The Efficacy, Safety, And Tolerability of Levofloxacin Quadruple Therapy For Helicobacter Pylori Eradication: A Randomized, Double-Blind Clinical Trial

DOI: https://doi.org/10.21203/rs.3.rs-53307/v2

Abstract

The incidence of microbial resistance is increasing, and new rescue regimens are needed in order to treat Helicobacter pylori (H. pylori) infection. To evaluate the efficacy, safety, and tolerability of levofloxacin based quadruple therapies in the eradication of H. pylori. In a randomized, double-blind clinical trial, 220 patients with dyspepsia and H. pylori infection were randomly assigned to receive either bismuth subcitrate 240 mg, pantoprazole 20 mg, amoxicillin 1000 mg twice a day, and levofloxacin 500 mg daily for seven days (BPAL-7), or ten days (BPAL-10). The eradication of H. pylori was evaluated two months after the end of treatment, and adverse drug reactions (ADRs) were assessed during the intervention. According to intention-to-treat and per-protocol, the eradication rate was significantly lower in the BPAL-7 regimen 49.1 % (95 % CI: 39.3-57.8) and 47.6 % (95 % CI: 39.7-58.4), respectively compared to the BPAL- 10 regimen 62.7 % (95 % CI: 53.6-72.8) and 62.4 % (95 % CI: 55.1-72.8), respectively. The incidence of ADRs was not statistically significant between BPAL-7 (33.6 %) and BPAL-10 (36.7 %) groups. Although the ADRs were negligible in both groups, these regimens could not be an ideal alternative therapy for H. pylori because of low eradication rates compared to standard regimens.

Trial registration: The study reviewed and approved by the Iranian Registry of Clinical Trials (IRCT201406141155N19). 

Introduction

Helicobacter pylori (H. pylori) affects about 80% of the total population in developing countries and 20–50% in developed countries. The infection as a worldwide health problem is associated with acute and chronic gastritis, peptic ulcer disease, and gastric cancer [1–3]. The eradication of H. pylori has a main role in the prevention and treatment of these complications [4, 5]. However, the major concerns of H. pylori treatment are low patients compliance, adverse drug reactions (ADRs), and microbial resistance to medicines [6, 7].

The efficacy of present pharmacological treatments for H. pylori infection has evaluated in different studies [8–14]. The co-administration of a proton-pump inhibitor (PPI) and two antibiotics (triple therapy), or addition of bismuth salts to the triple therapy (bismuth-based quadruple therapy) for a period of 14 days are the most common regimens [15]. Among antibacterial agents, amoxicillin or metronidazole, along with clarithromycin, are the first-line treatment for eradication of H. pylori [9, 16]. Nevertheless, microbial resistance is one of the challenging factors of treatment, which causes low efficacy of these regimens. Hence, effective antibiotics should be selected according to the regional pattern of H. pylori resistance [17, 18].

The prevalence of H. pylori infection is relatively high among the Iranian population [19, 20]. Moreover, novel strains resisted to clarithromycin and metronidazole are prevalent in some geographical part of Iran [21, 22]. Therefore, a body of evidence suggested new antibiotic regimens with higher efficacy (eradication rate of > 80%), lower ADRs and cost, and acceptable patient compliance. The efficacy of levofloxacin as a new-generation quinolone in the treatment of H. pylori infection has assessed in several studies, and levofloxacin-containing regimens have shown various eradication rates [23–29].

The current study aimed to evaluate the efficacy, safety, and tolerability of seven- and ten-day period of bismuth subcitrate, pantoprazole, amoxicillin, and levofloxacin regimens in the eradication of H. pylori among patients referred to Gastrointestinal Outpatient Clinic of Razi hospital, Rasht, Iran.

Methods

Trial design

This study was a phase III open-label, randomized, double-blind controlled trial carried out between July 2015 to November 2015 at Gastrointestinal and Liver Diseases Research Center (GLDRC), Rasht, Iran. All included participants were randomly divided into one of the therapeutic regimens and signed informed consent. The eradication rate of H. pylori was assessed two months after the end of the intervention, and the incidence of ADRs and patient compliance were at the end of treatment.

