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G A S T R O E N T E R O L O G Y jgh_6477 44..48

Effects of multistrain probiotic-containing yogurt on

second-line triple therapy for Helicobacter pylori infectionHyuk Yoon,* Nayoung Kim,*, Ji Yeon Kim,* So Youn Park,* Ju Hee Park,* Hyun Chae Jung* and

In Sung Song*

*Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul; and Department of Internal

medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea

Abstract

Background and Aims: The adjuvant effects of probiotic-containing yogurt on second-

line triple therapy for Helicobacter pylori (H. pylori) infection have not been evaluated.

Methods: A total of 337 patients with persistent H. pylori infection, after first-line triple

therapy, were randomly assigned to receive either triple therapy with (yogurt group,

n = 151) or without (control group, n = 186) Will yogurt. Triple therapy consisted of

400 mg moxifloxacin q.d., 1000 mg amoxicillin b.i.d., and 20 mg esomeprazole b.i.d. for

14 days. Will yogurt contains Lactobacillus acidophilus, Lactobacillus casei, Bifidobacte-

rium longum, and Streptococcus thermophilus. H. pylori eradication was evaluated by the13C-urea breath test, histology, or the rapid urease test.

Results: The eradication rates by intention-to-treat analysis were 66.7% and 68.9% in the

control and yogurt groups, respectively (P = 0.667). The eradication rates by per-protocol

analysis were 78.5% and 86% in the control and the yogurt groups, respectively

(P = 0.110). The adverse event rates were 25.3% and 28.5% in the control group and yogurt

group, respectively (P = 0.508).

Conclusions: The addition of yogurt containing probiotics to moxifloxacin-containing

second-line treatment neither improved H. pylori eradication rates nor reduced the adverse

events of treatment.

Key words

drug therapy, eradication, Helicobacter pylori

infection, moxifloxacin, probiotics.

Accepted for publication 31 July 2010.

Correspondence

Dr Nayoung Kim, Department of Internal

Medicine, Seoul National University Bundang

Hospital, 300 Gumi-dong, Bundang-gu,

Seongnam, Gyeonggi-do 463-707, South

Korea. Email: [email protected]

Introduction

The eradication of Helicobacter pylori (H. pylori) has attempted

to prevent the development of gastrointestinal diseases, such as

peptic ulcers and gastric malignancies. However, the eradication

rates with conventional proton-pump inhibitor (PPI)-based triple

therapy have become unacceptably low over the last decade;1 this

is thought to be mainly due to increasing antibiotic resistance.2,3

To overcome this problem, alternative therapies, including qua-

druple therapy, sequential therapy, and triple therapy using new

antimicrobials, such as levofloxacin, have been introduced.4 In

addition, other strategies to increase eradication rates include

adjuvant therapies added to conventional treatments, such as

probiotics.

Although there is some controversy as to whether supplemen-

tation with probiotics improves the H. pylori eradication rates,511

several meta-analyses and review articles have suggested that

probiotics can improve the H. pylori eradication rate by approxi-

mately 510%.1215 We also previously reported that the addition

of probiotic-containing yogurt to triple therapy significantly

increased H. pylori eradication rates by per-protocol (PP) analy-

sis (87.5% versus 78.7%, P = 0.037) in Korea.16 However, there

have been very few reports on the effects of probiotics on

second-line treatment for H. pylori infection, and current studies

report conflicting results. That is, a report from Italy showed that

10-day quadruple therapy with probiotic supplementation did not

improve H. pylori eradication rates (PP/intention to treat [ITT]:

97.1%/94.3% with probiotics vs 93.8%/85.7% without probiot-

ics, P = not significant).17 By contrast, a study from Taiwan con-

cluded that pretreatment with probiotics improved the efficacy of

7-day quadruple therapy (PP/ITT: 90.8%/85% vs 76.6%/71.1%,

P < 0.05).18 Furthermore, instead of quadruple therapy, we fre-

quently use moxifloxacin-containing triple therapy as a second-

line treatment regimen; this is because this regimen has been

shown to have a similar efficacy and is better tolerated than qua-

druple therapy.19,20

Therefore, a randomized, prospective, open-labeled study, with

a relatively large population, was undertaken to evaluate whether

the addition of a commercially-available yogurt containing mul-

tistrain probiotics to a 14-day moxifloxacin-containing triple

therapy, after initial treatment failure, could improve H. pylori

eradication rates and reduce the adverse effects of treatment.

