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• World J Gastroenterol
• v.16(18); 2010 May 14

Systematic review and meta-analysis of Saccharomyces boulardii in adult patients

Correspondence to: Lynne V McFarland, PhD, Department of Health Services Research and Development, Puget Sound Veterans Administration Healthcare System, S-152, 1100 Olive Way #1400, Seattle, WA 98101, United States. [email protected]

Telephone: +1-206-2771095 Fax: +1-206-7642935

This article reviews the evidence for efficacy and safety of Saccharomyces boulardii ( S. boulardii ) for various disease indications in adults based on the peer-reviewed, randomized clinical trials and pre-clinical studies from the published medical literature (Medline, Clinical Trial websites and meeting abstracts) between 1976 and 2009. For meta-analysis, only randomized, blinded controlled trials unrestricted by language were included. Pre-clinical studies, volunteer studies and uncontrolled studies were excluded from the review of efficacy and meta-analysis, but included in the systematic review. Of 31 randomized, placebo-controlled treatment arms in 27 trials (encompassing 5029 study patients), S. boulardii was found to be significantly efficacious and safe in 84% of those treatment arms. A meta-analysis found a significant therapeutic efficacy for S. boulardii in the prevention of antibiotic-associated diarrhea (AAD) (RR = 0.47, 95% CI: 0.35-0.63, P < 0.001). In adults, S. boulardii can be strongly recommended for the prevention of AAD and the traveler’s diarrhea. Randomized trials also support the use of this yeast probiotic for prevention of enteral nutrition-related diarrhea and reduction of Heliobacter pylori treatment-related symptoms. S. boulardii shows promise for the prevention of C. difficile disease recurrences; treatment of irritable bowel syndrome, acute adult diarrhea, Crohn’s disease, giardiasis, human immunodeficiency virus-related diarrhea; but more supporting evidence is recommended for these indications. The use of S. boulardii as a therapeutic probiotic is evidence-based for both efficacy and safety for several types of diarrhea.

INTRODUCTION

Probiotics have become increasingly popular in the US and are rapidly reaching levels of use in Europe and Asia, which have a longer history of use compared with the US[ 1 - 3 ]. Probiotics are “live microorganisms, which when administered in adequate amounts, confer a health benefit on the host”[ 4 , 5 ]. In one survey, of 435 users of dietary supplements, 50% of women and 33% of men reported use of probiotics[ 6 ].

Probiotics are generally recommended to help strengthen host systems and assist in recovery from certain diseases. However, the general public and many health care providers are still confused about how best to utilize probiotics and which ones are effective for specific diseases. There are several challenges in choosing the appropriate probiotic; including the wide diversity of probiotic strains, quality control of commercially-available probiotic products and the degree of evidence-based trials for each disease and probiotic. The ability of an organism to be an effective probiotic has been found to be strain-specific and microbial organisms are defined by their genus, species and strain. For example, Lactobacillus rhamnosus ( L. rhamnosus ) GG is a specific bacterial strain, which has been shown to be an effective probiotic for several diarrheal diseases, but other strains within the L. rhamnosus species may not be an effective probiotic. Similarly, other species under the same genus ( Lactobacillus ) may not be effective probiotics[ 7 ]. To add to this confusion, probiotic products are available in diverse forms: capsules of freeze-dried or lyophilized cultures, heat-dried culture supernatants, mixed in diary food (such as yogurts, cheese, milks, or ice cream) or other food (kefir, chocolate, wafers)[ 8 - 10 ]. The variety of probiotic products are also regulated under different guidelines according to the ways of use (food, dietary supplement, over-the-counter use or prescription). Different standards of quality assurance also vary with the type of product, indication for use and country.

Despite these challenges, the awareness of probiotics as a therapeutic modality has increased dramatically and the frequency of peer-reviewed randomized clinical trials have kept abreast with the global interest in this innovative method of therapy. Numerous probiotic strains have been investigated for clinical efficacy, including multiple bacterial strains: Lactobacilli , Bifidobacteria , Streptococci , Clostridia and fungal strains: Saccharomyces boulardii (S. boulardii), S. cerevisiae , and Monascus purpureus [ 11 - 13 ]. This review examines evidences for Saccharomyces probiotics and focuses on S. boulardii for the efficacy and safety of different diseases in adult patients. The two goals of this study were: (1) to provide guidance for clinicians and patients on how to appropriately use S. boulardii as a therapeutic probiotic and (2) to review the evidence for efficacy and safety of S. boulardii for various disease indications in adults.

SEARCH STRATEGY FOR SYSTEMATIC REVIEW

PubMed, Medline and Google Scholar were searched for articles unrestricted by language from 1976 to 2009. Three on-line clinical trial registers were searched: Cochrane Central Register of Controlled Trials ( www.cochrane.org ), metaRegister of Controlled Trials ( www.controlled-trials.com/mrct ) and National Institutes of Health ( www.clinicaltrials.gov ). Secondary and hand searches of reference lists, other studies cross-indexed by authors, reviews, commentaries, books and meeting abstracts also were performed. Search terms included: Saccharomyces boulardii , probiotics, yeast, diarrhea, risk factors, randomized controlled trials, placebo-controlled, and associated author names. Search strategies were broad-based initially, then narrowed to the disease of interest to increase the search network[ 14 ].

META-ANALYSIS

If sufficient numbers of clinical trials (> 5) were found on one type of disease indication, a meta-analysis for the efficacy of S. boulardii was performed; otherwise a systematic review was done. The procedure for the meta-analysis followed standard meta-analysis methodology with clearly delineated parameters, a priori inclusion and exclusion criteria and standardized data extraction[ 15 , 16 ]. Abstracts of all citations and retrieved studies were reviewed and rated for inclusion. In some cases, only published abstracts from meetings were available. Published abstracts from meetings were included to lessen the potential for publication bias due to failure to publish negative findings. Information on study design, methods, interventions, outcomes, adverse effects and treatments was extracted from each article using a standardized extraction table. When necessary, authors were contacted for data not reported in the original article.

The primary objective of the meta-analysis was to determine the overall efficacy of S. boulardii within one specific type of disease indications (antibiotic-associated diarrhea, Clostridium difficile disease, traveller’s diarrhea, irritable bowel syndrome, inflammatory bowel disease or other types of diarrhea). Inclusion criteria were: randomized, controlled, blinded efficacy trials in humans published as full articles or meeting abstracts in peer-reviewed journals. Exclusion criteria included: use of other strains of Saccharomyces (such as Saccharomyces cerevisiae ) or other strains of probiotics, pre-clinical studies, safety studies, case reports or case series, phase I studies in volunteers, reviews, duplicate reports, trials of unspecified treatments, uncontrolled studies, prebiotic treatments only (no living organisms) or insufficient data in article.

To estimate pooled relative risks across studies, heterogeneity between and within trials was evaluated using the Cochrane Q and I 2 tests[ 17 ]. Relative risks (RR) and 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method. The relative risks of responding to S. boulardii therapy were pooled using a random-effect model if significant heterogeneity was found or a fixed-effect model if the studies were homogenous. P values less than 0.05 were considered significant. Analyses were performed using Stata software version 9.2 (Stata Corporation, College Station, Texas). A funnel scatterplot and Begg’s test were used to assess publication bias[ 18 ].