Ethical consideration

The protocol of the study was approved by the local ethical committee of Guilan University of Medical Sciences (Ethics committee code; 1930175713), and also performed according to the declaration of Helsinki for human subjects. The study reviewed and approved by the Iranian Registry of Clinical Trials (IRCT201406141155N19).

Patients

Patients complaining of dyspeptic symptoms referred to the Gastrointestinal Outpatient Clinic of Razi hospital, Rasht, Iran, were enrolled. The main inclusion criteria were a positive rapid urease test and 15 to 65 years of age. Patients with coexisting serious illnesses, including liver cirrhosis, renal failure, heart failure, gastrointestinal malignancies, and history of seizure or hematologic diseases, allergy to medications, and previous incomplete treatment course as well as pregnant or nursing mothers were excluded.

Randomization and intervention

A block randomization method was used in order to assign patients randomly into permuted treatment blocks and ensure equal numbers in each group of treatment. One of these groups received a seven-day period of bismuth subcitrate 240 mg, pantoprazole 20 mg, amoxicillin 1000 mg twice a day, and levofloxacin 500 mg daily (BPAL-7), and the other received a ten-day period of the same regimen (BPAL-10).

Patients were recommended to take bismuth subcitrate, pantoprazole, and levofloxacin before meals, and amoxicillin after meals at the scheduled times. It also advised avoiding smoking, drinking alcoholic or caffeinated beverages, eating spicy foods, and taking non-steroidal anti-inflammatory drugs or medications containing a monoamine oxidize inhibitor.

Demographic criteria, including age, gender, cigarette smoking, and alcohol drinking, were recorded.

Evaluation of H. pylori eradication

Two months after the end of the intervention, a Heliprobe 14C-Urea Breath Test (14C-UBT, Kibion AB, Uppsala, Sweden) with a 95% sensitivity and 100% specificity was performed to evaluate the H. pylori eradication. The treatment success was defined as the result of < 50 disintegrations per minute (DPM). Taking the medicines were stopped during these two months to avoid interaction with the results of 14C-UBT.

Assessment of ADRs and patient compliance

All patients were informed about potential ADRs, including pyrosis, anorexia, nausea, vomiting, bitter taste, abdominal colic, epigastric pain, headache, and back pain. The ADRs were evaluated during the intervention, using a 0–10 scoring system (mild: 0–3, the ADRs exist but insufferable; moderate: 4–6, ADRs sometimes interfere daily life activity; severe: 7–10, ADRs interfere continuously with daily life activities). Acceptable patient compliance was defined as consumption of > 80 % of the prescribed medicines [30].

Statistical analyses

The eradication rate of two regimens was determined using Intention-to-treat (ITT) and per-protocol (PP) analysis. Patients declined to proceed with the treatment, or those with poor compliance were excluded from PP analysis; however, all patients, including patients who used the treatments out of the protocols or dropouts were included in ITT analysis. The eradication rate of H. pylori, odd ratios, and 95% confidence interval were evaluated for each regimen. Chi-square and t tests were employed to compare qualitative and quantitative variables between two treatment groups, respectively. All statistical analyses were performed using SPSS, version 18.0 software (SPSS Inc, Chicago, IL, United States). A P < 0.05 was considered statistically significant.

Results

Characteristics of the patients

A total of 220 patients with H. pylori infection were randomly assigned to either BPAL-7 (n = 110) or BPAL-10 (n = 110) groups. Three patients in the BPAL-7 group (one female with severe epigastric pain and diarrhea, and two males with severe anorexia and back pain) and one patient in the BPAL-10 group (one female with severe epigastric pain and nausea) were excluded from the trial because of drug intolerance and low compliance. A flow diagram describing patient selection and study outcomes is shown in Fig. 1.

No significant differences were observed between the two groups in terms of age, gender, cigarette smoking, alcohol drinking (P > 0.05). The Basic demographic characteristics of the patients are demonstrated in Table 1.

