylori infection have been considered positive in terms of histologic evaluation and insensitivity to clarithromycin or azithromycin, the individual’s agreement to participate in the study and avoiding the use of antibiotics over the last month were the inclusion criteria in the study. The size of the required sample in this study was estimated by means of the formula for estimation of the sample size by considering the level of confidence as 95%, test power as 80% and the number of the patients as 53 in each group.
In our study, sampling has been done in the systematic random sampling method. Based on the inclusion and exclusion criteria in the study and admission of the patients to the project, finally 106 patients entered the study who had not previously received H. pylori eradication therapy; they underwent endoscopic examination and three biopsy samples were taken from their ant rum and the endoscopic findings of the patients were recorded; the samples were sent to the pathology laboratory for the pathologic study in terms of infection with H. pylori and then the patients who had a pathological infection with H. pylori in the Giemsa stain method, were divided into the two random clarithromycin and azithromycin groups. Both groups were given regimens for 40 days. The regimen was thus: the patients in group clarithromycin firstly used amoxicillin 1000 mg and pantoprazole 40 mg each twice a day and for 5 days after eating, then pantoprazole 40 mg, tinidazole 500 mg and clarithromycin 500 mg each twice a day and for 5 days;
and after the lapse of 10 days after the starting of drug treatment, people visited in order to become informed of the development or lack of development of the effects [so we provided the patient with a questionnaire that includes common adverse effects and the patient personally responded to this questionnaire]. Thus, we prevented the incidence of informative bias. Finally, Pantoprazole 40 mg was used by this group twice a day for 30 days. The aforementioned regimen was also used by the patients in the azithromycin group with the difference that the latter group used azithromycin 250 mg, instead of clarithromycin, twice a day for 5 days. 2 weeks after the treatment period [40-day period], the urease breath test was performed on the patients by the HELIPROPE device made in Sweden and the result of UBT test was reported as positive or negative. The rate of H. pylori eradication was based on the negative result of urease breath test. The research data were entered into the computer after collection and removal
of defects and were analyzed by means of SPSS Software version 20. The statistical tests used for data analysis consisted of Chi-square test and Student's t- test. P values less than 0.05 were considered significant.
Meanwhile, studied person's information was entered to data collection forms without naming and all of this information is saved for researchers. It should be noted that researchers observed principles of treaty of Helsinki in all the phases of this research.
THE RESULTS
In this research, 106 individuals entered the study and in the clarithromycin group 21 individuals [39.6%]
have been men and 32 individuals [60.4%] women, and in the azithromycin group 6 individuals [11.3%] have been men and 47 individuals [88.7%] women. In table 1, the demographic features have been illustrated.
Table 1: Demographic features of the groups Variable Groups
P value
Claritromycin Azithromycin
Gender Male
21(31.6) 6(11.3)
0.01 47(88.7) 32(60.4) Female
Age (years) 14.23
± 44.43 12.70
± 42.05 0.37
Duration (years) 4.22
± 3.11 5.7
± 3.9 0.389
Clinical symptoms Epigastric pain
39(73.6) 36(67.9)
0.18
Melena 2(3.8)
0
pyresis 1(1.9)
3(5.7)
Regurgitation 1(1.9)
3(5.7)
Bloating + epigastric pain 4(7.5)
6(11.3)
pyresis + epigastric pain 2(3.8)
3(5.7)
Regurgitation + epigastric pain 1(1.9)
1(1.9)
Vomiting + nausea 3(5.7)
1(1.9)
Lack of development of adverse effects was 56.6%[30/53] and 66.6%[35/53] in the clarithromycin and azithromycin groups respectively and there was no significant relationship between the two groups in terms of lack of development of adverse effects [p=0.21].
Development of adverse effects was 43.4% [23/53] and 33.4% [18/53] in the clarithromycin and azithromycin groups respectively. From among the adverse effect,
only with regard to the bad taste in the mouth there was a significant difference between the two groups and this was 32.1% [17/53] and 18.9%[10/53] for the clarithromycin and azithromycin groups respectively [p=0.049]; but there was no significant difference between the two groups with regard to the other adverse effects [p>0.05] [table 2].
