Keywords Clarithromycin resistance - Clarithromycin - Helicobacter pylori - levofloxacin resistance
- levofloxacin - Syria - triple therapy
Introduction
Syria is expected to have high prevalence of Helicobacter pylori infection.[2 ]H. pylori is Gram-negative spiral-shaped bacteria.[3 ],[4 ],[5 ] Chronic infection causes diseases such as chronic gastritis, duodenal and peptic
ulcers,[3 ] gastric cancer, and primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma,[5 ],[6 ],[7 ] which can be cured by eradication of H. pylori.[6 ],[8 ] The most used protocols in Syria are triple therapy using clarithromycin or levofloxacin
with proton pump inhibitor and amoxicillin. There are known resistant types of H.
pylori against those drugs around the world,[9 ],[10 ],[11 ],[12 ],[13 ],[14 ],[15 ] and there is no standard method for testing the susceptibility of H. pylori to antibiotics.
Therefore, due to limited data about the efficacy of those protocols in the Syrian
patients, we conduct this trial to evaluate the efficacy of those drugs and report
our eradication rate.
Subjects and Methods
The study was carried out from December 2015 to January 2017 in a referral hospital
in Damascus, Syria. Study protocol was approved by the ethics committee of the hospital,
and it was registered as standard randomized clinical trial (Clinicaltrial.gov, identifier-NCT02541786).
Treatment-naive participants were selected from patients who presented to the gastroenterology
clinic undergoing gastroscopy for upper gastrointestinal symptoms and had infection
of gastric H. pylori confirmed by histology.[16 ] A written consent was obtained from all participants. The indication of treatment
was based on American College of Gastroenterology Guideline on the management of H.
pylori infection [17 ] including peptic ulcer, chronic gastritis, primary gastric MALT lymphoma, and intestinal
metaplasia. Authors randomized participants using a computer program. Exclusion criteria
of the study were age below 18 and more than 80, history of renal and liver diseases,
allergic reaction to the treatment, history of constant NSAID use, pregnancy, and
use of antibiotics for 4 weeks before the study. Group (A) was treated with clarithromycin
(500 mg), amoxicillin (1000 mg), and esomeprazole (20 mg), each at every 12 h for
14 days,[1 ] while Group (B) was treated with levofloxacin (500 mg), amoxicillin (1000 mg), esomeprazole
(20 mg), each at every 12 h for 14 days.[1 ] After finishing the treatment period, participants were invited to the clinic for
checking drugs side effects. To confirm patient compliance, we asked the patients
to bring their remaining medication and counted the rest of their pills. Participants
who took at least 90% of their administered drugs were considered as good compliance.
Side effects such as headache, nausea, and vomiting were detected by self-report of
patients. All participants underwent upper endoscopy after 6 weeks of treatment completion.
During endoscopy, five biopsies were retrieved as follows: two from the antrum, one
from the incisura, and two from gastric body.[18 ] All biopsy samples were stained with hematoxylin and eosin and Giemsa [19 ] in the pathology department. The pathologists were blinded to the treatment arm,
and all results were confirmed by two pathologists. Data entry were conducted by a
trained doctor, and variables included participants' demographics, smoking history,
medications history, findings of physical examinations, endoscopy, and results of
biopsy after the treatment completion in a questionnaire. Numerical data were shown
as mean and qualitative data expressed as a ratio. Statistical tools such as the Chi-square
test and t-test were used at appropriate places, and statistical significance was
calculated with a two-tailed test. A P < 0.05 was considered as statistically significant.
All statistical analyses were done by the R [20 ] statistics software.
Results
A total of 452 patients were found to have H. pylori gastric infection which was confirmed
by biopsy. Eighty treatment-naive patients were enrolled in this study (40 patients
for each group) and three patients from each group were lost to follow-up; [Figure 1 ] and [Table 1 ] summarizes the baseline characteristics of the patients. The gender, mean age, and
Drug side effects were similar between treatment groups, except Rash, which occurred
more frequently in the Levofloxacin group 13 patients in Group (A) were cured, with
an eradication rate of 35.1% according to per-protocol analysis (PPA) and 32.5% according
to intention-to-treat analysis (ITT), while in Group (B), 11 patients were cured,
with an eradication rate of 29.7% PPA and 27.5% ITT with P = 0.80.
