A systematic review of the safety of probiotics.

Review

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A systematic review of the safety of probiotics 1.

Introduction

2.

Search strategy

3.

Result

4.

Expert opinion

Tina Didari, Sara Solki, Shilan Mozaffari, Shekoufeh Nikfar & Mohammad Abdollahi† †

Tehran University of Medical Sciences, Faculty of Pharmacy, Department of Toxicology and Pharmacology, Tehran, Iran

Introduction: There is growing evidence on the use of probiotics in various diseases, especially in gastrointestinal (GI) diseases. Although probiotics have been found helpful in many illnesses, they do not always seem to be safe. Through interference with commensal microflora, they can result in opportunistic performances in the host due to bacterimia and fungemia. Since considerable numbers of consumers use probiotic products worldwide, assurance of safety of these products is necessary. Areas covered: This review evaluates all the existing information about the safety of probiotics in humans and animal models up to May 2013. In all eligible published studies in which adverse effects and tolerability of probiotics were investigated and reported, no language limitations were applied. The main key search terms were ‘probiotics,’ ‘safety,’ ‘side effects,’ ‘clinical trial’ and ‘adverse effects.’ The vast majority of trials investigated Bifidobacterium (B) and Lactobacillus (L) species. Expert opinion: The main observed adverse effects of probiotics were sepsis, fungemia and GI ischemia. Generally, critically ill patients in intensive care units, critically sick infants, postoperative and hospitalized patients and patients with immune-compromised complexity were the most at-risk populations. While the overwhelming existing evidence suggests that probiotics are safe, complete consideration of risk-benefit ratio before prescribing is recommended. Keywords: adverse effects, bifidobacterium, hazardous, lactobacillus, neonate, pregnancy, probiotics, safety, systematic review Expert Opin. Drug Saf. (2014) 13(2):227-239

1.

Introduction

Probiotics are vital microorganisms that provide health advantages to their consumers when digested in sufficient quantity as World Health Organization (WHO) defined. They are applied as both food and biologic supplements. There is growing evidence on their important contribution in health recovery and disease management as the functional foods [1], including digestible form of probiotics used in bio-yogurt starter [2], table olives [3], fermented soymilk [4] and other fermented products. Recently, probiotics have been applied as a platform for delivery of drugs, enzymes and nutrients [5]. As bio-drugs, probiotics have extensive applications in the recent century [6] with various advantages [7]. By affecting immunological factors, intestinal permeability and bacterial translocation, and secreting various metabolites, probiotics influence health in many organs [8,9]. Probiotics are mostly beneficial in gastrointestinal (GI) diseases such as irritable bowel disease [10-12], inflammatory bowel disease (IBD) [13-17], necrotizing enterocolitis (NEC) [18], pouchitis in ileal pouchanal anastomosis [19], acute diarrhea [20] in travelers and infectious or antibioticassociated diarrhea [21-23]. They protect intestinal epithelial cells by altering gut microbiota and modulating immune responses [24,25]. Moreover, preventive effect of probiotics in colon cancer through inhibition of intestinal cells from apoptosis 10.1517/14740338.2014.872627 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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The reference lists of retrieved articles were also reviewed o find additional applicable studies.

Article highlights. .

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Probiotics are vital microorganisms that provide health advantages to their consumers when digested in sufficient quantity as WHO stated. Although there are numbers of investigations on the beneficial effects of probiotics in treatment of various diseases, studies that examine safety or adverse events are scarce. Besides preventive and treatment effects of probiotics in some diseases, several experimental and clinical trials indicated that they are not completely safe. Serious hazards of probiotics are rare but exist. Critically ill patients in ICU, critically sick infants, postoperative and hospitalized patients and patients with immune-compromised complexity are the most at-risk populations. Before prescribing the probiotics, there should be a complete consideration of risk-benefit ratio issues.

This box summarizes key points contained in the article.

has been demonstrated [9,26]. Probiotics have been indicated to improve the liver function by decreasing hepatic fatty acids and cholesterol levels [24,27]. In addition, they influence carbohydrate metabolism and have been used in management of obesity [28]. Furthermore, beneficial effects in relieving allergic diseases have been observed by modulating inflammatory markers [29,30]. However, besides their preventive and therapeutic effects in diseases, findings of several experimental and clinical trials have indicated that they are not completely safe or free of potential risks [23]. Severe adverse effects due to probiotics are rare but might occur. Due to a wide variety of beneficial effects of probiotics on several illnesses, their probable side effects have been mostly not been noticed. Opportunistic performances in the host [31] and fungemia [32] have been reported as probiotics’ side effects. Interference with commensal microflora due to their exogenous effect in the GI tract and changing the microbial flora are suggested as the mechanism of adverse effects [23,33]. Several groups of patients who are hospitalized due to serious diseases and organ transplant and those with recent surgery or immune deficiency are more prone to adverse outcomes [30]. Therefore, since considerable numbers of consumers use probiotic products worldwide, assurance of safety of these products is necessary. This present review summarizes the present knowledge on the safety of probiotics.

2.

Search strategy

Electronic databases, including PubMed, Web of Science, Google Scholar and Scopus, were searched, and data were collected from 1984 up to May 2013. Main key terms for search were ‘probiotics,’ ‘safety,’ ‘side effects,’ ‘clinical trial’ and ‘adverse effects.’ All published studies in which adverse effects and tolerability of probiotics were considered and investigated were included without any language limitations. 228

3.

Result

Overview To review the safety profile of probiotics, eligible randomized or non-randomized controlled clinical trials, case series, case reports and experimental studies, which evaluated safety of probiotics or reported any adverse effects besides investigating efficacy, were evaluated. The vast majority of trials have investigated Bifidobacterium (B) and Lactobacillus (L) species. Other types of probiotics included Saccharomyces boulardii (S. boulardii) (yeast), Streptococci (S), Enterococcus (E), Propionibacterium (P) and Escherichia coli (E. coli) strain Nissle 1917. To take a variety of probiotics’ advantages, they have been evaluated as biologic and food supplements in different diseases. The major observed adverse effects of probiotics were sepsis, fungemia and GI ischemia. Generally, according to the observed results, critically ill patients in intensive care unit (ICU), critically sick infants, postoperative and hospitalized patients and generally patients with immune-compromised complexity are the most at-risk populations. Papers have been summarized in Tables 1 -- 6. 3.1

