A comparative study of levofloxacin-based versus clarithromycin-based triple therapy for first-line Helicobacter pylori eradication in Iran

A comparative study of levofloxacin-based versus clarithromycin-based triple therapy for first-line Helicobacter pylori eradication in Iran | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A comparative study of levofloxacin-based versus clarithromycin-based triple therapy for first-line Helicobacter pylori eradication in Iran Mohamad Seraj Nasiri Toosi, Mohamad Taher, Mohsen Nasiri Toosi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7439471/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Rising clarithromycin resistance in Iran necessitates the evaluation of alternative first-line Helicobacter pylori regimens. Helicobacter pylori is a primary cause of peptic ulcer disease and gastric cancer, making its effective eradication a global health priority. This study aimed to compare the efficacy, safety, and patient adherence of a levofloxacin-based triple therapy with the standard clarithromycin-based regimen. Aims This study aimed to compare the efficacy, safety, and patient adherence of a levofloxacin-based triple therapy against the standard clarithromycin-based triple therapy for the first-line eradication of Helicobacter pylori in an Iranian patient population. Methods This non-randomized, non-parallel, open-label clinical trial was conducted at Imam Khomeini Hospital complex affiliated with Tehran University of Medical Sciences, Tehran, Iran. Adults who were aged 18 to 65 years treatment-naïve patients with confirmed H. pylori infection based on a positive fecal Ag test were sequentially enrolled to receive either a 10-day regimen of levofloxacin, amoxicillin, and omeprazole (n = 61) or clarithromycin, amoxicillin, and omeprazole (n = 65). Eradication was confirmed by a fecal antigen test. Results Of 126 patients, 91 completed the final follow-up for per-protocol (PP) analysis. In the PP analysis, eradication rates were 81.6% (31/38) for the levofloxacin group and 66.0% (35/53) for the clarithromycin group (P = .101). In the intention-to-treat (ITT) analysis of all 126 patients, rates were 50.8% and 53.8%, respectively (P = .734). The incidence of side effects was similar (44.2% vs. 44.4%), though constipation was more frequent with levofloxacin (P = .017) and halitosis with clarithromycin (P = .022). Conclusion The levofloxacin-based regimen did not demonstrate statistically significant superiority over the clarithromycin-based regimen. With comparable safety and suboptimal efficacy for both regimens, these findings underscore the need for local resistance surveillance to guide first-line therapy. Trial Registration Iranian Registry of Clinical Trials, IRCT20210209050313N1. Registered on 200210520 Helicobacter pylori Levofloxacin Clarithromycin Eradication Drug Resistance Iran Introduction Helicobacter pylori (H. pylori) is the most prevalent chronic bacterial infection in humans and a primary cause of chronic gastritis, peptic ulcer disease, and gastric malignancies such as adenocarcinoma and MALT lymphoma[ 1 , 2 ]. In Iran, the prevalence of H. pylori is estimated to be between 40% and 90%, with increasing antibiotic resistance posing a significant threat to effective treatment[ 3 , 4 ]. Standard first-line therapy typically consists of a proton pump inhibitor (PPI) combined with clarithromycin and amoxicillin. However, the efficacy of this regimen is declining worldwide, primarily due to rising clarithromycin resistance[ 5 ]. The Maastricht VI/Florence Consensus report recommends avoiding clarithromycin-based triple therapy in regions where the resistance rate exceeds 15%[ 2 ]. Recent data from Tehran indicate clarithromycin resistance may be as high as 29.6%[ 6 , 7 ]. This necessitates the investigation of alternative, more effective first-line regimens. Levofloxacin, a fluoroquinolone antibiotic, is often used in second-line or rescue therapies[ 8 ], though some studies have explored its efficacy as a first-line agent[ 9 ]. Given that levofloxacin resistance rates in Tehran have been reported at 24.4%[ 3 ], its role as a first-line agent remains uncertain but warrants investigation. This study aimed to compare the efficacy, safety, and patient adherence of a 10-day levofloxacin-based triple therapy with the standard 10-day clarithromycin-based triple therapy for the first-line eradication of H. pylori in an Iranian patient population. Methods Study Design and Population This non-randomized, non-parallel, Open-label clinical trial was conducted at the gastroenterology clinic of Imam Khomeini Hospital in Tehran, Iran, between March 2021 and May 2023. We enrolled 126 adult patients (aged 18-65 years) with a confirmed H. pylori infection, diagnosed via a positive fecal antigen