doi:10.1111/j.1440-1746.2010.06477.x

44 Journal of Gastroenterology and Hepatology26 (2011) 4448

2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd


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Methods

Patients

Between January 2007 and January 2010, patients with persistent

H. pylori infection, after a course of first-line triple therapy, were

enrolled at Seoul National University Bundang Hospital, Seong-nam, Gyeonggi-do, Korea. Triple therapy included 40 mg esome-

prazole b.i.d., 500 mg clarithromycin b.i.d., and 1000 mg

amoxicillin b.i.d. for 7 days. Persistent H. pylori infection was

defined based on the results of at least one of the following: (i) a

positive13C-urea breath test (UBT); (ii) histological evidence of H.

pylori by modified Giemsa staining in the stomach; and (iii) a

positive rapid urease test (CLO test; Delta West, Bentley, WA,

Australia) by gastric mucosal biopsy. Patients that had a history of

having used PPI, histamine-2 receptor antagonists, or antibiotics

within the previous 2 months were excluded. All patients provided

informed consent, and the study was approved by the institutional

review board of Seoul National University Bundang Hospital.

Study design

Patients were enrolled in this randomized, prospective, open-

labeled study. The patients were randomly allocated to one of two

groups using a computer-generated table and received either

moxifloxacin-containing triple therapy (moxifloxacin +

esomeprazole + amoxicillin) with (MEA + yogurt group) or

without (MEA-only group) Will yogurt (KoreaYakult; Chungnam,

South Korea). Moxifloxacin-containing triple therapy consisted of

400 mg moxifloxacin q.d., 1000 mg amoxicillin b.i.d., and 20 mg

esomeprazole b.i.d. for 14 days. One bottle (150 mL) of Will

yogurt before breakfast, started on the same day as triple therapy,

was ingested for 4 weeks by the MEA + yogurt group members.

Will yogurt contains Lactobacillus acidophilus (L. acidophilus)

HY 2177 (> 105 c.f.u/mL), Lactobacillus casei (L. casei) HY 2743

(> 105 c.f.u/mL), Bifidobacterium longum HY 8001 (> 106 c.f.u/

mL), and Streptococcus thermophilus B-1 (> 108 c.f.u/mL).

Patients were instructed to refrain from antibiotics for at least

4 weeks and from PPI for at least 2 weeks before testing for H.

pylori eradication to minimize the chance of false negative results.

Four weeks after completing triple therapy, H. pylori eradica-

tion was evaluated by a UBT. However, modified Giemsa staining

and the rapid urease test (CLO test) were performed in the patients

with peptic ulcer disease, gastric dysplasia, or cancer, for whom a

follow-up endoscopic examination was necessary. At this time,

compliance was assessed by a physician by direct questioning, and

patients were interviewed for adverse events. Compliance wasconsidered to be satisfactory when drug intake and ingestion of

yogurt exceeded 85%. Each adverse event was scored according to

severity from 1 to 5.

UBT

Patients fasted for 4 h before testing. Then, 100 mg of13C-urea

powder (UBiTkit; Otsuka Pharmaceutical, Tokyo, Japan) was dis-

solved in 100 mL water and administered orally; a second breath

sample was collected 20 min later. The collected samples were

analyzed using an isotope-selective, non-dispersive infrared spec-

trometer (UBiT-IR300; Otsuka Pharmaceutical, Japan). The cut-

off value used for H. pylori eradication was 2.5.

Statistical analysis

The eradication rates ofH. pylori were determined by ITT and PP

bases. All enrolled patients were included in the ITT analysis.

However, for the PP analysis, patients that were lost to follow up,

had taken less than 85% of the prescribed drugs or yogurt, or those

that had dropped out due to severe adverse events were excluded.

SPSS for Windows (version 16.0; SPSS, Chicago, IL, USA) was

used for the statistical analysis. Continuous variables were ana-

lyzed using the Students t-test, and categorical variables using the

c2-test or Fishers exact test. All results were considered statisti-

cally significant when the P-values were less than 0.05.

Results

Patient populationFigure 1 shows a schematic diagram of this study. A total of 337

patients entered into the study. Among these patients, 186 were

assigned to the MEA-only group, and 151 patients to the

MEA + yogurt group. The difference in the number of patients in

each group was due to 17 patients, who were initially assigned to

the MEA + yogurt group, refusing the yogurt due to underlying

conditions, such as diabetes mellitus or lactose intolerance; these

patients were then assigned to the MEA-only group. The demo-

graphic and clinical characteristics of the two study groups are

summarized in Table 1. Sex, the mean age of the patients, and

disease profiles of the two groups were similar. There was no

difference in the drop-out rate between the MEA + yogurt group

and the MEA-only group.

