safety of probiotics in patients receiving nutritional support: a systematic review of case reports,...

8/18/2019 Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized cont…

1/17

Safety of probiotics in patients receiving nutritional support: a

systematic review of case reports, randomized controlled trials, andnonrandomized trials1–3

Kevin Whelan and Clio E Myers

ABSTRACT

Background: Probiotics are increasingly used in patients receiving

nutritional support; however, some case reports and trials have ques-

tioned their safety in such patients.

Objective: The objective was to investigate the safety of probiotics

in patients receiving nutritional support through a systematic review

of case reports, randomized controlled trials (RCTs), and non-

randomized trials.Design: The systematic review followed Cochrane and PRISMA

(Preferred Reporting Items for Systematic Reviews and Meta-

Analyses) recommendations. Six electronic databases were

searched, a hand search of conference proceedings and reference

lists was performed, and experts were contacted. Case reports,

RCTs, and nonrandomized trials of probiotic use in patients also

receiving enteral or parenteral nutrition were included in the review.

Two reviewers independently screened the relevant articles and ex-

tracted the data.

Results: In total, 1966 articles were identified, of which 72 fulfilled

the inclusion criteria. There were 20 case reports of adverse events

in 32 patients, all of which were infections due to Lactobacillus

rhamnosus GG or Saccharomyces boulardii; the risk factors in-cluded central venous catheters and disorders associated with in-

creased bacterial translocation. There were 52 articles reporting 53

trials in which 4131 patients received probiotics. Most trials showed

either no effect or a positive effect on outcomes related to safety

(eg, mortality and infections). Only 3 trials showed increased com-

plications, which were largely noninfectious in nature and in spe-

cific patient groups (eg, transplant and pancreatitis). In 2 of these

trials, the probiotic was administered through a postpyloric tube.

Conclusion: Many probiotics have been used safely in patients re-

ceiving nutritional support, although some probiotic products

(strains or combinations) have been shown to increase the risk of

complications in specific patient groups. Am J Clin Nutr doi:

10.3945/ajcn.2009.28759.

INTRODUCTION

Probiotics are live microorganisms that, when administered in

adequate amounts, confer a health benefit on the host (1). The

most common probiotics are the bacteria lactobacilli and bifi-

dobacteria and the yeast Saccharomyces boulardii. The health

benefits of specific strains involve effects on infections, immune

function, inflammation, and gastrointestinal transit, which result

from microbial competition, bacteriocin production, and specific

and nonspecific immune stimulation (2, 3). In view of their

functional characteristics and apparent safety profile in healthy

persons, probiotics have been investigated for their role in dis-

ease management. This includes the treatment of eczema (4),

lactose maldigestion (5), irritable bowel syndrome (6), and in-

flammatory bowel disease (7).

The safety of probiotics is supported by the fact that many

strains are of human origin and have a long history of safe use.

Despite their widespread use, the incidence of bacteremia at-

tributable to probiotic strains remains extremely low (8). How-

ever, the safety of probiotics in patient groups has been

questioned because of the potential for bacterial translocation

across the gastrointestinal epithelium, the potential for transfer of

antibiotic resistance to other microorganisms, and the risks of

infection in otherwise immunocompromised patients (9). Many

case reports have described infections resulting from probiotic

use; however, a systematic review of these reports has not been

conducted.

Of particular relevance to clinical nutrition is the use of

probiotics in patients receiving nutritional support, such as en-

teral nutrition (EN) or parenteral nutrition (PN). Probiotics have

been used in such patients for the prevention of EN-associated

diarrhea (10), antibiotic-associated diarrhea (AAD) (11), Clos-

tridium difficile–associated diarrhea (CDAD) (12), the pre-

vention of necrotizing enterocolitis in preterm neonates (13),

and the prevention of infections and sepsis in the critically ill

(14).

The use of probiotics in patients receiving nutritional support

presents specific safety issues. Interventions that increase gastric

pH (eg, gastric acid–suppressing drugs) or administration that

bypasses gastric acid completely (eg, postpyloric EN) will result

in increased probiotic survival in the small intestine. In addition,

central venous catheters (CVCs) used in the delivery of PN have

been identified as a potential risk factor for probiotic infection

1 From King’s College London, Nutritional Sciences Division, Diet and

Gastrointestinal Health, London, United Kingdom (KW and CEM), and

King’s College Hospital NHS Foundation Trust, Department of Nutrition

and Dietetics, London, United Kingdom (CEM).2 This systematic review was internally funded.3 Address correspondence to K Whelan, Nutritional Sciences Division,

King’s College London, 150 Stamford Street, London SE1 9NH, United

Kingdom. E-mail: [email protected].

Received September 30, 2009. Accepted for publication December 28,

2009.

doi: 10.3945/ajcn.2009.28759.

Am J Clin Nutr doi: 10.3945/ajcn.2009.28759. Printed in USA. 2010 American Society for Nutrition 1 of 17

AJCN. First published ahead of print January 20, 2010 as doi: 10.3945/ajcn.2009.28759.