Table 2: Comparison of distribution of adverse effect in the groups
Variable groups
Frequency (percent) P value
Clarithromycin Azithromycin
Headache 2 (3.8)
5 (9.4)
0.220.5 1 (1.9) 0 Insomnia
Dizziness 1 (1.9)
1 (1.9)
1 10 (18.9) 17 (32.1) Bad taste in the mouth
0.049
Itching 1 (1.9)
2 (3.8)
0.5 1 (1.9) 0
0.5 1 (1.9) 0
0.5 3 (5.7) 1 (1.9) Anorexia
0.31 0 2 (3.8) Bloating
0.250.5 3 (5.7) 2 (3.8) fatigue
Rash 1 (1.9)
1 (1.9)
1 5 (9.4) 4 (7.5) Nausea and vomiting
0.21
The overall H. pylori eradication of all the patients was [67/106] 63.2%. It was 63.3% [33/53] and 64.2%
[34/53] in the clarithromycin and azithromycin groups respectively. There is no statistically significant difference between the two groups [p=0.84]; the compliance in both treatment groups was 100% and there was no significant difference between the two treatment groups in this regard [p value=1].
DISCUSSION
This study is aimed at comparison of H. pylori eradication therapy with regard to the two sequential regimen containing azithromycin and the sequential regimen containing clarithromycin and also the comparison of the compliance of these two therapies and also determination of the adverse effects from these two therapies.
Due to its molecular structure, this bacterium rapidly becomes resistant to antibiotics and requires multiple antibiotic combinations [1, 2, and 4]. The acceptable regimen for H. pylori eradication must be based on the intention-to-treat treatment success of 85-90% in analysis and must also be of low risk [adverse effects of less than 50%], suitable and cheap [22, 23].
In a clinical trial, the sequential treatment regimen for H. pylori containing clarithromycin had an effective level of about 88% [24], while in our study H. pylori eradication with the sequential treatment regimen containing clarithromycin was 62.3% which indicates the lower level of H. pylori eradication in the treatment conducted in this study. In the study by Sulivan et al.
which was carried out in 2002, two groups of the patients with H. pylori infection were randomly divided into two groups; the first group was treated with bismuth , clarithromycin, amoxicillin and lansoprazole, and the other group was treated with bismuth , azithromycin, amoxicillin and lansoprazole. In this study, the level of H. pylori eradication in the group receiving clarithromycin and the group receiving azithromycin was 81% and 52% respectively [25]; and in the study that was carried out by Minakari et al. in 2010 in Al-Zahra [A.S.] Medical Education Center in Isfahan [Iran], 150 patients with H. pylori infection were randomly divided into two groups; the first group was treated with azithromycin, ofloxacin, bismuth and omeprazole, and the second group was treated with amoxicillin, clarithromycin and bismuth and based on the given results, the level of H. pylori eradication in the second group that had received clarithromycin was significantly higher than the first group [azithromycin]
[38]. In the study that was performed by Dr. Rogha et al. in Shariati Medical Center in Isfahan [Iran], it was shown that the regimen containing azithromycin can be effective for H. pylori eradication [27] and in another
study that used a similar mechanism with sequential treatment and was carried out by Vcev A et al., in 71%
of the patients receiving azithromycin and 81% of the patients receiving clarithromycin, the H. pylori microbe was eradicated [28].
In this study on the level of therapeutic efficacy, the sequential treatment of H. pylori containing azithromycin was 64.2% and the sequential treatment of H. pylori containing clarithromycin was 62.3% and there is no statistically significant difference between these two in terms of therapeutic efficacy; and as therapeutic efficacy must have rate of H. pylori eradication about 85-90%, these two treatment regimens used in this clinical trial are not considered as appropriate treatments in terms of therapeutic efficacy.
Also, the overall H. pylori eradication, by including both groups, was 63.2%. Comparison of the treatment compliance of the two groups also showed that none of the patients participating in this clinical trial abandoned treatment and in both groups the compliance was 100%.
