Bismuth-based quadruple therapy for Helicobacter pylori Ð a singletriple capsule plus lansoprazole

W. A. DE BOER*à , R. J . X. M. VAN ETTEN*, B. A. M. VAN DE WOUW*, P. M. SCHNEEBERGER  ,

A. H. A. M. VAN OIJENà & J. B. M. J. JANSENà*Department of Internal Medicine and  Medical Microbiology, Sint Anna Hospital, Oss, the Netherlands; and àDepartment of

Gastroenterology, University of Nijmegen Radboud Hospital, Nijmegen, the Netherlands

Accepted for publication 14 September 1999

INTRODUCTION

Helicobacter pylori infection of the gastric mucosa is

causally related to peptic ulcer disease and cure of this

infection has therefore become the treatment goal in

ulcer patients.1±5 Several guidelines suggest that

patients with non-ulcer dyspepsia should also be treated

for the infection and a serological based `test and treat'

strategy for young dyspeptics is gaining popularity.3, 4

Even though the indications for treatment are expand-

ing, no consensus exists as to the most optimal therapy.

Physicians and drug companies tried to identify a single

antibiotic to cure the infection. The hope of ®nding such

a `golden' or `magic bullet', however, has diminished

over the years and presently physicians have to choose

from a wide range of 14-day dual and 7±10-day triple

or quadruple therapies.2, 5±8 Physicians seem to prefer

the simpler regimens.

Fourteen day bismuth-based triple therapy is the oldest

effective and most widely investigated anti-Helicobacter

therapy.2, 5±9 Treatment duration can be shortened to

7 days if a proton pump inhibitor is added (quadruple

therapy).8±10 This regimen has produced one of the

highest cure rates.11±21 Patients, however, have to take

many pills per day and the regimen is perceived as

complex. Fear of non-compliance has delayed its global

acceptance.

SUMMARY

Background: Recently a new `all in one' single capsule

with the three components of bismuth-based triple

therapy became available in trials for treating

Helicobacter pylori.

Aim: To investigate the ef®cacy and tolerability of this

new capsule when combined with lansoprazole.

Methods: A total of 66 consecutive infected patients

from a single centre received two single triple capsules

four times daily and lansoprazole 30 mg b.d. for 7 days.

Each capsule contained 60 mg of bismuth subcitrate,

125 mg of tetracycline and 125 mg of metronidazole.

Endoscopy with biopsies for CLO-test, histology and

culture from antrum and corpus was performed before

and at least 5 weeks after treatment.

Results: The per protocol cure rate was 56/64 (88%,

95% CI: 79±95%); by intention-to-treat 56/65 (86%,

95% CI: 78±95%). The per protocol cure rate in

metronidazole sensitive strains was 40/43 (93%, 95%

CI: 85±100%); in resistant strains 5/9 (56%, 95% CI:

23±88%). There was one drop-out due to adverse

events.

Conclusions: It is possible to combine the components

of bismuth-based triple therapy into a single capsule.

Based on the results it can be assumed that the

capsule releases its content in the stomach. When

combined with lansoprazole it reaches high cure rates,

especially in metronidazole sensitive strains. This new

approach simpli®es bismuth-based anti-Helicobacter

therapy.

Correspondence to: Dr W. A. de Boer, Sint Anna Hospital, Department ofInternal Medicine, Postbus 10, 5340 BE Oss, the Netherlands.

Aliment Pharmacol Ther 2000; 14: 85±89.

Ó 2000 Blackwell Science Ltd 85

Recently a new `all in one' capsule became available

with all the components of bismuth triple therapy

combined in a single capsule.22 It is the greatest

advance in Helicobacter therapy of the last year and

the initial results show that the separate drugs are

delivered to their site of action.22 This new patient

friendly formulation of bismuth-based triple therapy

should greatly improve acceptance as a result of the

decrease in the number of different pills. We have

expanded our experience with this capsule; here we

report on its ef®cacy and tolerability when combined

with lansoprazole into a 7-day dual therapy, which is

an easy equivalent of quadruple therapy.