Copyright (C) 2010 by the American Society for Nutrition


2/17

(15). Finally, patients receiving nutritional support may have risk

factors for bacterial translocation (eg, critical illness) or be

immunocompromised and therefore harbor other risk factors for

infection.

The convincing safety profile of probiotics in healthy persons

cannot be assumed to translate to patients receiving nutritional

support who may have increased probiotic survival in conjunction

with additional risk factors for probiotic infection. The aim of this

study was to investigate the safety of probiotics in patients receivingnutritional support through a systematic review of case reports,

randomized controlled trails (RCTs), and nonrandomized trials.

METHODS

When possible, the systematic review was undertaken in line

with the recommendations of the guidelines of the Cochrane

Handbook for Systematic Reviews of Interventions and with

particular reference to adverse events (16). This systematic re-

view adhered to the relevant criteria of the PRISMA (Preferred

Reporting Items for Systematic Reviews and Meta-Analyses)

statement (17). The following methods used in the systematic

review, including identification, screening, eligibility, and in-clusion, were agreed between the authors in advance.

References were identified by searching an electronic data-

base, hand-searching conference abstracts and key reference lists,

and contacting experts in the area. The search strategy was

developed by the authors in conjunction with a senior information

specialist. An electronic search of the following 6 electronic

databases was undertaken: MEDLINE (US National Library of

Medicine, Bethesda, MD; Ovid interface: http://ovidsp.ovid.com)

from 1950 to July 2009, EMBASE (Elsevier BV, Netherlands;

Ovid interface: http://ovidsp.ovid.com) from 1980 to July 2009;

CINAHL (CINAHL Information Systems, USA; EBSCO host

interface: http://search.ebscohost.com) from 1982 to 2009, CEN-

TRAL (The Cochrane Library, Chichester, United Kingdom;Wiley InterScience: http://mrw.interscience.wiley.com/cochrane/

cochrane_clcentral_articles_fs.html) for all years, Nutrition and

Food Sciences (CAB International, United Kingdom; CAB Direct

interface: http://www.cabi.org/nutrition/) for all years, and Web of

Science (ISI Thomson Scientific, United Kingdom; Web of

Knowledge portal: http://isiknowledge.com) from 1900 to July

2009. The final search date was 30 July 2009. The search used

combinations of the terms probiotics, safety, and nutritional sup-

port as both MeSH headings and key or free text words and in-

cluded a wide range of derivations to ensure as wide a search

strategy as possible. A list of the search strategy used is available

online as supplemental material (see “Supplemental data” in the

online issue).Hand searching of abstracts from the 2000 to 2009 annual

conferences of the following organizations was undertaken to obtain

conference reports that would not be identifiable through electronic

searching: the American Society for Parenteral and Enteral Nu-

trition ( J Parent Enteral Nutr ), the European Society for Clinical

Nutrition and Metabolism (Clin Nutr , Clin Nutr Suppl, and

e-SPEN ), and the British Association for Parenteral and Enteral

Nutrition (Proc Nutr Soc). In addition, hand-searching of the ref-

erence lists of relevant reviews and studies fulfilling the inclusion

criteria was undertaken to identify further relevant references.

Experts in probiotics or nutritional support were contacted to

obtain published or unpublished references not identified during

electronic or hand-searching. Information was requested from

experts in probiotics, including authors of reviews or trials on

probiotic safety (n = 37), authors of case reports of probiotic

adverse events (n = 11), and the scientific departments of

manufacturers of probiotics (n = 14) or nutritional support

products (n = 6).

The research question and inclusion and exclusion criteria

were developed by using a PICOS structure (Patient, In-

tervention, Comparators, Outcome, Study Design) (18). Theinclusion criteria were any articles reporting the administration of

a probiotic to patients who were also receiving nutritional sup-

port. Details of the inclusion and exclusion criteria are described

in Table 1.

The references were imported into a bibliographic database to

automatically exclude duplicates (Reference Manager, version

12). Then, 2 researchers independently reviewed the title and

abstract of each reference to assess its eligibility. The full article

was obtained for all potentially eligible references, and the in-

clusion criteria were applied to each. When articles contained

insufficient information to assess their eligibility or to extract

relevant data, the corresponding author was contacted for further

information and this occurred for 31 such articles. When dis-agreements regarding eligibility and data extraction occurred (11

articles), they were resolved through further contact with report

authors, discussion, and consensus.

The 2 researchers independently extracted the data from eli-

gible articles. Data relating to the patient or group, the in-

tervention, the comparator group (where relevant), the outcomes

measured (adverse events, mortality, and morbidity), and the

study design were extracted as detailed in Table 1.

