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Clinical trial: effectiveness of Lactobacillus rhamnosus (strains

E ⁄ N, Oxy and Pen) in the prevention of antibiotic-associated

diarrhoea in childrenM. RUSZCZY NSKI* , A. RADZIKOWSKI & H. SZAJEWSKA*

*2nd Department of Pediatrics, The

Medical University of Warsaw and

The Medical University of Warsaw,

Warsaw, Poland

Correspondence to:

Dr H. Szajewska, 2nd Department of

Paediatrics, The Medical University of

Warsaw, 01-184 Warsaw, Dzialdowska1, Poland.

E-mail: [email protected]

Publication data

Submitted 6 March 2008

First decision 18 March 2008

Resubmitted 7 April 2008

Accepted 8 April 2008

Epub OnlineAccepted 12 April 2008

SUMMARY

Background

Convincing evidence that probiotic administration can lower the risk of

antibiotic-associated diarrhoea is limited to certain micro-organisms.

Aim

To determine the efficacy of administration of Lactobacillus rhamnosus(strains E ⁄ N , Oxy and Pen) for the prevention of antibiotic-associated

diarrhoea in children.

Methods

Children (aged 3 months to 14 years) with common infections were

enrolled in a double-blind, randomized, placebo-controlled trial in

which they received standard antibiotic treatment plus 2 · 1010 colony

forming units of a probiotic (n = 120) or a placebo (n = 120), adminis-

tered orally twice daily throughout antibiotic treatment. Analyses were

by intention to treat.

Results

Any diarrhoea (‡3 loose or watery stools ⁄ day for ‡48 h occurring dur-

ing or up to 2 weeks after the antibiotic therapy) occurred in nine

(7.5%) patients in the probiotic group and in 20 (17%) patients in the

placebo group (relative risk, RR 0.45, 95% confidence interval, CI

0.2–0.9). Three (2.5%) children in the probiotic group developed AAD

(diarrhoea caused by Clostridium difficile or otherwise unexplained diar-

rhoea) compared to nine (7.5%) in the placebo group (RR 0.33, 95% CI

0.1–1.06). No adverse events were observed.

Conclusion

Administration of L. rhamnosus (strains E ⁄ N , Oxy and Pen) to children

receiving antibiotics reduced the risk of any diarrhoea, as defined in

this study.

Aliment Pharmacol Ther 28, 154–161

Alimentary Pharmacology & Therapeutics

154 ª 2008 The Authors

Journal compilation ª 2008 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2008.03714.x



INTRODUCTION

Antibiotic-associated diarrhoea (AAD) is caused by the

administration of antibiotics and is characterized by

an acute inflammation of the intestinal mucosa.

Almost all antibiotics, particularly those that act on

anaerobes, can cause diarrhoea; however, the risk of

developing diarrhoea is higher with the use of amin-

openicillins, a combination of aminopenicillins and

clavulanate, second- and third-generation cephalospo-

rins, and clindamycin.1, 2 The reported incidence of

AAD in children receiving broad-spectrum antibiotics

depends on the definition of diarrhoea used, the incit-

ing antimicrobial agents, and host factors, and it

ranges from 11% to 40%.3, 4 Clinical symptoms vary

widely and can range from mild diarrhoea to colitis to

pseudomembranous enterocolitis. The latter condition,

which may lead to death, is most commonly caused

by toxins produced by Clostridium difficile .5

Measuresto prevent AAD include the use of probiotics, which

are ‘live micro-organisms administered in adequate

amounts which confer a beneficial health effect on

the host.’6 In children, a reduction in the risk of

developing AAD with the administration of certain

probiotic micro-organisms has been documented in

several meta-analyses of randomized controlled trials

(RCTs),7, 8 including one performed by us.9 However,

as of today, very few probiotics have been tested, and

it is clear that not all probiotics are created equal. The

beneficial effects of probiotics seem to be strain-spe-

cific. Extrapolating data on different strains may

result in misleading conclusions. While many micro-

organisms may be effective in preventing AAD, the

efficacy of each one needs to be confirmed in ade-

quately powered, double-blind RCTs.10 Accordingly,

the objective of this study was to assess the efficacy

of Lactobacillus rhamnosus strains E ⁄ N , Oxy and Pen

(hereafter, referred to collectively as L. rhamnosus)

administration in the prevention of AAD in children

requiring antibiotic treatment for common acute

infections.