PATIENTS AND METHODS

We performed a single centre, open, therapeutic pilot

study of the new investigational single triple capsule.

Our centre was a community hospital in a rural part

of the Netherlands where the background rate of

metronidazole resistance is 10±20%.23 Between

December 1997 and June 1998 consecutive patients

in need of anti-Helicobacter therapy were offered

treatment with this new compound plus lansoprazole.

Presence of H. pylori had to be proven by an index

endoscopy with at least two out of three positive

biopsy-based diagnostic tests (CLO-test, histology,

culture) before inclusion. Cure was determined by a

second endoscopy at least 5 weeks after the end of

treatment during which eight biopsies were taken for

CLO-test (one biopsy antrum and corpus), histology

(Giemsa stain; two biopsies antrum and corpus) and

culture (one biopsy antrum and corpus). Cure was

established if all biopsy based tests were negative.

Antimicrobial susceptibility for metronidazole and

clarithromycin was assessed by the E-test. The MIC

above which the strain was considered metronidazole

resistant was 8 mg/L and for clarithromycin this was

2 mg/L.

The single triple capsule contains 60 mg of colloidal

bismuth subcitrate (as Bi2O3 equivalent), 125 mg of

tetracycline hydrochloride and 125 mg of metronidaz-

ole (AXCAN pharma, Mont Saint Hilaire, Canada).

Patients were treated from day 1 to day 7 with

lansoprazole 30 mg b.d. and the `single triple' four

times daily two capsules. Lansoprazole was given before

breakfast and before dinner. The new capsule was given

after the three meals and before retiring after taking a

small evening snack.

RESULTS

A total of 66 consecutive patients entered the study (39

male/27 female), mean age 56.8 years (range 18±85).

Twenty-nine had duodenal ulcer disease, nine had

gastric ulcer disease and 28 had gastritis only. Seven

patients had presented with bleeding, of whom three

also had a medical history which documented a

previous bleeding. Three patients, all with chronic

recurrent duodenal ulcer disease, had been operated

on in the past for duodenal perforation. Twenty-nine

(44%) were smokers.

One patient was diagnosed with metastatic cancer

shortly after inclusion and died only a couple of weeks

later, before a follow-up endoscopy could be performed;

she is left out of the analysis. All remaining 65 patients

®nished the regimen as prescribed and are included in

the intention-to-treat analysis. One patient was lost to

follow-up before the second endoscopy. All remaining

64 patients are included in the per protocol analysis.

Sixty-two had an endoscopy; two refused endoscopy

and treatment outcome was determined by a validated

urea breath test and a validated follow-up serology

instead; both were cured.24, 25 Fifty-four patients tested

negative on all biopsy based tests and were therefore

cured of their infection.

The cure rate per protocol therefore was 56/64 (88%,

95% CI: 79±96%) and the cure rate in the intention-

to-treat analysis was 56/65 (86%, 95% CI: 78±95%). At

the index endoscopy 63/66 (96%) had a positive culture

result. We were able to determine the antibiogram in

54/63 (86%) of the positive cultures. Forty-®ve strains

were metronidazole sensitive and nine (14%) were

metronidazole resistant. We did not ®nd a clarithromy-

cin resistant strain. The per protocol cure rate in the

metronidazole sensitive strains was 40/43 (93%, 95%

CI: 85±100%); in the resistant strains 5/9 (56%, 95%

CI: 23±88%) and 11/12 (92%, 95% CI: 76±100%) in

those in which the resistance pattern was unknown.

Eight patients were not cured. The culture results post-

treatment are shown in Table 1. Interestingly a met-

ronidazole sensitive strain was isolated from the biopsies

of one patient in whom a resistant strain was found

before treatment.

Side-effects

Tolerability was excellent. We achieved 100% compli-

ance in 59/64 (92%) patients. One patient stopped the

86 W. A. DE BOER et al.

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 85±89

study medication after 2 days, but ®nished the treat-

ment course later-on, one stopped after 5 days because

of adverse events and three patients returned, respect-

ively, four, four and 12 capsules from the total amount

of 70 capsules (56 single triple capsules plus 14

lansoprazole capsules).