H. pylori eradication rates

The H. pylori eradication rates are shown in Table 2. The eradica-

tion rates by ITT analysis were similar in the two groups (MEA-

only group: 66.7% [95% confidence interval [CI]; 59.973.5%] vs

MEA + yogurt group: 68.9% [95% CI; 61.576.3%], P = 0.667).

In the MEA + yogurt group, the eradication rate by PP analysis

was higher than in the MEA-only group (MEA-only group: 78.5%

[95% CI; 72.184.9%] vs MEA + yogurt group: 86% [95% CI;

79.792.2%]); the difference between the two groups was not

significant (P = 0.110).

Adverse events

The percentage of patients with adverse events were 25.3% and

28.5% for the MEA-only group and MEA + yogurt group, respec-

tively; there was no significant difference between the groups

(P = 0.508). Details of the adverse events are shown in Table 3.

The most common adverse event was diarrhea in both groups. It

was more frequently observed in the MEA + yogurt group than in

the MEA-only group; however, the difference was not statistically

significant (P = 0.231). The other adverse events were similar in

both groups. Severe adverse events (with a score of 4 or 5)

occurred at a rate of 8.1% (15/186) and 7.3% (11/151) in the

H Yoon et al. Helicobacter pylori therapy

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MEA-only group and MEA + yogurt group, respectively

(P = 0.790). The percentage of patients who discontinued therapy

because of adverse events was similar in both groups (Table 1).

Discussion

In this study, the PP eradication rate of the MEA + yogurt group

(86%) was higher than that of the MEA-only group (78.5%);

however, this difference was not statistically significant. This

result is different from that of our previous study, which added the

same commercial yogurt to PPIclarithromycinamoxicillin

therapy.16 This could be explained by several factors: (i) it might be

related to an insufficient sample size. The enrolled number of

patients in the MEA + yogurt group was 151, which was smaller

than the 186 in the MEA-only group; (ii) the different results

might be explained by the different antibiotics used for the triple

therapy. That is, moxifloxacin was used for the second-line therapy

in this study instead of clarithromycin; this suggests that the inter-

action of the probiotics with moxifloxacin might be less synergis-

tic than with clarithromycin. In Taiwan, Sheu et al. demonstrated

that supplementation with the same probiotic-containing yogurt

(AB yogurt), which increased the eradication rate of first-line

treatment by ITT analysis,6 also improved the efficacy of second-

line quadruple therapy.18 The different response to the addition of

probiotic-containing yogurt with quadruple therapy and moxi-

floxacin containing triple therapy might be related to different

trends in antibiotic resistance. That is, the resistance to metronida-

zole in Korea has decreased from 34.8% in 20032005 to 27.6% in

20072009.21 By contrast, in the case of moxifloxacin, the resis-

tance rate has rapidly increased from 5.6% in 2004 to 12% in

20052006, and 28.2% in 20072008 in Korea.22 Thus, the adju-

vant effect of probiotics might be too modest to overcome the

increased moxifloxacin resistance rate ofH. pylori. To resolve this

issue of resistance to moxifloxacin, it is suggested that more potent

quinolones, such as satifloxacin, be tried, as they have the lowest

Figure 1 Flow schematic of the study

included in intention-to-treat (ITT) and per-

protocol (PP) analyses. MEA + yogurt,

moxifloxacin-containing triple therapy

(moxifloxacin + esomeprazole + amoxicillin)

with Will yogurt; MEA only, moxifloxacin-containing triple therapy without Will yogurt.

Table 1 Patient baseline demographics

MEA only MEA + yogurt P-value

Included in ITT analysis (n) 186 151

Male/female (n) 85/101 66/85 0.715

Mean age SD (years) 55.0 12 .5 5 3.7 11.1 0.313

Disease, n (%) 0.123

Beni gn ga stric ul ce r 1 5 (8.1%) 2 0 (13 .2%)

Duodenal ulcer 38 (20.4%) 36 (23.8%)

Gastric dysplasia or cancer 32 (17.2%) 15 (9.9%)

Non-ulcer dyspepsia 101 (54.3%) 80 (53.0%)Drop out, n (%) 28 (15.1%) 30 (19.9%) 0.244

Non-compliance 5 (2.7%) 8 (5.3%) 0.216

Follow-up loss 20 (10.8%) 19 (12.6%) 0.601

Discontinued therapy

because of adverse

events

3 (1.6%) 3 (2.0%) 1.0

ITT, intention-to-treat; MEA + yogurt, moxifloxacin-containing triple

therapy (moxifloxacin + esomeprazole + amoxicillin) with Will yogurt;

MEA only, moxifloxacin-containing triple therapy without Will yogurt.