Different evaluated probiotics 3.2.1 Lactobacillus species 3.2

Prevalence of sepsis due to L. rhamnosus GG has been studied during the years 1995 -- 2000 in Finland’s healthy population. Although use of probiotics as dairy product in Finland has been dramatically increased over the past years, the incidence of sepsis has not increased. These results provide strong evidence of the safety of Lactobacillus strain GG products [34]. In 1995, Saxelin et al. investigated Lactobacillus species in blood culture of people who lived in the southern Finland during 4 years. The results showed that Lactobacillus was not the cause of infections and the investigators concluded that this probiotic is not pathogenic [35]. Different Lactobacillus species such as L. rhamnosus GG, L. plantarum and L. casei have been evaluated in clinical trials, case series and case reports. Five cases of neonates with underlying diseases were reported who had received L. rhamnosus GG to prevent small-intestinal bacterial overgrowth or treatment of antibiotic-associated diarrhea. Consumption of probiotics resulted in bacteremia in all cases and endocarditis in one case who had cardiac stenosis. Furthermore, there was one case report on the use of L. casei in pediatric unit for short bowel syndrome and no adverse effect was reported [36]. Moreover, a cohort study performed in neonatal intensive care unit (NICU) on premature newborns with NEC showed that administration of L. rhamnosus Lcr35 (Lcr Restitou) do not cause adverse outcomes [37]. Further trials, including 2 case series and 11 controlled clinical trials, have investigated various species of Lactobacillus in critically ill adults and pediatric patients in ICU, premature infants and organ transplant

Expert Opin. Drug Saf. (2014) 13(2)

A systematic review of the safety of probiotics

or post-surgical patients. Except for two reported cases of bowel distention in adults and two cases of functional ileus in children, no or few side effects occurred and the probiotics were reported well tolerable. In a trial to examine the effectiveness of probiotics in neonatal colic in comparison to placebo, no side effects were reported in probiotics-received group (Table 1) [38]. Bifidobacterium species B. breve, B. lactis and B. langum have been prescribed in one case series and four randomized controlled clinical trials in preterm infants admitted to NICU. Functional ileus was observed in two of the infants during the treatment. Other trials reported no adverse effects, and the probiotics were well tolerated. Eighty children between 3 months and 3 years old with rotavirus diarrhea were divided into placebo and treatment groups. In combination of rotavirus diarrhea medication, commercial sachets of Bifidobacterium (Bifilac) were administered in treatment group and no adverse effects were reported during or after treatment [39]. However, a newborn with omphalocele showed sepsis after 10 days administration of B. breve BBG01 (Table 2) [40].


3.2.2

Combination of Lactobacillus and Bifidobacterium

3.2.3

Nine controlled clinical trials were conducted to investigate the efficacy of the combination of Lactobacillus and Bifidobacterium besides their safety in neonates and adult patients in ICU with NEC, sepsis and constipation, or those who had a recent surgery. The results of these clinical trials revealed no complication as a consequence of probiotic use in comparison to control group. The mixed preparation of Lactobacillus and Bifidobacterium was well tolerated (Table 3). Saccharomyces boulardii Thirty cases of preterm infants and adults with underlying disease who had surgery showed fungemia as a consequence of S. boulardii administration to prevent or treat diarrhea. Four controlled clinical trials were performed to evaluate the efficacy of S. boulardii in preterm infants, critically ill adults in ICU and patients on total enteral nutrition. The probiotics resulted in no significant adverse effects such as fungemia or sepsis, and were well tolerated. However, one of the reported fungemia cases occurred in an infant who had not received S. boulardii but was in the cot adjacent to an infant with fungemia after probiotics digestion (Table 4) [41]. 3.2.4

VSL#3 Two randomized placebo-controlled clinical trials showed the tolerability of VSL#3 probiotics form (containing eight strains if probiotics; L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. Bulgaricus, B. longum, B. breve, B. infantis and S. salivarius subsp. Thermophilus) in patients. In the first trial, VSL#3 was administered to 28 ICU patients once daily for 7 consecutive days. Probiotic-induced sepsis was 3.2.5

not observed in the treatment group [42]. The second clinical trial revealed that oral administration of VSL#3 twice daily for 9 months in 40 patients with chronic pouchitis did not associate with any potential risks (Table 5) [43]. Synbiotics Synbiotic preparations containing Bifidobacterium and Lactobacillus species in addition to prebiotics (such as fiber, pectin and starch) were found effective in several diseases. Despite the results of 6 trials that reported no complications or serious adverse effects in preterm infants and adults, in 1 controlled clinical trial, synbiotic preparation was administered 118 days in 296 patients with acute severe pancreatitis. The results demonstrated infection as an adverse effect in 30% (46 out of 152 patients) of synbiotic-received patients in comparison to 28% (41 out of 144 patients) in placebo-received patients. The rate of mortality was 16% (24 out of 152 patients) and 6% (9 out of 144 patients) of synbiotic and placebo groups, respectively. Furthermore, intestinal ischemia occurred in nine patients during symbiotic treatment that resulted in death of eight cases [44]. In a randomized double-blind placebo-controlled trial performed between 2000 and 2003, probiotics supplement that included L. rhamnosus GG, L. rhamnosus LC705, B. breve Bb99 and Propionibacterium freudenreichii subsp. shermanii was administered to pregnant women 1 month before delivery. Their infants received daily dose of probiotics and prebiotics combination up to 6 months uninterruptedly and followed up for 24 months. In comparison to placebo group (n = 464), synbiotics (n = 461) did not cause side effects after combination therapy [45]. Combination of B. bifidum, B. lactis, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus and L. salivarius 109 cfu/g was used in a cohort study with crossover design in hospitalized patients in order to evaluate probiotics effectiveness on ampicillin-resistant E. faecium. No significant adverse effects were observed during treatment (Table 6) [46]. 3.2.6

3.3

Different populations of consumers Pregnant women

3.3.1

L. rhamnosus GG and B. lactis were added to daily diets of pregnant women during their first trimester to evaluate the efficacy of probiotics on serum glucose level. Probiotics consumption was not associated with any side effects when compared to control group [47]. Other populations The vast majority of examined population in the reviewed studies was preterm infants in NICU. Critically ill adults in ICU and surgical units were also candidates to receive probiotic preparations. In a clinical trial, different probiotics including L. rhamnosus GG, S. boulardii, Bacillus clausii, mix of L. delbrueckii and bulgaricus, S. thermophilus, L. acidophilus and E. faecium SF68 were administered to 571 children in the age range of 3 -- 36 months to control diarrhea. Probiotics exhibited no adverse effects in comparison to placebo [48]. In 3.3.2


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Table 1. Trials reported safety of Lactobacillus species. Ref.