test. Patients were excluded if they had received previous eradication therapy; had a known allergy to any of the study medications; had a history of major gastrointestinal surgery, significant renal impairment (defined as a Glomerular Filtration Rate < 30 mL/min/1.73m²), severe hepatic disease (Child-Pugh Class B, C), or active malignancy; were pregnant or lactating; or had used PPIs or antibiotics within the four weeks prior to enrollment; or lived outside of tehran city. Ethical Approval The study protocol was approved by the Ethics Committee of Tehran University of Medical Sciences (Approval No: IR.TUMS.IKHC.REC.1400.041) and was conducted in accordance with the Declaration of Helsinki. The trial was registered in the Iranian Registry of Clinical Trials (IRCT20210209050313N1). All participants provided written informed consent before inclusion in the study. Treatment Regimens Patients were assigned to one of two 10-day treatment groups. The first 65 eligible patients received the clarithromycin-based regimen (Clarithromycin 500 mg, Amoxicillin 1 g, and Omeprazole 20 mg, all taken twice daily). The subsequent 61 patients received the levofloxacin-based regimen (Levofloxacin 500 mg once daily, Amoxicillin 1 g twice daily, and Omeprazole 20 mg twice daily). Following the 10-day antibiotic course, all patients received omeprazole 20 mg once daily for an additional four weeks. Outcomes and Follow-Up The primary outcome was the successful eradication of H. pylori, defined as a negative fecal antigen test performed at least four weeks after the cessation of all antibiotic and PPI therapy. Secondary outcomes included the incidence and type of adverse effects and patient adherence to the treatment regimen. Adherence and side effects were assessed using a structured telephone questionnaire administered after the completion of the 10-day antibiotic course. Complete adherence was defined as taking >80% of the prescribed medications. Sample size calculation The sample size was calculated a priori based on response rates from previous studies[8] (p1=0.57, p2=0.80) to achieve 80% power with an alpha of 0.05. A P-value < .05 was considered statistically Statistical Analysis Data were analyzed using SPSS Statistics, version 25 (IBM Corp., Armonk, NY). Categorical variables were compared using the Chi-squared test or Fisher's exact test, as appropriate. Continuous variables were compared using the independent samples t-test. Efficacy was assessed by both intention-to-treat (ITT) and per-protocol (PP) analyses. For the ITT analysis, all patients who received at least one dose of medication were included. For the PP analysis, only patients who completed the treatment regimen and the final follow-up assessment were included. Results Patient Characteristics Of the 126 patients enrolled, 65 were assigned to the clarithromycin group and 61 to the levofloxacin group. A total of 91 patients (72.2%) completed the per-protocol follow-up (38 in the levofloxacin group, 53 in the clarithromycin group). The baseline demographic characteristics, including mean age, gender, and weight, were comparable between the two groups with no statistically significant differences.(Table 1) Eradication Rates In the per-protocol analysis, the eradication rate was 81.6% (31/38) in the levofloxacin group and 66.0% (35/53) in the clarithromycin group. This difference did not reach statistical significance (P = .101). In the intention-to-treat analysis, the eradication rate was 50.8% (31/61) in the levofloxacin group and 53.8% (35/65) in the clarithromycin group. This difference was also not statistically significant (P = .734). Adverse Effects and Adherence The overall incidence of adverse effects was nearly identical between the two groups, reported by 44.2% of patients in the levofloxacin group and 44.4% in the clarithromycin group (P = .982). A detailed comparison of specific side effects is shown in Table 2. Constipation was significantly more common in the levofloxacin group (9.6% vs. 0%, P = .017). Conversely, halitosis was significantly more frequent in the clarithromycin group (20.6% vs. 5.8%, P = .022). No other significant differences in adverse events were observed. Treatment adherence was high in both cohorts, with 76.9% in the levofloxacin group and 71.0% in the clarithromycin group reporting complete adherence. The difference was not statistically significant (P = .472). Discussion In this high-resistance setting in Tehran[3,7], our study found that a 10-day levofloxacin-based triple therapy achieved suboptimal eradication rates that were not significantly superior to a standard clarithromycin-based regimen. With success rates below the >90% efficacy target recommended by guidelines like the Maastricht VI/Florence Consensus report[2], these findings highlight the challenge of empirical first-line treatment in our region. This contrasts with some earlier studies conducted in Iran, such as the one by Haji-Aghamohammadi et al.