The studies were then categorized into 1) case reports of

adverse events, 2) safety trials (trials of any design whose major

aim was to investigate adverse events or safety and that un-

dertook routine sampling/screening for these), which were di-

vided into RCTs and nonrandomized trials; and 3) nonsafetytrials (trials that did not qualify as safety trials but that reported

clinical outcomes relevant to safety, eg, mortality, morbidity, and

adverse events), which were also divided into RCTs and non-

randomized trials. A meta-analysis was not conducted because

of the necessarily wide eligibility of patient groups, probiotic

strains and doses, type and method of monitoring of adverse

events and clinical outcomes, and study designs. Assimilating

clinical outcome data (eg, mortality and morbidity) into a meta-

analysis may actually negate safety issues in specific patient

groups and therefore was not undertaken.

RESULTSA total of 1966 nonduplicated articles were identified in the

search. The titles and abstracts were reviewed, and only 134 were

deemed potentially eligible. After a review of the full article, 72

fulfilled the inclusion criteria: 20 case reports and 52 papers

relating to trials of probiotics (Figure 1).

Case reports

Of the 134 full articles obtained, 44 were case reports of

adverse events, of which 24 were excluded because a probiotic

was not administered or the patient was not receiving nutritional

support. Therefore, 20 case reports of adverse events of probiotic

2 of 17 WHELAN AND MYERS


3/17

administration in 32 patients receiving nutritional support were

included (19–38) (Figure 1).

The patients ranged from 1 mo to 89 y of age, had diagnoses of

various major organ disorders, and were receiving EN (n = 17),

PN (n = 12), or both (n = 3 ) (Table 2). The adverse events

occurred after the administration of the probiotic bacteria Lac-

tobacillus rhamnosus GG (n = 5) or the yeast S. boulardii (n =

27). There was variation in how the doses were reported (cells/d,

mg/d, capsules/d, and sachets/d), and no dose was obtainable for

4 patients. Doses for S. boulardii were frequently reported in

mg/d and ranged widely from 150 (27) to 3000 mg/d (32). When

information was obtainable, the probiotics were administered

via nasogastric tube (NGT; n = 9), percutaneous endoscopic

gastrostomy (PEG; n = 6), jejunostony (n = 1), or orally (n = 4).

Probiotics were used for the prevention or treatment of AAD

(n = 5), C. difficile (n = 5), small intestinal bacterial overgrowth

(SIBO; n = 3), EN (n = 2), rotavirus (n = 1), or of unspecified

origin (n = 16).

Depending on the organism, the adverse events that occurred

were bacteremia (n = 5) or fungemia (n = 27), which were di-

agnosed based on clinical signs and confirmation of the pro-

biotic as the source of the infection using culture analysis ( n =

TABLE 1

Detailed inclusion and exclusion criteria and data extracted1

PICOS Inclusion and exclusion criteria Data extraction

Patient Patients of any age receiving EN and/or PN. In reports of

mixed patient groups (eg, intensive care unit), only those

in whom more than half were receiving EN and/or PN

were eligible.

When there were 2 reports related to the same patient group

(eg, a conference abstract subsequently published in full),

the most complete was eligible to avoid duplication of

patient numbers.

Location, age when probiotic was started, diagnoses (case

reports only), patient group (trials only), type of nutrition

support.

Intervention Oral and/or enteral administration of a probiotic. Reports in

which this was given in addition to other compounds (eg,

prebiotics) were also eligible.

Genus, species, and strain of the probiotic as given in the

article. When this was not available, genus and species

alone were extracted.

The dose of probiotic, route of administration, and any

additional compounds given were also extracted.

The reason for probiotic use was extracted from case studies.

Comparators Reports withor without a comparatorgroup. Reports without

a control group were included because the aim was to

investigate potentially rare adverse events (16).

Numbers in the intervention and comparator group, when

relevant (trials only). In studies with multiple comparator

groups (eg, EN and live probiotics compared with EN and

heat-killed probiotics compared with PN), the most

similargroupto a control group wasused(ie, EN andheat-

killed probiotics) where possible.Outcome Reports of presence or absence of adverse events.

Reports of the clinical endpoints of mortality and

morbidity (eg, infections) were included to offer insights

into safety, as were clinical endpoints indicative of

morbidity (eg, length of stay).

Reports not recording adverse events or relevant clinical

endpoints, but that were otherwise eligible, were also

included.

Details of an adverse event, microbiological method of

identification, risk factors (as suggested by authors and

literature), treatment, and outcome (case reports only).

Presence or absence of adverse events or safety issues (as

reported by the reference). When no information on

safety, adverse events, side effects, or tolerance was given,

this is reported.

The effect of the intervention on clinical endpoints (trials

only).

For duplicate reports (eg, an abstract followed by subsequent

full paper) only the most complete population was

included; however, if relevant data (eg, adverse events)

werein the brief report but not in the completereport, they

were extracted and reported within the complete report.

In studies with multiple comparator groups, the clinicalendpoints between the intervention group with the most

similar comparator group were compared.