Study design

[38]

RCT

[69]

RCT

[70]

RCT

[37] [60]

Cohort (crossover) RCT

[71]

RCT

[72]

RCT

[73]

RCT

[74]

RCT

[75]

RCT

[76]

RCT

[77]

Case series

[78]

Case series

[36]

Case report

[79]

2 case reports

[51]

Case report

[51]

Case report

[80]

Case report

Probiotics/dosage

L. reuteri 108 cells/day L. casei rhamnosus 2 109 cells/day L. plantarum 299v 8 1010 -- 9.6 1010 cells/day L. rhamnosus Lcr35 (Lcr Restitou) 2 108 cells/12 h L. rhamnosus GG 1010 cells/day L. rhamnosus GG 6 109 cells/day L. plantarum 299V 2 1010 cells/day L. plantarum 299V 2 1010 cells/day L. plantarum 1010 cells/day L. johnsonii 108 cells/day L. rhamnosus GG 2 108cells/day L. casei Shirota 107 cells/day L. plantarum 299v 1 -- 2 1011 cells/day L. casei 4.5 109 cells/day L. rhamnosus GG 1 capsule/day L. rhamnosus GG 1010 cfu/day L. rhamnosus GG 1010 cfu/day L. rhamnosus GG ¼ capsule/day

Study population and disease category

Probiotics safety evaluation

Infants with colic

Well tolerated

Critically ill adult in ICU

No adverse effects

Critically ill adult in ICU

No adverse effects

Preterm infants with NEC in NICU

No adverse effects

Critically ill children in ICU

No adverse effects

Preterm infants in ICU

No adverse effects

Adults in post-surgery ICU

Few adverse effects

Adults in post-surgery ICU (liver transplant) Adults with acute pancreatitis in surgical unit Elderly patients in general wards

Well tolerated

No adverse effects

Preterm infants in ICU

No adverse effects

Critically ill children in ICU

Child with short bowel in pediatric unit

Functional ileus in two patients Bowel distension in two patients No adverse effects

Infants with short bowel and cholestasis

Bacteremia

Infant with cardiac stenosis and AAD

Bacteremia, endocarditis Bacteremia

Critically ill adults in ICU

Child with cerebral palsy microcephaly and AAD Infant with short bowel

No adverse effects

Bacteremia

": Increase; AAD: Antibiotic-associated diarrhea; cfu: Colony-forming unit; ICU: Intensive care unit; L: Lactobacillus; NEC: Necrotizing enterocolitis; NICU: Neonatal intensive care unit; RCT: Randomized controlled trial.

addition, E. coli strain Nissle 1917 that was administered to infants and toddlers daily to treat acute diarrhea did not result in any adverse effects (Tables 1 -- 6) [49].

3.4

The most common adverse effects Bacteremia

3.4.1

One clinical trial conducted during years 1990 -- 2000 studied the outcomes and predisposing factors to lactobacillus bacteremia. By evaluating and characterizing Lactobacillus strains in patients with bacterimia, L. rhamnosus was considered to be one of the most common species characterized in bacteremia. In this study, immune-deficient and post-surgical patients were suggested to be more at risk to sepsis [50]. Bacteremia was observed most likely in a patient who had received Lactobacillus species (Table 1). Although there are several investigations that reported no association between blood 230

bacteremia and lactobacillus consumption [34,50], in 2005, two separated cases reported L. GG in blood due to daily use of this probiotic through gastrostomy tubes. One of these cases was a new-born child who had received L. GG as an oral capsule after cardiac surgery for 22 days, and another patient was a 6-year-old child who received L. GG for 44 days. The observed bacteremia in both cases was associated to Lactobacillus administration [51]. Fungemia One of the prevalent observed side effects of probiotics was fungemia in critically ill patients in ICU (Table 4). According to the results of some case reports, S. boulardii-associated fungemia resulted in death. Fungemia was reported in three cases of ICU patients who had received S. boulardii in order to prevent antibiotic-associated diarrhea. The duration of probiotic 3.4.2




Table 2. Trials reported safety of Bifidobacterium species. Ref.

Study design

[81]

RCT

[82]

RCT

[83]

RCT

[84]

RCT

[85]

RCT

[81]

Case series

[40]

Case report

Probiotics/dosage



B. breve YIT4010 109 cells/day B. breve 1.6 108 cells/day B. breve M-16V 3.2 108 cells/day B. lactis 6 109 cells/kg/day B. infantis 35624 106, 108, 1010 cells/ml B. breve YIT4010 109 cells/day B. breve BBG-01 109 cells/day

Preterm infants in NICU

No adverse effects


Well tolerated


No adverse effects


No adverse effects

Women with IBS

No adverse effects


Functional ileus in two patients Sepsis


B: Bifidobacterium; IBS: Irritable bowel syndrome; NICU: Neonatal intensive care unit; RCT: Randomized controlled trial.

Table 3. Trials reported safety of Bifidobacterium and Lactobacillus combination. Ref.

Study design

[47]

RCT

[86]

RCT

[87]

RCT

[88]

RCT

[89]

RCT

[90]

RCT

[91]

RCT

[92]

CT

[93]

CT

Probiotics/dosage


L. rhamnosus, B. lactis 1010 cells/day L. acidophilus, B. longum, B. infantis, B. bifidum 2 109 cells/day L. rhamnosus GG, B. longum BB536 4 108 cells/day L. rhamnosus GG, L. acidophilus, B. longum, B. infantis, B. bifidum 109 cells/day L. acidophilus, B. infantis 250 mg/kg/day L. acidophilus NCDO1748, B. bifidum NCDO1453 250 mg/kg/day L. casei, B. breve 2 1010 cells/day L. acidophilus, B. infantis 2 109 cells/day L. casei, B. breve 6 108 cells/day


Pregnant women with high blood glucose level Preterm infants with NEC in NICU

No adverse effects


No adverse effects


No adverse effects


No adverse effects


No adverse effects

Adults in surgical unit (post-hepatectomy) Preterm infants with NEC in NICU

No adverse effects

Adults with systematic inflammatory response syndrome in ICU

Well tolerated

No adverse effects No adverse effects

B: Bifidobacterium; CT: Controlled trial; ICU: Intensive care unit; L: Lactobacillus; NEC: Necrotizing enterocolitis; NICU: Neonatal intensive care unit; RCT: Randomized controlled trial.

treatment was from 14 to 56 days. It should be considered that central venous catheter (CVC) was used in these cases. It has been suggested that initiation of fungemia was due to CVC and digestive translocation of S. boulardii [52]. Others adverse effects Examining the protective effect of probiotics in 291 patients with severe acute pancreatitis, synbiotic preparation was administered daily for 28 days with 90-day follow-up. Synbiotic

preparation contained two strains of Bifidobacterium (bifidum, lactis) and four strains of Lactobacillus (acidophilus, casei, salivaris, lactis) with corn starch and maltodextrins prebiotics. Eight out of nine patients with intestinal ischemia died during synbiotic treatment [44].

3.4.3

Experimental studies There are several animal experiments that evaluated the efficacy of probiotics besides their safety and toxicity. 3.5


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Table 4. Trials reported safety of Saccharomyces boulardii species.


Ref.