Table 1

Demographic characteristics of the study patients

Characteristics

BPAL-7 regimen

(n = 107)

BPAL-10 regimen

(n = 109)

P value

Gender, male

Age

39 (36.5)

41.46 ± 13.25

40 (36.7)

44.16 ± 12.70

0.888

0.649

Cigarette smoking

Yes

No


4 (3.7)

103 (96.3)


7 (6.4)

102 (93.6)


0.353

Alcohol drinking

Yes

No


1 (0.9)

106 (99.1)


3 (2.7)

106 (97.3)

0.313
Values were demonstrated as numbers (percentages) and Mean ± SD for categorical and continuous variables, respectively.
Chi-square and t tests were performed to compare categorical and continuous variables between groups, respectively.
BPAL-7 and BPAL-10; bismuth-based quadruple therapy containing pantoprazole, amoxicillin, and levofloxacin for seven and ten days, respectively.

Eradication rates

The eradication rate of BPAL-7 regimen (49.1%, 95% CI: 39.3–57.8) was lower than that of BPAL-10 regimen (62.7%, 95% CI: 53.6–72.8) on ITT analysis (OR = 1.75, P < 0.05). Additionally, PP analysis also demonstrated a lower eradication rate in BPAL-7 regimen (47.6%, 95% CI: 39.7–58.4) compared to that of BPAL-10 regimen (62.4%, 95% CI: 55.1–72.8) (OR = 0.54, P < 0.05). The eradication rates of the two regimens are represented in Table 2. Univariate analyses were shown no association between age, gender, cigarette smoking, and alcohol drinking with an eradication rate of H. pylori in both groups (P > 0.05).

Table 2

The eradication rates of the BPAL-7 and BPAL-10 regimens.

Analyses

BPAL-7 regimen

(n = 107)

BPAL-10 regimen

(n = 109)

P value

Intention-to-treat

54 (49.1)

69 (62.7)

0.037

Per-protocol

51 (47.6)

68 (62.4)

0.024
Values were demonstrated as numbers (percentages).
14C-urea breath test was conducted to confirm the eradication of H. pylori two months after the end of treatment.
Chi-square test was performed to compare variables between groups.
BPAL-7 and BPAL-10; bismuth-based quadruple therapy containing pantoprazole, amoxicillin, and levofloxacin for seven and ten days, respectively.

ADRs and patient compliances

Both BPAL-7 and PBAL-10 regimens were well-tolerated by a majority of patients. The number of patients with ADRs was not statistically significant between the BPAL-7 group (36 patients, 33.6%) and the BPAL-10 group (40 patients, 36.7%). ADRs were rated as mild (55 patients, 25%), moderate (17 patients, 7.7%), and severe (4 patients, 1.8%). The most-reported ADRs were epigastric pain, nausea, vomiting, and bitter taste in both regimens (Table 3).

Table 3

The adverse drug reactions associated with the BPAL-7 and BPAL-10 regimens.

ADRs

BPAL-7 (n = 107)

  

BPAL-10 (n = 109)

Mild

Moderate

Severe

  

Mild

Moderate

Severe

Pyrosis

31 (29.0)

4 (3.7)

1 (0.9)

  

23 (21.1)

10 (9.2)

1 (0.9)

Anorexia

25 (23.4)

4 (3.7)

2 (1.9)

  

21 (19.3)

4 (3.7)

1 (0.9)

Nausea

19 (17.8)

2 (1.8)

1 (0.9)

  

25 (22.9)

0 (0.0)

0 (0.0)

Vomiting

2 (1.9)

1 (0.9)

0 (0.0)

  

0 (0.0)

0 (0.0)

1 (0.9)

Bitter taste

19 (17.8)

0 (0.0)

1 (0.9)

  

10 (9.2)

2 (1.8)

1 (0.9)

Abdominal colic

12 (11.2)

0 (0.0)

0 (0.0)

  

9 (8.2)

3 (2.7)

0 (0.0)

Epigastric pain

17 (15.9)

7 (6.5)

1 (0.9)

  

22 (20.2)

3 (2.7)

1 (0.9)

Headache

15 (14.0)

2 (1.9)

1 (0.9)

  

16 (14.7)

7 (6.4)

1 (0.9)

Back pain

6 (5.6)

1 (0.9)

2 (1.9)

  

9 (8.3)

6 (5.5)

1 (0.9)
Values were demonstrated as numbers (percentages).
Adverse drug reactions were evaluated during the study.
Chi-square test was performed to compare variables between groups. None of variables were shown statistically significant differences between two regimens in each category.
ADRs; adverse drug reactions, BPAL-7 and BPAL-10; bismuth-based quadruple therapy containing pantoprazole, amoxicillin, and levofloxacin for seven and ten days, respectively.