Table 2 Helicobacter pylori eradication rates

MEA only MEA + yogurt P-value

ITT analysis

Eradication rate 66.7% (124/186) 68.9% (104/151) 0.667

95% CI 59.973.5 61.576.3

PP analysis

Eradication rate 78.5% (124/158) 86.0% (104/121) 0.110

95% CI 72.184.9 79.792.2

CI, confidence interval; ITT, intention-to-treat; MEA + yogurt,

moxifloxacin-containing triple therapy (moxifloxacin + esomeprazole +

amoxicillin) with Will yogurt; MEA only, moxifloxacin-containing triple

therapy without Will yogurt; PP, per-protocol.

Helicobacter pylori therapy H Yoon et al.




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minimal inhibitory concentration of quinolones;23 (iii) the treat-

ment duration was different. That is, the duration of moxifloxacin

containing triple therapy was 14 days, which is longer than the

7 days of first-line triple therapy. Several mechanisms have been

proposed to explain the inhibition of H. pylori by probiotics.13

Among these, in the competition for nutrients or adhesion sites in

gastric epithelial cells, the viability of probiotics during antibiotic

treatment is important for the successful inhibition of H. pylori.

One study reported that the administration of moxifloxacin to

healthy patients for 7 days did not markedly affect the number of

lactobacilli and bifidobacteria in the feces.24 However, as moxi-

floxacin treatment was for 14 days in this study, we cannot com-pletely exclude the possibility that the probiotics were suppressed

by moxifloxacin; and (iv) it is possible that the dose of probiotics

administered was not sufficient. Although there is no scientific

evidence, the minimal effective dose of probiotic bacteria has been

frequently reported to be at least 108109 c.f.u/day.25 In fact, in the

randomized, controlled trials in previous meta-analyses,12,14,15 the

amount of probiotics administered was generally more than

109 c.f.u/day. However, in this study, the dose of L. acidophilus

and L. casei given to the MEA + yogurt group of patients were

both only 1.5 107 c.f.u/day. Although supplementation with the

same dose of lactobacilli improved the H. pylori eradication rate of

first-line treatment by PP analysis in the previous study,16 there is

the possibility that this amount of lactobacilli might be relatively

insufficient in the present study, in which the moxifloxacin resis-

tance rate of H. pylori was as high as 28.2%.

There is controversy as to whether the addition of probiotics to

eradication treatment can reduce the adverse events of treatment.

Although probiotic supplementation had a positive impact on

adverse events during H. pylori eradication treatment in a meta-

analysis reported in 2007,12 subsequent meta-analyses reported

that the effect of probiotics on adverse events varies or is not

significant.14,15 Since the alteration of the intestinal microflora is

associated with diarrhea during H. pylori eradication treatment,

the administration of probiotics might decrease the frequency of

diarrhea. However, in the present study, there was no significant

difference in the total adverse events between the two groups; the

frequency of diarrhea did not differ.

In conclusion, the addition of a commercial yogurt containing

multistrain probiotics to moxifloxacin-containing triple therapy as

a second-line treatment for H. pylori infection neither improved

H. pylori eradication rates nor reduced the adverse events of

treatment.

Acknowledgments

This work was supported by a grant from the Seoul National

University Bundang Hospital Research Fund (no. 06-2009-026).

References

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Table 3 Adverse events

Adverse events MEA only

(n = 186)

MEA + yogurt

(n = 151)

P-value

Diarrhea 17 (9.1%) 20 (13.2%) 0.231

Dyspepsia 15 (8.1%) 9 (6.0%) 0.455

Nausea or vomiting 11 (5.9%) 9 (6.0%) 0.986Metallic taste 6 (3.2%) 3 (2.0%) 0.736

Abdominal pain 5 (2.7%) 2 (1.3%) 0.466

Anorexia 2 (1.1%) 2 (1.3%) 1.0

Abdominal distension 1 (0.5%) 2 (1.3%) 0.589

Itching or rash 1 (0.5%) 2 (1.3%) 0.589

Constipation 2 (1.1%) 0.504

Headache 2 (1.1%) 0.504

Regurgitation 1 (0.5%) 1.0

Dizziness 1 (0.5%) 1.0

Total 47 (25.3%) 43 (28.5%) 0.508

MEA + yogurt, moxifloxacin-containing triple therapy (moxi-

floxacin + esomeprazole + amoxicillin) with Will yogurt; MEA only,

moxifloxacin-containing triple therapy without Will yogurt.

H Yoon et al. Helicobacter pylori therapy

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