Study design

[94]

RCT

[95]

RCT

[96]

CT

[97]

RCT

[98]

Case report

[41]

Case report

[99]

Case report

[100]

Case report

[101]

Case report

[102]

Case report

[103]

Case report

[104]

Case report

[105]

Case report

[105]

Case report

[106]

Case report

[106]

Case report

[106]

Case report

[107]

Case report

[107]

Case report

[107]

Case report

[107]

Case report

[107]

Case report

[107]

Case report

[99]

Case report

[108]

Case report

[109]

Case report

[109]

Case report

[109]

Case report

Probiotics/ dosage S. boulardii 50 mg/kg/day S. boulardii 2000 mg/day S. boulardii 1000 mg/day S. boulardii 1 g/day S. boulardii 3 109 cfu S. boulardii 2 sachets/day S. boulardii NA S. boulardii 600 mg/day S. boulardii 4 sachets/day S. boulardii 150 mg/day S. boulardii 1500 mg/day S. boulardii 150 mg/day S. boulardii 4 sachets/day S. boulardii 750 mg/day S. boulardii 1500 mg/day S. boulardii 2000 mg/day S. boulardii 1500 mg/day S. boulardii 1500 mg/day S. boulardii 1000 mg/day S. boulardii 3000 mg/day S. boulardii 2000 mg/day S. boulardii 3000 mg/day S. boulardii 1500 mg/day S. boulardii 2000 mg/day S. boulardii 6 capsule/day S. boulardii NA S. boulardii NA S. boulardii NA




Well tolerated

Critically ill adults in ICU with diarrhea

Well tolerated

Patients on TEN with diarrhea

No adverse effects

Adult patients with CDD

No adverse effects

Preterm infant (to prevent SIBO)

Fungemia

Cardiopathy infant with diarrhea

Fungemia

Leukemia infant with AAD

Fungemia

Pneumonia Enteritis child with diarrhea Adult patient with diarrhea

Fungemia Fungemia

Adult patient with diarrhea

Fungemia

Adult patient with colectomy (to prevent AAD) Adult patient with diabetes foot necrosis Adult patient with pneumonia (to prevent diarrhea) Cystic fibrosis child (to prevent diarrhea) HIV adult (to prevent diarrhea)

Fungemia

Fungemia

Esophageal cancer (to prevent AAD)

Fungemia

Adult patient with pulmonary disease (to prevent diarrhea) Adult patient with cardiac arrest (to prevent diarrhea) Adult patient after aortic surgery (to prevent diarrhea) Adult patient after stroke (to prevent diarrhea) Adult patient with respiratory failure (to prevent diarrhea) Adult patient with peritonitis (to prevent diarrhea) Adult patient with respiratory failure (to prevent diarrhea) Adult patient with pneumonia and diarrhea Adult patient with oropharyngeal cancer and diarrhea Adult patient after cardiac surgery with CDAD Adult patient with MV replacement and CDAD Adult patient with MV replacement and CDAD

Fungemia

Fungemia, death Fungemia Fungemia

Fungemia, death Fungemia, death Fungemia Fungemia Fungemia, death Fungemia Fungemia Fungemia Fungemia, death Fungemia, death Fungemia, death

AAD: Antibiotic-associated diarrhea; CDAD: Clostridium difficile-associated diarrhea; CDD: Clostridium difficile-associated disease; Cfu: Colony-forming unit; CT: Controlled trial; ICU: Intensive care unit; MV: Mitral valve; NA: Not available; NICU: Neonatal intensive care unit; RCT: Randomized controlled trail; S: Saccharomyces; SIBO: Small intestinal bacterial overgrowth; TEN: Total enteral nutrition.

232




Table 4. Trials reported safety of Saccharomyces boulardii species (continued). Ref.

Study design

Probiotics/ dosage


[110]

Case report

[111]

Case report

[112]

Case report

[52]

Case report

[52]

Case report

[52]

Case report

S. boulardii 600 mg/day S. boulardii 1500 mg/day S. boulardii 300 mg/day S. boulardii 250 mg sachet S. boulardii 250 mg sachet S. boulardii 250 mg sachet

Adult patient after neurosurgery with diarrhea Adult patient with pulmonary disease and diarrhea Adult patient with anorexia nervosa (to prevent CDAD) Adult patient after thoracic trauma (to prevent AAD) Adult patient with rupture of cerebral aneurysm (to prevent AAD) Adult patients with acute myocardial infarction (to prevent AAD)

Probiotics safety evaluation Fungemia, death Fungemia Fungemia Fungemia Fungemia Fungemia

AAD: Antibiotic-associated diarrhea; CDAD: Clostridium difficile-associated diarrhea; CDD: Clostridium difficile-associated disease; Cfu: Colony-forming unit; CT: Controlled trial; ICU: Intensive care unit; MV: Mitral valve; NA: Not available; NICU: Neonatal intensive care unit; RCT: Randomized controlled trail; S: Saccharomyces; SIBO: Small intestinal bacterial overgrowth; TEN: Total enteral nutrition.

Administration of L. rhamnosus HN001 (DR20E), L. acidophilus HN017 and B. lactis HN019 (DR10E) to mice for 4 weeks showed no noticeable change in their general health position [53]. Another study on acute oral toxicity of probiotics in an animal model (BALB/c mice) revealed that daily use of probiotics (L. rhamnosus HN001, L. acidophilus HN017, B. lactis HN019) for 11 days did not lead to any side effects on general health status, body-weight gain and/or intestinal mucosal morphology in animals [54]. Rinkinen et al. observed that administration of L. rhamnosus GG, B. lactis Bb12, L. pentosus UK1A, L. pentosus SK2A, E. faecium M74 and E. faecium SF273 to healthy dogs did not cause any toxic effects [55]. VSL#3 probiotic was administered to mice for treatment of ulcerative colitis. The results demonstrated the effectiveness of this probiotic without any side effects [56]. Safety of probiotics as the functional foods Functional foods have been developed to use foods as a vehicle for probiotics [3]. Microencapsulated L. reuteri NCIMB 30242 in a yogurt formulation was applied to men and women (120 subjects) for 6 weeks to diminish hypercholesterolemia. At the end of the study, results demonstrated that administration of twice-daily dose (5 1010 cfu) of this probiotic was safe and well tolerated [57]. Supplemented yogurt with two probiotic strains, L. rhamnosus GR-1 (1 103 cfu) and L. reuteri RC-14 (2 107 cfu), was consumed by patients with IBD for 6 months. No adverse effects were reported during consumption [58]. 3.6

4.

Expert opinion

Probiotics are defined as vital microorganisms that are used as functional foods or supplements to provide health advantages

in preventing or treatment of diseases [59]. Probiotics are used daily, but some clinical trials, case reports and randomized controlled trials demonstrated that they are not completely safe for patients and consumers. Daily use of probiotics caused some complications in different populations. High-risk groups consist of patients with immune-compromised complexity, post-surgery, critically ill and long-time-hospitalized patients, elderly population and critically sick infants [50-52]. At the first glance, positive effects of probiotics may cover their adverse effects, but in high-risk groups, their adverse outcomes may cause different health complications. Although there are numbers of investigations on the beneficial effects of probiotics in treatment of various diseases, studies that examine safety or adverse events are scarce [42,51]. Nevertheless, probiotics are thought to safely affect the GI as the main target [33,57], and they may enter blood circulation as sepsis has been reported after consumption of Lactobacillus GG [51], especially in high-risk groups [50]. As mentioned above, several studies have reported induction of sepsis associated with administration of L. rhamnosus GG [60]. It is thought that adhesion of probiotics to the intestinal mucosa gives rise to translocation into the blood circulation [61]. Furthermore, S. boulardii prescription as oral sachets in ICU patients with CVC caused fungemia [52]. These results bring up serious attention to avoid use of S. boulardii in patients with CVC or those with synthetic cardiac valve replacement [61]. In a multicenter randomized controlled trial without alleviation of acute pancreatitis, colon ischemia occurred in patients who received mixed probiotics [44]. There are some reports indicating that use of probiotics was not associated with any side effect when used to manage eczema and nosocomial infection [60,62]. A meta-analysis and a cohort study


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Table 5. Trials reported safety of VSL#3 (L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. bulgaricus, B. longum, B. breve, B. infantis and S. thermophilus). Ref.

