Dong J, Yu XF, Zou J. Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication: A meta-analysis. World J Gastroenterol 2009; 15(48): 6102-6110
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Dr. Jian Zou, Department of Gastroenterology, Huadong Hospital, Fudan University, 221 Yan An Xi Road, Shanghai 200040, China. firstname.lastname@example.org
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World J Gastroenterol. Dec 28, 2009; 15(48): 6102-6110 Published online Dec 28, 2009. doi: 10.3748/wjg.15.6102
Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication: A meta-analysis
Jie Dong, Xiao-Feng Yu, Jian Zou
Jie Dong, Xiao-Feng Yu, Jian Zou, Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai 200040, China
ORCID number: $[AuthorORCIDs]
Author contributions: Dong J and Zou J contributed equally to this work; Zou J designed the research; Dong J, Yu XF and Zou J performed the research; Dong J, Yu XF and Zou J analyzed the data; Dong J and Zou J wrote the paper.
Correspondence to: Dr. Jian Zou, Department of Gastroenterology, Huadong Hospital, Fudan University, 221 Yan An Xi Road, Shanghai 200040, China. email@example.com
Telephone: +86-21-62483180 Fax: +86-21-62484981
Received: July 19, 2009 Revised: September 1, 2009 Accepted: September 8, 2009 Published online: December 28, 2009
AIM: To evaluate whether adding azithromycin to first-line Helicobacter pylori (H pylori) eradication improved eradication and reduced side effects.
METHODS: Eligible articles were identified by searches of electronic databases. We included all randomized trials that compared azithromycin-containing with standard triple-therapy regimens for first-line treatment of H pylori infection. Statistical analysis was performed with Review Manager 5.0.10. Sub-analyses were also performed.
RESULTS: We identified 14 randomized trials (1431 patients). Pooled H pylori eradication rates were 72.01% (95% CI: 58.09%-85.93%) and 69.78% (95% CI: 66.47%-73.09%) for patients with or without azithromycin by intention-to-treat analysis, and the odds ratio (OR) was 1.17 (95% CI: 0.64-2.14). The occurrence of side effects differed significantly and was 15.81% (95% CI: 12.50%-19.12%) and 25.20% (95% CI: 21.44%-28.96%) for treatment with or without azithromycin, respectively, and the summary OR was 0.58 (95% CI: 0.41-0.82). Furthermore, the azithromycin-containing group had a lower occurrence of diarrhea, nausea and taste disturbance.
CONCLUSION: Our review suggests that azithromycin-containing triple-therapy regimens could be equally effective in eradication of H pylori compared with standard first-line triple-therapy regimens.
Infection caused by Helicobacter pylori (H pylori), one of the most common pathogens worldwide, causes chronic gastritis and increases the risk of peptic ulcer and gastric cancer. Although some H pylori-positive individuals are asymptomatic, many experience symptoms such as dyspepsia. It is increasingly common to screen patients, even those with mild symptoms, for H pylori infection, and to treat them actively. The first-line treatment for H pylori infection, as recommended by the Maastricht III Consensus Report, is 7-d triple therapy that includes clarithromycin, amoxicillin and a proton-pump inhibitor (PPI). Even though this triple therapy is effective and its short duration helps maintain patient compliance, a considerable number of patients experience undesirable side effects.
In first-line therapy, eradication rates using combinations of PPI-based triple therapies range from 75% to 98%, with most of them near 80%. This signifies that up to 20% of patients are expected to be treatment failures, a value which could be even higher in areas with a high prevalence of resistant H pylori strains. The recommended second-line therapy is a quadruple regimen composed of tetracycline, metronidazole, bismuth salts and a PPI; however, the efficacy of this regimen is limited by poor compliance, treatment duration, number and dose of the prescribed drugs, and bacterial antibiotic resistance.