Data relating to clinical (eg, stool frequency) and

physiologic (eg, stool microbiology) outcomes not

indicative of disease endpoints were not extracted.

Study design Randomized controlled trials, controlled trials (eg,

nonrandomized, historical controls), case series, and case

reports were eligible, all of which were all relevant to the

measurement of adverse events and safety (16).

Although the search was undertaken in English, foreign

language reports that wereidentified were translated when

possible.

Type of study design and numbers in the intervention and

comparator groups (trials only).

1 EN, enteral nutrition; PN, parenteral nutrition; PICOS, Patient, Intervention, Comparators, Outcome, Study Design.

SAFETY OF PROBIOTICS 3 of 17


4/17

32), sometimes in conjunction with other phenotypic analyses

(eg, API strips, morphology; n = 14), or genotypic analyses such

as restriction digest and gel electrophoresis (RD-GE, n = 14),

polymerase chain reaction and gel electrophoresis (PCR-GE; n =5), or DNA/RNA sequencing (n = 2). In 12 patients, phenotypic

analyses alone were used to confirm the probiotic as the in-

fective organism. Two patients also developed endocarditis, one

after L. rhamnosus GG (20) and one after S. boulardii (35). In one

patient, the vegetation was attached to a prosthetic mitral valve

(35) and in the other between a CVC tip and the right atrium (20).

The risk factors for these adverse events, as identified by the

authors and from the literature, were varied. A majority of

patients had received antibiotics (n = 27) or had intravenous

access (n = 30) via a CVC or a peripheral venous catheter. Other

less frequently cited were those risk factors associated with

bacterial translocation (eg, C. difficile colitis, sepsis, and mu-

cositis) or immune suppression (eg, preterm birth, sepsis, and

HIV).

Treatment of the adverse event frequently included stopping

the probiotic (n = 25) and removing or changing the CVC whenpresent (n = 17). The antibiotics prescribed in the 5 cases of

bacteremia included ampicillin (n = 4), ceftriaxone, penicillin,

and gentamicin (all n = 1), whereas the antifungals prescribed in

20 (74%) of the incidents of fungemia included fluconazole (n =

13), amphotericin B (n = 8), voriconazole (n = 1), and caspi-

fungin (n = 1). In 8 (25%) patients, the adverse event reportedly

resulted in death.

Trials

Of the 134 full articles obtained, 72 reported trials. Of these, 20

were excluded because they reported duplicate patient groups,

FIGURE 1. Diagram of citations included and excluded during the systematic review. RCT, randomized controlled trial.



5/17


6/17

T A B L E

2

( C o n t i n u e d )

P a t i e n t

I n t e r v e n t i o n ( p r o b i o t i c )

O u t c o m e

R e f e r e n c e

A g e 2

D i a g n o s i s 3

N S

S p e c i e s / s t r a i n

D o s e

R o u t e 4

P u r p o s e 5

A d v e r s e e v e n t

I d e n t i fi c a t i o n 6

R i s k f a c t o r 7

T r e a t m e n t

O u t c o m e 8

3 6 y

H I V / A I D S

L y m p h o m a

P N

S .

b o u l a r d i i

1 5 0 0 m g / d

—

T r e a t d i a r r h e a

F u n g e m i a

C u l t u r e ,

A P I s t r i p s ,

R D - G E

A n t i b i o t i c s , C V C ,

c h e m o t h e r a p y , H I V

P r o b i o t i c s t o p p e d ,

fl u c o n a z o l e

R e c o v e r y

4 7 y

E s o p h a g e a l

c a n c e r

E N

S .

b o u l a r d i i

2 0 0 0 m g / d

—

T r e a t A A D

F u n g e m i a

C u l t u r e ,

A P I s t r i p s ,

R D - G E

A n t i b i o t i c s , C V C


C V C r e m o v e d ,


R e c o v e r y

7 8 y

P u l m o n a r y

d i s e a s e

E N

S .

b o u l a r d i i

1 5 0 0 m g / d

—

P r e v e n t d i a r r h e a

F u n g e m i a

C u l t u r e ,

A P I s t r i p s ,

R D - G E


P r o b i o t i c s t o p p e d

R e c o v e r y

L h e r m e t a l ,

2 0 0 2 ( 3 2 )

5 0 y

C a r d i a c a r r e s t

E N

S .

b o u l a r d i i

1 5 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c



C V C c h a n g e d

D e a t h

5 1 y

A o r t i c s u r g e r y

E N

S .

b o u l a r d i i

1 0 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c


m a l n u t r i t i o n


C V C c h a n g e d ,


D e a t h

7 1 y

S t r o k e

E N

S .

b o u l a r d i i

3 0 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c



C V C c h a n g e d

R e c o v e r y

7 5 y

R e s p i r a t o r y

f a i l u r e

E N

S .

b o u l a r d i i

2 0 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c



C V C c h a n g e d

R e c o v e r y

7 7 y

P e r i t o n i t i s

E N

S .