Saccharomyces cerevisiae strains have a long history of use in baking and brewing preparation, but have only infrequently been investigated for probiotic properties[ 19 , 20 ]. Another closely related strain, S. boulardii , was discovered by a French microbiologist, Henri Boulard in 1920 when he was in IndoChina searching for new strains of yeast that could be used in fermenting processes. He was a visitor during a cholera outbreak and noticed that some people who did not develop cholera were drinking a special tea. This tea was made by taking the outer skin from a tropical fruit (lychee and mangosteens) and cooking them down to make tea. He succeeded in isolating the agent responsible. It was a special strain of yeast he named “ Saccharomyces boulardii ”. The patent for this yeast was bought by Laboratories Biocodex in 1947, which began researching and manufacturing protocols. As shown in Figure ​ Figure1, 1 , interest in this strain has increased, as reflected by the increasing number of scientific publications, encompassing both pre-clinical papers in mechanisms of action, animal models of efficacy, pharmacokinetics, early studies in safety and dose-ranging. In addition, there are currently 53 randomized controlled clinical trials, encompassing 8475 subjects, investigating the safety and efficacy of S. boulardii in pediatric and adult patients spanning several disease indications, of which 43 (81%) found significant efficacy for S. boulardii . As a recent review article on the efficacy of S. boulardii was published for pediatric indications[ 21 ], this study will focus on S. boulardii use in adult patients. There have been 27 randomized controlled trials, with 31 treatment arms testing S. boulardii in adult patients for a variety of diseases and most (84%) found a significantly protective efficacy of this probiotic. There have been only a few randomized clinical trials using other strains of Saccharomyces probiotics, which will be discussed later in this paper.

Frequency of peer-reviewed publications on Saccharomyces boulardii from 1976 to 2009.

Probiotics may be either bacterial or yeast microbes. Yeast probiotics, such as S. boulardii , are different from bacterial probiotics (different physiologic structures, large in size, do not acquire antibiotic-resistant genes and are not affected by antibiotics)[ 12 ]. Not only is there a confusing array of probiotic products on the global market, but the taxonomy of Saccharomyces strains has been debated[ 22 ]. One strain has received considerable discussion about its valid nomenclature[ 23 , 24 ]. It was originally named S. boulardii in the 1950’s. Advances in typing methods opened a debate as to whether this strain should be reclassified as a strain of S. cerevisiae or remain a separate species. Early work using PCR electrophoretic karotyping or rRNA sequencing methods reported that S. boulardii was indistinguishable from other strains of S. cerevisiae [ 24 , 25 ]. Newer metabolomic tools (microsatellite polymorphism analysis and retrotransposon hybridization analyses) show that S. boulardii has a unique clustering different from other strains of S. cerevisiae [ 26 - 28 ]. In addition, S. boulardii differs from other strains of S. cerevisiae by several metabolic and genetic characteristics[ 29 , 30 ]. S. boulardii persists longer in gnotobiotic mice models (10 d) compared with rapid clearance of other strains of S. cerevisiae (< 1 d)[ 31 ]. S. boulardii is also different physiologically and metabolically and its optimum growth temperature is 37°C and it is resistant to low pH and is tolerant to bile acids; whereas other strains of S. cerevisiae prefer cooler temperatures (30-33°C) and do not survive well in acid pH ranges[ 32 - 34 ]. S. boulardii can be distinguished from other strains of S. cerevisiae by advanced typing methods, by differences in metabolism and physiology and by the ability to have anti-pathogen effects (as discussed in the mechanisms of action section).

GUIDELINES FOR CHOOSING APPROPRIATE PROBIOTICS

Challenges in providing guidance to patients regarding the appropriate choice of probiotic include the wide diversity of available products on the market, variances in quality control, stability and formulations in those products, and the requirement to match the type of probiotic with the disease indication. The efficacy of probiotics have been shown to be both strain-specific and disease-specific[ 11 , 35 , 36 ].

Product to product variation

There are many different Saccharomyces products available commercially. Table ​ Table1 1 lists some examples of products that contain S. boulardii , sold as probiotics either as lyophilized or heat-dried powders in capsules, or as one of several strains in a probiotic mixture in capsules or in liquid beverages[ 12 , 13 , 21 , 37 - 66 ]. The quality of these products from different sources have been found to vary. Choosing a probiotic product from a manufacturer with a regulated quality control program is a sound policy. Unfortunately, many of the products available commercially may lack regulated quality control programs. Studies of other probiotics have found a wide diversity in both quality and contamination in products available on the Internet[ 67 ]. Marcobal et al[ 68 ] tested 14 commercial probiotics in the US and found 93% were incorrectly labeled (57% had contaminants and 36% did not list strains on the label). Masco et al[ 69 ] tested 58 different probiotic products from Europe, UK, Asia, Japan and Canada and found only 38% had the dose stated on the label and 29% did not contain strains listed on the label. Not all products were found to have high standards of manufacture and quality control, as only some conform to Good Manufacturing Practices. Although most products state they contain at least 1 × 10 9 S. boulardii /mg, independent assays have determined 50% of the products contained a dose less than on the label. In one study comparing six S. boulardii products, all had identical PCR typing profiles, but only 50% [Floratil (Merck), Flomicin (NeoChemical), and Florazin (Herald’s)], had the same concentration identified on their label. One product [Lactipan (Sigma Pharm)] had 2 × 10 4 fewer S. boulardii than stated on its label. One product [Floratil (Merck)], had the highest concentration (1 × 10 9 /100 mL) and maintained high levels (9.5 × 10 8 ) six months later[ 70 ]. Even if the label states it contains S. boulardii , a variation in efficacy may occur due to lower than stated dose or inaccurate strain composition. Four S. boulardii products were tested (along with one S. cerevisiae product) in Brazil. Only two (50%) of the S. boulardii products were protective in a Salmonella typhimurum mouse model (two S. boulardii products were ineffective, as well as the one S. cerevisiae product)[ 71 ]. Without access to specific quality control assays for commercially available probiotic products, the choice of a high quality product can be difficult. One method of selecting a probiotic product is to find a product in which the manufacturing company has sponsored original clinical trials, as this indicates a degree of commitment that may not be present in companies that do not sponsor original research. As shown in Table ​ Table1, 1 , only a few S. boulardii probiotic products are supported by original research. Although at present, most probiotic clinical trials are sponsored by private companies, as more national funding becomes available, this situation may change.

Examples of commercially available probiotics containing “ Saccharomyces boulardii ”

How the probiotic product is manufactured may significantly affect its potency over time (shelf-life). Probiotics may be available as lyophilized preparations, heat-dried preparations or contained in diary or drink food products. S. boulardii is usually available in capsules of either lyophilized or heat-dried preparations. Heat-dried capsule products may be identified by their labels, which usually state that the products should be refrigerated after opening and they lose their potency rapidly. Lyophilized preparations of S. boulardii are stable over one year at room temperature, as long as it is protected from moisture[ 72 ]. Lyophilized products are stable at room temperature and have the advantage of portability and convenience and maintain high viability counts over prolonged periods. Heat-dried preparations are not stable at room temperature and must be refrigerated. A study of four S. boulardii products in Germany found a lyophilized product [Perenterol Forte (Thiemann)] outperformed three heat-killed S. boulardii preparations in terms of higher viable cells and quicker start-up times[ 73 ].

Single strain or probiotic “cocktails”

As shown in this review, all the randomized controlled trials using S . boulardii probiotics have utilized a single strain preparation. Although mixtures of probiotics, which may contain S . boulardii , are available on the market, no randomized controlled trials have been done showing that these mixtures are superior to the single stain preparations. Pre-clinical studies in animal models have found promising results in a probiotic mixture ( L. rhamnosus , L. acidophilus, Bifidobacterium and S. boulardii ) for reducing E. coli diarrhea in rats, but no human clinical trials have been performed with this mixture[ 65 ]. Another potential limitation to probiotic mixtures is antagonism between the different probiotic strains and conflicting mechanisms of actions that may tend to attenuate the therapeutic responses of the probiotic strains[ 74 ].

Mechanisms of action

An advantage of probiotics is that they are living organisms incorporating a delivery system (most probiotics survive to the target organ) bringing an arsenal of anti-pathogenic strategies into play. S. boulardii has several different types of mechanisms of action (Figure ​ (Figure2) 2 ) which may be classified into three main areas: luminal action, trophic action and mucosal-anti-inflammatory signaling effects[ 8 , 75 - 77 ]. Within the intestinal lumen, S. boulardii may interfere with pathogenic toxins, preserve cellular physiology, interfere with pathogen attachment, interact with normal microbiota or assist in reestablishing short chain fatty acid levels. S. boulardii also may act as an immune regulator, both within the lumen and systemically.