METHODS

Study design

This was a double-blind, randomized, placebo-con-

trolled, clinical trial intended to evaluate the efficacy,

safety and tolerability of L. rhamnosus in the preven-

tion of AAD in children. We followed the protocol of

a similar study carried out earlier at our center, which

was coordinated by one of the investigators of this

study (H.S.) and is described elsewhere.11

Participants

This study was conducted between February 2005 and

January 2008. Children were recruited from two paedi-

atric hospitals in Warsaw, Poland, and from the pri-

vate practice of one of the investigators (A.R.). Eligible

patients were those aged 3 months to 14 years with

common infections (e.g. respiratory tract infection, oti-

tis media, urinary tract infection, skin infection) who

started treatment with oral or intravenous antibiotics

within 24 h of enrolment. Exclusion criteria included

the presence of a severe or generalized bacterial infec-

tion, antibiotic treatment within the previous

2 months, prophylactic antibiotic treatment, using a

probiotic product for medicinal purposes within theprevious 7 days, immunodeficiency, chronic gastroin-

testinal disease, and acute or chronic diarrhoea.

Interventions

Patients were randomized to receive antibiotic therapy,

as appropriate, plus either 2 · 109 colony forming

units of L. rhamnosus or a comparable placebo (nonfat

milk and saccharose). Both the active treatment and

placebo were taken orally twice daily for the duration

of the antibiotic treatment. The study products were

supplied by Biomed (Lublin, Poland), who had no role

in the conception, design, or conduct of the study or

in the analysis or interpretation of the data. Randomi-

zation codes were secured until all data entry was

complete and data were analysed. The probiotic com-

bination used in this study is commercially available

as Lakcid Forte. The strains are deposited at the Insti-

tute of Biochemistry and Biophysics, The Polish

Academy of Sciences, under the numbers 2593

(L. rhamnosus Pen), 2594 (L. rhamnosus E ⁄ N ) and 2595

(L. rhamnosus Oxy ). Each patient (or a parent, in the

case of very young subjects) received a diary to recordthe frequency of daily bowel movements, as well as

any symptoms they considered important. Stool

number and consistency were recorded daily. In the

event of loose or watery stools, patients were advised

to contact their physicians and bring stool samples in

for analysis. The presence of viral pathogens was

investigated in all diarrhoeal stool samples using a

rapid, qualitative, chromatographic immunoassay that

C L I N I C A L T R I A L : L . R H A M N O S U S I N T H E P R EV EN T I O N O F A N T I B I O T I C - A S S O C I A T ED D I A R R H O EA 155

ª 2008 The Authors, Aliment Pharmacol Ther 28, 154–161




simultaneously detects rotaviruses and adenoviruses

(VIKIA Rota – Adeno; BioMerieux, Lyon, France).

Standard microbiological techniques were used to iso-

late and identify bacterial pathogens (Salmonella spp.,

Shigella spp., Escherichia coli, Campylobacter spp.).

Clostridium difficile toxins A and B were identified by

enzyme immunoassay (C. difficile Tox. A ⁄ B II EIA kit;

TechLab Inc., Blacksburg, VA, USA). Treatment com-

pliance was assessed by direct interview of the patient

(or parent) and review of the diary cards (which docu-

mented the number of daily capsules taken). Treatment

responses also were assessed by evaluation of the daily

diaries.

Randomization

Investigators at the Medical University of Warsaw pre-

pared randomization lists using a permuted block of

six (three received placebo and three, active treat-ment). Separate randomization lists were prepared for

each site. To ensure allocation concealment, an inde-

pendent subject prepared the randomization schedule

and oversaw the packaging and labelling of trial treat-

ments. All investigators, participants, outcome asses-

sors and data analysts were blinded to the assigned

treatment throughout the study.

Outcome measures

The primary outcome measures were the frequencies

of any diarrhoea and AAD. Any diarrhoea was defined

as ‡3 loose or watery stools per day for a minimum of

48 h, occurring during and ⁄ or up to 2 weeks after the

end of the antibiotic therapy. AAD was diagnosed in

cases of diarrhoea, defined clinically as above, caused

by C. difficile (the major enteropathogen in AAD) or

for otherwise unexplained diarrhoea (i.e. negative lab-

oratory stool test for rotavirus and adenovirus and

negative stool culture). The secondary outcome mea-

sures were the frequencies of C. difficile diarrhoea, ro-

taviral diarrhoea, Salmonella spp. diarrhoea, or

Shigella spp. diarrhoea; the need for discontinuationof the antibiotic treatment, hospitalization to manage

the diarrhoea (in outpatients), or intravenous rehydra-

tion in any of the study groups and adverse events.