b o u l a r d i i

3 0 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c



C V C c h a n g e d ,

a m p h o t e r i c i n B

D e a t h

8 2 y

R e s p i r a t o r y

f a i l u r e

E N

S .

b o u l a r d i i

1 5 0 0 m g / d

—


F u n g e m i a

C u l t u r e ,

R D - G E ,

p h e n o t y p i c



C V C c h a n g e d

R e c o v e r y

L o l i s e t a l ,

2 0 0 8 ( 3 3 )

5 6 y

P n e u m o n i a

S e p s i s

P N

S .

b o u l a r d i i

2 0 0 0 m g / d

N G T


F u n g e m i a

C u l t u r e , D N A

s e q u e n c i n g


s e p s i s



c a s p o f u n g i n

R e c o v e r y

H e n r y e t a l ,

2 0 0 4 ( 3 4 )

6 5 y

O r o p h a r y n g e a l

c a n c e r

P N

S .

b o u l a r d i i

6 c a p s u l e s / d

O r a l


F u n g e m i a

C u l t u r e


m u c o s i t i s


a m p h o t e r i c i n B

R e c o v e r y

M u n o z

e t a l ,

2 0 0 5 ( 3 5 )

7 2 y

C a r d i a c s u r g e r y

E N , P N

S .

b o u l a r d i i

—

N G T

T r e a t C D A D

F u n g e m i a

C u l t u r e ,

P C R - G E

A n t i b i o t i c s ,

C .

d i f fi c i l e , C V C

—

D e a t h

7 4 y

M V r e p l a c e m e n t

E N , P N

S .

b o u l a r d i i

—

N G T

T r e a t C D A D

F u n g e m i a

C u l t u r e ,

P C R - G E


C .

d i f fi c i l e , C V C ,

s t e r o i d s



D e a t h

7 6 y

M V r e p l a c e m e n t

C a r d i a c a r r e s t

E N , P N

S .

b o u l a r d i i

—

N G T

T r e a t C D A D

F u n g e m i a

E n d o c a r d i t i s

C u l t u r e ,

P C R - G E


C .

d i f fi c i l e , C V C ,

p r o s t h e t i c M V



D e a t h

R i j i n d e r s

e t a l ,

2 0 0 0 ( 3 6 )

7 4 y

N e u r o s u r g e r y

E N

S .

b o u l a r d i i

6 0 0 m g / d

N G T

T r e a t E N d i a r r h e a

F u n g e m i a

C u l t u r e

C V C , c o l i t i s

C

V C r e m o v e d ,


D e a t h




7/17

a probiotic was not administered, or an insufficient number of

patients were receiving nutritional support. For the 4 duplicate

patient groups, no relevant information (eg, adverse events) was

contained within the earlier abstract/article that was not con-

tained within the complete article. In total, 52 citations were

included reporting 53 trials [one article reported a case series and

an RCT (39)], in which 4131 patients received probiotics and

3643 patients were in a relevant comparator group (Figure 1).

One trial in patients undergoing hepatectomy compared pro-biotics given pre- and postoperatively with those given post-

operatively only; therefore, both groups contributed to the overall

patient numbers receiving probiotics (78). Of the 53 trials, only 3

were classified as safety trials (1 RCT and 2 nonrandomized

trials) (39–41), and 50 were nonsafety trials (40 RCTs and 10

nonrandomized trials) (39, 42–90) (Table 3).

The trials were based in a variety of locations including

neonatal, pediatric, or adult ICUs; surgical units; burns units;

general wards; or in the community, and the disorders reflected

these locations, including preterm infants, critical illness, post-

operative, trauma, pancreatitis, and burns (Table 3). The inclusion

and exclusion criteria therefore varied widely depending on the

patient group under investigation. The probiotics included singlestrains of lactobacilli, bifidobacteria, or S. boulardii, the com-

bined use of single strains or proprietary mixtures of 3 strains.

As with the case reports, there was variation in how the doses

were reported (cells/d, cells kg21 d21, mg/d, mg kg21 d21,

mL/d, and cells L21 d21). When it was reported as cells/d, it

ranged widely from 107 (40) to 1.8 · 1012 cells/d (56). In a small

number of trials, the probiotic was given with other supplements,

including prebiotics, fiber, or glutamine. The probiotics were

administered via NGT, PEG, nasojejunal tube (NJT), jejunos-

tomy, orogastric tube (OGT), or orally; within some trials, a range

of methods was often used depending on the access routes

available.

The 3 safety trials were classified as such because a stated aimwas to investigate the safety of probiotic administration and

because they undertook routine screening for adverse events or

complications (39–41). The only safety RCT was an open-label

trial in 15 critically ill adults receiving EN in addition to PN in

some cases (41). Eight patients received L. plantarum 299v (1–2 ·

1011 cells/d in fermented oatmeal formula) via an NGT for the

duration of their ICU stay and 7 patients acted as a control (no

placebo given). Safety was investigated through weekly micro-

biological screening of samples (eg, blood, urine, tracheal se-

cretions, and wounds), whereas CVC tips were screened on

removal or as clinically indicated. All samples were analyzed

for the presence of the probiotic or other organisms, and none

were found to contain any lactobacillus. Two patients developedbowel distension at the higher probiotic dose, but there were no

other adverse events (41).