The compliance rates were 97.3 % and 99.1 % for the BPAL-7 and PBAL-10 regimens, respectively. Three patients in the BPAL-7 regimen and one patient in the PBAL-10 regimen excluded from the PP analysis because of failure to ingest > 80 % of the medications.

Discussion

The finding of the present study showed a lower rate of H. pylori eradication in the BPAL-7 regimen compared to the BPAL-10 regimen among patients with dyspepsia and H. pylori infection. Both BPAL-7 and PBAL-10 regimens were well-tolerated and had acceptable patient compliance.

Recent guidelines suggest the eradication rate of triple therapy with a PPI, amoxicillin or metronidazole, and clarithromycin as first-line regimens have decreased, particularly due to an increase in microbial resistance to clarithromycin [1]. Moreover, some recommended bismuth-based quadruple therapy regimens also have an eradication rate of less than 80% [31]. Therefore, more effective regimens are needed to eradicate the H. pylori infection.

A body of evidence suggested to using levofloxacin, a new generation fluoroquinolone with in vitro anti-H. pylori activity, as an alternative agent in clarithromycin-resistant cases. Levofloxacin containing triple, quadruple, and sequential regimens have demonstrated a various range of eradication rates [32–34].

A study compared a triple therapy consisting of esomeprazole, levofloxacin (500 mg daily), and amoxicillin with a standard regimen consist of esomeprazole, metronidazole, bismuth, and tetracycline for a period of 14 days. The eradication rate of levofloxacin containing regimen (96.3% ) was higher than the standard regimen (86.0%) in ITT analysis [24].

Gisbert et al. from Spain demonstrated the eradication rate of ranitidine bismuth citrate, levofloxacin, and amoxicillin as first-line triple therapy for H. pylori was 84.4 and ADRs, mainly including diarrhea, were reported in 9.5% of the patients [35]. This group carried out a trial with 1000 patients on the efficacy of omeprazole, levofloxacin, and amoxicillin for ten days. They reported an eradication rate of 73.8% and ADRs of 20%, which most commonly included nausea, metallic taste, and abdominal pain [25]. The dosage of levofloxacin was higher in these studies (500 mg twice a day). In a recent multicenter study conducted by Gisbert et al., 14 days treatment by esomeprazole, amoxicillin, levofloxacin (500 mg daily), and bismuth as a rescue therapy achieved more than 90% of eradiation rate [26]. In another Spanish study, the eradication rate of omeprazole, levofloxacin (500 mg twice a day), and amoxicillin combination for a ten-day period also had about 20% failure rate [36].

A study from Kosovo randomized 105 patients to either seven or ten days levofloxacin-based regimens, including omeprazole, levofloxacin (500 mg daily), and amoxicillin. The eradication rates were 86.2% and 93.6%, respectively. About 5% of patients experienced ADRs, mostly nausea and diarrhea [27].

Several Taiwanese studies evaluated the efficacy of levofloxacin-containing regimens as rescue therapy for the eradication of H. pylori. Kuo et al. reported the eradication rate of esomeprazole, amoxicillin, and levofloxacin (500 mg daily) regimen for seven days is similar to a second line quadruple standard regimens (about 60–70%) [37]. Four years later, the same group published a study comparing a levofloxacin-containing quadruple therapy (esomeprazole, bismuth, tetracycline, and 500 mg of levofloxacin once daily) for ten days with high-dose metronidazole- containing standard quadruple regimen. Based on their findings, eradication rates of about 80% was reached for both regimens [38]. On the other hand, Hsu et al. showed a ten-day quadruple therapy consist of esomeprazole, bismuth, tetracycline, and levofloxacin (500 mg daily) achieved a very high eradication rate (95.8%) at this geographical area. ADRs were detected in 25.0% of patients [39]. In another study, the efficacy of adding bismuth to a levofloxacin-based triple regimen (rabeprazole, bismuth, amoxicillin, and 500 mg of levofloxacin daily) assessed. The results revealed no further significant eradication rat (67.6%), but no more ADRs were noted [40].