Data on adverse events were collected through a

standard side-effect questionnaire, which has previous-

ly been described.26 The form was unavailable for one

patient. Twenty-nine (45%) had no adverse events, 28

(44%) had mild adverse events not interfering with

daily activities, 3 (5%) had moderate adverse events

interfering with daily activities and 4 (6%) had severe

adverse events, making work impossible. Only one

(2%) female patient dropped out at day 5 due to

stomach pain, headaches, diarrhoea, nausea and

vomiting.

DISCUSSION

The single triple capsule combined with lansoprazole is

well tolerated and 92% of patients ®nished the treat-

ment regimen as prescribed. This demonstrates that a

good compliance can be achieved with this regimen. It

is also highly effective and reaches the ef®cacy level that

is required for modern anti-H. pylori regimens. The

results coincide with the results previously reported for

quadruple therapy with the four drugs given separate-

ly.8, 10±21 The cure rate in patients carrying metron-

idazole resistant strains however, was suboptimal. We

have not observed this in earlier studies when the

quadruple regimen was given as separate drugs.8, 21 It

must be noted however, that the total daily dose of

tetracycline (1000 mg) and of metronidazole

(1000 mg) in this regimen is less then that which we

have previously applied. The total daily dose of met-

ronidazole might be of particular importance in the case

of resistant organisms.9 A recent study showed that the

dosing of metronidazole was more important than the

dosing of tetracycline.27 Increasing the dose of metron-

idazole to 1500 mg/day might be necessary in areas

with a high rate of metronidazole resistance. This can be

achieved by increasing the amount of metronidazole in

the capsule, increasing the number of capsules per day

or perhaps by simply taking metronidazole separately

alongside the capsule.

It has previously been demonstrated that treatment

failures occur more often in patients without ulcers,

whereas patients with ulcer disease are more easily

cured.28±30 This is explained by a difference in the

infecting strains.30 Numerically, more failures occurred

in the most dif®cult category of patients, those without

ulcers who carried a metronidazole resistant strain. This

study, however, has insuf®cient statistical power to

detect the difference between these patient groups.

In this study we have demonstrated that combining

the triple therapy components together into a single

capsule is a valuable and effective approach. Apparently

the capsule releases its content in the stomach and

judging from the high cure rate it must be assumed that

adequate mucosal levels can be achieved. A slightly

longer (10-day) treatment with the single triple capsule

containing a higher dose of metronidazole could

improve the ef®cacy in metronidazole resistant strains.

The new capsule simpli®es bismuth-based triple and

quadruple therapy into an attractive mono-or dual-

therapy. Presently bismuth-based quadruple therapy is

usually reserved for second line therapy.31, 32 If pro-

moted as ®rst line therapy it must compete with 1-week

proton pump inhibitor- or RBC-based triple therapies

which are taken only twice daily. This single capsule

regimen however, is probably still more troublesome for

patients and so it might primarily gain popularity as a

back-up regimen.

If, however, a low dose of a proton pump inhibitor can

be added into the single capsule we then would have

the ideal `golden bullet' to treat H. pylori infection. It

would be a monotherapy for 1 week, well tolerated and

with an extremely high cure rate. We eagerly await

further studies employing this new and patient-friendly

concept in Helicobacter therapy. The proposed simpli®-

cation of this well investigated multidrug regimen may

Table 1. Culture results before and after therapy

After treatment

Cured

Not cured

metronidazole

sensitive

Not cured

metronidazole

resistant

Not cured

unknown

resistance

Metronidazole

sensitive

pre-treatment

40 2 1 0

Metronidazole

resistant

pre-treatment

5 1 3 0

Unknown

resistance

pre-treatment

11 0 0 1

SINGLE TRIPLE CAPSULE PLUS LANSOPRAZOLE FOR H. PYLORI 87

Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 85±89

eventually lead to wide acceptance of single capsules in

the treatment of H. pylori infection.

ACKNOWLEDGEMENTS

We thank AXCAN pharma of Mont-Saint-Hilaire,

Canada for providing the single capsule and supporting

this research.

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