One safety trial was a case series of 66 preterm infants on

neonatal ICU who were receiving EN of expressed breast milk or

formula (in addition to PN until EN was sufficient) (39). Patients

received B. breve (109 cells/d) via an NGT per an “early and

short-term” protocol (before 7 d of age and continued for 7 d) or

a “delayed and longer-term” protocol (after 7 d of age and

continued for between 7 and 48 d). Adverse events were mon-

itored throughout. Two infants who received “delayed and

longer-term” administration had mild functional ileus and

aggregates of cornstarch from the probiotic product were T A B L E

2


P a t i e n t


O u t c o m e

R e f e r e n c e

A g e 2

D i a g n o s i s 3

N S

S p e c i e s / s t r a i n

D o s e

R o u t e 4

P u r p o s e 5

A d v e r s e e v e n t

I d e n t i fi c a t i o n 6

R i s k f a c t o r 7

T r e a t m e n t

O u t c o m e 8

N i a u l t e t a l ,

1 9 9 9 ( 3 7 )

7 8 y

P u l m o n a r y d i s e a s e

E N

S .

b o u l a r d i i

1 5 0 0 m g / d

N G T


F u n g e m i a

C u l t u r e





R e c o v e r y

C h e r i fi e t a l ,

2 0 0 4 ( 3 8 )

8 9 y

C .

d i f fi c i l e

A n o r e x i a n e r v o s a

E N

S .

b o u l a r d i i

3 0 0 m g / d

P E G

P r e v e n t C D A D

F u n g e m i a

C u l t u r e


C .

d i f fi c i l e ,

m a l n u t r i t i o n , P V C

F l u c o n a z o l e

R e c o v e r y

1

E N , e n t e r a l n u t r i t i o n ; P N , p a r e n t e r a l

n u t r i t i o n ; M V , m i t r a l v a l v e ; N G T , n a s o g a s t r i c t u b e ; P E G , p e r c u t a n e o u s e n d o s c o p i c g a s t r o s t o m y ; J e j , j e j u n o s t o m y ; A A D , a n t i b i o t i c - a

s s o c i a t e d d i a r r h e a ; C D A D ,

C l o s t r i d i u m d i f fi c i l e – a s s o c i a t e d d i a r r h e a ; S I B O , s m a l l i n t e s t i n a l b a c t e r i a l o v e r g r o w t h ; R D - G E , r e s t r i c t i o n d i g e s t a n d g e l e l e c t r o p h o r e

s i s ; P C R - G E , p o l y m e r a s e c h a i n r e a c t i o n a n d

g e l e l e c t r o p h o r e s i s ; C V C ,

c e n t r a l v e n o u s c a t h e t e r ; P V C , p e r i p h e r a l v e

n o u s c a t h e t e r ; G I , g a s t r o i n t e s t i n a l .

2

A g e i s r e p o r t e d f r o m t h e t i m e t h e p r o b i o t i c w a s s t a r t e d ( w h e r e a v a i l a b l e ) . F o r p a t i e n t s . 1 y , a g e a t l a s t b i r t h d a y i s r e p o r t e d ; f o r t h o s e , 1 y , a g e t o t h e n e a r e s t m o n t h i s r e p o r t e d .

3

P r i m a r y d i a g n o s i s g i v e n i n c a s e r e p o

r t .

4

R o u t e o f p r o b i o t i c a d m i n i s t r a t i o n .

5

P u r p o s e o f p r o b i o t i c a d m i n i s t r a t i o n .

6

M i c r o b i o l o g i c a l m e t h o d o f i d e n t i fi c a t i o n o f p r o b i o t i c .

7

R i s k f a c t o r s f o r a d v e r s e e v e n t , i n c l u d i n g t h o s e s u g g e s t e d b y r e p o r t a u t h o r s a n d t h

o s e c o m m o n l y f o u n d i n t h e l i t e r a t u r e .

8

O u t c o m e r e l a t e s t o r e c o v e r y o r d e a t h

f r o m t h e a d v e r s e e v e n t . R e c o v e r y i n d i c a t e s

t h a t , a f t e r t r e a t m e n t , t h e p a t i e n t s u r v i v e d t h e

a d v e r s e e v e n t ( e v e n i f t h e y s u b s e q u e n t l y d i e

d o f a s e e m i n g l y u n r e l a t e d

e v e n t ) , w h e r e a s d e a t h i n d i c a t e s t h a t t h e y d i e d o f s y m p t o m s p o t e n t i a l l y l i n k e d w i t h t h e a

d v e r s e e v e n t .