Schematic of intestinal tract, illustrating the different potential mechanisms of action of Saccharomyces boulardii (Sb). On the left, effects of different pathogenic microbes are depicted. On the right, seven different protective effects of S. boulardii are depicted. Within the lumin of the intestine, S. boulardii may degrade toxins of pathogens, interfere with pathogenic adherence, modulate normal microbiota and preserve normal intestinal physiology. S. boulardii may also indirectly restore normal short chain fatty acid (SCFA) balance. S. boulardii may also increase secretory IgA (sIgA) levels or act as an immune regulator by influencing cytokine levels.

Anti-toxin effects: S. boulardii may interfere with pathogenesis within the intestinal lumen by several mechanisms: either by blocking pathogen toxin receptor sites[ 78 ], or acting as a decoy receptor for the pathogenic toxin[ 79 ] or by direct destruction of the pathogenic toxin. Castagliuolo et al[ 80 ] found a 54 kDa serine protease produced by S . boulardii directly degrades C. difficile toxin A and B. The efficacy of other strains of Saccharomyces has also been investigated. Only S. boulardii produces a protease capable of degrading Clostridium difficile toxins and receptors sites on the enterocyte cell surface, unlike other strains of Saccharomyces[ 78 , 81 ]. Buts et al[ 82 ] found a 63 kDa phosphatase produced by S . boulardii destroys the endotoxin of pathogenic E. coli . Several investigators showed that S. boulardii could reduce the effects of cholera toxin and this may be due to a 120 kDa protein produced by S. boulardii [ 83 , 84 ].

Antimicrobial activity: S . boulardii is capable of directly or indirectly interfering with intestinal pathogens. S. boulardii may directly inhibit the growth of pathogens (such as Candida albicans , Salmonella typhimurum , Yersinia enterocolitium , Aeromonas hemolysin [ 43 , 85 , 86 ]). In animal models testing for the ability to inhibit pathogen growth, several studies using non- S. boulardii strains of S. cerevisiae did not find any effect unlike the protective effects of S. boulardii [ 31 , 70 ]. A few studies have tested other strains of S. cerevisiae and found promising results. Brandao et al[ 79 ] tested S. cerevisiae strain W303 in rats and found less histologic damage due to cholera toxin compared with saline controls, but no clinical trials have been done using this strain. S. boulardii may also act by enhancing the integrity of the tight junction between enterocytes, thus preserving intestinal integrity and function[ 87 , 88 ]. Wu et al[ 88 ] found less crypt hyperplasia and cell damage in a Citrobacter rodentium -induced mice model of colitis when mice were treated with 1 × 10 9 S. boulardii per day for 7 d. Garcia Vilela et al[ 62 ] found decreased intestinal permeability when patients with Crohn’s disease were given S . boulardii (1.6 × 10 9 /d for 4 mo) compared with placebo. S. boulardii has also been shown to reduce the translocation of pathogens in rat and pig animal models[ 64 , 89 , 90 ]. S. boulardii can also interfere with pathogenic attachment to intestinal receptor sites[ 88 , 91 , 92 ]. Gedek et al[ 93 ] also found that S . boulardii acts as a decoy by causing EPEC cells to directly bind to the surface of S . boulardii cells rather than enterocytes.

Cross-talk with normal microbiota: Newer techniques, including metagenomics and PCR probes have documented that a typical human may carry over 40 000 bacterial species in the collective intestinal microbiome[ 94 ]. The normal intestinal flora has many functions, including digestion of food, but the one that is most germane for this discussion is called “colonization resistance”[ 77 , 95 , 96 ]. This involves the interaction of many bacterial microflora and results in a barrier effect against colonization of pathogenic organisms. Normal microflora may act by competitive exclusion of nutrients or attachment sites, produce bacteriocins, or produce enzymes detrimental to pathogenic growth. Factors that disrupt this protective barrier, for example antibiotic use or surgery, results in host susceptibility to pathogen colonization until such time as the normal microflora can become re-established. Typically, it takes six to eight weeks for normal microbiota to recover after antibiotic exposure or disease resolution[ 97 ]. Probiotics are uniquely qualified to fit into this window of susceptibility and may act as surrogate normal microflora until recovery is achieved. S. boulardii has no effect on normal microbiota in healthy human controls[ 98 , 99 ]. In contrast, when S. boulardii is given to antibiotic-shocked mice or patients with diarrhea, normal microbiota is re-established rapidly[ 99 , 100 ].

Restoration of metabolic activities: S. boulardii has been shown to be able to increase short chain fatty acids (SCFA), which are depressed during disease, indicating altered colonic fermentation[ 98 , 101 , 102 ].

Trophic effects: S. boulardii can reduce mucositis[ 103 ], restore fluid transport pathways[ 84 , 101 , 104 ], stimulate protein and energy production[ 105 ], or act through a trophic effect by releasing spermine and spermidine or other brush border enzymes that aid in the maturation of enterocytes[ 106 , 107 ].

Immune response: S. boulardii may also regulate immune responses, either acting as an immune stimulant or by reducing pro-inflammatory responses. S . boulardii may cause an increase in secretory IgA levels in the intestine[ 56 , 108 - 110 ]. It has also been found associated with higher levels of serum IgG to C. difficile toxins A and B[ 111 ]. S . boulardii may also interfere with NF-κB-mediated signal transduction pathways, which stimulate pro-inflammatory cytokine production[ 76 , 112 , 113 ]. Chen et al[ 114 ] found that S. boulardii blocks activation of ERK1/2 and MAP kinases, which typically stimulate IL-8 production and cell necrosis in mice ileal loop models and in in vitro models. S. boulardii has also been shown to cause the trapping of T helper cells into mesenteric lymph nodes, thereby reducing inflammation[ 115 ].

Properties of S. boulardii

To be an effective probiotic, it must survive passage to its target organ (most commonly the colon). Organisms need to survive at body temperature (37°C), be resistant to stomach acids and bile acids, and exist in the competitive milieu of the intestinal tract. Probiotic strains of Saccharomyces have been shown to have these abilities. Although the optimal temperature for most strains of Saccharomyces range from 22-30°C, S. boulardii survives best at 37°C, giving it a unique advantage of being one of the few yeasts that do best at human body temperatures.

Survival to target sites: Although much of the oral dose is destroyed (usually stool levels are 100-1000 times lower than the oral dose), surviving oral doses have been found to be effective (usually at levels over 10 8 organisms/g stool)[ 116 ]. S. boulardii is resistant to antibacterial agents and survives gastric acidity[ 34 , 117 ]. In human volunteers, the concentration in the colon was found to be dose-dependent[ 118 ]. When S . boulardii was given to healthy volunteers at doses typically used therapeutically (1-2 × 10 10 /d), colonic levels were 2 × 10 8 /g stool[ 118 ]. Few clinical trials using probiotics have documented the level of organisms present in the terminal site (colonic lumen in their study subjects). However, in one trial of patients with recurrent C. difficile infection (CDI) given S. boulardii (2 × 10 10 /d) for 28 d, patients who had a subsequent CDI recurrence were found to have significantly lower numbers of S. boulardii (2 × 10 4 /g stool) compared with those without recurrence (1 × 10 6 /g stool)[ 119 ].

Pharmocokinetics: S . boulardii , when given orally, achieves steady-state concentrations within three days and is cleared within 3-5 d after it is discontinued[ 34 , 119 , 120 ]. Blehaut et al[ 120 ] gave eight healthy human volunteers S . boulardii (oral dose of 5 × 10 9 ) for six days and followed them for time-to-clearance. They determined S . boulardii has half-life of 6 h, fecal steady-state concentrations (2 × 10 7 /g) were reached by day 3 and the yeast was cleared after four days after administration. Klein et al[ 118 ] confirmed these findings in their studies of human volunteers and also found S . boulardii levels were 23 times higher in volunteers with disturbed intestinal microbiota (due to ampicillin exposure) than volunteers who were not given ampicillin. Elmer et al[ 121 ] found that some types of fiber (psyllium) increased S . boulardii levels by 22%, while other types of fiber (pectin) showed no effect.