[8] , which found a significant advantage for levofloxacin-based therapy. However, our results are more aligned with international studies where resistance patterns are shifting[9]. The 81.6% eradication rate in the levofloxacin group (PP analysis) is promising but falls short of an ideal first-line therapy. This may reflect the emerging resistance to fluoroquinolones in our region, which has been previously reported at rates approaching those of clarithromycin[3]. The 66.0% success rate of the clarithromycin regimen is suboptimal and confirms its declining utility as a reliable first-line option in our setting, consistent with international guidelines for regions with >15% resistance[2]. Both treatment regimens were well-tolerated, with similar overall rates of side effects and high patient adherence. The distinct side effect profiles—constipation with levofloxacin and halitosis with clarithromycin—could be a factor in shared decision-making with patients. The lack of significant difference in overall tolerability suggests that neither regimen has a clear advantage in this regard.(Table 2) Our study has several important limitations. The main limitation is its non-randomized, sequential-enrollment design, which can introduce selection bias. For instance, temporal changes in patient referral patterns or underlying disease severity could have inadvertently created systematic differences between the two treatment groups that were not captured in the baseline demographics. While international guidelines increasingly recommend bismuth quadruple therapy in high-resistance regions, this study was designed to directly compare the two triple-therapy backbones most commonly used in our clinical practice. Further limitations include the high rate of loss to follow-up (28%), which reduced the effective sample size for the per-protocol analysis. This attrition reduces the statistical power of our study and could introduce attrition bias if the reasons for not completing follow-up differed systematically between the groups, even though discontinuation due to adverse effects was minimal .Another significant limitation is that eradication failure was not correlated with individual patient antibiotic susceptibility testing; we relied on regional resistance data, which may not reflect the specific resistance patterns in our cohort. Finally, the single-center nature of the study may limit the generalizability of the findings to other regions in Iran. While international guidelines increasingly recommend bismuth quadruple therapy in high-resistance regions, this study was designed to directly compare the two triple-therapy backbones most commonly used in our clinical practice. Further limitations include the high rate of loss to follow-up (28%), which reduced the effective sample size for the per-protocol analysis. This attrition was primarily due to patients not returning for follow-up appointments rather than treatment discontinuation, as only one patient in the levofloxacin group stopped the regimen due to adverse effects. Another significant limitation is that eradication failure was not correlated with individual patient antibiotic susceptibility testing; we relied on regional resistance data, which may not reflect the specific resistance patterns in our cohort. Finally, the single-center nature of the study may limit the generalizability of the findings to other regions in Iran. In conclusion, our findings suggest that in our clinical setting in Tehran, levofloxacin-based triple therapy does not offer a significant efficacy advantage over the standard clarithromycin-based regimen as a first-line treatment for H. pylori eradication. Both regimens exhibit suboptimal success rates, underscoring the urgent need for therapies that can overcome local resistance patterns, such as bismuth-based quadruple therapy. Future studies should focus on large-scale, randomized trials that incorporate susceptibility testing to guide empirical treatment choices. Declarations The authors have no competing interests to declare that are relevant to the content of this article. The data that support the findings of this study are available from the corresponding author upon reasonable request. Conflict of Interest The authors declare no conflict of interest. Acknowledgements The authors would like to thank the patients who participated in this study and the staff of the gastroenterology clinic at Imam Khomeini Hospital for their support. Author Contributions Mohamad Seraj Nasiri Toosi: Conceptualization, Investigation, Writing – Original Draft. Mohamad Taher: Supervision, Methodology, Writing – Review & Editing. Mohsen Nasiri Toosi: Supervision, Methodology, Writing – Review & Editing. Arash Miroliai: Supervision – Review & Editing. Foroogh Alborzi: Supervision – Review & Editing. Simin Dashti Khavidaki: Review & Editing. