Efficacy of two-week therapy with doxycycline-based quadruple regimen versus levofloxacin concomitant regimen for helicobacter pylori infection: a prospective single-center randomized controlled trial

Eastern Mediterranean region countries have a high prevalence rate of Helicobacter Pylori (H.Pylori) infection [1]. Chronic infection of H. pylori contributes to multiple diseases such as peptic ulcer disease and subsequent bleeding [2‐4], dyspepsia, gastric adenocarcinoma [5], mucosa-associated lymphoid tissue (MALT) lymphoma [6], idiopathic thrombocytopenic purpura [7], and unexplained iron deficiency anaemia [8]. World health organization has listed the H.Pylori infection as a class 1 carcinogen [9]. Eradication of H.Pylori cures previous diseases and can decrease the risk of gastric cancer [10]. Eradication rate of H. pylori infection is declining globally due to increased antibiotic resistance particularly clarithromycin and levofloxacin [11]. In the eastern Mediterranean area, the resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, and tetracycline were 29%, 61%, 23%, 14%, 10% respectively [12]. Several researchers reviewed many therapeutic regimens including sequential, concomitant, and hybrid to find the best treatment protocol [13]. The results of conventional triple therapy in Syria were disappointing [14]. Currently tetracycline is unavailable in Syria, so we used doxycycline in the bismuth quadruple regimen [15, 16]. Although tinidazole isn’t superior to metronidazole in treating Helicobacter Pylori infections [17], we used tinidazole instead of metronidazole in both regimens, as H. pylori had high metronidazole resistance rate [18]. Metronidazole is a commonly overused drug in Syria, mainly prescribed for gynaecological and gastrointestinal diseases [19] Besides, tinidazole (b.i.d) is more tolerable by patients. There is a lack of data about the efficacy of doxycycline-based quadruple regimen and levofloxacin-containing quadruple concomitant regimen in Syrian patients, we conducted this trial to evaluate the efficacy and report the eradication rate of these regimens according to Intention-to-treat analysis (ITT) and per-protocol analysis (PPA).

This was a prospective single-center open-label parallel randomized superiority controlled clinical trial. It was conducted at gastroenterology department, Damascus hospital, Syria. We recruited appropriate candidates from patients who visited our clinic for evaluation of dyspeptic symptoms by upper gastrointestinal endoscopy between February 2020 and August 2020. Exclusion criteria were (1) younger than 18 years and older than 80 years; (2) prior eradication treatment for H pylori; (3) documented reactions to any of the studied medications;(4) recent use of antibiotics, bismuth, or proton pump inhibitors (PPIs) in the preceding month; (5) pregnant or lactating women; (6) previous gastric surgery; (7) alcohol or opioid abuse; and (8) severe concurrent medical illnesses, such as liver failure, renal failure, or terminal malignancy.

We collected 226 patients diagnosed with H. pylori infection confirmed by biopsy. Seventy-eight treatment-naive patients were enrolled in this study (39 patients for each group), only one patient in D-group didn’t complete the follow-up. [Fig. 1 and Table 1] summarizes the flow chart and baseline characteristics of the patients. The gender, mean age and pharmacological side effects were similar among treatment groups, except for melena, which occurred more frequently in the D-group.

H. pylori infection was eradicated in 30 patients from the D-group, and 32 patients from the L-group. Table 2 summarised the eradication rates according to ITT and PPA analysis. We didn’t report serious adverse effects.

Researchers globally observe a decline in the rate of H pylori eradication following standard triple therapies, thus requiring a search for new therapeutic approaches [45–48]. This randomized clinical trial included 78 patients from an area of high prevalence (>15%) of clarithromycin and levofloxacin resistant helicobacter pylori strains [1, 12, 14, 30, 31]. Both concomitant and bismuth-containing quadruple therapies are recommended as alternative first-line treatment according to the previously mentioned guidelines, particularly in regions with a high prevalence of clarithromycin resistance [13, 15].

The eradication rate for levofloxacin concomitant protocol was 82.05% according to ITT analysis, while doxycycline-based therapy had a PPA eradication rate of 78.94%, and 76.92% according to ITT analysis. The overall eradication rate of levofloxacin concomitant was about 3% higher than doxycycline-based therapy but the difference didn’t reach statistical significance. The result of levofloxacin containing therapy can be regarded as Grade D standard, while the result of bismuth-containing therapy can be regarded as Grade F as proposed recently [32]. The former results are better than our preceding study outcomes regarding the treatment of H. pylori [14]. Our results are agreeing with a meta-analysis by Essa et al. and similar research by Federico et al. Both studies showed that concomitant therapy is effective in the eradication of H.Pylori [26, 33]. Similarly, meta-analysis by Niv et al. found that the Doxycycline-based quadruple regimen had good efficacy in the treatment of Helicobacter Pylori infection [16] .Even though this research treated patients for a longer period [34], our results didn’t show the effectiveness mentioned in previous studies, this may be due to the existence of Helicobacter Pylori resistant strains [35]. Antibiotics are overused,especially macrolides and fluoroquinolones, for treating respiratory, urinary and gynaecological infections [36‐38]. Chokshi et al. reported that the main contributors of emerging antibiotic resistance in developing countries are clinical mismanagement, antibiotics availability, poor quality of available antibiotics, and insufficient surveillance of resistance development [39]. We checked compliance by counting remaining pills which raised suspicions about outpatient incompliance to antibiotic regimens [40‐42].

Our study has a few limitations (1) The only method to investigate medication history was to interrogate patients. Electronic medical were lacking, The patient was considered “naïve” if he/she wasn’t previously treated for H. pylori infection ;(2) We depended on patients to evaluate the compliance ;and (3) We didn’t perform a susceptibility test of H. pylori to antibiotics, because it’s unavailable in Syria.

The success rate of the standard triple therapy with clarithromycin or levofloxacin has declined substantially due to increasing antimicrobial resistance. (ACG) Clinical guideline and Maastricht Consensus recommended alternative regimens, including bismuth-containing quadruple therapy or non-bismuth concomitant therapy, as first-line therapies, particularly in areas with a high prevalence of clarithromycin resistance like Syria. Levofloxacin concomitant therapy wasn’t superior to doxycycline based quadruple therapy, we didn’t record any serious adverse event in both regimens. We encourage further researches to determine the optimal first-line empirical therapy for Helicobacter-Pylori Infection in the Syrian population.