Gastroenterologists and microbiologists continue the search for new therapies because of the increasing number of target subjects for H pylori and the physiological and pharmacoeconomic burden of a second course of therapy. Among the new options against H pylori brought to light recently, azithromycin has attracted substantial interest. Azithromycin is a macrolide antibiotic that has been shown to reach high concentrations in gastric tissue after oral administration; furthermore, these high concentrations are maintained for several days, which make it potentially useful in the eradication of H pylori. Clinical trials with triple therapy regimens that contain azithromycin have reported eradication rates of approximately 60%-80%, depending on the regimen and azithromycin dose used[4,5]. However, results from some other available trials utilizing azithromycin have yielded conflicting results. The primary aim of the present meta-analysis was to evaluate whether adding azithromycin to H pylori eradication regimens could improve eradication and reduce side effects.
MATERIALS AND METHODS
Selection of studies
Studies evaluating azithromycin-containing triple therapy for the eradication of H pylori were considered. For the meta-analysis, the selection criteria were as follows: (1) articles that reported comparative randomized controlled trials (RCTs); (2) studies had to include at least two branches of treatment that consisted of (a) triple first-line therapy (one PPI and two antibiotics) and (b) azithromycin-containing triple regimen; (3) study population consisted of subjects who had never been treated for H pylori infection previously; and (4) data for successful eradication and/or side effects were available.
Search strategy for identification of studies
Trials were identified by searching the Cochrane Controlled Trials Register (Issue 2, 2009), PubMed (1966 to May 2009), Embase (1980 to May 2009), Science Citation Index (1945 to May 2009) and the Chinese Biomedical Database (1981 to May 2009). A search strategy was constructed by using a combination of the following words: (Helicobacter pylori OR H pylori) AND (azithromycin). Articles published in any language were included. Reference lists from the trials selected by electronic searching were hand-searched to identify further relevant trials. We also conducted a manual search of abstracts from 1995 to May 2009 from the following congresses: International Workshop of the European Helicobacter Study Group, American Digestive Disease Week (DDW), and United European Gastroenterology Week (UEGW). Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria were recorded. References of reviews on H pylori treatment with azithromycin, and from the articles selected for the study, were also examined for articles that met the inclusion criteria. Authors of some identified trials were asked whether they knew of additional studies, including unpublished randomized ones. In case of duplicate reports, or studies obviously reporting results from the same study population, only the latest published results were used.
Standardized data abstraction sheets were prepared. Data were exacted for study quality, dose and duration of azithromycin treatment, anti-H pylori regimens, and the number, sex and age of enrolled subjects, diagnostic methods of testing H pylori infection before enrolling and after completing the study, and scoring systems for assessing side effects. Key outcome data, such as eradication rates, occurrence of diarrhea, nausea, taste disturbance and abdominal pain were abstracted from all included studies. All articles were examined independently for eligibility by two reviewers. Disagreements were resolved by consulting a third reviewer. Quality was assessed using the Jadad score system based on three items, randomization, double blinding and description of withdrawals/dropouts. We considered that they were low quality when scores were < 3.
Data were entered into the Cochrane Collaboration review manager programme RevMan 5.0.10 (released on May 16, 2008). The outcome measure examined was the OR of improving H pylori eradication rates and reducing side effects with azithromycin compared to without azithromycin-containing triple regimens. Categorical variables were compared with the χ2 test, and P < 0.05 was considered statistically significant. Eradication rates and side effects were analyzed based on a fixed-effects model using the methods of Mantel-Haenszel, both by intention-to-treat and per-protocol. Heterogeneity between the studies was assessed by χ2 test. Statistical significance of heterogeneity was set at 0.10. If significant heterogeneity existed, it would have been inappropriate to combine the data for further analysis using a fixed-effects model, while the random model was used for calculations.