CLINICAL EFFICACY: ACUTE DISEASES

S. boulardii probiotics have been tested for clinical efficacy in several types of acute diseases including antibiotic-associated diarrhea, C. difficile infections, Helicobacter pylori ( H. pylori ) disease, acute adult diarrhea, enteral nutrition-related diarrhea, and traveler’s diarrhea.

Antibiotic-associated diarrhea

Epidemiology of antibiotic-associated diarrhea: The reported incidence of antibiotic-associated diarrhea (AAD) ranges from 12/100 000 to 34/100[ 122 ] depending upon the type of antibiotic, host factors (age, health status, etc .), etiology, hospitalization status and presence of a nosocomial outbreak. The highest frequency of AAD is found (26%-60%) during healthcare associated outbreaks, when susceptible patients are clustered by time, exposure and proximity[ 123 ]. Healthcare associated (hospital, long-term care facilities, nursing homes) outbreaks of AAD are to be expected because inciting agents (antibiotics), infectious agents and a susceptible patient population are intermixed. Historically, most cases of AAD were reported in hospitalized patients[ 122 ]. More recently, although AAD still occurs in hospital settings, rates of 6-33/100 have been reported in outpatient populations[ 124 , 125 ] and lower rates (12/100 000 to 14/100) in non-hospitalized adults[ 126 , 127 ]. Lower rates observed in outpatients may be due to their generally higher health status compared with hospitalized patients and also to the lack of exposure to nosocomial pathogens that commonly contaminate hospital environments. Higher incidences are still found in healthcare associated pediatric and adult patients (ranging from 5-34/100 patients)[ 128 - 130 ].

The clinical presentation of AAD may be mild (uncomplicated diarrhea) or more severe (colitis), or result in toxic megacolon or death[ 122 ]. The onset of AAD may occur while the patient is on antibiotics, but delayed-onset AAD is more common[ 122 ]. In addition, the onset of AAD may vary according to the type of antibiotic. Elmer et al[ 131 ] found a variable time of onset using the hamster model of AAD and different types of antibiotics. Early onset of AAD was associated with clindamycin, amoxicillin and ampicillin, while delayed-onset AAD was associated with erythromycin, ciprofloxacin and clarithromycin. Consequences of AAD may result in extended hospital stays, increased medical care costs and increased diagnostic procedures[ 122 , 132 ]. Prevention of AAD has rested on discontinuing the inciting antibiotic or switching to an antibiotic with a narrower spectrum of action, but there are no other current effective preventive measures for AAD.

Efficacy evidence for AAD: There have been ten randomized controlled trials in adults using S. boulardii for the prevention of AAD (Table ​ (Table2 2 )[ 37 , 42 , 44 , 54 , 55 , 58 , 133 - 136 ]. These studies have used a variety of daily doses, durations of treatment, length of follow-up and types of patient population. Of the ten controlled trials, 8 (80%) showed significant efficacy for the prevention of AAD compared with controls. One of the earliest trials by Adam et al[ 37 ], randomized 388 hospitalized patients to 200 mg of S. boulardii [4 × 10 9 cfu (colony forming units)/d] or placebo for seven days and found a significant reduction in AAD in the S. boulardii group (4.5%) compared with the controls (17.5%, P < 0.05). The protective effect of S. boulardii was confirmed in later studies. Monteiro et al[ 55 ] enrolled 240 patients receiving oral antibiotics and found significantly fewer patients randomized to S. boulardii developed AAD (15.7%) compared with placebo (27.7%, P < 0.05). McFarland et al[ 54 ] enrolled 193 hospitalized patients receiving beta-lactam antibiotics and randomized them to either 1 g of S. boulardii or placebo for the duration of the antibiotic treatment plus three additional days. Significantly fewer patients developed AAD while on the beta-lactam antibiotics or in the seven week follow-up period when given S. boulardii (7.2%, P < 0.05) compared with 14.6% of those given placebo. This study confirmed an earlier study by Surawicz et al[ 58 ] of 180 hospitalized adults randomized to either S. boulardii or placebo for the duration of their antibiotic treatment plus an additional two weeks. Of the 23% patients who were contacted 2-3 wk after the study, only one patient given placebo developed delayed-onset AAD. Only 9.5% of those randomized to S. boulardii developed AAD compared with 21.8% of those on placebo ( P < 0.05). Can et al[ 135 ] enrolled 151 adult inpatients receiving various types of antibiotics, who were then randomized to S. boulardii or placebo for the duration of the antibiotic treatment. Significantly fewer patients (1.4%, P < 0.05) of those given S. boulardii developed AAD compared with the control group (9.0%). Three trials have been in conducted in patients with H. pylori infections receiving triple therapy (usually two antibiotics and an acid suppressor), which is associated with a high rate of AAD development. Duman et al[ 44 ] enrolled 389 patients with peptic ulcer or non-ulcer dyspepsia in nine hospitals in Turkey to observe if lower rates of side-effects could be achieved. This study compared 204 patients who received 1 g of S . boulardii (2 × 10 10 /d for 2 wk) and triple therapy with 185 controls, who received only the triple therapy. Of the 389 patients, 376 completed the treatment phase and the four-week follow-up. Significantly fewer patients given S . boulardii (6.9%) developed AAD compared with the control group (15.6%, P = 0.007). Two other randomized controlled trials in adult patients receiving triple therapy for H. pylori infections were conducted and both showed a significant reduction in AAD for those treated with S. boulardii . Cremonini et al[ 134 ] randomized 85 H. pylori carriers to placebo, L. rhamnosus GG, S. boulardii or a mix of L. acidophilus and Bifidobacterium lactis and found significantly fewer patients developed AAD in only the S. boulardii group (5%, P = 0.05) compared with placebo (30%). Cindoruk et al[ 42 ] also found a significant reduction in AAD in adult patients treated with triple therapy for H. pylori infections for those randomized to S. boulardii (14.5%, P < 0.05) compared with placebo (30.6%). None of these trials reported any adverse reactions associated with S. boulardii .

Randomized, controlled trials for the prevention of antibiotic associated diarrhea (AAD) using S. boulardii

It is important to have a sufficiently long follow-up period (usually 4-6 wk after cessation of antibiotics) to capture delayed-onset AAD. Several studies have shown that AAD may occur in patients on antibiotics, but AAD may also be delayed for up to two months (in up to 38% of patients) after antibiotics are discontinued[ 54 , 129 ]. Most studies of AAD followed patients for 4-6 wk after antibiotic treatment to document delayed-onset AAD[ 42 , 44 , 135 ]. In contrast, Lewis et al[ 133 ] found no significant reduction in AAD in a study of 69 elderly patients randomized to 226 mg of S. boulardii (4.5 × 10 9 cfu/d) or placebo for 14 d. This failure may have been due to a flawed study design, in that patients were only followed while on antibiotics and no follow-up was done after antibiotics were discontinued. The study by Lewis et al[ 133 ] therefore, may have missed a significant number of AAD cases due to a too short follow-up period. Short or no follow-up after antibiotic exposure may explain why some studies[ 133 , 136 ] did not find a significant protective effect of S. boulardii [ 137 ]. No adverse reactions associated with S . boulardii were noted in any of these studies. No other strains of Saccharomyces have been found to be effective to prevent AAD.

Meta-analyses for AAD: The literature search yielded 322 unique citations on S. boulardii , of which 278 were excluded: non- S. boulardii studies ( n = 19), reviews ( n = 84), pre-clinical studies including animal models of efficacy, mechanism of action, in vitro assays or strain characterization ( n = 130), case reports or case series ( n = 15), and phase II safety or pharmacokinetic studies ( n = 30). Of the 44 randomized controlled trials with S. boulardii screened, 34 were excluded (pediatric populations, n = 17; or non-AAD indications in adults, n = 17) and 10 were included (AAD in adult populations). As significant heterogeneity was found among studies, a random effect model was used. The random effect model gave a χ 2 = 10.8, P = 0.29, indicating that the heterogeneity was well controlled. A meta-analysis of the ten randomized, controlled trials in adults presented in this review found that S . boulardii was significantly protective for AAD (Figure ​ (Figure3), 3 ), with a pooled relative risk of 0.47 (95% confidence interval 0.35-0.63, P < 0.001). Begg’s test did not find any significant publication bias ( P = 0.93), nor did the funnel plot (data not shown). The number needed-to-treat (NTT) to prevent one case of AAD was 10.2.

