|Year : 2017 | Volume
| Issue : 3 | Page : 155-161
Efficacy of levofloxacin-doxycycline-based rescue therapy for Helicobacter pylori eradication: A prospective open-label trial in Saudi Arabia
Fahad I Alsohaibani1, Sarah A Alharfi1, Majid A Almadi2
1 Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, Riyadh 11211, KSA
2 Department of Medicine, Division of Gastroenterology, King Saud University Medical City, King Saud University, Riyadh 11461, KSA
|Date of Web Publication||12-Jul-2017|
Fahad I Alsohaibani
Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, P. O. Box: 3354, Riyadh 11211
Background: Helicobacter pylori eradication is achieved in 60%–80% with first-line therapy. Different second-line therapeutic options are available. However, the success of second-line therapy has not been addressed or reported from Saudi Arabia.
Objectives: The primary objective was to evaluate the efficacy of the 10-day course of levofloxacin, doxycycline and esomeprazole in non-responders to first-line therapies for H. pylori eradication in Saudi Arabia. Secondary objectives included were symptoms' response to treatment, factors associated with eradication of H. pylori and adverse events associated with the treatment.
Patients and Methods: A prospective, open-label, single-arm study was conducted. Patients were recruited from a tertiary care hospital in Saudi Arabia from June 2013 to April 2014. A total of 55 patients had previously received standard triple therapy and/or sequential therapy from 2011 to 2014 and failed to eradicate the infection. The rescue treatment was given for 10 days consisting of levofloxacin 500 mg once daily, doxycycline 100 mg twice daily and esomeprazole 20 mg twice daily. Urea breath test (UBT) was done at a minimum of 6 weeks after completion of the treatment to confirm the H. pylori eradication.
Results: From 55 patients recruited, 32 had failed to respond to previous standard triple therapy, 15 patients failed to respond to sequential therapy and 8 patients failed to both regimens. Persistent H. pylori infection was confirmed by rapid urease test, histology or UBT. H. pylori eradication was achieved in 20 out of 51 patients (39.22%, per protocol analysis, 36.36% by intention to treat analysis). Therapy was well tolerated and side effects were generally mild.
Conclusion: Rescue treatment with levofloxacin and doxycycline-based therapy for 10 days was well tolerated but effective only in 39.22% of patients infected with H. pylori in Saudi Arabia. More trials to determine the most efficacious rescue therapy in Saudi Arabia are needed.
Keywords: Doxycycline, Helicobacter pylori, levofloxacin, Saudi Arabia
|How to cite this article:|
Alsohaibani FI, Alharfi SA, Almadi MA. Efficacy of levofloxacin-doxycycline-based rescue therapy for Helicobacter pylori eradication: A prospective open-label trial in Saudi Arabia. J Health Spec 2017;5:155-61
|How to cite this URL:|
Alsohaibani FI, Alharfi SA, Almadi MA. Efficacy of levofloxacin-doxycycline-based rescue therapy for Helicobacter pylori eradication: A prospective open-label trial in Saudi Arabia. J Health Spec [serial online] 2017 [cited 2020 Jul 11];5:155-61. Available from: http://www.thejhs.org/text.asp?2017/5/3/155/210434
| Introduction|| |
Helicobacter pylori infection is prevalent worldwide, with different parts of the world showing variable figures based on the method used, ethnicity and geographic regions. For instance, the prevalence in Asian-Pacific countries varies from 15% to 95%, while in Africa 24%–91%, Europe 27%–54% and North America 7%–79%. The estimated prevalence of H. pylori infection in Saudi Arabia has been reported in the range of 46%–85%,,,, and was found in 22% of patients who had endoscopy for dyspepsia.H. pylori-infected people are at risk of developing many complications, such as peptic ulcer disease, chronic gastritis and gastric malignancies. By eradicating the infection, these complications can be prevented and thus is strongly recommended.,,