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. References Levi F, Lucchini F, Negri E, Zatonski W, Boyle P, La Vecchia C. Trends in cancer mortality in the European Union and accession countries, 1980–2000 Ann Oncol . 2004;15:1425–1431; Crowe SE. Helicobacter pylori Infection N Engl J Med . 2019;380:1158–1165. Malfertheiner P, Megraud F, Rokkas T Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report et al. 2022. Khademi F, Sahebkar AH, Vaez H, Arzanlou M, Peeridogaheh H. Characterization of clarithromycin-resistant Helicobacter pylori strains in Iran: A systematic review and meta-analysis. J Glob Antimicrob Resist. 2017;10:171–8. Moosazadeh M, Lankarani KB, Afshari M. Meta-analysis of the Prevalence of Helicobacter Pylori Infection among Children and Adults of Iran. Int J Prev Med. 2016;7:48. Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther. 2006;23:35–44. Sholeh M, Maleki F, Krutova M The increasing antimicrobial resistance of Helicobacter pylori in Iran: A systematic review and meta-analysis et al. 2020;25:e12730. Alihosseini S, Ghotaslou R, Heravi FS, Ahmadian Z, Leylabadlo HE. Management of antibiotic-resistant Helicobacter pylori infection: current perspective in Iran. J Chemother. 2020;32:273–85. Haji-Aghamohammadi AA, Bastani A, Miroliaee A, Oveisi S, Safarnezhad S. Comparison of levofloxacin versus clarithromycin efficacy in the eradication of Helicobacter pylori infection. Casp J Intern Med. 2016;7:267–71. Molina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication et al. 2010;31:1077–1084. Tables Table 1. Baseline Demographic and Clinical Characteristics of Patients Variable Levofloxacin Group (n=61) Clarithromycin Group (n=65) P-value Age (years), mean ± SD 44.2 ± 11.6 43.4 ± 10.3 .713 Gender, n (%) .831 - Male 27 (44.3) 30 (46.2) - Female 34 (55.7) 35 (53.8) Weight (kg), median (IQR) 72.5 (19.0) 75.0 (18.0) .632 Values are presented as mean ± standard deviation (SD, n (%), or median (interquartile range, IQR). Table 2. Incidence of adverse effects in the treatment groups. Adverse Effect Levofloxacin Group (n=52) n (%) Clarithromycin Group (n=63) n (%) P-value Any adverse effect 23 (44.2) 28 (44.4) .982 Constipation 5 (9.6) 0 (0.0) .017 halitosis 3 (5.8) 13 (20.6) .022 Diarrhea 4 (7.7) 5 (7.9) >.999 Headache 6 (11.5) 5 (7.9) .541 Dizziness 5 (9.6) 4 (6.3) .729 P-values calculated using Fisher’s exact test or Chi-squared test. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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In Iran, the prevalence of H. pylori is estimated to be between 40% and 90%, with increasing antibiotic resistance posing a significant threat to effective treatment[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eStandard first-line therapy typically consists of a proton pump inhibitor (PPI) combined with clarithromycin and amoxicillin. However, the efficacy of this regimen is declining worldwide, primarily due to rising clarithromycin resistance[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The Maastricht VI/Florence Consensus report recommends avoiding clarithromycin-based triple therapy in regions where the resistance rate exceeds 15%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Recent data from Tehran indicate clarithromycin resistance may be as high as 29.6%[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This necessitates the investigation of alternative, more effective first-line regimens.\u003c/p\u003e\u003cp\u003eLevofloxacin, a fluoroquinolone antibiotic, is often used in second-line or rescue therapies[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], though some studies have explored its efficacy as a first-line agent[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Given that levofloxacin resistance rates in Tehran have been reported at 24.4%[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], its role as a first-line agent remains uncertain but warrants investigation. This study aimed to compare the efficacy, safety, and patient adherence of a 10-day levofloxacin-based triple therapy with the standard 10-day clarithromycin-based triple therapy for the first-line eradication of H. pylori in an Iranian patient population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design and Population\u003c/p\u003e\n\u003cp\u003eThis non-randomized, non-parallel, Open-label clinical trial was conducted at the gastroenterology clinic of Imam Khomeini Hospital in Tehran, Iran, between March 2021 and May 2023. We enrolled 126 adult patients (aged 18-65 years) with a confirmed H. pylori infection, diagnosed via a positive fecal antigen test. Patients were excluded if they had received previous eradication therapy; had a known allergy to any of the study medications; had a history of major gastrointestinal surgery, significant renal impairment (defined as a Glomerular Filtration Rate \u0026lt; 30 mL/min/1.73m\u0026sup2;), severe hepatic disease (Child-Pugh Class B, C), or active malignancy; were pregnant or lactating; or had used PPIs or antibiotics within the four weeks prior to enrollment; or lived outside of tehran city.