Study design

[42]

RCT

[43]

RCT

Probiotics VSL#3 1.8 1012 cells/day VSL#3 6 g/day



Critically ill adults in ICU

No adverse effects

Adults with chronic pouchitis

No adverse effects


B: Bifidobacterium; ICU: Intensive care unit; L: Lactobacillus; RCT: Randomized controlled trial; VSL#3: A probiotic combination of L. casei, L. plantarum, L. acidophilus, L. delbrueckii subsp. bulgaricus, B. longum, B. breve, B. infantis and S. thermophilus.

Table 6. Trials that reported safety of symbiotics. Ref.

Study design

[113]

RCT

[114]

RCT

[44]

RCT

[72]

RCT

[73]

RCT

[115]

RCT

[46]

Cohort (crossover)

[116]

RCT

Probiotics/dosage ABC Dophilus (10 g fiber/day) 109 cells/day Synbiotic2000 Forte (10 g fiber/day) 4 1011 cells/day Ecologic 641 1010 cells/day Synbiotic2000 8 1010 cells/day Synbiotic2000 8 1010 cells/day Synbiotic2000 Forte (20 g fiber/day) 2 1010 cells/day Ecologic AAD (B. bifidum, B. lactis, E. faecium, L. acidophilus, L. paracasei, L. plantarum, L. rhamnosus, L. salivarius) 109 cells/g L. acidophilus, L. paracasei, L. rhamnosus, B. lactis, 108 -- 109 cfu



Preterm infants with NEC in NICU

No adverse effects

Adults with trauma in ICU

No adverse affects

Adults with severe acute pancreatitis in ICU Adults in ICU Surgical unit (Pancreato duodenectomy) Adults in ICU Surgical unit (liver transplant) Critically ill adults in ICU

"Mortality and bowel ischemia No serious adverse effects

No adverse affects

Adult patients in hospital

No adverse affects

Women with constipation

No adverse effects

Well tolerated

ABC Dophilus consists of B. infantis, B. bifidus and Streptococcus thermophilus; Ecologic 641 consists of L. acidophilus, L. casei, L. salivarius, L. lactis, B. bifidum and B. lactis; Ecologic AAD contains B. bifidum, B. lactis [2], E. faecium, L. acidophilus [2], L. paracasei, L. plantarum, L. rhamnosus and L. salivarius 109 cells/g. Synbiotic 2000/Synbiotic2000 Forte consists of Pediococcus pentosaceus, Leuconostoc mesenteroides, L. paracasei, L. plantarum, b-glucan, inulin, pectin and resistant starch. ": Increase; B: Bifidobacterium; Cfu: Colony-forming unit; ICU: Intensive care unit; NEC: Necrotizing enterocolitis; NICU: Neonatal intensive care unit; L: Lactobacillus; RCT: Randomized controlled trial.

showed that administration of probiotics is not associated with any adverse effect in NEC neonates [37,63]. Rising concerns about probiotics are related to their viability in high-risk hosts. In such hosts, probiotics have been observed to result in several complications. To decrease hazardous effects of probiotics in high-risk groups, use of ultraviolet radiation or heat has been suggested to kill probiotics. These kinds of probiotics retain their original properties, but they lose their immune-stimulatory functions [64]. Considering the importance of purity in probiotic productions, some 234

valuable molecular approaches have been introduced to differentiate bacterial strains. This approach will result in prevention of contamination of probiotic products and probable consecutive side effects with undesired bacterial strains. 16 S ribosomal RNA (16 S rRNA) genes are important genes for classification and identification of probiotic strains from other bacterial and fungal strains before preparing food supplements and dairy products. To detect 16 S rRNA genes in probiotic products, two useful molecular techniques consisting of terminal restriction fragment length polymorphism and




species-specific polymerase chain reaction have been applied to detect these genes in the industrial scale [65]. Besides the genetic characteristics of intestinal microbiota in each individual, environmental factors, diet and use of antibiotics are other elements that might influence the effect of probiotics in adults. Therefore, observing different effects in various age groups of consumers would not be surprising [66,67]. Moreover, the probiotics virulence factors influence their safety due to their association in gene transfer that may result in antimicrobial resistance in intestinal bacterial populations [64,68]. In this article, we reviewed the safety of various strains and different doses of probiotics obtained from clinical trials, case reports and animal experiments. However, studies with longer duration in both patients and healthy population would be more helpful to get a better conclusion. Current studies have some limitations in various items such as data heterogeneity, bias of lifestyle of studied population, diversity in the normal flora of individuals, genetics differences, age and sex Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

4.

Lopez-Varela S, Gonzalez-Gross M, Marcos A. Functional foods and the immune system: a review. Eur J Clin Nutr 2002;56:S29-33 Lourens-Hattingh A, Viljoen BC. Yogurt as probiotic carrier food. Int Dairy J 2001;11:1-17 Lavermicocca P, Valerio F, Lonigro SL, et al. Study of adhesion and survival of lactobacilli and bifidobacteria on table olives with the aim of formulating a new probiotic food. Appl Environ Microbiol 2005;71:4233-40 Shimakawa Y, Matsubara S, Yuki N, et al. Evaluation of Bifidobacterium breve strain Yakult-fermented soymilk as a probiotic food. Int J Food Microbiol 2003;81:131-6

5.

Yuvaraj S, Peppelenbosch MP, Bos NA. Transgenic probiotica as drug delivery systems: the golden bullet? Expert Opin Drug Deliv 2007;4:1-3

6.

Sutton A. Product development of probiotics as biological drugs. Clin Infect Dis 2008;46:128-32

7.

Zuccotti GV, Meneghin F, Raimondi C, et al. Probiotics in clinical practice: an overview. J Int Med Res 2008;36:1-53

8.

de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol 2008;111:1-66

of evaluated populations and different duration of treatment or follow-up periods. We advise scientists to focus on safety of probiotics, especially in high-risk subjects like newborns and elderly people. Nevertheless, probiotics are known as safe commensal bacteria, and the safety of probiotics is a discussable issue. Considering the risk-benefit ratio before prescribing the probiotics is recommended.