Forest plot of meta-analysis of ten randomized controlled trials measuring protective effect after treatment with S. boulardii or placebo for the prevention of antibiotic-associated diarrhea in adult patients. The x-axis depicts effect size, with black dot denoting the relative risk and the line indicating 95% CI, with the size of the grey box proportional to the study size. Relative risks to the left of RR = 1 denote study favored the probiotic, RR to the right denotes the study favors the placebo. Overall, pooled RR was 0.47 (0.35-0.63).

In the established medical literature, meta-analysis has been used to combine different probiotic strains and studies to obtain a pooled estimate of the efficacy of probiotics for the prevention of AAD. A note of caution, however, while most meta-analyses have concluded that probiotics are effective for preventing AAD[ 123 , 138 ], it is inappropriate to conclude that all probiotic strains are effective. The effectiveness of probiotics is strain-specific and disease-specific, so each probiotic strain must be linked to the disease. Most probiotic meta-analyses have focused on one type of disease indication with a variety of probiotic strains (e.g. antibiotic associated diarrhea)[ 123 , 138 , 139 ]. When there are sufficient numbers of clinical trials, a meta-analysis limited to one disease indication and one type of probiotic strain may reduce the heterogeneity of studies[ 140 ]. Szajewska et al[ 141 ] limited her meta-analysis to randomized controlled trials of one type of probiotic ( S. boulardii ) in adults and children. Pooling the results from five trials (involving 1076 subjects), a significantly protective effect of S . boulardii was found (pooled RR = 0.43, 95% CI: 0.23-0.78). As an alternative, some meta-analyses have done sensitivity analysis, separating out sub-groups by patient type (e.g. just adults or just children) or by type of probiotic strain[ 123 , 142 ]. One sensitivity analysis found with sufficient evidence that only two probiotic strains had significant efficacy for the prevention of AAD, i.e. S. boulardii and L. rhamnosus GG. However, L. rhamnosus GG probiotics may be contraindicated that this strain is susceptible when the patient is prescribed a type of antibiotic[ 123 ]. Although many meta-analyses have been done, pooling studies must be performed with these limitations in mind.

Epidemiology of C. difficile disease: For over two decades, Clostridium difficile infections continue to persist as a leading cause of nosocomial gastrointestinal illness[ 143 - 146 ]. The incidence rates of CDI have been increasing globally. In the US, CDI doubled to 301 200 cases from 2001 to 2005[ 147 ]. It is estimated that 450 000-750 000 CDI cases will occur per year by 2010 in the US[ 148 , 149 ]. Outbreaks of an emergent strain, BI/NAP1/027, caused large outbreaks of severe CDI with a high mortality rate in Canada between 2003-2005[ 150 ]. Studies have documented that CDI extends patients’ hospital stays from 4 to 36 d[ 151 - 154 ]. In a study of 1034 CDI cases in Massachusetts in 2000, the average cost ranged from $10 212-$13 675/patient[ 155 ], leading to a nation-wide cost of $3.2 billion/year for CDI. There are only two standard antibiotics for CDI (vancomycin and metronidazole) and the response rate of metronidazole has been declining[ 152 ]. In addition, 20%-60% of patients may develop recurrent episodes of CDI despite additional antibiotic treatment. Although other investigational antibiotics are under development, no new antibiotics are superior to the two standard antibiotics.

Efficacy evidence for C. difficile disease: Probiotics may offer promise as an adjunctive therapy (given along with standard antibiotics vancomycin or metronidazole) for CDI. A meta-analysis of six randomized controlled trials of different probiotics ( S. boulardii , Lactobacillus rhamnosus GG, L. planatarum 299v, and a mix of L. acidophilus and Bifidobacterium bifidum showed probiotics, in general, had a overall significant efficacy to prevent subsequent recurrences of C. difficile disease (RR = 0.59, 95% CI: 0.41-0.85, P = 0.005)[ 123 ]. However, due to limited number of trials, no meta-analysis was conducted for one probiotic strain.

S . boulardii shows promise for C. difficile infection control at several levels: it produces a 54-kDa serine protease that directly degrades Clostridium difficile toxins and also directly destroys the colonic receptor site for C. difficile [ 76 ], S . boulardii increases the immune response to Clostridium difficile toxins A and B[ 108 ], and animal models of C. difficile disease respond to this yeast. In addition, case reports or small case series of patients with recurrent C. difficile diarrhea treated with S. boulardii showed improvement. Toothaker and Elmer found that significantly fewer (51%) hamsters challenged with C. difficile died if given S . boulardii (5% solution) compared with the saline controls (80%)[ 156 ]. Subsequent studies confirmed this efficacy in other animal models: gnotobiotic mice[ 41 , 157 , 158 ], rats[ 89 , 103 ], and turkeys[ 159 ]. Since 1989, case reports or small case series have reported that patients with recurrent CDAD were either cured or improved by S . boulardii treatment[ 40 , 59 , 160 , 161 ].

There was a case report[ 162 ] and two small case series with 3-4 patients[ 163 , 164 ] with recurrent C. difficile disease who seemed to have responded to S. cerevisiae administration. However, since no comparison groups or controls were used, there is no foundation to claim the efficacy of other strains of Saccharomyces for C. difficile disease.

There have been two randomized, double blinded, controlled trials for the use of S. boulardii and antibiotics for patients with recurrent C. difficile disease (Table ​ (Table3 3 )[ 53 , 60 ]. In a multisite, randomized, double-blinded, placebo-controlled trial of 168 patients with recurrent C. difficile disease, standard antibiotics were combined with Saccharomyces boulardii or placebo[ 60 ]. Three antibiotic regimens were used for 10 d: either high-dose vancomycin (2 g/d), low-dose vancomycin (500 mg/d) or metronidazole (1 g/d). Then either S. boulardii or placebo (1 g/d for 28 d) was added to the antibiotic treatment. The patients were followed up for two months for subsequent Clostridium difficile recurrences. A significant decrease in recurrences was observed only in patients treated with the high-dose vancomycin and S. boulardii treatment (16.7%) compared with patients who received high-dose vancomycin and placebo (50%, P = 0.05). There were no significant reductions in recurrence rates in either the low-dose vancomycin or metronidazole treatment group, regardless if S. boulardii was used. No serious adverse reactions were noted in any of these patients. By the end of the antibiotic treatment, only high-dose vancomycin completely cleared C. difficile toxin from the colon, low-dose vancomycin and metronidazole could not clear the toxin. A subsequent investigation of 163 patients with recurrent CDI confirmed this finding[ 165 ]. In this study, stool samples were assayed at the end of antibiotic treatment to determine if there was a difference in toxin clearance by the type or dose of antibiotic. Treatment with high-dose (2 g/d) of vancomycin completely cleared C. difficile toxin, but 11% of those treated with lower doses of vancomycin and 41% treated with metronidazole were positive for C. difficile at the end of antibiotic treatment. S . boulardii may be more effective if complete C. difficile toxin clearance is achieved before sole reliance upon the yeast probiotic is required.

Randomized controlled trials for the treatment of C. difficile disease using S. boulardii

An earlier randomized, controlled double-blinded study had also found efficacy of the combination treatment using a standard antibiotic (vancomycin or metronidazole) and S. boulardii for patients with C. difficile disease[ 53 ]. This study did not control the dose or duration of either vancomycin or metronidazole (it was under the physician’s discretion), but randomized patients to either S. boulardii (1 g/d) or placebo for 28 d. All patients were followed up for two months for subsequent recurrences. Approximately half of the enrolled patients had their first episode and half had recurrent C. difficile disease. Twenty-six percent of the 57 patients given S . boulardii had a recurrence of C. difficile disease, which was significantly fewer as compared with 45% of the 67 given placebo ( P < 0.05). The strongest effect was found in the 60 patients with recurrent C. difficile disease; significantly fewer patients (35%) given S. boulardii had a recurrence compared with 65% of patients given placebo ( P = 0.04). Two adverse reactions were associated with S . boulardii (thirst and constipation). No randomized controlled trials using stains of S. cerevisiae for this disease were found in the literature.

