Furazolidone-containing short-term triple therapies are effective in the treatment of Helicobacter...
Transcript of Furazolidone-containing short-term triple therapies are effective in the treatment of Helicobacter...
Furazolidone-containing short-term triple therapies are effectivein the treatment of Helicobacter pylori infection
W.-Z. LIU*, S.-D. XIAO*, Y. SHI*, S.-M. WU*, D.-Z. ZHANG*, W.-W. XU* & G. N. J. TYTGAT *Shanghai Institute of Digestive Disease, Shanghai Second Medical University, Shanghai, China
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
Accepted for publication 23 November 1998
INTRODUCTION
Several indications to eradicate Helicobacter pylori are
now well established.1, 2 However, the ideal regimens
for the treatment of H. pylori infection have not yet been
de®ned. The combination of metronidazole/tetracycline/
bismuth or metronidazole/clarithromycin/proton pump
inhibitor are currently considered standard regimens for
the treatment of H. pylori infection.3±5 The eradication
rates are higher than 80% if the H. pylori strains are
sensitive to metronidazole. However, metronidazole
resistance is a rising problem world-wide, particularly
in developing countries, which limits the usefulness of
this drug.6±9
Furazolidone, a nitrofuran that has been in clinical use
for over 30 years, has a favourable safety pro®le and is
relatively inexpensive. It was used in China for the
treatment of peptic ulcer disease long before H. pylori
was discovered as an aetiological agent in this
disease.10, 11 In the last decade, furazolidone has been
found to be effective in the eradication of H. pylori,12±14
SUMMARY
Background: A furazolidone-containing therapeutic reg-
imen for Helicobacter pylori infection has attracted
special interest in the face of a rising world-wide
metronidazole resistant H. pylori, and the expense of
currently used antimicrobial regimens.
Aim: To evaluate the ef®cacy of furazolidone-containing
regimens in eradicating H. pylori.
Methods: One-hundred and forty H. pylori positive
patients with endoscopically con®rmed duodenal ulcer
or functional dyspepsia received one of four different
regimens to eradicate H. pylori. In the ®rst trial, the
patients were randomly assigned to receive a 1-week
course of furazolidone 100 mg b.d. and clarithromycin
250 mg b.d., with either tripotassium dicitrato bismut-
hate (TDB) 240 mg b.d. (FCB group) or lansoprazole
30 mg daily (FCL group). In the second trial, the
patients were randomly assigned to receive a 1-week
course of clarithromycin 250 mg b.d. and omeprazole
20 mg daily, with either furazolidone 100 mg b.d. (FCO
group) or metronidazole 400 mg b.d. (MCO group).
Endoscopy was repeated 4 weeks following completion
of therapy with re-assessment of H. pylori status on
gastric biopsies by histology and culture.
Results: Four patients (1 in FCB, 1 in FCO and 2 in MCO
groups) dropped out because they refused a follow-up
endoscopy. Eradication rates of H. pylori on an inten-
tion-to-treat basis in the FCB, FCL, FCO and MCO groups
were 91% (32/35, 95% CI: 82±99%), 91% (32/35, CI:
82±99%), 86% (30/35, CI: 74±97%) and 74% (26/35,
CI: 60±89%) (all P > 0.05), respectively. Mild side-
effects occurred in 15% of the 140 patients. In MCO
group, the eradication rate in the patients infected with
metronidazole-sensitive isolates of H. pylori was 86%,
but dropped to 67% in those with metronidazole-
resistance strains (P � 0.198).
Conclusion: One-week regimens containing furazolidone
and clarithromycin in combination with TDB or a
proton pump inhibitor ful®l the criteria for successful
H. pylori therapy.
Correspondence to: Prof. S.-D. Xiao, Shanghai Institute of Digestive Disease,
Shanghai Second Medical University, 145 Shan-dong Zhong road, Shanghai
200001, China.E-mail: [email protected]
Aliment Pharmacol Ther 1999; 13: 317±322.