Sample size

We estimated that a minimum sample size of 232 par-

ticipants would be needed. The sample size calculation

was based on the results of the study previously coor-

dinated by one of us (H.S.) in the same setting;11

results from this study showed a 15% reduction in the

proportion of children with diarrhoea compared with

an expected 23% baseline failure rate with placebo, a

1:1 allocation ratio, 80% power, an a-level of 0.05,

and a 20% dropout rate.

Statistical analysis

All statistical analyses were performed with the com-

puter software StatsDirect [version 2,5,6, (2006-04-15);

Iain E. Buchan]. The Student’s t -test was used to com-

pare means of continuous variables approximating a

normal distribution. For non-normally distributed

variables, the Mann–Whitney U -test was used. The

chi-squared test or Fisher exact test was used, as

appropriate, to compare percentages. The relative risk

(RR), 95% confidence interval (CI), and number neededto treat (NNT) were calculated using the same com-

puter software. The difference between study groups

was considered significant when the P -value was

<0.05 or when the 95% CI for RR did not exceed 1.0

(equivalent to P < 0.05). All statistical tests were two

tailed and performed at the 5% level of significance.

We report the analysis based on intention-to-treat

principle.

Ethical considerations

Parents were fully informed about the aims and proce-

dures of the study, and informed consent was obtained

from at least one parent. The study protocol was

reviewed and approved by the Ethical Committee at

the Medical University of Warsaw.

RESULTS

Figure 1 is a flow diagram showing the subjects’ pro-

gression through the study. Of the 240 children

recruited in the study, we assigned 120 children to

receive L. rhamnosus and 120 to receive the placebo.Overall, three of the randomized children (one in the

probiotic group and two in the placebo group) discon-

tinued the study intervention and started to use one of

the commercially available probiotic products. How-

ever, no patient was lost to follow-up. Thus, all 240

children enrolled were available for the analysis. The

baseline characteristics of these children are shown in

Table 1.

156 M. R U S Z C Z YN S K I et al .





The outcome measures are summarized in Table 2.

Overall, diarrhoea was diagnosed in 29 of 240 (12%)

children and AAD in 12 of 240 (5%) children. The

addition of L. rhamnosus vs. placebo to the antibiotic

therapy reduced the risk of any diarrhoea [9 ⁄ 120

(7.5%) vs. 20 ⁄ 120 (16.7%), RR 0.45, 95% CI 0.2–0.9].

For every 11 patients who receive daily L. rhamnosus

with antibiotics, one fewer patient will develop diar-

rhoea (the number needed to treat was 11, 95% CI 6–

106). Lactobacillus rhamnosus also reduced the risk of

AAD when compared with placebo, although the dif-

ference between groups was of borderline significance

[3 ⁄ 120 (2.5%) vs. 9 ⁄ 120 (7.5%), RR 0.33, 95% CI 0.1–

1.06]. The risk of developing documented C. difficile

diarrhoea was similar in both groups [3 ⁄ 120 (2.5%) in

the probiotic group vs. 7 ⁄ 120 (5.8%) in the placebo

group, RR 0.4, 95% CI 0.1–1.5]. In addition, compared

with controls, L. rhamnosus did not significantly

reduce the risk of developing diarrhoea caused by

other enteropathogens (e.g. rotavirus, adenovirus, Sal-

monella). One child in the probiotic group and two

children in the placebo group needed intravenous

rehydration (no significant difference between groups).There was no need for discontinuation of the antibiotic

treatment or hospitalization of outpatients for man-

agement of the diarrhoea.

Table 3 summarizes characteristics of the patients

who experienced diarrhoea. The time until onset of the

diarrhoea was similar in the placebo and probiotic

groups (6.2 Æ 4.2 vs. 5.8 Æ 5.2 days respectively;

P = 0.4), as well as the duration of diarrhoea

(4.1 Æ 2.1 vs. 4.4 Æ 2.2 days respectively; P = 0.6)

Broad-spectrum penicillins caused 20 of 29 (69%)

cases of diarrhoea. Whereas the proportion of childrenwith diarrhoea caused by broad-spectrum penicillins

was lower in the probiotic group than in the placebo

group, the difference – given the small number of

patients experiencing diarrhoea – was not statistically

significant (5 ⁄ 9 vs. 15 ⁄ 20 respectively; RR 0.7, 95% CI

0.3–1.3). Lactobacillus rhamnosus was well tolerated,

and no adverse event associated with this therapy (or

with the use of placebo) was reported.