Acknowledgment This invited paper is the outcome of an in-house financially nonsupported study.

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.

9.

Davis CD, Milner JA. Gastrointestinal microflora, food components and colon cancer prevention. J Nutr Biochem 2009;20:743-52

10.

Nikfar S, Rahimi R, Rahimi F, et al. Efficacy of probiotics in irritable bowel syndrome: a meta-analysis of randomized, controlled trials. Dis Colon Rectum 2008;51:1775-80 This is the first meta-analysis that investigated the efficacy of probiotics in IBS.

.

11.

Hosseini A, Nikfar S, Abdollahi M. Are probiotics effective in management of irritable bowel syndrome. Arch Med Sci 2012;8:403-5

12.

Hosseini A, Nikfar S, Abdollahi M. Probiotics use to treat irritable bowel syndrome. Expert Opin Biol Ther 2012;12:1323-34

13.

Rahimi R, Nikfar S, Rahimi F, et al. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn’s disease. Dig Dis Sci 2008;53:2524-31

14.

15.

Ghasemi-Niri S, Abdolghaffari A, Fallah-Benakohal S, et al. On the benefit of whey-cultured Lactobacillus casei in murine colitis. J Physiol Pharmacol 2011;62:341-6 Ghasemi-Niri SF, Solki S, Didari T, et al. Better efficacy of lactobacillus casei in combination with bifidobacterium bifidum or saccharomyces boulardii in


recovery of inflammatory markers of colitis in rat. Asian J Anim Vet Adv 2012;7:1148-56 16.

Saadatzadeh A, Atyabi F, Fazeli MR, et al. Biochemical and pathological evidences on the benefit of a new biodegradable nanoparticles of probiotic extract in murine colitis. Fundam Clin Pharmacol 2012;26:589-98

17.

Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol 2010;7:503-14 This study describes the beneficial effects of live microorganisms in gastrointestinal disorders.

.

18.

Luedtke SA, Yang JT, Wild HE. Probiotics and Necrotizing Enterocolitis: finding the Missing Pieces of the Probiotic Puzzle. J Pediatr Pharmacol Ther 2012;17:308-28

19.

Elahi B, Nikfar S, Derakhshani S, et al. On the benefit of probiotics in the management of pouchitis in patients underwent ileal pouch anal anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci 2008;53:1278-84

20.

Salari P, Nikfar S, Abdollahi M. A metaanalysis and systematic review on the effect of probiotics in acute diarrhea. Inflamm Allergy Drug Targets 2012;11:3-14

21.

Murdock F, Fields M. B-vitamin content of natural lactic acid fermented cornmeal. J Food Sci 1984;49:373-5

235

T. Didari et al.

22.

de Vrese M, Marteau PR. Probiotics and prebiotics: effects on diarrhea. J Nutr 2007;137:803-11

23.

Sharp RR, Achkar J-P, Brinich MA, Farrell RM. Helping patients make informed choices about probiotics: a need for research. Am J Gastroenterol 2009;104:809-13

24.


25.

26.

27.

28.

29.

.

30.

31.

32.

.

33.

236

Gratz SW, Mykkanen H, El-Nezami HS. Probiotics and gut health: a special focus on liver diseases. World J Gastroenterol 2010;16:403-10 Fukuda S, Toh H, Hase K, et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011;469:543-7

34.

..

Salminen MK, Tynkkynen S, Rautelin H, et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 2002;35:1155-60 A good article about the association between probiotics consumption and bacteremia.

35.

Saxelin M, Chuang N-H, Chassy B, et al. Lactobacilli and bacteremia in southern Finland, 1989--1992. Clin Infect Dis 1996;22:564-6

36.

Candy DC, Densham L, Lamont LS, et al. Effect of administration of Lactobacillus casei shirota on sodium balance in an infant with short bowel syndrome. J Pediatr Gastroenterol Nutr 2001;32:506-8

Aureli P, Capurso L, Castellazzi AM, et al. Probiotics and health: an evidencebased review. Pharmacol Res 2011;63:366-76

37.

Morishita T, Tamura N, Makino T, Kudo S. Production of menaquinones by lactic acid bacteria. J Dairy Sci 1999;82:1897-903

Bonsante F, Iacobelli S, Gouyon JB. Routine probiotic use in very preterm infants: retrospective comparison of two cohorts. Am J Perinatol 2013;30:41-6

38.

Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM. 17938 for the Management of Infantile Colic in Breastfed Infants: a randomized, doubleblind, placebo-controlled trial. J Pediatr 2013;162:257-62

Molinaro F, Paschetta E, Cassader M, et al. Probiotics, prebiotics, energy balance, and obesity: mechanistic insights and therapeutic implications. Gastroenterol Clin North Am 2012;41:843-54

39.

Isolauri E, Rautava S, Salminen S. Probiotics in the development and treatment of allergic disease. Gastroenterol Clin North Am 2012;41:747-62 A good article about probiotics and allergic diseases.

40.

Rautava S. Potential uses of probiotics in the neonate. Semin Fetal Neonatal Med 2007;12:45-53

41.

Wagner R, Balish E. Potential hazards of probiotic bacteria for immunodeficient patients. Bull de l’Inst Pasteur 1998;96:165-70 Marteau P, Shanahan F. Basic aspects and pharmacology of probiotics: an overview of pharmacokinetics, mechanisms of action and side-effects. Best Pract Res Clin Gastroenterol 2003;17:725-40 An interesting review of the side effects of probiotics. Taranto MP, Vera JL, Hugenholtz J, et al. Lactobacillus reuteri CRL1098 produces cobalamin. J Bacteriol 2003;185:5643-7

..

Narayanappa D. Randomized double blinded controlled trial to evaluate the efficacy and safety of Bifilac in patients with acute viral diarrhea. Indian J Pediatr 2008;75:709-13 Ohishi A, Takahashi S, Ito Y, et al. Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr 2010;156:679-81 Perapoch J, Planes A, Querol A, et al. Fungemia with Saccharomyces cerevisiae in two newborns, only one of whom had been treated with ultra-levura. Eur J Clin Microbiol Infect Dis 2000;19:468-70 An interesting case report of fungemia in two hospitalized infants that one received probiotic and another was in the cot adjacent to the first infant.

42.

Alberda C, Gramlich L, Meddings J, et al. Effects of probiotic therapy in critically ill patients: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2007;85:816-23

43.

Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind,


placebo-controlled trial. Gastroenterology 2000;119:305-9 44.

Besselink M, van Santvoort H, Buskens E, et al. Probiotic prophylaxis in patients with predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Ned Tijdschr Geneeskd 2008;152:685-96

45.

Kukkonen K, Savilahti E, Haahtela T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebocontrolled trial. Pediatrics 2008;122:8-12

46.

de Regt MJ, Willems RJ, Hene´ RJ, et al. Effects of probiotics on acquisition and spread of multiresistant enterococci. Antimicrob Agents Chemother 2010;54:2801-5

47.