Epidemiology of H. pylori : H. pylori colonizes the gastric mucosa and usually induces a chronic, asymptomatic carrier state, but some people may develop gastroduodenal ulcers as a result. Carriage of H. pylori is a risk factor for developing gastric lymphoma or adenocarcinoma in later life. The prevalence of H. pylori carriage is 50%-80% worldwide[ 166 , 167 ]. Standard treatment for H. pylori involves a two-week course of triple therapy (usually clarithromycin, amoxicillin and an acid suppressor such as lansoprazole or omeprazole), that also has gastrointestinal side effects.

Efficacy for H. pylori : S. boulardii induces morphologic changes in H. pylori cells consistant with cellular damage[ 21 ] and was shown to reduce 12% of H. pylori colonization in infected children in one trial[ 46 ]. Of four randomized controlled trials testing S . boulardii in H. pylori infections, two were in children[ 46 , 168 ] and two (Table ​ (Table4) 4 ) were in adults[ 42 , 134 ]. Cremonini et al[ 134 ] first explored the efficacy of probiotics to eradicate H. pylori in 85 asymptomatic carriers. They randomized patients to one of three probiotic treatments ( S . boulardii , L. rhamnosus GG or a mixture of L. acidophius and Bifidobacterium lactis ) or placebo for 14 d. All patients were treated with the triple therapy for the first week. By the end of the second week, eradication rates were similar for all groups (81% for S . boulardii vs 80% of placebo). A promising result of this study was a lower rate of antibiotic-associated diarrhea (5%) in all the probiotic groups compared with 30% of the placebo group. A subsequent study by Cindoruk et al[ 42 ] assessed S . boulardii for both eradication of H. pylori and the reduction of side-effects of the standard triple treatment. This study enrolled 124 adults with H. pylori dyspepsia in Turkey who were receiving the triple therapy and randomized to either 1 g of S . boulardii (2 × 10 10 /d for 2 wk) or placebo. Patients were followed up for six weeks for side-effects and H. pylori clearance. Although there was no significant difference in H. pylori eradication (71% in S . boulardii vs 60% in placebo), significantly fewer patients randomized to S . boulardii reported epigastric distress (14.5%, P < 0.05) compared with placebo (43.5%), as well as lower global dyspepsia symptom scores. The frequency of AAD was also significantly reduced in those receiving S . boulardii (14.5%) compared with the placebo group (30.6%). These studies indicate that S . boulardii may not be effective in eradicating H. pylori itself, but it is effective in reducing the side-effects of the standard triple therapy.

Randomized, controlled trials for acute disease conditions using S. boulardii

Acute adult diarrheas

Epidemiology of acute adult diarrhea: Acute adult diarrhea is a broad classification for diarrhea that includes illnesses that may develop quickly, but are typically short-lived and are sporadic. The etiologies of acute adult diarrhea may include infectious agents ( Entamoeba histolytica , E. coli , or Salmonella) or may be idiopathic. Diarrhea in adults occurring in outbreaks or due to other situations (antibiotic-associated diarrhea, C. difficile -associated diarrhea, traveler’s diarrhea, inflammatory bowel disease or irritable bowel disease) are not included in this classification.

Clinical efficacy for acute adult diarrhea: Two randomized controlled trials using S . boulardii showed that this probiotic may be effective in treating acute diarrhea due to a variety of causes. Hochter et al[ 169 ] enrolled 92 German adult outpatients with acute diarrhea and randomized them to S . boulardii (8 × 10 9 /d) or placebo for eight days. By the third day, the 43 given S . boulardii had a significantly lower diarrhea severity score (5.5 ± 6.8, P = 0.04) compared with the 49 given placebo (6.7 ± 8.7). Mansour-Ghanaei et al[ 51 ] enrolled 57 patients with acute Entamoeba histolytic dysentery and treated them with S . boulardii (1.5 × 10 10 /d for 10 d) or nothing (control). Both groups also received metronidazole and iodoquinol for 10 d. At the end of four weeks, all the patients given S . boulardii were cured compared with 19% of those not given the yeast. Unfortunately, the number of trials in this area is small and the etiologies were different in the two trials, so conclusions are limited. No randomized controlled trials using stains of S. cerevisiae for this disease were found in the literature.

Enteral nutrition-related diarrhea

Epidemiology of enteral nutrition-related diarrhea: Diarrhea is a common complication associated with enteral tube feeding and may result in a loss of nutrition in an already seriously ill patient. The frequency of diarrhea in enteral tube fed patients has been reported as high as 50%-60%[ 170 ] and complications may include life-threatening acidosis, increased morbidity and mortality and increased healthcare costs. Schneider et al[ 102 ] reported a significant increase in short-chain fatty acids in 10 enteral-fed patients receiving S . boulardii (1 g/d for 6 d) compared with 15 healthy controls.

Clinical efficacy for enteral nutrition related diarrhea: Three randomized, controlled trials have assessed the ability of S. boulardii to reduce diarrhea in patients receiving this type of nutritional intake (Table ​ (Table4). 4 ). Tempe et al[ 61 ] compared 40 enteral-fed patients randomized to either S . boulardii (1 × 10 10 /d) or placebo for 11-21 d and found significantly fewer patients (8.7%) given S . boulardii developed diarrhea compared with placebo (16.9%). Schlotterer et al[ 171 ] randomized 18 patients with burns who were receiving enteral nutrition to S . boulardii (4 × 10 10 /d) or placebo for 8-28 d. Those given S . boulardii suffered fewer diarrhea days (3/204 d, 1.5%) than those given placebo (19/208 d, 9.1%, P < 0.001). The efficacy of S . boulardii was confirmed in a later study of 128 intensive care unit (ICU) patients randomized to either S . boulardii (4 × 10 10 /d) or placebo for 21 d[ 39 ]. Those given S . boulardii reported significantly fewer diarrheal days (7.7%) than those given placebo (12.7%). No adverse reactions associated with S . boulardii were reported in any of these three trials.

Traveler’s diarrhea

Epidemiology of traveler’s diarrhea: Traveler’s diarrhea (TD) is a common health complaint among travelers; globally 12 million cases are reported every year[ 172 ]. Rates of TD range from 5% to 50%, depending upon the destination, with equatorial countries having the highest rates of TD. TD usually occurs as sporadic cases, but outbreaks of TD may occur in large groups traveling or located together (tourists on cruise ships, group tours, military personnel, disaster-relief groups). The etiologies of TD vary widely, but commonly include enterotoxigenic and entroaggregative E. coli , Campylobacter jejuni , Salmonella typhimurum , viruses (Norwalk or Rotavirus) or parasites ( Entamoeba histolytica , Giardia lamblia ). Traditional preventive measures including frequent handwashing, avoiding high-risk foods and water and ingestion of bismuth subsalicyclate showed only modest protection[ 173 ].

Clinical efficacy for TD: A meta-analysis of 12 randomized, controlled trials of various probiotics (including S. boulardii , Lactobacilli and mixtures of different probiotic strains) for the prevention of TD found a significant reduction in the risk of TD if probiotics were used (RR = 0.85, 95% confidence interval 0.79-0.91)[ 174 ]. Two randomized controlled trials have been done with S. boulardii that included a total of four different probiotic treatment arms (Table ​ (Table4). 4 ). Kollaritsch et al[ 175 ] enrolled 1231 Austrian tourists traveling to hot climates and randomized travelers to either of two doses of S. boulardii (250 or 500 mg/d) or placebo for 3 wk. The treatment was started 5 d prior to the trip and continued through the duration of the trip. Traveler’s diarrhea developed in 43% given placebo and significantly fewer in those given the low-dose S. boulardii (34%) and the higher dose S. boulardii (32%). A second study by Kollaritsch et al[ 49 ] was done with 3000 Austrian tourists traveling to northern African, the Middle East and the Far East. Travelers were randomized to either 250 mg/d (5 × 10 9 ) S. boulardii , 1000 mg/d (2 × 10 10 ) S. boulardii or placebo, starting five days before leaving and throughout the duration of their trip (median of 3 wk). Only 1016 (34%) completed the study, but S. boulardii significantly reduced the incidence of traveler’s diarrhea in a dose-dependent manner. Of the travelers given placebo, 39% developed diarrhea whereas only 34% of those given the lower dose and 29% of those given the higher dose of S. boulardii developed traveler’s diarrhea ( P < 0.05). No adverse reaction was noted by the travelers in either of these studies.