Over the past decade, a progressive decrease in eradication rates of H. pylori has been observed globally due to an increase in metronidazole and clarithromycin resistance.,, Approximately 20%–30% of the patients treated with first-line regimens will remain infected with the organism. Despite that, the current guidelines by different organisations still recommend triple therapy consisting of amoxicillin (or metronidazole in penicillin-allergic patients), clarithromycin and a proton pump inhibitor (PPI) for 10–14 days as the first-line treatment for the eradication of H. pylori. After failure of eradication using this standard regimen, the Maastricht IV/Florence Consensus report recommends performing endoscopy, culture and standard susceptibility testing to be considered before giving a second-line treatment such as bismuth-containing quadruple or levofloxacin-containing triple therapy.,, In Saudi Arabia, H. pylori resistance to metronidazole has been reported previously in the range of 35.2% – 78.5% as compared to clarithromycin resistance (4% – 28%). Meanwhile, resistance to amoxicillin and tetracycline is rare.,,
Tetracycline is an antibiotic contained in bismuth-containing quadruple therapy and has been found to be effective in the treatment of H. pylori not responding to the first-line treatments., Doxycycline is a broad-spectrum tetracycline analogue antibiotic that is administered twice daily, that might improve tolerability and compliance. Levofloxacin-based therapy has been evaluated in many studies as a first-line therapy to cure H. pylori infection. A recent meta-analysis of seven trials with 894 receiving standard triple therapy and 888 patients treated with 7 days of first-line levofloxacin showed that an eradication rate was 81.4% in the standard group versus 79.05% in levofloxacin group (risk ratio [RR] 0.97; 95% confidence interval [CI]: 0.93, 1.02). A 10-day regimen of levofloxacin combined with amoxicillin in addition to a PPI may be used as a second- or third-line treatment to eliminate H. pylori infection with eradication rates ranging between 66% and 87%.,,,
There are no studies from Saudi Arabia describing the efficacy of second- or third-line rescue treatments for H. pylori eradication using levofloxacin and doxycycline; therefore, we conducted a prospective, open-label, single arm study to find the efficacy and tolerability of a 10-day course of levofloxacin, doxycycline and esomeprazole as a rescue therapy for treating H. pylori infection in patients who failed standard triple and/or sequential therapy. As secondary endpoints, we planned to evaluate the response of patients' symptoms to the treatment regimen and the eradication of H. pylori. We also planned to evaluate the eradication rates based on the number of attempts for H. pylori eradication as well as the type of regimen received (triple therapy vs. sequential). We also were able to perform a culture and standard susceptibility testing in a subset of the study population.
| Patients and Methods|| |
This open-label prospective study was conducted in a tertiary care hospital in Saudi Arabia. Patients were enrolled from June 2013 to April 2014. Patients were eligible for enrolment if they were 18 years of age or older; received previous treatment with triple therapy, sequential therapy or both and had evidence of persistence H. pylori infection by a positive urea breath test (UBT), histology or rapid urease test (HP Fast. GI supply™, PA, USA). Patients were excluded if they were previously treated with quadruple or levofloxacin-based therapy; had an allergy to doxycycline, levofloxacin or esomeprazole; were pregnant or lactating or had any significant hepatic, renal or cardiopulmonary disorders or active malignancy. The study was approved by the Institute's Ethics Committee and the Research Promotion Committee (RAC # 2131064, ClinicalTrials.gov Identifier NCT02884713).
The first-line therapy was either standard triple therapy consisting of amoxicillin 1 g, clarithromycin 500 mg and omeprazole or esomeprazole 20 mg; orally twice daily for 14 days or sequential therapy in the form of amoxicillin 1 g and esomeprazole 20 mg twice per day for 5 days, then clarithromycin 500 mg, tinidazole 500 mg and esomeprazole 20 mg twice per day for the next 5 days. Patients who had persistent H. pylori infection were given a choice to participate in the current study after obtaining informed consent. Therapy consisted of levofloxacin 500 mg once daily, doxycycline 100 mg twice daily and esomeprazole 20 mg twice daily and for a total of 10 days.