Laitinen K, Poussa T, Isolauri E. Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: a randomised controlled trial. Br J Nutr 2009;101:1679-87

48.

Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 2007;335:340

49.

Henker J, Laass M, Blokhin BM, et al. The probiotic Escherichia coli strain Nissle 1917 (EcN) stops acute diarrhoea in infants and toddlers. Eur J Pediatr 2007;166:311-18

50.

Salminen MK, Rautelin H, Tynkkynen S, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004;38:62-9

51.

Land MH, Rouster-Stevens K, Woods CR, et al. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 2005;115:178-81 Good study on incidence of bacteremia as a consequence of probiotics digestion in critically ill patients.

..

52.

Cassone M, Serra P, Mondello F, et al. Outbreak of Saccharomyces cerevisiae subtype boulardii fungemia in patients neighboring those treated with a probiotic preparation of the organism. J Clin Microbiol 2003;41:5340-3

53.

Zhou J, Shu Q, Rutherfurd K, et al. Safety assessment of potential probiotic lactic acid bacterial strains Lactobacillus



rhamnosus HN001, Lb. acidophilus HN017, and Bifidobacterium lactis HN019 in BALB/c mice. Int J Food Microbiol 2000;56:87-96

64.

54.

Zhou J, Shu Q, Rutherfurd K, et al. Acute oral toxicity and bacterial translocation studies on potentially probiotic strains of lactic acid bacteria. Food Chem Toxicol 2000;38:153-61

65.

55.

Rinkinen M, Jalava K, Westermarck E, et al. Interaction between probiotic lactic acid bacteria and canine enteric pathogens: a risk factor for intestinal Enterococcus faecium colonization? Vet Microbiol 2003;92:111-19

56.

57.

58.

59.

60.

Soo I, Madsen KL, Tejpar Q, et al. VSL# 3 probiotic upregulates intestinal mucosal alkaline sphingomyelinase and reduces inflammation. Can J Gastroenterol 2008;22:237-42 Jones ML, Martoni CJ, Tamber S, et al. Evaluation of safety and tolerance of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation: a randomized, placebo-controlled, double-blind study. Food Chem Toxicol 2012;50:2216-23 Lorea Baroja M, Kirjavainen P, Hekmat S, Reid G. Anti-inflammatory effects of probiotic yogurt in inflammatory bowel disease patients. Clin Exp Immunol 2007;149:470-9 Weichselbaum E. Potential benefits of probiotics-main findings of an in-depth review. Br J Community Nurs 2010;15:110-14 Honeycutt TC, El Khashab M, Wardrop RM III, et al. Probiotic administration and the incidence of nosocomial infection in pediatric intensive care: a randomized placebocontrolled trial. Pediatr Crit Care Med 2007;8:452-8

61.

Saarela M, Mogensen G, Fonde´n R, et al. Probiotic bacteria: safety, functional and technological properties. J Biotechnol 2000;84:197-215

62.

Boyle R, Bath-Hextall F, Leonardi-Bee J, et al. Probiotics for the treatment of eczema: a systematic review. Clin Exp Immunol 2009;39:1117-27

63.

Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010;125:921-30

Kataria J, Li N, Wynn JL, Neu J. Probiotic microbes: do they need to be alive to be beneficial? Nutr Rev 2009;67:546-50 Marcobal A, Underwood MA, Mills DA. Rapid determination of the bacterialcomposition of commercial probiotic products by terminal restriction fragmentlength polymorphism analysis. J Pediatr Gastroenterol Nutr 2008;46:608-11

66.

Salminen S, Isolauri E. Intestinal colonization, microbiota, and probiotics. J Pediatr 2006;149:115-20

67.

Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635-8

68.

Franz CM, Huch M, Abriouel H, et al. Enterococci as probiotics and their implications in food safety. Int J Food Microbiol 2011;151:125-40

69.

70.

71.

72.

73.

74.

Forestier C, Guelon D, Cluytens V, et al. Oral probiotic and prevention of Pseudomonas aeruginosa infections: a randomized, double-blind, placebocontrolled pilot study in intensive care unit patients. Crit Care 2008;12:R69 Klarin B, Wullt M, Palmquist I, et al. Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol Scand 2008;52:1096-102 Manzoni P, Mostert M, Leonessa M, et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis 2006;42:1735-42 Rayes N, Hansen S, Seehofer D, et al. Early enteral supply of fiber and Lactobacilli versus conventional nutrition: a controlled trial in patients with major abdominal surgery. Nutrition 2002;18:609-15 Rayes N, Seehofer D, Hansen S, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002;74:123-8 Qin H, Zheng J, Tong D, et al. Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with


acute pancreatitis. Eur J Clin Nutr 2007;62:923-30 75.

Fukushima Y, Miyaguchi S, Yamano T, et al. Improvement of nutritional status and incidence of infection in hospitalised, enterally fed elderly by feeding of fermented milk containing probiotic Lactobacillus johnsonii La1 (NCC533). Br J Nutr 2007;98:969-77

76.

Millar M, Bacon C, Smith S, et al. Enteral feeding of premature infants with Lactobacillus GG. Arch Dis Child 1993;69:483-7

77.

Srinivasan R, Meyer R, Padmanabhan R, Britto J. Clinical safety of Lactobacillus casei shirota as a probiotic in critically ill children. J Pediatr Gastroenterol Nutr 2006;42:171-3

78.

Klarin B, Johansson M-L, Molin G, et al. Adhesion of the probiotic bacterium Lactobacillus plantarum 299v onto the gut mucosa in critically ill patients: a randomised open trial. Crit Care 2005;9:R285

79.

Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004;38:457-8

80.

De Groote MA, Frank DN, Dowell E, et al. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005;24:278-80

81.

Kitajima H, Sumida Y, Tanaka R, et al. Early administration of Bifidobacterium breve to preterm infants: randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 1997;76:101-7

82.

Li Y, Shimizu T, Hosaka A, et al. Effects of Bifidobacterium breve supplementation on intestinal flora of low birth weight infants. Pediatr Int 2004;46:509-15

83.

Wang C, Shoji H, Sato H, et al. Effects of oral administration of Bifidobacterium breve on fecal lactic acid and short-chain fatty acids in low birth weight infants. J Pediatr Gastroenterol Nutr 2007;44:252-7

84.

Mihatsch WA, Vossbeck S, Franz AR, Kron M. Effect of enteral administration of a probiotic strain of bifidobacteria on the incidence of nosocomial infections in preterm infants. Pediatr Res 2004;55:448

85.

Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in

237

T. Didari et al.

patients. Intensive Care Med 1997;23:517-23


women with irritable bowel syndrome. Am J Gastroenterol 2006;101:1581-90 86.

Samanta M, Sarkar M, Ghosh P, et al. Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr 2009;55:128-31

87.

Rouge´ C, Piloquet H, Butel M-J, et al. Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebocontrolled trial. Am J Clin Nutr 2009;89:1828-35

88.