\u003c/p\u003e\n\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Committee of Tehran University of Medical Sciences (Approval No: IR.TUMS.IKHC.REC.1400.041) and was conducted in accordance with the Declaration of Helsinki. The trial was registered in the Iranian Registry of Clinical Trials (IRCT20210209050313N1). All participants provided written informed consent before inclusion in the study.\u003c/p\u003e\n\u003cp\u003eTreatment Regimens\u003c/p\u003e\n\u003cp\u003ePatients were assigned to one of two 10-day treatment groups. The first 65 eligible patients received the clarithromycin-based regimen (Clarithromycin 500 mg, Amoxicillin 1 g, and Omeprazole 20 mg, all taken twice daily). The subsequent 61 patients received the levofloxacin-based regimen (Levofloxacin 500 mg once daily, Amoxicillin 1 g twice daily, and Omeprazole 20 mg twice daily). Following the 10-day antibiotic course, all patients received omeprazole 20 mg once daily for an additional four weeks.\u003c/p\u003e\n\u003cp\u003eOutcomes and Follow-Up\u003c/p\u003e\n\u003cp\u003eThe primary outcome was the successful eradication of H. pylori, defined as a negative fecal antigen test performed at least four weeks after the cessation of all antibiotic and PPI therapy. Secondary outcomes included the incidence and type of adverse effects and patient adherence to the treatment regimen. Adherence and side effects were assessed using a structured telephone questionnaire administered after the completion of the 10-day antibiotic course. Complete adherence was defined as taking \u0026gt;80% of the prescribed medications.\u003c/p\u003e\n\u003cp\u003eSample size calculation\u003c/p\u003e\n\u003cp\u003eThe sample size was calculated a priori based on response rates from previous studies[8] (p1=0.57, p2=0.80) to achieve 80% power with an alpha of 0.05. A P-value \u0026lt; .05 was considered statistically\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical Analysis\u003c/p\u003e\n\u003cp\u003eData were analyzed using SPSS Statistics, version 25 (IBM Corp., Armonk, NY). Categorical variables were compared using the Chi-squared test or Fisher\u0026apos;s exact test, as appropriate. Continuous variables were compared using the independent samples t-test. Efficacy was assessed by both intention-to-treat (ITT) and per-protocol (PP) analyses. For the ITT analysis, all patients who received at least one dose of medication were included. For the PP analysis, only patients who completed the treatment regimen and the final follow-up assessment were included.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient Characteristics\u003c/p\u003e\n\u003cp\u003eOf the 126 patients enrolled, 65 were assigned to the clarithromycin group and 61 to the levofloxacin group. A total of 91 patients (72.2%) completed the per-protocol follow-up (38 in the levofloxacin group, 53 in the clarithromycin group). The baseline demographic characteristics, including mean age, gender, and weight, were comparable between the two groups with no statistically significant differences.(Table 1)\u003c/p\u003e\n\u003cp\u003eEradication Rates\u003c/p\u003e\n\u003cp\u003eIn the per-protocol analysis, the eradication rate was 81.6% (31/38) in the levofloxacin group and 66.0% (35/53) in the clarithromycin group. This difference did not reach statistical significance (P = .101).\u003c/p\u003e\n\u003cp\u003eIn the intention-to-treat analysis, the eradication rate was 50.8% (31/61) in the levofloxacin group and 53.8% (35/65) in the clarithromycin group. This difference was also not statistically significant (P = .734).\u003c/p\u003e\n\u003cp\u003eAdverse Effects and Adherence\u003c/p\u003e\n\u003cp\u003eThe overall incidence of adverse effects was nearly identical between the two groups, reported by 44.2% of patients in the levofloxacin group and 44.4% in the clarithromycin group (P = .982). A detailed comparison of specific side effects is shown in Table 2. Constipation was significantly more common in the levofloxacin group (9.6% vs. 0%, P = .017). Conversely, halitosis was significantly more frequent in the clarithromycin group (20.6% vs. 5.8%, P = .022). No other significant differences in adverse events were observed.