Bruns et al[ 176 ] tested S . cerevisiae Hansen CBS 5926 (Perenterol ® , Germany) to treat travelers who had developed TD in Tunisia. Travelers with TD were randomized to 600 mg of S . cerevisiae (1 × 10 10 /d) for five days or an active control treatment and the duration of their TD tracked. Of 60 enrolled, 43 completed the trial, but the duration of diarrhea was not significantly different between those given S . cerevisiae (2.1 d) and those given ethacridine-lactate and tannalbuminate (1.4 d). This strain is known as S. boulardii outside of Germany. No other randomized controlled trials have been done for the treatment of TD using S. boulardii . These limited numbers of studies indicate that probiotics may be more effective in preventing TD, rather than treating the diarrhea once it becomes symptomatic.

CLINICAL EFFICACY: CHRONIC DISEASES

S. boulardii has been tested for clinical efficacy in several types of chronic diseases including Crohn’s disease, irritable bowel syndrome, giardiasis and human immunodeficiency virus (HIV)-related diarrhea.

Inflammatory bowel disease

Epidemiology of inflammatory bowel disease: inflammatory bowel diseases (IBDs) are chronic, immune-related inflammatory diarrheas, which include ulcerative colitis, pouchitis and Crohn’s disease. The incidence of Crohn’s disease varies by countries, with the highest incidences (8-66/100 000) found in Wales, New Zealand, Canada, Scotland, France, Netherlands, intermediate rates (4-7/100 000) in UK, USA, Europe, Australia, and the lowest rates (0.2-3/100 000) in South America, China, Korea, Japan[ 177 ]. In Crohn’s disease, typically the lower small intestine and colon are the most affected organs. Symptoms include diarrhea, abdominal pain or cramping and loss of appetite. Unlike ulcerative colitis, lesions of Crohn’s disease are deep and patchy and often involve thickened areas resulting in intestinal obstruction, which can be life threatening. Disruption of the intestinal wall also allows intestinal bacteria to translocate and incite the immune system. Complications of Crohn’s disease are common, in that 40% of Crohn’s patients report lower GI bleeding, intestinal obstruction, or perforation[ 178 ]. Lifetime risk for surgery in Crohn’s patients is extremely high (70%-80%)[ 179 ]. Unfortunately, the cause of Crohn’s disease is not known, so current therapies are directed at symptom relief. But 10%-60% suffer recurrences of Crohn’s disease after treatment is completed[ 180 ].

Clinical efficacy for IBD: Guslandi et al[ 48 ] enrolled 25 adults with mild to moderate ulcerative colitis in a pilot study and treated them with a combination of mesalazine (3 g/d) and S . boulardii (1.5 × 10 10 /d) for 4 wk. All of these patients had histories of poorly tolerated steroid courses. Most (68%) of the patients responded to the probiotic treatment. This study had a promising result, but the implications were uncertain as patients treated for only a short time, were not followed up for subsequent flare-ups of their disease and there was no control group in this pilot study. Garcia Vilelea et al[ 62 ] enrolled 31 patients with Crohn’s disease in remission (at the time of enrollment). All patients continued their maintenance medications during the trial (mesalamine, azathioprine or others). Patients were randomized to either S . boulardii (2 × 10 9 /d) for three months or placebo. Those treated with S . boulardii were found to have a significant reduction in colonic permeability compared with those given placebo, thus reducing the risk of translocation in these patients.

Two randomized controlled clinical trials have been done testing S . boulardii for patients with Crohn’s disease (Table ​ (Table5 5 )[ 47 , 57 ]. Plein et al[ 57 ] randomized 20 patients with Crohn’s disease to either 750 mg of S . boulardii (1.5 × 10 10 /d) or placebo for seven weeks. All patients continued their maintenance medications during the trial. At the end of seven weeks, patients treated with S . boulardii were significantly improved (mean = 3.3 ± 1.2 stools/d, P < 0.05) compared with the placebo group (mean = 4.6 ± 1.9 stools/d). Guslandi et al[ 47 ] studied the effect of S . boulardii on the rate of Crohn’s disease relapses in a study of 32 patients with Crohn’s disease in Italy. Adults (23-49 years old) who were in remission were randomized to either 1 g of S . boulardii (2 × 10 10 /d) and mesalamine (2 g/d) or mesalamine alone (3 g/d) for 6 mo. Significantly fewer patients treated with S . boulardii (6%, P = 0.04) relapsed than the control group (38%). No adverse reactions associated with S . boulardii were reported in any of these trials.

Randomized, controlled trials for chronic disease conditions using S. boulardii

Crohn’s disease is a challenging condition for clinical trials in that it is sporadic, has no defined etiology, has multiple measurable disease outcome and requires lengthy treatment and follow-up period. S . boulardii offers promise to this group of patients who are in need of a safe and effective therapy for this chronic condition. The probiotic protection seems to be strain specific. A study tested another strain of S. cerevisiae (Baker’s yeast) in 19 adults with Crohn’s disease, but found the disease was worse in those receiving this strain than in controls[ 181 ].

Irritable bowel syndrome

Epidemiology of irritable bowel syndrome: Irritable bowel syndrome (IBS) is a frequent disorder characterized by a triad of symptoms (bloating, abdominal pain, and intestinal transit disturbances). The prevalence of IBS is high (3%-20%) in the general population and IBS may account for 25%-50% of gastroenterologist practice[ 182 ]. Consequences of IBS include worse quality of life[ 183 ], higher health care costs ($1.7 billion in health care costs)[ 184 ], and higher incidences of depression[ 185 ].

Clinical efficacy for IBS: Standard treatments target symptom relief, but have not been more effective than placebo. IBS is a recent focus of probiotic clinical trials. A meta-analysis of 20 randomized, controlled trials (with 23 treatment arms) including 1404 subjects found a pooled relative risk (RR) for improvement in global IBS symptoms in 14 probiotic treatment arms (RR = 0.77, 95% CI: 0.62-0.94)[ 36 ]. One of those trials (Table ​ (Table5) 5 ) randomized 34 patients with IBS to S . boulardii (9 × 10 9 /d) or placebo for four weeks[ 52 ]. A significant decrease in the daily number of stools was found in the S . boulardii group and 87.5% of this group reported their IBS had improved compared with 72% of the placebo group ( P < 0.05). No adverse reactions were noted in this trial. More trials using S . boulardii for IBS are required.

Epidemiology of giardiasis: This condition is characterized by long lasting diarrhea with symptoms ranging from mild to severe diarrhea, weight loss, abdominal pain and weakness. The incidence may be high in developing countries such as Colombia (13%) and lower in developed countries such as Germany (12/100 000)[ 186 , 187 ]. It is also found in people enjoying outdoor hiking and camping who drink contaminated untreated water that appears clean.

Clinical efficacy for giardiasis: Besirbellioglu et al[ 38 ] randomized 65 adults with giardiasis in Turkey to either S . boulardii (1 × 10 10 /d) or placebo for 10 d. Both groups also received metronidazole for the same duration. Two weeks later, both groups reported a resolution of their diarrhea, but none of those on S . boulardii had detectable giardia cysts, while significantly more (17%) on placebo still carried giardia cysts.

HIV diarrhea

Epidemiology of HIV-related diarrhea: Patients infected with HIV are susceptible to a variety of diseases and may also develop chronic life-threatening diarrhea. The prevalence of diarrhea in HIV patients ranges from 50%-60% in developed countries and nearly 100% in developing countries[ 188 ].