Randomized

n = 240

Allocated to placebo

group n = 120

Allocated to probiotic

group n = 120

Discontinued

intervention n = 2

Analysed

n = 120

Analysed

n = 120

Discontinued

intervention n = 1

Figure 1. Flow diagram of the subjects’ progression

through the study.

Table 1. Baseline characteristics of study children

Placebo

(n = 120),n (%)

Probiotic

(n = 120),n (%)

Mean (s.d.) age (months) 53.5 (44.25)

Median 39

54.8 (45.3)

Median 44Gender (f ⁄ m) 56 ⁄ 64 54 ⁄ 66

Diagnosis

Upper respiratory tract

infections

13 (11) 19 (16)

Otitis media 27 (23) 18 (15)

Lower respiratory tract

infections

53 (44) 49 (41)

Urinary tract infection 20 (17) 24 (20)

Other (lymphadenitis,

osteomyelitis, skin

infection, stomatitis,

scarlet fever, erythema

nodosum)

7 (6) 10 (8)

Antibiotic usedPenicillins 5 (4) 10 (8)

Broad-spectrum penicillins

(ampicillin, amoxicillin,

amoxicillin plus

clavulanate)

68 (57) 51 (43)

Cephalosporins 34 (28) 55 (46)

Macrolides (clarithromycin,

roxithromycin)

11 (9) 4 (3)

Clindamycin 2 (2) –

Mean (s.d.) duration of

treatment (days)

8.2 (3.2)

(min. 3–

max. 30)

8 (2)

(min. 3–

max. 15)

Route of administrationOral 65 (54) 69 (58)

Intravenous 48 (40) 39 (32)

Intravenous, then oral 5 (4) 12 (10)

Intramuscular 2 (2) –

Setting

Outpatient 50 (42) 56 (47)

Hospital 70 (58) 64 (53)






DISCUSSION

Principal findings

In our randomized, double-blind, placebo-controlledstudy, L. rhamnosus strains E ⁄ N , Oxy and Pen (Lakcid

Forte), compared with placebo as an adjunct to antibi-

otic therapy, more effectively reduced the risk of any

diarrhoea in children undergoing antimicrobial therapy

for common infectious diseases. For every 11 patients

who receive daily probiotics with antibiotics, one fewer

patient will develop diarrhoea (the number needed to

treat was 11, 95% CI 6–106). The risk of AAD diarrhoea

(diarrhoea caused by C. difficile or diarrhoea with neg-

ative laboratory test results for enteropathogens) and

the risk of C. difficile diarrhoea also appeared to be

lower in our group of children receiving probiotic

compared with those receiving placebo; however,the difference between groups was not statistically

significant. As in the previous study carried out in the

same setting,11 we evaluated potentially important

consequences of AAD (e.g. the need for discontinuation

of antibiotic treatment, hospitalization, or intravenous

rehydration). Despite the rather conservative definition

of diarrhoea used in this trial (‡3 loose or watery stools

per day for a minimum of 48 h), no diarrhoeal episodes

Table 2. Outcome measures

Outcome measure

Placebo

(n = 120),n (%)

Probiotic

(n = 120),n (%)

Relative risk

(95% confidence

interval) P -value

Diarrhoea 20 (16.7) 9 (7.5) 0.45 (0.2–0.9) 0.03

Antibiotic-associated diarrhoea (C. difficile + diarrhoea withunexplained cause*)

9 (7.5) 3 (2.5) 0.33 (0.1–1.06) 0.08

Cause of diarrhoea

Clostridium difficile toxins 7 (5.8) 3 (2.5) 0.4 (0.1–1.5) 0.2

Rotavirus 10 (8.3) 5 (4.1) 0.5 (0.18–1.35) 0.2

Adenovirus 1 (0.8) – 0 (0–3.8) >0.99Salmonella 1 (0.8) 1 (0.8) 1 (0.1–9.5) >0.99

Unexplained diarrhoea* 2 (1.7) – 0 (0–1.9) 0.25

Need for discontinuation of antibiotic treatment – – –

Need for hospitalization of outpatients to manage diarrhoea – – –

Need for intravenous rehydration 2 1 0.5 (0.07–3.8) >0.99

Adverse effects during intervention – – –

* Negative laboratory stool test for rotavirus and adenovirus and negative stool culture for bacterial enteropathogens.