\u003c/p\u003e\n\u003cp\u003eTreatment adherence was high in both cohorts, with 76.9% in the levofloxacin group and 71.0% in the clarithromycin group reporting complete adherence. The difference was not statistically significant (P = .472).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this high-resistance setting in Tehran[3,7], our study found that a 10-day levofloxacin-based triple therapy achieved suboptimal eradication rates that were not significantly superior to a standard clarithromycin-based regimen. With success rates below the \u0026gt;90% efficacy target recommended by guidelines like the Maastricht VI/Florence Consensus report[2], these findings highlight the challenge of empirical first-line treatment in our region. This contrasts with some earlier studies conducted in Iran, such as the one by Haji-Aghamohammadi et al.[8] , which found a significant advantage for levofloxacin-based therapy. However, our results are more aligned with international studies where resistance patterns are shifting[9].\u003c/p\u003e\n\u003cp\u003eThe 81.6% eradication rate in the levofloxacin group (PP analysis) is promising but falls short of an ideal first-line therapy. This may reflect the emerging resistance to fluoroquinolones in our region, which has been previously reported at rates approaching those of clarithromycin[3]. The 66.0% success rate of the clarithromycin regimen is suboptimal and confirms its declining utility as a reliable first-line option in our setting, consistent with international guidelines for regions with \u0026gt;15% resistance[2].\u003c/p\u003e\n\u003cp\u003eBoth treatment regimens were well-tolerated, with similar overall rates of side effects and high patient adherence. The distinct side effect profiles\u0026mdash;constipation with levofloxacin and halitosis with clarithromycin\u0026mdash;could be a factor in shared decision-making with patients. The lack of significant difference in overall tolerability suggests that neither regimen has a clear advantage in this regard.(Table 2)\u003c/p\u003e\n\u003cp\u003eOur study has several important limitations. The main limitation is its non-randomized, sequential-enrollment design, which can introduce selection bias. For instance, temporal changes in patient referral patterns or underlying disease severity could have inadvertently created systematic differences between the two treatment groups that were not captured in the baseline demographics. While international guidelines increasingly recommend bismuth quadruple therapy in high-resistance regions, this study was designed to directly compare the two triple-therapy backbones most commonly used in our clinical practice. Further limitations include the high rate of loss to follow-up (28%), which reduced the effective sample size for the per-protocol analysis. This attrition reduces the statistical power of our study and could introduce attrition bias if the reasons for not completing follow-up differed systematically between the groups, even though discontinuation due to adverse effects was minimal .Another significant limitation is that eradication failure was not correlated with individual patient antibiotic susceptibility testing; we relied on regional resistance data, which may not reflect the specific resistance patterns in our cohort. Finally, the single-center nature of the study may limit the generalizability of the findings to other regions in Iran. While international guidelines increasingly recommend bismuth quadruple therapy in high-resistance regions, this study was designed to directly compare the two triple-therapy backbones most commonly used in our clinical practice. Further limitations include the high rate of loss to follow-up (28%), which reduced the effective sample size for the per-protocol analysis. This attrition was primarily due to patients not returning for follow-up appointments rather than treatment discontinuation, as only one patient in the levofloxacin group stopped the regimen due to adverse effects. Another significant limitation is that eradication failure was not correlated with individual patient antibiotic susceptibility testing; we relied on regional resistance data, which may not reflect the specific resistance patterns in our cohort. Finally, the single-center nature of the study may limit the generalizability of the findings to other regions in Iran.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our findings suggest that in our clinical setting in Tehran, levofloxacin-based triple therapy does not offer a significant efficacy advantage over the standard clarithromycin-based regimen as a first-line treatment for H. pylori eradication. Both regimens exhibit suboptimal success rates, underscoring the urgent need for therapies that can overcome local resistance patterns, such as bismuth-based quadruple therapy. Future studies should focus on large-scale, randomized trials that incorporate susceptibility testing to guide empirical treatment choices.