In the meta-analysis, sub-analyses of H pylori eradication efficacy were planned, depending on: (1) the type of drugs co-prescribed with azithromycin (combination with amoxicillin and a PPI was the most widely prescribed); (2) the duration and dose of azithromycin therapy; (3) age of the subjects involved; and (4) quality of the studies (based on quality score proposed by Jadad, see appropriate section). Finally, we used funnel plot asymmetry to detect any publication bias in the meta-analysis, and Egger’s regression test to measure funnel plot asymmetry.
Description of the studies
The bibliographical search yielded a total of 69 studies. Of these, 12 articles were excluded owing to publication type, i.e. two reviews, seven letters, two comments, and one editorial. We excluded 18 articles (10 non-clinical trials and eight unrelated articles) after examining the title and abstract, which left 39 potentially relevant articles for more detailed assessment. Of these potential eligible articles, 12 trials without a control group were excluded, and then we excluded another 17 articles, because of no combining with triple eradication regimens[7-11], containing azithromycin in two regimens[12-19], comparison of different treatment course of azithromycin[20,21], no triple first-line therapy in control group, and investigating relation between H pylori eradication and coronary heart disease. Furthermore, we identified four additional articles from the Chinese Biomedical Database (1981 to May 2009). Finally, 14 RCTs met the inclusion criteria[24-37]. The flowchart of reviews showed the detailed process of selection (Figure 1). The characteristics of 14 trials included in the meta-analysis are summarized in Table 1, including quality score.
Table 1 Characteristics of included studies comparing Helicobacter pylori (H pylori) eradication efficacy of azithromycin-containing triple therapy versus standard triple therapy.
Figure 1 Flowchart of study selection.H pylori: Helicobacter pylori.
Fourteen studies that described H pylori eradication rates were selected for the meta-analysis. Four of these reported significantly improved eradication rates, and the remaining 10 had similar efficacy for H pylori eradication. Pooled eradication rates were achieved in 499 of 693 patients with azithromycin supplementation (72.01%, 95% CI: 58.09%-85.93%) and in 515 of 738 patients with azithromycin without regimen (69.78%, 95% CI: 66.47%-73.09%) by intention-to-treat analysis, the OR was 1.17 (95% CI: 0.64-2.14) (Figure 2). Overall, per-protocol eradication rates were 75.81% (95% CI: 72.44%-79.18%) and 72.44% (95% CI: 69.05%-75.83%) for azithromycin supplementation and azithromycin without regimen, respectively (OR 1.22, 95% CI: 0.61-2.43).
Figure 2 Effect of azithromycin-containing triple therapy versus standard triple therapy on eradication rates by intention-to-treat analysis.
Total side effects were initially performed for meta-analysis. Data for the occurrence of side effects were obtained from 10 RCTs. Five of these studies reported a significant decrease in the occurrence of gastrointestinal side effects. The total number of side effects with azithromycin supplementation differed significantly from azithromycin without regimen: 15.81% (95% CI: 12.50%-19.12%) and 25.20% (95% CI: 21.44%-28.96%), and the summary OR was 0.58 (95% CI: 0.41-0.82) (Figure 3A). Individual symptoms during eradication therapy, such as nausea, diarrhea, abdominal pain, and taste disturbance were also analyzed. Incidence of diarrhea (2.13% vs 6.98%) (Figure 3B), nausea (3.85% vs 10.14%) (Figure 3C) and taste disturbance (3.17% vs 11.05%) (Figure 3D) were lower in the azithromycin supplementation group (OR: 0.33 vs 0.37 vs 0.28, 95% CI: 0.12-0.96 vs 0.14-0.96 vs 0.11-0.70).
Figure 3 Effect of azithromycin-containing triple therapy versus standard triple therapy on the incidence of total side effects (A), diarrhea (B), nausea (C), and taste disturbance (D).