Ó 1999 Blackwell Science Ltd 317
and furthermore, serial passage of H. pylori culture
containing furazolidone did not result in the develop-
ment of furazolidone-resistance, suggesting that resis-
tance will not emerge quickly.15 However, ef®cacious
furazolidone-containing regimens have not yet been
established. In the present study we used furazolidone
and clarithromycin in combination with either tripo-
tassium dicitrato bismuthate or a proton pump inhibitor
to evaluate the ef®cacy of furazolidone as a replacement
for metronidazole in standard 'triple therapy' regimens
currently advocated for the eradication of H. pylori.
MATERIALS AND METHODS
Study design
The study consisted of two trials. In trial one, we used
furazolidone and clarithromycin in combination with
either lansoprazole or tripotassium dicitrato bismuthate
to compare the ef®cacy of proton pump inhibitor-based
triple vs. bismuth-based triple therapy. In trial two, we
used omeprazole, an alternative proton pump inhibitor
and clarithromycin in combination with either furazoli-
done or metronidazole to compare the ef®cacy of
furazolidone with metronidazole in the eradication of
H. pylori, particularly for metronidazole-resistant iso-
lates of H. pylori.
Patients and endoscopy
The patients were recruited from those visiting the
endoscopy unit at the Shanghai Institute of Digestive
Disease. H. pylori infected patients diagnosed with
duodenal ulcer or functional dyspepsia were eligible to
enter the study. Informed consent was obtained from
the patients entered into the study. All patients had no
history of previous anti-H. pylori therapy. Pregnancy,
major organic or systemic diseases, previous gastric
surgery, or use of either antibiotics or proton pump
inhibitors in the preceding 4 weeks precluded entry into
the study.
Endoscopy was performed within 3 days prior to
treatment and again 4 weeks after the cessation of
treatment.
Assessment of H. pylori status
At endoscopy, two biopsy specimens were taken from
the antrum as well as the gastric corpus for histology
(Haematoxylin & Eosin and Warthin±Starry stains).
Two additional biopsy specimens were obtained from
the antrum, one for culture and one for rapid urease
testing. H. pylori sensitivity to clarithromycin, metron-
idazole, and furazolidone were performed on culture
isolates using the in vitro disk diffusion method.
The diagnosis of H. pylori infection was based upon
positive culture and/or positive histology. Rapid urease
testing served only as a screening test to facilitate the
initiation of therapy immediately after endoscopy.
H. pylori eradication was de®ned as absence of H. pylori
by culture and histology from gastric biopsies obtained
4 weeks after completion of triple therapy.
Treatment
Patients included in this study were randomly assigned
to receive one of the 1-week regimens listed in Table 1.
All medicines were taken after meals.
The speci®c treatment regimen was known to the
patient and the physician in charge, but the microbi-
ologist and pathologist were blinded with regard to the
treatment arm. During the treatment period of 7 days,
the patients were required to keep a diary documenting
symptoms and compliance with the medication.
Antimicrobials, bismuth-containing drugs, acid pump
inhibitors and H2-receptor antagonists were not allowed
during the 4 weeks preceding the second endoscopy.
Statistical analysis
Intention-to-treat analysis was used to assess the
eradication rates of H. pylori in all groups. Eradication
rates, duodenal ulcer healing rates and frequencies of
side-effects were compared using the v2 test. The
signi®cance level was set at P < 0.05.
RESULTS
One hundred and forty patients were included in this
study, with 35 patients in each group. Four patients
(one in the FCB group, one in the FCO group and two in
the MCO group) were excluded from analysis regarding
eradication and ulcer healing because they refused a
follow-up endoscopy. One hundred and thirty-six pa-
tients completed a course of treatment and underwent
follow-up endoscopy. Relevant demographic and endo-
scopic data at entrance are provided in Table 2.
318 W. Z. LIU et al.
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 317±322
Eradication rates of H. pylori
H. pylori eradication rates are provided in Table 3.
There were no signi®cant differences in the eradication
rate between the FCB and FCL groups (P > 0.05), or
between the FCO and MCO groups (P > 0.05) on the
basis of intention-to-treat analysis.