Adherence to medications and side effects related to study medications was checked by a phone call interview after 2 weeks from the day of recruitment, and the rate of adherence was classified based on the consumption of the medication as >80%, 60% – 80% or <60%.
The primary endpoint was a negative UBT after a minimum of 6 weeks after completion of treatment. The UBT was performed at the Nuclear Medicine department (using 3 μCi of C-14 given orally), and after 20 min, radiolabeled CO2 was recovered from the breath of the patient. Patients abstained from PPIs and bismuth-containing agents for 2 weeks and antibiotics for at least 4 weeks before the UBT. All relevant information from patients were collected and prospectively entered into a data collection sheet.
In data analysis, we included descriptive statistics computed for continuous variables, including means as well as standard deviations (SDs), maximum and minimum values, as well as 95% CIs. Frequencies were used for categorical variables. When we conducted hypothesis testing, the paired t-test and Fisher's exact test where appropriate was used. One-way analysis of variance was used to test for differences among groups when comparing more than one. As the primary endpoint was to evaluate the eradication rate in this cohort of patients, no sample size calculation was performed. Software STATA 11.2 (Stata Corp., College Station, TX, USA) was used in data analysis. A statistical significance threshold of P ≥ 0.05 was adopted.
| Results|| |
A total of 55 patients were eligible and consented for enrolment [Table 1] and [Figure 1]. The mean age was 42.3 years (SD 13.7) and females represented 36.4% of the study population. All 55 patients had completed at least one attempt of first-line treatment to eradicate H. pylori. One course was received by 72.7% and 21.8% had treatment twice while 5.5% received treatment thrice. A triple therapy regimen containing amoxicillin, clarithromycin and a PPI for 14 days was used as the first-line therapy in 72.7% while sequential therapy was used in 41.8%.
|Figure 1: Flow diagram of the 55 recruited patients and results of the treatment.|
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The persistence of H. pylori infection was confirmed by a UBT in 94.6%, and in three patients, the diagnosis was made by histology and rapid urease test after performing gastroscopy and obtaining gastric biopsies. Patient symptoms before the initiation of treatment were mainly heartburn (70.91%), abdominal pain (65.45%), dyspepsia (45.45%), nausea (38.89%), hunger pain (30.91%), early satiety (20.00%), vomiting (18.18%) and belching (10.91%) [Figure 2].
Some of the patients who were included in the trial had undergone a culture and sensitivity test before enrolling in the study (n = 27). In this subpopulation, H. pylori was found to be sensitive to levofloxacin (91.67%), rifampin (81.82%), tetracycline (80.00%), amoxicillin (66.67%), clarithromycin (45.00%) and metronidazole (23.53%). Furthermore, H. pylori had intermediate sensitivity to clarithromycin in 5.00% [Figure 3].
|Figure 3: Antibiotic sensitivity for the patients who had a culture and sensitivity performed before enrolling in the study.|
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From the recruited patients, 51 out of 55 completed the study protocol. Three patients (5.45%) did not show up for UBT on multiple occasions after the completion of treatment, and one patient could not tolerate treatment due to an allergic reaction that manifested as a skin rash and itching (1.81%). As per protocol (PP) analysis, 39.22% (20 out of 51) became H. pylori negative by UBT compared to 36.36% (20 out of 55) in intention to treat (ITT) analysis.
The majority of patients (93.3%) were adherent to the medication (defined as >80% of the pills were used), while the remainder reported consuming 60%–80% of the medication course. One patient was unable to continue the treatment because of the development of itching and skin rash. Adverse events were mild and the most common was nausea (23.26%), followed by abdominal pain (13.95%), headache (13.95%), dizziness (9.30%) and a minor rash (4.65%). None of the participants developed any serious adverse events. After completion of the second-line treatment, 62.79% of patients had persistent gastrointestinal symptoms.