8/17


9/17

T A B L E

3


R e f e r e n c e

P a t i e n t d e t a i l s

S t u d y d e t a i l s


O u t c o m e s

L o c a t i o n

P a

t i e n t g r o u p

N S

D e s i g n

N o . o f p r o b i o t i c s /

c o m p a r a t o r s 2

S p e c i e s / s t r a i n 3

D o s e

R o u t e 4

C l i n i c a l o u t c o m e s

r e l e v a n t t o s a f e t y 5

A d v e r s e e v e n t s 6

U n d e r w o o d e t a l ,

2 0 0 9 ( 5 2 )

N e o n a t a l

I C U

P r e t e r m

i n f a n t s

E N , P N

R C T

6 1 / 2 9

L . r h a m n o s u s

G G o r

B i fi d o b a c t e r i u m

i n f a n t i s

B .

b i fi d u m

B .

l o n g u m

L . a c i d o p h i l u s

( b o t h w i t h

i n u l i n )

1 0 9

c e l l s / d

N G T , O G T ,

o r a l

W e i g h t g a i n ( N S )

N o a d v e r s e e v e n t s , w e l l

t o l e r a t e d

L i n e t a l ,

2 0 0 5 ( 5 3 )

N e o n a t a l

I C U

P r e t e r m

i n f a n t s

E N , P N

R C T

1 8 0 / 1 8 7

B . i n f a n t i s


2 5 0 m g

k g 2 1

d 2 1

O G T , o r a l

M o r t a l i t y ( r e d u c e d i n

p r o b i o t i c ) , N E C

( r e d u c e d i n p r o b i o t i c ) ,

s e p s i s ( r e d u c e d i n

p r o b i o t i c )

N o p r o b i o t i c b a c t e r e m i a ,

n o c o m p l i c a t i o n s f r o m

p r o b i o t i c

L i n e t a l ,

2 0 0 8 ( 5 4 )

N e o n a t a l

I C U

P r e t e r m

i n f a n t s

E N , P N

R C T

2 1 7 / 2 1 7

B .

b i fi d u m

N C D O 1 4 5 3


N C D O 1 7 4 8

2 5 0 m g

k g 2 1

d 2 1

O G T , o r a l

M o r t a l i t y ( r e d u c e d i n

p r o b i o t i c ) , N E C ( r e d u c e d

i n p r o b i o t i c ) , s e p s i s

( i n c r e a s e d i n p r o b i o t i c )


n o a d v e r s e e v e n t s

H o n e y c u t t e t a l ,

2 0 0 7 ( 5 5 )

P e d i a t r i c

I C U

C r i t i c a l l y i l l

c h

i l d r e n

E N

R C T

3 1 / 3 0

L . r h a m n o s u s G G

1 0 1 0

c e l l s / d

N G T , o r a l

M o r t a l i t y ( N S ) , n o s o c o m i a l

i n f e c t i o n s ( N S )



A l b e r d a e t a l ,

2 0 0 7 ( 5 6 )

A d u l t I C U


E N

R C T

1 9 / 9

V S L # 3

1 . 8 ·

1 0 1 2

c e l l s / d

N G T

M o r t a l i t y ( N S ) , M O D S ( N S )

N o l a c t o b a c i l l u s s e p s i s ,


K n i g h t e t a l ,

2 0 0 9 ( 5 7 )

A d u l t I C U


E N

R C T

1 3 0 / 1 2 9

S y n b i o t i c 2 0 0 0

F o r t e ( 2 0 g

fi b e r / d )

2 ·

1 0 1 0

c e l l s / d

N G T , O G T

M o r t a l i t y ( N S ) , p n e u m o n i a

( N S ) , I C U a n d h o s p i t a l

l e n g t h o f s t a y ( N S )

N o c o m p l i c a t i o n s , s i n g l e

L e u c o n o s t o c d e t e c t e d

f r o m a t r a c h e a l a s p i r a t e

D a d a k e t a l ,

2 0 0 6 ( 5 8 )

A d u l t I C U


E N , P N

R C T

6 / 5

S y n b i o t i c 2 0 0 0

F o r t e

—

N G T , N J T

M o r t a l i t y ( N S )

N o i n f o r m a t i o n g i v e n

J a i n e t a l ,

2 0 0 4 ( 5 9 )

A d u l t I C U


E N , P N

R C T

4 5 / 4 5

T r e v i s ( 1 5 g p r e b i o t i c / d )

2 ·

1 0 1 0

c e l l s / d

N G T , o r a l

M o r t a l i t y ( N S ) , s e p s i s ( N S )


F o r e s t i e r e t a l ,

2 0 0 8 ( 6 0 )

A d u l t I C U


E N

R C T

1 0 2 / 1 0 6

L a c t o b a c i l l u s

c a s e i r h a m n o s u s

2 ·

1 0 9

c e l l s / d

N G T , o r a l

N o r e l e v a n t c l i n i c a l

e n d p o i n t s c o m p a r e d

b e t w e e n g r o u p s

N o l a c t o b a c i l l u s s e p s i s

M c N a u g h t e t a l ,

2 0 0 5 ( 6 1 )