Figure 1: Flow of the study
Table 1
Baseline characteristics of patients
Clarithromycin (%)
Levofloxacin (%)
P
SD: Standard deviation
Gender
Male
15 (37.5)
14 (35)
1.00
Female
25 (62.5)
26 (65)
Age (mean years±SD)
38.58±14.96
37.20±11.13
0.642
Smoking
6 (15)
5 (12.5)
1.00
Alcoholic
0
1 (2.5)
1.00
Drug side effects
Anorexia
14 (35)
14 (35)
1.00
Nausea
16 (40)
16 (40)
1.00
Vomiting
4 (10)
1 (2.5)
0.359
Headache
12 (30)
5 (12.5)
0.056
Rash
1 (2.5)
6 (15)
0.048
Unpleasant taste
28 (60)
20 (50)
0.06
Odds ratio [21 ],[22 ] with 95% confidence interval according to ITT was 0.788 [0.302,2.005]., while the
odds ratio with 95% confidence interval according to PPA was 0.781 [0.294,2.037].
Discussion
Our study shows that the resistance rate is high in both treatment protocols. Globally,
the rate of H. pylori clarithromycin resistance ranges from 5.46% to 30.8%,[23 ] and the occurrence of resistance is increasing worldwide with the highest rate in
Asian countries. In early 2017, the World Health Organization listed H. pylori as
clarithromycin-resistant bacteria.[15 ],[24 ] The rate of levofloxacin resistance was 25.28% and it was higher in Asia compared
to Europe (15%). The incidence of amoxicillin resistance in H. pylori seems to increase
in South America (97.5%) and Asia,[23 ],[25 ] which can be explained by macrolides in treating upper respiratory infections and
fluoroquinolones in treating urinary tract infections. There are many factors that
may explain the resistance in treatment of H. pylori-like mechanisms of resistance
developed by H. pylori to antibiotic used in the treatment of infection, such as the
presence or absence of cagA gene.[26 ] Gender women are developing resistance to clarithromycin, while males are developing
resistance to levofloxacin,[13 ] and finally, with regard to the patients' age, the resistance is more common for
clarithromycin in children or young adults than it is in older members.[9 ]
The previous results are unexpected for us, especially for levofloxacin which prompts
us to seek effective ways to treat our patients.
Our study has a number of limitations. The sample size, despite the small size of
our sample, was the largest size that can be used with pilot studies.[27 ] Drugs used in this study are locally manufactured, i.e., clarithromycin (KLACID),
levofloxacin (FLOXALIVE), amoxicillin (maxicilline), and esomeprazole (esostom). We
cannot confirm that the drug resistance was a cause of our results, as we did not
culture of an endoscopic biopsy samples because culturing the H. pylori organism is
difficult and we do not have this technique. Adherence to medication was from the
patient's history. We cannot confirm that all patients were naive to macrolides or
fluoroquinolones because there are no detailed medical records for patients in Syria,
neither in hospitals nor in the clinic settings. The only method to investigate past
medication was to interrogate patients, which was useful if the antibiotics were used
for last 2–3 weeks before enrolment. Furthermore, in Syria as in other developing
countries, there is a significant misuse of antibiotics, and all antibiotics are easy
to get from local pharmacies even without doctor's prescription.[28 ]
Conclusions
Treatment regimens using locally produced clarithromycin or levofloxacin were equally
ineffective in the treatment of H. pylori infections, which may reveal the existence
of resistance to the former two drugs. Using therapeutic regimens that do not contain
clarithromycin or levofloxacin is a rational option.
Financial support and sponsorship
Unipharma Universal Pharmaceutical Industries.
Conflicts of interest
There are no conflicts of interest.