Healing rates of duodenal ulcer
The healing rates of active duodenal ulcer in each of the
treatment groups are provided in Table 4. There were
no signi®cant differences in healing rate between the
treatment groups (P > 0.05).
Resistance of H. pylori to antimicrobials and its impact
on ef®cacy of treatment
One hundred and thirty strains of H. pylori were
successfully isolated, and analysed for their sensitivity
to clarithromycin, metronidazole or furazolidone. The
primary resistance rates of the H. pylori strains to
the antibiotics used in this study are shown in
Table 5.
Table 1. One-week H. pylori treatment
regimensStudy phase Regimen Drugs combination Dosage
Trial one
FCB Furazolidone 100 mg b.d.
Clarithromycin 250 mg b.d.
Tripotassium dicitrato
bismuthate
240 mg b.d.
FCL Furazolidone 100 mg b.d.
Clarithromycin 250 mg b.d.
Lansoprazole 30 mg b.d.
Trial two
FCO Furazolidone 100 mg b.d.
Clarithromycin 250 mg b.d.
Omeprazole 20 mg q.d.s.
MCO Metronidazole 400 mg b.d.
Clarithromycin 250 mg b.d.
Omeprazole 20 mg q.d.s.
Table 2. Demographic and endoscopic data
of patients in the treatment groups at
entrance
FCB FCL FCO MCO
No. of patients 35 35 35 35
Sex F/M 9/26 10/25 8/27 12/23
Age (s.d.) 44 � 12 41 � 14 44 � 15 43 � 13
Diagnosis
Duodenal ulcer
active stage 18 18 15 14
in remission 3 1 3 5
Functional dyspepsia 14 16 17 16
Table 3. H. pylori eradication rates in the treatment groups (in-
tention-to-treat analysis)
Group Eradication 95% CI
FCB 91% (32/35) 82±99%
FCL 91% (32/35) 82±99%
FCO 86% (30/35) 74±95%
MCO 74% (26/35) 60±89%
Table 4. Healing rates of active duodenal ulcers
Group Healing rates of duodenal ulcer
FCB 94% (17/18)
FCL 100% (18/18)
FCO 93% (14/15)
MCO 86% (12/14)
FURAZOLIDONE SHORT-TERM TRIPLE THERAPIES 319
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 317±322
No isolates were resistant to furazolidone. Primary
resistance to clarithromycin was 6% (8/130). Of the 8
patients with H. pylori strains that were resistant to
clarithromycin, only one (in group FCB) responded to
therapy. Among the 16 patients who failed eradication,
seven were infected with H. pylori strains that were
primarily resistant to clarithromycin. Of the remaining
nine patients, three (one from each of FCL, FCO and
MCO groups) had H. pylori strains which demonstrated
resistance to clarithromycin only after treatment. The
primary resistance rate of H. pylori strains to metron-
idazole was 39% (50/130). In the MCO group, H. pylori
eradication was achieved in 67% (8/12) of patients with
isolates resistant to metronidazole compared with 86%
(18/21) of patients with isolates sensitive to metron-
idazole (P � 0.198).
Side-effects
Medication side-effects are listed in Table 6. Twenty-one
of 140 (15%) patients reported probable medication-
related side-effects, which were mild and disappeared
after the medication was discontinued. None of these
side-effects resulted in a cessation of treatment. There
were no signi®cant differences in the rate of side-effects
between the treatment groups (P > 0.05).