Nevertheless, the studies indicate that about 10% of the patients under H. pylori treatment abandon their treatment [29]; thus, these two treatment groups have an acceptable the compliance. Regarding the adverse effects, in the group receiving sequential treatment containing azithromycin, 33.4% developed adverse effects and in the group receiving sequential treatment containing clarithromycin, 43.4% developed side effects. The only side effect that had a significant difference between these two treatments was the bad taste in the mouth which was significantly higher in the clarithromycin group than in the azithromycin group.
As a treatment regimen must have adverse effects less than 50% [22, 23], in this regard the two treatment strategies used in this clinical trial have an acceptable adverse effects.
This study was primarily conducted in Isfahan and this is one of the strengths of this study but it has not been performed due to lack of laboratory facilities for H.
pylori culture and antibiotic susceptibility assessment;
therefore, it is recommended that this study be conducted in the other parts of the country and due to the low H. pylori eradication level in these two methods, it is recommended that by adding probiotics to these two methods, eradication rate of H. pylori be assessed. Also, some centers should be launched for H.
pylori culture and antibiotic susceptibility assessment so that by a study on different methods of H. pylori treatment regimen, an appropriate treatment regimen, with the lowest costs and adverse effects and the highest eradication rate of H. pylori can be obtained.
CONCLUSION
Based on the results of our study, there was no significant difference between the two groups in terms of H. pylori eradication. Also, according to the given results, it can be concluded that the two therapies used are not considered as appropriate treatments for H.
pylori eradication; nevertheless, these two treatments have an acceptable the compliance and also adverse effects and it is therefore recommended that the other H. pylori eradication treatment regimens be used and more studies be carried out in this field.
ACKNOWLEDGMENT
We sincerely thank all patients participating in this study because it would be impossible without their cooperation. This research was supported by Najafabad Islamic Azad University.
REFERENCES
1. Massarrat S, Saberi-Firoozi M, Soleimani A, Himmelmann GW, Hitzges M, Keshavarz H. Peptic ulcer disease, irritable bowel syndrome and constipation in two populations in Iran. Eur J Gastroenterol Hepatol 1995;7:427 – 33.
2. Malekzadeh R, Sotoudeh M, Derakhshan MH, Mikaeli J, Yazdanbod A, Merat S. Prevalence of gastric precancerous lesions in Ardabil, a high incidence province for gastric adenocarcinoma in the North-West of Iran. J Clin Pathol 2004;57:37 – 3. O’Connor A, Gisbert j, McNamara D , O’Morain42.
C.Treatment of Helicobacter pylori Infection.
Helicobacter 2010;15:46-52.
4. Malfertheiner P, Megraud F, O’Morain C, Hungin AP, Jones R, Axon A, et al. Current concepts in the management of Helicobacter pylori infection—the Maastricht 2 – 2000 Consensus Report.Aliment Pharmacol Ther 2002;16:167 – 80.
5. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH onsensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA 1994; 272:65.
6. Laine L, Suchower L, Frantz J, Connors A, Neil G.
Twicedaily, 10-day triple therapy with omeprazole, amoxicillin, and clarithromycin for Helicobacter pylori eradication in duodenal ulcer disease: results of three multicenter, double-blind, United States trials. Am J Gastroenterol 1998;93:2106–12.
7. Calvet X, Ducons J, Guardiola J, Tito L, Andreu V, Bory F, et al. One-week triple vs. quadruple therapy for Helicobacter pylori infection – a randomized trial. Aliment Pharmacol Ther 2002;16:1261–7.
8. Ables AZ, Simon I, Melton ER. Update on Helicobacter pylori treatment. Am FamPhysician . 2007;75[3]:351-358
9. Paoluzi OA, Visconti E, Andrei F, Tosti C, Lionetti R, Grasso E, et al. Ten and eight-day sequential therapy in comparison to standard triple therapy for eradicating elicobacter pylori infection: a randomized controlled study on efficacy and tolerability. J Clin Gastroenterol 2010;44:261–6.
10.Malfertheiner P, Megraud F, O’Morain C, Bazzoli F, El- Omar E, Graham D, et al. Current concepts in the management of Helicobacter pylori infection:
the Maastricht III Consensus Report. Gut 2007;56:772–81.