Predictors of eradication
There was no association between the achievement of eradication and the prior use of triple therapy or not (60.00% vs. 40.00%, P = 0.22), prior use of sequential therapy or not (50.00% vs. 50.00%, P = 0.39), with the culture and sensitivity test before the initiation of the second-line eradication therapy, with the number of antibiotic eradication regimens used before the study (one course 85% vs. two courses 10% vs. three courses 5%, P = 0.25).
When evaluating the patients' symptoms, there was significant improvement in all of the symptoms regardless of whether the infection was eradicated or not except for belching and early satiety which did not show significant improvement [Table 2]. However, when stratifying the patients' symptoms with regard to whether the infection was eradicated or not; there was no improvement in any of the symptoms in those who had H. pylori eradicated. On the other hand; patients who did not achieve eradication had improvements in nausea, vomiting, dyspepsia, heartburn and hunger pain [Table 2].
|Table 2: Response of symptoms to therapy in the total study population and stratified by response to therapy|
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| Discussion|| |
Saudi Arabia has a relatively high prevalence of H. pylori and a recent randomised trial demonstrated a low eradication rate whether a sequential or standard triple therapy was used (62.4% and 67.6% respectively) which is of concern, thus the need to evaluate the efficacy of a second-line rescue therapy. In this study, for the first time in Saudi Arabia, we tested the efficacy of levofloxacin, doxycycline and esomeprazole as a regimen for H. pylori-infected patients who had failed to respond to the first-line standard triple and/or sequential therapy.
Due to the limited availability of tetracycline in Saudi Arabia and the frequent dosage requirement (4 times/day), we opted to use doxycycline especially because of its similar antimicrobial spectrum and better tolerability and safety profile when compared to tetracycline. In addition, there are many trials that have used doxycycline in first-, second- or third-line regimens for H. pylori eradication [Table 3]. A meta-analysis by Niv comparing eradication treatments of H. pylori with or without doxycycline was in favour of doxycycline odds ratio 1.29 (95% CI: 1.05–1.59, P = 0.02). No significant difference in eradication was found when regimens containing doxycycline were compared to those with tetracycline.
|Table 3: Trials included doxycycline for the treatment of Helicobacter pylori|
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Our ITT analysis showed that 36.36% of our patients achieved H. pylori eradication with this second-line treatment which is much lower than that reported in other trials., Although we reported H. pylori sensitivity to levofloxacin and tetracycline was (91.67%) and (80.00%), respectively, a possible explanation for the low cure rate is H. pylori resistance to antimicrobials such as levofloxacin and doxycycline in vivo as both antibiotics are largely prescribed in Saudi Arabia for infections of respiratory system and the genitourinary tract and acne. In addition, we only had available culture and sensitivity for a proportion of the patients who were included in the trial and that might not be a representative of the whole cohort.
In a study from Portugal, this antibiotic regimen failed to eradicate H. pylori in any of their patients with multidrug-resistant H. pylori. Although two meta-analyses comparing second-line treatments showed relatively high eradication rates with levofloxacin-based regimens and better results when compared to quadruple-based therapy, this was not the case in our cohort. One demonstrated a pooled eradication rate of 81% for levofloxacin-based regimens as compared to 70% for bismuth-containing quadruple. However, another meta-analysis compared the 7-day bismuth-based quadruple therapy to the 10-day regimen of levofloxacin-based triple therapy which showed a higher rate of eradication with the levofloxacin-based triple therapy RR = 1.41 (95% CI: 1.25–1.59).
After the failure of a clarithromycin-containing treatment and in areas of high clarithromycin resistance (defined as >15%), the 2012 Maastricht consensus guideline recommends either a bismuth-containing quadruple therapy or levofloxacin-containing triple therapy. There are several theories to explain the low efficacy of triple therapy including high bacterial load, strains type and low adherence; however, H. pylori resistance to clarithromycin seems by far to be the most important factor. In Europe, global clarithromycin resistance rate had increased from 9% in 1998 to 17.6% in 2008.,
Antimicrobial susceptibility and resistance by gastric tissue culturing are recommended when the first-line therapy fails. If susceptibility testing is not feasible or available, a trail of a second-line empiric therapy rather than repeating a similar course is justified. It is recommended to avoid all antimicrobials - mainly clarithromycin - if it has been used more than once by the patient in the past for any medical indication. Although we did have antimicrobial susceptibility for a subset of the study population that knowledge did not aid or modify the treatment outcome, this could be due to the fact that this was only available for a subset of the study population and was underpowered to find any association.