Sub-analyses for the meta-analysis were planned depending on subject age, symptoms before enrollment, course of azithromycin, and choice of antibiotics. We divided all eligible trials into long- and short-course subgroups, Az+A subgroup, Az+Lev subgroup and Az+M/T subgroup. There was no significant difference between the long-course and short-course subgroups; the summary ORs were 0.89 (95% CI: 0.43-1.85) and 1.56 (95% CI: 0.60-4.08), respectively (Figure 4A). For antibiotics sub-analysis, Az+A subgroup, Az+Lev subgroup and Az+M/T subgroup all had no significant difference; the summary ORs were 1.11 (95% CI: 0.32-3.89), 1.19 (95% CI: 0.51-2.81) and 1.20 (95% CI: 0.53-2.69), respectively (Figure 4B).
Figure 4 Meta-analysis of eradication rates by treatment course (A) and different antibiotics (B).
We found that the funnel plot had a slightly asymmetrical distribution, but Egger’s regression test suggested no significant asymmetry of the funnel plot (P = 0.84), which indicated no evidence of substantial publication bias.
For H pylori eradication therapy, clinical trails are undertaken to search for simpler but equally or more effective regimens. The modern macrolides are a focus of attention from that point of view. Azithromycin, a new-generation macrolide, has some special attributes that make it a promising compound in regimens for H pylori eradication. Following the administration of a single oral dose, azithromycin readily accumulates in the human gastric mucosa, subsequently redistributes from mucosal tissue to the mucus layer, and from the mucus to gastric juice. There, it reaches gastric tissue concentrations that persist above the minimal concentration for 90% inhibition (MIC90) for H pylori (0.25 μg/mL) over a 5-d period, thus leading to exposure of the microorganism to consistent amounts of this drug. The high tissue affinity and the absorption of the drug after oral administration are reduced when given during or after a meal. The pharmacological properties of azithromycin make it possible to use shorter courses, therefore, the problem was to define an optimal dose and duration of azithromycin in triple therapy.
Azithromycin is able to reach high gastric concentrations that persist for several days, and therefore, it can be administered at a dose of 500 mg once daily for only 3 d during a 7-d triple eradication regimen. The published trials that have used this antibiotic have yielded conflicting results, and have reported a wide range of eradication rates. Administration with meals markedly reduces azithromycin absorption, therefore, this might account for the low eradication rates observed in some studies. In treatment regimens in which azithromycin was given to fasting patients, the cure rate was in the range 86%-93%[13,37]. Recently, short-term treatments of only 3 d, using a PPI plus azithromycin 500 mg and tinidazole 1000-2000 mg daily, have been found to promote eradication in 81%-88% of cases[23,39]. In contrast with the results reported in early studies that have used azithromycin for 2 wk and in repeated daily doses, side effects are scarce if the drug is administered once daily for a few days. In subanalyses, we also found that H pylori eradication rate had no significant difference between the long-course and short course subgroups.
H pylori eradication depends on a number of factors, including patient compliance, side effects, bacterial resistance, poor drug distribution or concentration, geographic differences, and socio-economic conditions. Optimization of H pylori eradication therapy remains an ongoing challenge worldwide. Although a great deal of research has focused on treatment of H pylori since the discovery of its crucial role in gastrointestinal disease, currently up to 25% of patients enrolled in clinical trials are treatment failures, even using the widely accepted and efficacious regimens that have gained inclusion in consensus guidelines. A disappointing cure rate of < 80% after 7-d triple therapy was confirmed in the present study. Guidelines often suggest that an acceptable success rate for a particular therapy against H pylori infection should be > 80% on an intention-to-treat basis. However, clinical trials with azithromycin have displayed considerable variation with respect to the regimens used and the results obtained. Eradication rates varying between 93% and 22% have been reported[20,30,42]. The results of our meta-analysis demonstrated pooled H pylori eradication rates were 72.01% and 69.78% for patients with or without azithromycin by intention-to-treat analysis, respectively, and no significant difference was observed between the two regimens.