11.Kaboli SA, Zojaji H, Mirsattari D, Talaie R, Derakhshan F, Zali MR, et al. Effect of addition of vitamin C to clarithromycin- amoxicillin-omeprazol triple regimen on Helicobacter pylori eradication.
Acta Gastroenterol Belg 2009;72: 222-4.
12.Zojaji H, Talaie R, Mirsattari D, Haghazali M, Molaei M, Mohsenian N, et al. The efficacy of Helicobacter pylori eradication regimen with and without vitamin C supplementation. Dig Liver Dis 2009; 41: 644-7.
13.Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808–25.
14.Malekzadeh R, Mohamadnejad M, Siavoshi F, Massarrat S.Treatment of Helicobacter Pylori infection in Iran: low efficacy of recommended western regimens. Iran Arch Med 2004;7:1-8.
15.Zali MR.Facing resistance of H.pylori infection.
Gastroenterol Hepatol From Bed to Bench 2011;4:3- 16.Mégraud F. Basis for the management of drug- resistant Helicobacter pylori infection. Drugs 2004;
64: 1893-904.
17.Graham DY. Helicobacter Pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59:
1143-53.
18.Hasan SR, Vahid V, Reza PM, Roham SR. Short- duration furazolidone therapy in combination with amoxicillin, bismuth subcitrate, and omeprazole for eradication of Helicobacter pylori. Saudi J Gastroenterol 2010; 16:14-8.
19.Riahizadeh S, Malekzadeh R, Agah S, Zendehdel N, Sotoudehmanesh R, Ebrahimi-Dariani N, et al.
Sequential metronidazole-furazolidone or clarithromycin-furazolidone compared to clarithromycin-based quadruple regimens for the eradication of Helicobacter pylori in peptic ulcer disease: a double-blind randomized controlled trial.
Helicobacter 2010; 15:497-504
20.Safaralizadeh R, Siavoshi F, Malekzadeh R, Akbari MR, Derakhshan MH, Sohrabi MR, et al.
Antimicrobial effectiveness of furazolidone against metronidazole-resistant strains of Helicobacter pylori. East Mediterr Health J 2006; 12:286-93.
21.Kuipers E, Blaser M. Acid peptic disease:
epidemiology and pathobiology. In: Goldman L, Ausiello D, editors. Cecil medicine. 23th ed.
Philadelphia: Saunders Elsevier 2008; 1009-18.
22.Malekzadeh R, Mohamadnejad M, Siavoshi F,Massarrat S,treatment of helocobacter pylori infection in ran :low efficacy of recommended metronizadole regimens .arch iran med 2004 ;7:1-8.
23.Tytgut GNJ H. pylori and pept.Ic ulcer disease how to diagnosis,how to treat in podolski dk and fredman l.s GASTROENTROLOGY in the centennial year and beyond AGA 1997,DDW postgraduate course,Washington convention center,Washington DC.1997;23-26
24.Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med 2007; 146:556.
25.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 Oct;97[10]:2536-9
26.Minakari M, Davarpanah Jazi AH, Shavakhi A, Moghareabed N, Fatahi F. A randomized controlled trial: efficacy and safety of azithromycin, ofloxacin, bismuth, and omeprazole compared with amoxicillin, clarithromycin, bismuth, and omeprazole as second-line therapy in patients with Helicobacter pylori infection. Helicobacter 2010
;15:154-9.
27.Rogha M, Pourmoghaddas Z, Rezaee M, Shirneshan K, Shahi Z. Azithromycin effect on helicobacter pylori eradication: double blind randomized clinical trial2009 May-Jun;56[91-92]:722-4
28.Vcev A, Stimac D, Ivandić A, Vceva A, Takac B, Pezerović D. Pantoprazole, amoxycillin and either azithromycin or clarithromycin for eradication of Helicobacter pylori in duodenal ulcer Aliment Pharmacol Ther. 2000 Jan;14[1]:69-72.
29.de Boer WA, Tytgat GN. The best therapy for Helicobacter pylori infection: should efficacy or side-effect profile determine our choice? Scand J Gastroenterol 1995; 30:401.