The use of bismuth-based regimens or quadruple therapy has been proven to be of effective as the second-line therapies but still needs to be evaluated in our population.,, In a study by Rokkas et al., a total of 540 H. pylori-infected patients received the first-line triple therapy. The treatment was successful in curing H. pylori in 380 patients (ITT, 70.3%; PP, 76%). One hundred and twenty patients who remained positive for H. pylori received second-line bismuth-based quadruple therapy that eradicated H. pylori in 83 patients (ITT, 69%; PP, 73.5%). Third-line treatment using omeprazole, amoxicillin and levofloxacin in the 30 patients who had persistent H. pylori was successful in curing 21 patients (ITT, 70%; PP, 70%). The cumulative H. pylori eradication rates were 89.6% ITT and 98.1% PP.
Factors that were found to influence the eradication rates included the duration of treatment; a study that randomised patients with persistent H. pylori infection after first-line therapy to 1-week versus 2-week of quadruple therapy with potassium dicitrate bismuthate, metronidazole, tetracycline and esomeprazole found the eradication rates were higher with a longer duration of therapy, 64.3% and 77.2% in the 1-week group versus 82.6% and 93.6% in the 2-week group (P < 0.01). In addition, the number of antibiotic courses given has been found to affect the eradication rates. A study of 500 patients found that eradication rate of H. pylori using second-, third- and fourth-line rescue regimens to be 70%, 74% and 76%, respectively, with cumulative H. pylori curing rate with four successive regimens was 99.5%. Whether these factors would influence the eradication rates in our population remains to be seen, but we found no association between the number of prior antibiotic courses with the intention of eradication and the achieved eradication rate [Figure 4].
|Figure 4: Eradication of Helicobacter pylori in relation to the number of antibiotic courses taken in the past.|
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Although there was an improvement in patients' symptoms in those who achieved eradication, this did not achieve statistical significance due to the small number of patients [Table 2]. Of interest, when looking at those patients who did not achieve eradication as well as the study population as a whole, there was a significant improvement in the majority of the symptoms [Table 2]. This could be explained by the fact that the majority of the symptoms in these patients are functional and are unrelated to H. pylori infection per se.
Strengths of this study include its novelty in the region, as well as the rigorous follow-up of patients and ascertaining compliance to the study medication; this reduces the variables that might influence the outcomes. Furthermore, we attempted to detect any potential prognosticators of eradication based on prior antibiotic exposures and where available culture and sensitivity. Some of the limitations of our current study are that the absence of a comparator arm, a small sample size that might not be powered to detect any differences and predictors of eradication using the levofloxacin-doxycycline-based second-line therapy. Furthermore, the study was from a single tertiary care centre, which might not be representative of the general population.
We believe that there are areas that need to be addressed in future studies including the issue of culture-based treatments regimens, the role of bismuth-based therapies and quadruple therapies as a first-line treatment option due to high rate of resistance to clarithromycin in our population, as well as the role of the novel oral potassium-competitive acid blockers and their role in increasing the eradication rates. The results of this study clearly indicate that a levofloxacin-doxycycline-based regimen has suboptimal benefit in our population.
| Conclusion|| |
Rescue treatment regimen containing levofloxacin, doxycycline and esomeprazole for 10 days was found to be safe and well tolerated, but the efficacy in eradicating H. pylori infection was unexpectedly low.
Financial support and sponsorship
We would like to thank and extend their appreciation to the Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia, for supporting this research through the Research Group Project number RGP-279.
Conflicts of interest
There are no conflicts of ineterest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]