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eConflict of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors would like to thank the patients who participated in this study and the staff of the gastroenterology clinic at Imam Khomeini Hospital for their support.\u003c/p\u003e\n\u003ch3\u003eAuthor Contributions\u003c/h3\u003e\n\u003cp\u003eMohamad Seraj Nasiri Toosi: Conceptualization, Investigation, Writing \u0026ndash; Original Draft.\u003c/p\u003e\n\u003cp\u003eMohamad Taher: Supervision, Methodology, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eMohsen Nasiri Toosi: Supervision, Methodology, Writing \u0026ndash; Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eArash Miroliai: Supervision \u0026ndash; Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eForoogh Alborzi: Supervision \u0026ndash; Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eSimin Dashti Khavidaki: Review \u0026amp; Editing.\u003c/p\u003e\n\u003ch3\u003eData Availability Statement\u003c/h3\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLevi F, Lucchini F, Negri E, Zatonski W, Boyle P, La Vecchia C. Trends in cancer mortality in the European Union and accession countries, 1980\u0026ndash;2000 \u003cem\u003eAnn Oncol\u003c/em\u003e. 2004;15:1425\u0026ndash;1431; Crowe SE. Helicobacter pylori Infection \u003cem\u003eN Engl J Med\u003c/em\u003e. 2019;380:1158\u0026ndash;1165.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalfertheiner P, Megraud F, Rokkas T Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report et al. 2022.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKhademi F, Sahebkar AH, Vaez H, Arzanlou M, Peeridogaheh H. Characterization of clarithromycin-resistant Helicobacter pylori strains in Iran: A systematic review and meta-analysis. J Glob Antimicrob Resist. 2017;10:171\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoosazadeh M, Lankarani KB, Afshari M. Meta-analysis of the Prevalence of Helicobacter Pylori Infection among Children and Adults of Iran. Int J Prev Med. 2016;7:48.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther. 2006;23:35\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSholeh M, Maleki F, Krutova M The increasing antimicrobial resistance of Helicobacter pylori in Iran: A systematic review and meta-analysis et al. 2020;25:e12730.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlihosseini S, Ghotaslou R, Heravi FS, Ahmadian Z, Leylabadlo HE. Management of antibiotic-resistant Helicobacter pylori infection: current perspective in Iran. J Chemother. 2020;32:273\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHaji-Aghamohammadi AA, Bastani A, Miroliaee A, Oveisi S, Safarnezhad S. Comparison of levofloxacin versus clarithromycin efficacy in the eradication of Helicobacter pylori infection. Casp J Intern Med. 2016;7:267\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMolina-Infante J, Perez-Gallardo B, Fernandez-Bermejo M Clinical trial: clarithromycin vs. levofloxacin in first-line triple and sequential regimens for Helicobacter pylori eradication et al. 2010;31:1077\u0026ndash;1084.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Baseline Demographic and Clinical Characteristics of Patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eLevofloxacin Group (n=61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eClarithromycin Group (n=65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eAge (years), mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e44.2 \u0026plusmn; 11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e43.4 \u0026plusmn; 10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.713\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eGender, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.831\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e- Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e27 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e30 (46.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e- Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e34 (55.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e35 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eWeight (kg), median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e72.5 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e75.0 (18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.632\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eValues are presented as mean \u0026plusmn; standard deviation (SD, n (%), or median (interquartile range, IQR).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Incidence of adverse effects in the treatment groups.