DISCUSSION
A rapid increase in H. pylori resistance to metronidazole,
an important component of most H. pylori eradication
regimens, warrants careful consideration of alternative
agents. Because of demonstrated anti-H. pylori activity
as well as an anticipated lower rate of H. pylori
resistance to furazolidone, this agent has attracted the
attention of H. pylori researchers, and new furazolidone-
containing regimens have been proposed and tested.16±
18 Using a combination of furazolidone, amoxycillin and
bismuth for 2 weeks, eradication was achieved in 86%
of patients treated.17 Dual therapies, using either a
combination of furazolidone plus tripotassium dicitrato
bismuthate or furazolidone plus omeprazole, appear to
be somewhat less effective.16, 18
In the ®rst trial, we showed that the eradication rates
of these two furazolidone-containing triple regimens
were both higher than 90%, based on an intention-to-
treat analysis, suggesting that tripotassium dicitrato
bismuthate and proton pump inhibitor are similar in
ef®cacy with furazolidone and clarithromycin, even
though their mechanisms of action differ. The side-
effects of these regimens were mild and well-tolerated,
the dosages low, and the course of therapy relatively
short. These two regimens therefore ful®l the criteria for
successful H. pylori therapy.2, 5
In the second trial, the eradication rate of H. pylori in
FCO group was 86% (30/35), vs. 74% (26/35) in the
MCO group (P � 0.232). Similarly, the eradication rate
in MCO group was 67% in patients with metronidazole-
resistant isolates of H. pylori, compared with 86%
in patients with metronidazole-sensitive isolates
(P � 0.198). The existence of metronidazole-resistant
strains may account for a relatively lower eradication
rate in the MCO groups compared to the FCO group
regimen, although the difference did not reach statisti-
cal signi®cance.
No. ofPrimary resistance of H. pylori to the antibiotics
Group isolates CLA-R MET-R FUR-R CLA + MET-R
FCB 33 2 12 0 1
FCL 31 2 13 0 2
FCO 32 2 13 0 2
MCO 34 2 12 0 1
Total 130 8 (6%) 50 (39%) 0 (0) 6 (5%)
R: resistance, CLA: clarithromycin, MET: metronidazole, FUR: furazolidone.
Table 5. Primary resistance of H. pylori
to antibiotics used in this study
Table 6. Side-effects occurred in the patients of this study
FCB FCL FCO MCO
Taste disturbance 4 5 5 6
Nausea 1 1 1 2
Fatigue 1 Ð Ð Ð
Dizziness Ð Ð 1 Ð
Total 6 (17%) 6 (17%) 7 (20%) 8 (23%)
320 W. Z. LIU et al.
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 317±322
Among ®ve patients (two in the FCB group, three in
the FCL group) who failed to have their infection
eradicated in the ®rst trial, four patients were infected
with H. pylori strains resistant to clarithromycin. The
primary clarithromycin-resistance of H. pylori appeared
to be the explanation for treatment failure as reported
by others.19
FCB, FCL or MCO regimens are each effective 1-week
regimens for eradicating H. pylori and healing of duode-
nal ulcer, con®rming the observation of others that
Figure 1. Flow charts for results of H. pylori eradication trials. (a) FCB Group: furazolidone + clarithromycin + TDB. (b) FCL Group:
furazolidone + clarithromycin + lansoprazole. (c) FCO Group: furazolidone + clarithromycin + omeprazole. (d) MCO Group: metronidazole
+ clarithromycin + omeprazole.
FURAZOLIDONE SHORT-TERM TRIPLE THERAPIES 321
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 317±322
H. pylori eradication is an effective treatment for duodenal
ulcer disease.20, 21 Furazolidone is an attractive,
ef®cacious and relatively cheap alternative to metron-
idazole in 1-week regimens for H. pylori eradication.
ACKNOWLEDGEMENT
We wish to thank Dr Joseph Kolars for his help in the
reviewing of this manuscripts.
REFERENCES
1 NIH Consensus Development Panel. Helicobacter pylori in
peptic ulcer disease. J Am Med Assoc 1994; 272: 65±9.
2 The European Helicobacter pylori Study Group. Current Euro-
pean concepts in management of Helicobacter pylori infection.
The Maastricht Consensus Report. Gut 1997; 41: 8±13.
3 Van der Hulst RWM, Keller JJ, Rauws EA, Tytgat GNJ.
Treatment of Helicobacter pylori infection: arewiev of the world
literature. Helicobacter 1996; 1: 138±44.
4 Walsh JH, Peterson WL. The treatment of Helicobacter pylori
infection in the management of peptic ulcer disease. N Engl J
Med 1995; 333: 984±91.