An individual child may have had more than one enteropathogen.

Table 3. Characteristics of

patients with diarrhoea

Placebo

(n = 20)

Probiotic

(n = 9) P -value*

Mean (s.d.) age (months) 18.6 (13.7)

Median 15

32.6 (41)

Median 9

0.9

Time until onset of diarrhoea (s.d.) (days) 6.2 (4.2) 5.8 (5.2) 0.4

Duration of antibiotic treatment (s.d.) (days) 8.7 (5.4) 8 (1.3) 0.5

Duration of diarrhoea (s.d.) (days) 4.1 (2.1) 4.4 (2.2) 0.6

Antibiotic used, n (%)

Penicillins 1 (5) – >0.99Broad-spectrum penicillins (ampicillin, amoxicillin,

amoxicillin plus clavulanate)

15 (75) 5 (56) 0.8

Cephalosporins 3 (15) 4 (44) 0.4

Macrolides (roxithromycin) 1 (5) – >0.99

* Mann–Whitney test or chi-squared test or Fisher exact test (as appropriate).






required hospitalization of outpatients, and there was

no difference between groups in the need for intrave-

nous rehydration. No adverse events occurred.

We chose this product containing L. rhamnosus

strains E ⁄ N , Oxy and Pen as it fulfils the criteria for

being a probiotic and because of its common use in our

country, despite the lack of studies that have evaluated

its effectiveness. Recently, using classical microbio-

logical methods as well as PCR, DNA sequencing and

agar disc-diffusion techniques, it has been confirmed

that, as declared by the manufacturer, the preparation

we used contains three different strains, which belong

to the species of L. rhamnosus. It was found that they

differ from one another in colony and cell morphology,

carbohydrate utilization patterns (API tests), the nucle-

otide sequence of their DNAs coding for 16S rRNA, and

in antibiotic sensitivity. As a whole, the mixture was

shown to be resistant to 42 of 47 antimicrobial drugs

tested.12

Further human studies are warranted to clarify whether the study product is also effective for the pre-

vention or treatment of other diseases.

Consideration of possible mechanisms

This study did not directly address the mechanisms by

which L. rhamnosus strains E ⁄ N , Oxy and Pen reduce

the risk of developing diarrhoea during antibiotic ther-

apy. However, the rationale for the use of probiotics is

based on the assumption that the use of antibiotics

leads to a disturbance in the normal intestinal micro-

biota and that this is a key factor in the pathogenesis

of AAD and C. difficile infection.13 Probiotics are

believed to restore the equilibrium of the altered intes-

tinal microbiota. Several possible mechanisms by

which probiotics might exert their activity against

enteropathogens in humans have been proposed,

mostly based on results of in vitro and animal studies.

These include the synthesis of antimicrobial sub-

stances,14–16 competition for nutrients required for

growth of pathogens,17, 18 competitive inhibition of

adhesion of pathogens,19–22 and modification of toxins

or toxin receptors.23, 24

It is likely that several of theabove-described mechanisms operate simultaneously

and that they may well differ depending on the prop-

erties of an enteric pathogen and the probiotic strain.

Comparison with previous reports in children

None of the previous controlled trials has evaluated

L. rhamnosus strains E ⁄ N , Oxy and Pen for its effec-

tiveness in the prevention of AAD. One large RCT

involving 246 children, which was carried out in the

same setting as our study, has provided evidence that

the nonpathogenic yeast Saccharomyces boulardii is

effective in preventing any diarrhoea (RR 0.3, 95% CI

0.2–0.7) and AAD (RR 0.2, 95% CI 0.07–0.5) during

concurrent antibiotic therapy.11 These results are con-

sistent with data from adults.25 Two RCTs conducted

in children have provided evidence of a moderate ben-

eficial effect of Lactobacillus GG in the prevention of

this condition;26, 27 however, results in adults are con-

tradictory.28 One RCT involving use of a commercial

probiotic formula containing Bifidobacterium lactis

and Streptococcus thermophilus revealed a significant

difference in the incidence of AAD in infants receiving

probiotic-supplemented formula compared with non-

supplemented formula.29 One small RCT demonstrated

that L. acidophilus ⁄ B. bifidus used in children treated

with amoxicillin significantly reduced the mean stoolfrequency (2 Æ 0.3 vs. 2.7 Æ 0.5 stools per day). In

