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.


Lansoprazole 30 mg b.d.

Trial two

FCO Furazolidone 100 mg b.d.


Omeprazole 20 mg q.d.s.

MCO Metronidazole 400 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


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%)



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


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.

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