5 Lam SK, Talley NJ. Report of the 1997 Asia Paci®c Consensus
Conference on the Managemene of Helicobacter pylori Infec-
tion. J Gastroenterol Hepatol 1998; 13: 1±12
6 Xia HX, Buckley M, Hyde D, Keane CT, O'Morain CA. Effects of
antibiotic-resistance on clarithromycin-combined triple thera-
py for Helicobacter pylori. Gut 1995; 37(Suppl.): A55(Abstract).
7 Noach LA, Langenberg WL, Bertola MA, Dankert J, Tytgat
GNJ. Impact of metronidazole resistance on the eradication of
Helicobacter pylori. Scand J Infect Dis 1994; 26: 321±7.
8 Reddy R, Osato M, Gutierrez O, Kim JG, Graham DY. Met-
ronidazole resistance is high in Korea and Colombia and ap-
pears to be rapidly increasing in the US. Gastroenterology
1996; 110: A238 (Abstract).
9 SeBoer WAD, Tytgat GNJ. The best therapy for Helicobacter
pylori infection: Should ef®cacy or side-effect pro®le determine
our choice. Scand J Gastroenterol 1995; 30: 401±7.
10 Zheng ZT, Wang ZY, Chu YX, et al. Double-blind short term
trial of furazolidone in peptic ulcer. Lancet 1985; i: 1048±9.
11 Zheng ZT, Wang YB. Treatment of peptic ulcer disease with
furazolidone. J Gastroenterol Hepatol 1992; 7: 533±7.
12 Morgan D, Kraft W, Bender M, Pearson A. Nitrofurans in the
treatment of gastritis associated with Campylobacter pylori. The
Gastrointestinal Physiology Working Group of Cayetano
Heredia and The Johns Hopkins Universities. Gastroenterology
1988; 95: 1178±84.
13 Graham DY, Klein PD, Opekum AR, et al. In vivo suscepti-
bility of Campylobacter pylori. Am J Gastroenterol 1989; 84:
233±8.
14 Xiao SD, Liu WZ, Xia DH, et al. The ef®cacy of furazolidone
and metronidazole in the treatment of chronic gastritis asso-
ciated with Helicobacter (Campylobacter) pyloriÐa randomized
double-blind placebo-controlled clinic trial. HepatoGastroen-
terology 1990; 37: 503±6.
15 Haas CE, Nix DE, Schentag JJ. In vitro selection of resistant
Helicobacter pylori. Antimicrob Agents Chemother 1990; 34:
1737±41.
16 Xiao SD, Liu WZ, Lin GJ, et al. TDB combined therapy for
eradication of Helicobacter pylori. Chinese J Digestion 1995;
15(Suppl.): 18±16.
17 Segura AM, Gutierrez O, Otero W, Angel A, Genta RM, Gra-
ham DY. Furazolidone, amoxycillin, bismuth triple therapy for
Helicobacter pylori infection. Aliment Pharmacol Ther 1997;
11: 529±32.
18 Van Zwet AA, Thijs JC, Van der Wouden EJ, Kooy A. Low cure
rate of Helicobacter infection with omeprazole and furazolidone
dual therapy for one week. Aliment Pharmacol Ther 1997;
11: 533±5.
19 Cayla R, Zerbib F, Talbi P, et al. Pre- and post- treatment
clarithromycin resistance of Helicobacter pylori strains: a key
factor of treatment failure. Gut 1995; 37(Suppl. 2):
A152(Abstract).
20 Forne M, Viver JM, Espinos JC, et al. Impact of colloidal bis-
muth subcitrate in the eradication rates of Helicobacter pylori
infection-associated duodenal ulcer using a short treatment
regimen with omeprazole and clarithromycin: a randomized
study. Am J Gastroenterol 1995; 90: 718±21.
21 Hosking SW, Ling TKW, Chung SCS, et al. Duodenal ulcer
healing by eradication of Helicobacter pylori without anti-acid
treatment: randomized controlled trial. Lancet 1994; 343:
508±10.
322 W. Z. LIU et al.
Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 317±322