89.

90.

91.

92.

Underwood MA, Salzman NH, Bennett SH, et al. A Randomized placebo-controlled comparison of two prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short chain fatty acids. J Pediatr Gastroenterol Nutr 2009;48:216-25 Lin H-C, Su B-H, Chen A-C, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005;115:1-4 Lin H-C, Hsu C-H, Chen H-L, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008;122:693-700

96.

Schneider SM, Girard-Pipau F, Filippi J, et al. Effects of Saccharomyces boulardii on fecal short-chain fatty acids and microflora in patients on long-term total enteral nutrition. World J Gastroenterol 2005;11:6165-9

97.

McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994;271:1913-18

98.

99.

Lungarotti M, Mezzetti D, Radicioni M. Methaemoglobinaemia with concurrent blood isolation of Saccharomyces and Candida. Arch Dis Child Fetal Neonatal Ed 2003;88:F446 Lolis N, Veldekis D, Moraitou H, et al. Saccharomyces boulardii fungaemia in an intensive care unit patient treated with caspofungin. Crit Care 2008;12:414

100. Pletincx M, Legein J, Vandenplas Y. Fungemia with Saccharomyces boulardii in a 1-year-old girl with protracted diarrhea. J Pediatr Gastroenterol Nutr 1995;21:113-15 101. Viggiano M, Badetti C, Bernini V, et al. Saccharomyces boulardii fungemia in a patient with severe burns. Ann Fr Anesth Reanim 1995;14:356-8

Sugawara G, Nagino M, Nishio H, et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg 2006;244:706-14

102. Burkhardt O, K€ohnlein T, Pletz MW, Welte T. Saccharomyces boulardii induced sepsis: successful therapy with voriconazole after treatment failure with fluconazole. Scand J Infect Dis 2005;37:69-72

Hoyos AB. Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis 1999;3:197-202

103. Zunic P, Lacotte J, Pegoix M, et al. Saccharomyces boulardii fungemia. Apropos of a case. Therapie 1991;46:498-9 104. Lestin F, Pertschy A, Rimek D. Fungemia after oral treatment with Saccharomyces boulardii in a patient with multiple comorbidities. Dtsch Med Wochenschr 2003;128:2531-3

93.

Shimizu K, Ogura H, Goto M, et al. Synbiotics decrease the incidence of septic complications in patients with severe SIRS: a preliminary report. Dig Dis Sci 2009;54:1071-8

94.

Costalos C, Skouteri V, Gounaris A, et al. Enteral feeding of premature infants with Saccharomyces boulardii. Early Hum Dev 2003;74:89-96

105. Fredenucci I, Chomarat M, Boucaud C, Flandrois J. Saccharomyces boulardii fungemia in a patient receiving Ultralevure therapy. Clin Infect Dis 1998;27:222-3

95.

Bleichner G, Blehaut H, Mentec H, Moyse D. Saccharomyces boulardii prevents diarrhea in critically ill tube-fed

106. Hennequin C, Kauffmann-Lacroix C, Jobert A, et al. Possible role of catheters in Saccharomyces boulardii fungemia.

238


Eur J Clin Microbiol Infect Dis 2000;19:16-20 107. Lherm T, Monet C, Nougie`re B, et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med 2002;28:797-801 108. Henry S, D’Hondt L, Andre M, et al. Saccharomyces cerevisiae fungemia in a head and neck cancer patient: a case report and review of the literature. Acta Clin Belg 2004;59:220-2 109. Mun˜oz P, Bouza E, Cuenca-Estrella M, et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005;40:1625-34 110. Rijnders B, Van Wijngaerden E, Verwaest C, Peetermans W. Saccharomyces fungemia complicating Saccharomyces boulardii treatment in a non-immunocompromised host. Intensive Care Med 2000;26:825 111. Niault M, Thomas F, Prost J, et al. Fungemia due to Saccharomyces species in a patient treated with enteral Saccharomyces boulardii. Clin Infect Dis 1999;28:930 112. Cherifi S, Robberecht J, Miendje Y. Saccharomyces cerevisiae fungemia in an elderly patient with Clostridium difficile colitis. Acta Clin Belg 2004;59:223-4 113. Bin-Nun A, Bromiker R, Wilschanski M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005;147:192-6 114. Giamarellos-Bourboulis EJ, Bengmark S, Kanellakopoulou K, Kotzampassi K. Pro-and synbiotics to control inflammation and infection in patients with multiple injuries. J Trauma 2009;67:815-21 115. Knight DJ, Gardiner D, Banks A, et al. Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised, double-blind, placebocontrolled trial. Intensive Care Med 2009;35:854-61 116. Waitzberg DL, Logullo LC, Bittencourt AF, et al. Effect of synbiotic in constipated adult women--a randomized, double-blind, placebocontrolled study of clinical response. Clin Nutr 2012;32:27-33



Affiliation Tina Didari1, Sara Solki1, Shilan Mozaffari2,3, Shekoufeh Nikfar4,5 & Mohammad Abdollahi†2,3 † Author for correspondence 1 Islamic Azad University, Department of Microbiology, Pharmaceutical Sciences Branch, Tehran, Iran 2 Tehran University of Medical Sciences, Faculty of Pharmacy, Department of Toxicology and Pharmacology, Tehran, Iran E-mail: [email protected], [email protected] 3 Tehran University of Medical Sciences, Pharmaceutical Sciences Research Center, Tehran, Iran 4 Ministry of Health and Medical Education, Food and Drug Organization, Tehran, Iran 5 Tehran University of Medical Sciences, Faculty of Pharmacy, Department of Pharmacoeconomics and Pharmaceutical Administration, Tehran, Iran


239

Probiotics as potential antioxidants: a systematic review.

The Safety of Orthokeratology--A Systematic Review.

Effects of probiotics on child growth: a systematic review.

Early probiotics to prevent childhood metabolic syndrome: A systematic review.

Probiotics for weight loss: a systematic review and meta-analysis.

Risk and safety of probiotics.

Safety checklist briefings: a systematic review of the literature.

Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials.

A systematic review and meta-analysis of probiotics for the treatment of allergic rhinitis.

The fetal safety of Levetiracetam: a systematic review.

A review of avian probiotics.

The safety of acupuncture during pregnancy: a systematic review.

Probiotics for the prevention of pediatric upper respiratory tract infections: a systematic review.

The role of probiotics in prevention and treatment for patients with allergic rhinitis: A systematic review.

The effects of probiotics on depressive symptoms in humans: a systematic review.

Probiotics as beneficial agents in the management of diabetes mellitus: a systematic review.

Erratum to: The effects of probiotics on depressive symptoms in humans: a systematic review.

Safety of moxibustion: a systematic review of case reports.

Effect of Probiotics on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized, controlled trials.

Probiotics in the dental practice: a review.

Use and safety of azithromycin in neonates: a systematic review.

Probiotics: A review for NPs.