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eAdverse Effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eLevofloxacin Group (n=52) n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eClarithromycin Group (n=63) n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eAny adverse effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e23 (44.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e28 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.982\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e5 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003ehalitosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e3 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e13 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e4 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e5 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e\u0026gt;.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e6 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e5 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.541\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e5 (9.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e4 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 25%;\"\u003e\n \u003cp\u003e.729\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eP-values calculated using Fisher\u0026rsquo;s exact test or Chi-squared test.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Helicobacter pylori, Levofloxacin, Clarithromycin, Eradication, Drug Resistance, Iran","lastPublishedDoi":"10.21203/rs.3.rs-7439471/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7439471/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eRising clarithromycin resistance in Iran necessitates the evaluation of alternative first-line Helicobacter pylori regimens. Helicobacter pylori is a primary cause of peptic ulcer disease and gastric cancer, making its effective eradication a global health priority. This study aimed to compare the efficacy, safety, and patient adherence of a levofloxacin-based triple therapy with the standard clarithromycin-based regimen.\u003c/p\u003e\u003ch2\u003eAims\u003c/h2\u003e\u003cp\u003eThis study aimed to compare the efficacy, safety, and patient adherence of a levofloxacin-based triple therapy against the standard clarithromycin-based triple therapy for the first-line eradication of Helicobacter pylori in an Iranian patient population.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis non-randomized, non-parallel, open-label clinical trial was conducted at Imam Khomeini Hospital complex affiliated with Tehran University of Medical Sciences, Tehran, Iran. Adults who were aged 18 to 65 years treatment-na\u0026iuml;ve patients with confirmed H. pylori infection based on a positive fecal Ag test were sequentially enrolled to receive either a 10-day regimen of levofloxacin, amoxicillin, and omeprazole (n\u0026thinsp;=\u0026thinsp;61) or clarithromycin, amoxicillin, and omeprazole (n\u0026thinsp;=\u0026thinsp;65). Eradication was confirmed by a fecal antigen test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOf 126 patients, 91 completed the final follow-up for per-protocol (PP) analysis. In the PP analysis, eradication rates were 81.6% (31/38) for the levofloxacin group and 66.0% (35/53) for the clarithromycin group (P\u0026thinsp;=\u0026thinsp;.101). In the intention-to-treat (ITT) analysis of all 126 patients, rates were 50.8% and 53.8%, respectively (P\u0026thinsp;=\u0026thinsp;.734). The incidence of side effects was similar (44.2% vs. 44.4%), though constipation was more frequent with levofloxacin (P\u0026thinsp;=\u0026thinsp;.017) and halitosis with clarithromycin (P\u0026thinsp;=\u0026thinsp;.022).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe levofloxacin-based regimen did not demonstrate statistically significant superiority over the clarithromycin-based regimen. With comparable safety and suboptimal efficacy for both regimens, these findings underscore the need for local resistance surveillance to guide first-line therapy.\u003c/p\u003e\u003ch2\u003eTrial Registration\u003c/h2\u003e\u003cp\u003eIranian Registry of Clinical Trials, IRCT20210209050313N1. Registered on 200210520\u003c/p\u003e","manuscriptTitle":"A comparative study of levofloxacin-based versus clarithromycin-based triple therapy for first-line Helicobacter pylori eradication in Iran","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-01 03:29:13","doi":"10.21203/rs.3.rs-7439471/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"448c7c38-1dd2-4a63-b6c5-de79f9f0ac5a","owner":[],"postedDate":"October 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-29T08:38:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-01 03:29:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7439471","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7439471","identity":"rs-7439471","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}