contrast, using either L. acidophilus ⁄ B. infantis30 or

L. acidophilus ⁄ L. bulgaricus27 was not associated with

a significant reduction in the risk of AAD. More

detailed information on RCTs carried out in children is

available in three recently published meta-analyses.7–9

Strengths and limitations

We used adequate methods for the generation of the

allocation sequence and allocation concealment. We

made efforts to maintain blinding throughout partici-

pant selection, treatment, monitoring, data manage-

ment, and data analyses. Data were obtained from all

participants. These features minimize the potential for

bias.

In our study, we used a rather stringent definition of

AAD, which was defined as ‡3 loose or watery stools

per day for a minimum of 48 h. Such a stringent defi-

nition allowed us to differentiate between clinically

relevant conditions and clinically unimportant changes

in the consistency of stools. However, the definitions

of AAD in published studies vary. A potential limitation of this trial is that it does not

allow one to reach conclusions about the efficacy of

administering L. rhamnosus strains E ⁄ N , Oxy and Pen

in the prevention of C. difficile-associated diarrhoea, a

more clinically important condition. The trial included

only a small number of patients with C. difficile and

may have lacked the power to show a difference in

the frequency of developing C. difficile-associated






diarrhoea between patients who received probiotics vs.

placebo, should one exist. The design of this study

also does not allow one to reach conclusions about

the efficacy of L. rhamnosus strains E ⁄ N , Oxy and

Pen in preventing diarrhoea attributable to any single

antibiotic class. Larger trials will be necessary to

address these issues further. Patients were only fol-

lowed-up for 2 weeks after their antibiotic treatment.

As diarrhoea may occur up to 2 months after the end

of such treatment,5, 31, 32 some cases of AAD may have

been missed. Also, as we only evaluated the presence

of major enteropathogens in diarrhoeal stool samples,

one cannot exclude the possibility that some of the

cases of unexplained diarrhoea were caused by

unidentified infectious agents.

Safety

During administration of the study products, patients(or their caretakers) were asked to document any

potential side effects or adverse events, including only

mild effects. However, the nature and ⁄ or intensity of

them were ⁄ was not pre-specified. No side effects or

adverse effects were observed in our study. Also,

according to the manufacturer, the product has a long

history (almost 20 years) of use without established

risk to humans (unpublished reports). However, the

administration of probiotics is not without risk. Of

concern, there have been instances of bacteraemia

with use of selected probiotic bacteria in high-risk

populations.33 Endocarditis, pneumonia, and meningi-

tis have very rarely been reported in association with

lactobacilli administration.33–37 Serious consideration

must be given to one recent report describing an

increase in mortality observed in a trial involving

an experimental probiotic treatment for acute pancrea-

titis.38 Given these data, probiotic safety is an impor-

tant issue. Special consideration should be given to

high-risk groups (e.g. immunocompromised subjects,

patients with other life-threatening illnesses).

CONCLUSIONResults from this study contribute to the growing body

of literature documenting the benefit of probiotic

administration for reducing the risk of developing

diarrhoea during antibiotic treatment. Our findings

support the use of L. rhamnosus strains E ⁄ N , Oxy and

Pen as adjunctive treatment in children undergoing

antibiotic therapy for common infectious diseases

whenever the physician feels that preventing this usu-

ally self-limited complication is important. This study

was not designed and powered to investigate the effect

of the study product on the prevention of diarrhoeacaused by any specific pathogen (i.e. non-antibiotic

diarrhoea). Thus, no firm conclusions can be made

regarding such outcomes. However, our results, e.g. a

trend towards a lower risk of rotaviral diarrhoea in the

probiotic group compared with the placebo group,

suggest that L. rhamnosus strains E ⁄ N, Oxy and Pen

may effectively prevent or treat diarrhoea caused by

various enteropathogens. Larger trials will be neces-

sary to address these issues further.

ACKNOWLEDGEMENTSDeclaration of personal interests: None. Declaration of

funding interests: This study was funded in part by

Biomed, Lublin, Poland, and the Medical University of

Warsaw (Research Agreement UKI ⁄ 224 ⁄ 2004).

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Clinical trial: effectiveness of Lactobacillus rhamnosus (strains E ⁄N, Oxy and Pen) in the...

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