According to the results of the present study, the BPAL-7 and the PBAL-10 regimens were not clinically successful in the treatment of H. pylori with an eradication rate of 62.7 % and 49.1 % by ITT analyses, respectively. Both regimens achieved neither cut point of an ideal regimen (eradication rate of > 90 %), nor acceptable eradication rate of Maastricht and other guidelines (> 80 %) [41]. The low efficacy of these regimens is likely related to the regional pattern of bacterial resistance. The results of these regimens are consistent with a previous Iranian study evaluating the efficacy of a 14-day triple therapy, comprised of omeprazole, levofloxacin (500 mg daily), amoxicillin with success rate of 75 % [42]. However, studies conducted in other parts of Iran revealed fluoroquinolone-containing regimens including a 14-day of omeprazole, levofloxacin (250 mg twice a day) and amoxicillin as well as a 14-day of omeprazole, levofloxacin (500 mg twice a day), and amoxicillin as rescue therapies of H. pylori had eradication rate of 90 % and 86.7 %, respectively [43, 44]. Moreover, there are some other Iranian investigations that evaluated the efficacy of levofloxacin-based, sequential therapy in the treatment of H. pylori, and the eradication rate ranged from 70.8% to 85.1 % [45–47].

No relationship was observed between patient demographic characteristics including age, gender, cigarette smoking, and alcohol drinking and the success rate of both BPAL-7 and PBAL-10 regimens. Previous studies have also demonstrated the eradication rate of levofloxacin-containing regimens was not associated with age [45, 47, 44], gender [46, 45, 44], smoking status [48, 45], and education level [45].

Although high efficacy along with compatibility with the pattern of regional bacterial resistance are the main properties of an ideal pharmacological regimen for eradication of H. pylori, tolerability, patient compliance, simplicity, and cost-efficacy should not be neglected [30]. The compliance rates for the BPAL-7 and PBAL-10 regimens were 97.3 % and 99.1 %, respectively. In spite of high compliance rats, ADRs were reported in one-third of patients. The most-reported ADRs were epigastric pain, nausea, vomiting, and bitter taste. Generally, BPAL-7 and PBAL-10 regimens were patient compatible and well-tolerated.

Limitations

The main limitations of the present study are the lack of regional pattern of antibiotic resistance and a local estimate of H. pylori eradication rate as well as the small number of patients in the groups. The absence of pretreatment susceptibility assessment to levofloxacin is another drawback. Moreover, the finding may not be applicable to patients with previous treatment failure and recurrence disease.

Conclusion

The BPAL-7 and PBAL-10 regimens were patient compatible and well-tolerated. However, both regimens showed no satisfied eradication rate. Therefore, these regimens could not be ideal alternative therapies for H. pylori eradication in this region. It is better to evaluate the efficacy and tolerability of this regimen in other geographical regions, longer studies with more sample size.

Abbreviations

H. pylori: Helicobacter pylori; ADRs: adverse drug reactions; PPI: proton-pump inhibitor; ITT; intention-to-treat, PP; per-protocol, BPAL-7: bismuth-based quadruple therapy containing pantoprazole, amoxicillin, and levofloxacin for seven days; BPAL-10; bismuth-based quadruple therapy containing pantoprazole, amoxicillin, and levofloxacin for ten days

Declarations

Acknowledgments

The authors would especially like to thank the assistance and cooperation of the Health Deputy of Gastrointestinal and Liver Diseases Research Center (GLDRC) of Guilan University of Medical Sciences, Rasht, Iran. This study supported by Guilan University of Medical Sciences, Rasht, Iran.  

Authors’ contribution

FJ and FMG designed and supervised the procedure of the research. FMG, HS, and BM enrolled participants, collected data. FJ, SH, and MS analyzed data, and MF, FJ, MA, AMG and MS drafted the manuscript. MF, SH and AMG edited and revised the manuscript. All authors have read and approved the final draft of the paper. 

Funding

The study was financially supported by a grant from Guilan University of Medical Sciences, Rasht, Iran (grant number: 1930175713). Our organization has helped us to provide principal materials and drugs. 

Compliance with Ethical Standards

Conflicts of interest 

The authors report no conflicts of interest in this work.

Role of Funding Source

Guilan University of Medical Sciences funded the study, but had no role in the execution of the study, patient recruitment or data collection.

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