H pylori has cross resistance to macrolides; e.g. a strain that is resistant to clarithromycin is resistant to every other macrolide. The level of clarithromycin resistance is unfortunately showing a tendency to increase. The effect of drug synergism is of great value in combination treatment to heal H pylori infection. Lepper et al have demonstrated an in vitro synergistic effect of azithromycin and the PPI lansoprazole. They have speculated that this effect might enhance eradication rates even with macrolide-resistant H pylori strains, because of the unique pharmacological properties of the combination. Azithromycin could provide a potent anti-H pylori effect and could simplify the bulky triple therapy.
Antibiotic-associated gastrointestinal side effects such as diarrhea, nausea, vomiting, bloating and abdominal pain represent a serious drawback of anti-H pylori therapy, although they are mild in most cases, but usually result in non-compliance. The quadruple regimen is associated with a relatively high incidence of side effects. In contrast, azithromycin is generally well tolerated, and most side effects associated with its use are mild to moderate in severity and transient. In our systematic review, we found that the total number of side effects with azithromycin supplementation was significantly lower than with azithromycin without regimen: 15.81% vs 25.20%; the summary OR was 0.58 (95% CI: 0.41-0.82). Moreover, the incidence of diarrhea (2.13% vs 6.98%), nausea (3.85% vs 10.14%) and taste disturbance (3.17% vs 11.05%) were lower in the azithromycin supplementation group. Our results showed that azithromycin had a positive impact on some H pylori therapy-related side effects. Several methodological weaknesses may limit the validity and generalizability of our meta-analysis. For example, there were no studies involving patients from Africa and South America.
In summary, the conclusion of this systematic review and meta-analysis is that, for first-time treatment, azithromycin-containing triple therapy has equal efficacy to that of standard triple eradication therapy. A combination of azithromycin, amoxicillin and a PPI constitutes an encouraging empirical first-line strategy. Furthermore, azithromycin-containing triple therapy showed a lower occurrence of drug-related side effects.
Colonization with Helicobacter pylori (H pylori) causes a wide range of upper gastrointestinal disorders in humans. Unfortunately, eradication therapy is not always successful, and can even induce several side effects. Azithromycin has some special attributes that make it a promising compound in the regimens for H pylori eradication.
In first-line therapy, H pylori eradication rates using proton-pump inhibitor (PPI)-based triple therapy are about 80%. This signifies that up to 20% of patients are expected to be treatment failures and it could be even higher in areas with a high prevalence of resistant H pylori strains. In this study, the authors demonstrated that, for first-time treatment, azithromycin-containing triple therapy has equal efficacy to standard triple eradication therapy.
Innovations and breakthroughs
Recent studies have shown that azithromycin is a promising compound in regimens for H pylori eradication. Our meta-analysis demonstrated that azithromycin-containing triple therapy has equal efficacy to standard triple eradication therapy, and has a lower occurrence of side effects. A combination of azithromycin, amoxycillin and a PPI constitutes an encouraging empirical first-line strategy.
By understanding the effect of azithromycin in H pylori eradication, this study represents a new encouraging strategy for first-time treatment, and it could decrease the physiological and pharmacoeconomic burden of second courses of therapy.
Azithromycin is a new-generation macrolide and has some special attributes. It is able to reach high gastric concentrations that persist for several days, and therefore may be administered at a dose of 500 mg once daily for only 3 d during 7-d triple eradication therapy.
The authors performed a meta-analysis and demonstrated that azithromycin-containing triple therapy has equal efficacy to standard triple H pylori eradication therapy. This was an original and good study.
Peer reviewers: Siegfried Wagner, Professor, Medical Clinic II, Klinikum Deggendorf, Perlasberger Str. 41, Deggendorf 94469, Germany; Özlem Yilmaz, PhD, Associate Professor of Microbiology, Department of Microbiology and Clinical Microbiology, Dokuz Eylul University, School of Medicine, Inciralti 35340, Izmir, Turkey
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