A d u l t I C U


E N , P N

R C T

5 2 / 5 1

L . p l a n t a r u m

2 9 9 v ( P r o V i v a )

1 0 1 0

c e l l s / d

N G T , o r a l

M o r t a l i t y ( N S ) , s e p s i s ( N S ) ,

I C U l e n g t h o f s t a y ( N S )


K l a r i n e t a l ,

2 0 0 8 ( 6 2 )

A d u l t I C U


E N , P N

R C T

2 2 / 2 2

L . p l a n t a r u m

2 9 9 v

8 ·

1 0 1 0

– 9 . 6 ·

1 0 1 1

c e l l s / d

N G T , o r a l

M o r t a l i t y ( N S ) , I C U l e n g t h

o f s t a y ( N S ) , d i a r r h e a

( N S ) , b a c t e r e m i a ( N S ) ,

c a t h e t e r t i p i n f e c t i o n s

( N S )


t o l e r a t e d

T e m p e ´ e t a l ,

1 9 8 3 ( 6 3 )

A d u l t I C U


E N

R C T

2 0 / 2 0

S .

b o u l a r d i i

1 0 1 0

c e l l s

L 2 1

d 2 1

N G T

D i a r r h e a ( r e d u c e d i n

p r o b i o t i c )


B l e i c h n e r

e t a l ,

1 9 9 7 ( 6 4 )

A d u l t I C U


E N

R C T

6 4 / 6 4

S .

b o u l a r d i i

2 0 0 0 m g / d

N G T

D i a r r h e a ( r e d u c e d i n

p r o b i o t i c )


t o l e r a t e d




10/17

T A B L E

3


R e f e r e n c e

P a t i e n t d e t a i l s

S t u d y d e t a i l s


O u t c o m e s

L o c a t i o n

P a

t i e n t g r o u p

N S

D e s i g n

N o . o f p r o b i o t i c s /

c o m p a r a t o r s 2

S p e c i e s / s t r a i n 3

D o s e

R o u t e 4

C l i n i c a l o u t c o m e s

r e l e v a n t t o s a f e t y 5

A d v e r s e e v e n t s 6

F a l c a ˜ o e t a l ,

2 0 0 4 ( 6 5 )

A d u l t I C U

B r a i n i n j u r y

E N

R C T

1 0 / 1 0

L a c t o b a c i l l u s

j o h n s o n i i L a 1

( L C 1 ) ( g l u t a m i n e )

2 4 0 m L / d

N G T

S e p s i s ( N S ) , i n f e c t i o n s

( r e d u c e d i n p r o b i o t i c ) ,

I C U l e n g t h o f s t a y

( r e d u c e d i n p r o b i o t i c )


G i a m a r e l l o s -

B o u r b o u l i s

e t a l ,

2 0 0 9 ( 6 6 )

A d u l t I C U

T r a u

m a

E N , P N

R C T

3 6 / 3 6

S y n b i o t i c 2 0 0 0

F o r t e ( 1 0 g

fi b e r / d )

4 ·

1 0 1 1

c e l l s / d

N G T , P E G

M o r t a l i t y ( N S ) , s e p s i s

( r e d u c e d i n s y n b i o t i c )

A d m i n i s t r a t i o n w a s s a f e , n o

i n f e c t i o n s c a u s e d b y t h e

p r o b i o t i c

S p i n d l e r -

V e s e l e t a l ,

2 0 0 7 ( 6 7 )

A d u l t I C U

T r a u

m a

E N , P N

R C T

2 6 / 2 9

S y n b i o t i c 2 0 0 0

( 1 0 g fi b e r / d )

8 ·

1 0 1 0

c e l l s / d

N G T

M o r t a l i t y ( N S ) , i n f e c t i o n s

( r e d u c e d i n p r o b i o t i c )


B e s s e l i n k

e t a l ,

2 0 0 8 ( 6 8 )

A d u l t I C U

S e v e

r e a c u t e

p a

n c r e a t i t i s

E N

R C T

1 5 2 / 1 4 4

E c o l o g i c 6 4 1

1 0 1 0

c e l l s / d

N J T

M o r t a l i t y ( i n c r e a s e d i n

p r o b i o t i c ) , i n f e c t i o u s

c o m p l i c a t i o n ( N S ) , b o w e l

i s c h e m i a ( i n c r e a s e d i n

p r o b i o t i c ) , d i a r r h e a ( N S )

N o p r o b i o t i c i n f e c t i o n s ,

b o w e l i s c h e m i a r e p o r t e d

a s a d v e r s e e v e n t

H e i m b u r g e r

e t a l ,

1 9 9 4 ( 6 9 )

A d u l t I C U ,

safety of probiotics in patients receiving nutritional support: a systematic review of case reports,...

Documents