Clinical efficacy for HIV-related diarrhea: A blinded, placebo-controlled dose-ranging study was done in 11 HIV positive patients who had chronic diarrhea[ 45 ]. S . boulardii was given at 1-3 g/d and six patients reported diarrhea was controlled while taking 3 g/d after one month, while lower doses of S . boulardii were not as effective. Patients with HIV-associated diarrhea seem to be one group that requires a higher than typical dose of S . boulardii . Saint-Marc et al[ 189 ] randomized 35 Stage IV AIDS adult patients with chronic diarrhea to either S . boulardii (3 g/d or 6 × 10 10 /d) or placebo for one week (Table ​ (Table5). 5 ). Significantly more of those given S . boulardii (61%, P = 0.002) had their diarrhea resolved compared with placebo (12%) patients. S . boulardii was well tolerated by all HIV patients even treated with high doses of 3 g/d in these two studies.

SAFETY OF S. BOULARDII

The use of a living organism as therapy increases the potential risk in four general areas: transfer of antibiotic-resistance genes, translocation of the living organism from the intestine to other areas of the body, persistence in the intestines and the development of adverse reactions. The first three theorical concerns are of minimal impact on S . boulardii . Unlike other bacterial strains of probiotics, such as Enterococcus faecium and Lactobacillus rhamnosus , which have been shown to acquire antibiotic-resistance genes, S . boulardii has not developed any antibiotic or antifungal resistance[ 190 , 191 ]. Data from animal models shows reduced translocation with S . boulardii treatment[ 64 , 89 ], unlike other strains of S. cerevisiae [ 192 ]. As pharmacokinetic studies indicate, S . boulardii does not persist 3-5 d after oral ingestion is discontinued, so persistence is not a concern for this probiotic[ 118 ].

S . boulardii has been used as a probiotic since the 1950s in Europe and has been investigated in clinical trials worldwide. Safety and adverse event data collected during clinical trials, when patients are closely monitored for problems associated with the investigational treatment, has documented a remarkable safety profile of S . boulardii in adults. A wide diversity of adult patients have been followed up who were either randomized to S . boulardii as part of a clinical trial or were documented in case series or case reports for various disease indications (TD, n = 1596; AAD, n = 958; adult acute diarrhea, 156; enteral tube feeding, n = 103; IBD, n = 66; IBS, n = 16, HIV-related diarrhea, n = 18 and giardia infections, n = 50). These studies provide safety data for a total of 2963 adult patients and the only adverse reactions associated with S . boulardii was thirst (in 5 patients) and constipation (in 8 patients) in a trial of patients with C. difficile infections[ 53 ]. No case of S . boulardii fungemia has been reported in these diverse patient populations enrolled in clinical trials.

Infrequent cases of fungemia have been reported in case reports or case series in the literature. Most of the adult cases of S . boulardii fungemia are with serious co-morbidities and have central venous catheters. Most cases responded well to treatment with fluconazole or amphotericin B[ 193 ]. Some cases developed fungemia, not from the direct ingestion of S . boulardii probiotics, but acquired the yeast from contaminated environmental fomites[ 194 ]. Fungemia from S. cerevisiae (non-boulardii strains) have also been reported and are similar to S . boulardii cases, but have poorer prognosis[ 195 , 196 ]. A challenge to determining valid incidence of fungemia is the lack of available advanced yeast identification assays which can distinguish S. cerevisiae from S. boulardii .

CONTRAINDICATIONS/PRECAUTIONS

Even though fungemia with S . boulardii is infrequent, it may be prudent to closely follow up the adult inpatients who are severely ill or in intensive care units and have central catheter for episodes of unexplained fever. Some studies have recommended not to give S . boulardii to immunosuppressed patients or those with central catheters to reduce this risk[ 108 ].

Unlike many bacterial probiotics, there are few drug or antibiotic interactions with S . boulardii . However, if patients are on anti-fungal medications, a staggered dose regime (at least 4 h apart) is suggested[ 45 ].

The use of S . boulardii as a therapeutic probiotic is supported by its mechanisms of action, pharmacokinetics, and efficacy from animal models and clinical trials. The overall safety profile for S . boulardii is beneficial. S . boulardii can be recommended for several diseases. Other strains of Saccharomyces may have probiotic properties, but clinical efficacy evidence for other strains are still deficient. Guidelines for the most effective use of S. boulardii are given in Table ​ Table6 6 and generally, the daily dose is typically > 10 9 /d, the duration of treatment can vary from 7 d to 6 mo and it may be given alone or as an adjunctive treatment, depending upon the disease indication. S. boulardii is significantly effective for the prevention of AAD and prevention of TD. Trials also show evidence for S. boulardii in the reduction of side-effects of H. pylori treatment and the prevention of enteral nutrition-related diarrhea. More clinical trials are encouraged for the treatment of chronic diseases (Crohn’s disease, irritable bowel syndrome and HIV-related diarrhea) and the prevention of C. difficile disease recurrences.

Summary of recommendations for clinical use of S. boulardii in adults

Acknowledgments

The author had full access to all of the data in the Meta-nalysis and takes responsibility for the integrity of the data and accuracy of the data analysis. The author has been a paid speaker/consultant for the following companies: Acambis, Biocodex, Lallemand, Massachusetts Biologic Laboratories and Osel, Inc.. The author is not currently employed nor owns stock or equity in any of these companies. The views expressed in this article are those of the author and do not represent the views of the Department of Veterans Affairs.

Peer reviewer: Andrew S Day, MB, ChB, MD, FRACP, AGAF, Associate Professor, Department of Paediatrics, University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New Zealand

S- Editor Tian L L- Editor Ma JY E- Editor Ma WH

Perenterol: Indications, Mechanism of Action, Dosage, Side Effects, Warnings, Contraindications and Interactions

Saccharomyces boulardii is a tropical yeast strain first isolated from lychee and mangosteen fruits in 1923..

The active ingredient in parenteral is a fungus, yeast type; Saccharomyces boulardii is a microorganism that exerts an  antidiarrheal action  in the body.

Saccharomyces boulardii is a “probiotic” which helps fight disease-causing organisms in the gut, such as pathogenic bacteria and yeasts.

Active ingredient

The active ingredient in parenteral is a yeast: lyophilized Saccharomyces boulardii.

Presentation

Parenteral is presented to the market in:

• Sachets:   contains lyophilized Saccharomyces boulardii, at least 2 billion live cells (250 mg), lactose (32.5 mg), vanillin, flavors, and other excipients.
• Capsules:   Contains lyophilized Saccharomyces boulardii, at least 2 billion live cells (250 mg), lactose (32.5 mg), and other excipients.

Indications

Parenteral is indicated in the treatment of diarrhea such as:

Diarrhea in people taking antibiotics

Saccharomyces boulardii is used to treat and prevent diarrhea due to antibiotics in adults and children.

For every 9 to 13 patients treated with Saccharomyces boulardii, at least one will develop antibiotic-related diarrhea during antibiotic treatment.

Diarrhea after tube feeding

In patients who have had feeding tubes or tubes, Saccharomyces boulardii can prevent diarrhea.

Infant diarrhea

Saccharomyces boulardii also appears to shorten the duration of diarrhea in children with persistent diarrhea.

It helps reduce the time that acute diarrhea persists in infants and children, between 12 hours and one day.

Rotavirus diarrhea

Research shows that giving Saccharomyces boulardii to infants and children can shorten the duration of diarrhea caused by rotavirus by approximately one day.

Oral administration of Saccharomyces boulardii improves the appearance of acne skin.

Diarrhea is caused by the bacteria Clostridium difficile

Taking Saccharomyces boulardii and antibiotics appears to help prevent the recurrence of Clostridium difficile-associated diarrhea in people with a history of reproduction.

Taking Saccharomyces boulardii along with antibiotics also appears to help prevent the first bouts of diarrhea associated with Clostridium difficile.

But specialists do not recommend using Saccharomyces to prevent the first episodes.

Helicobacter pylori

Oral administration of Saccharomyces boulardii in conjunction with Helicobacter pylori treatment helps treat this infection; it also helps prevent side effects such as diarrhea and nausea caused by the impact of the standard Helicobacter pylori treatment.

HIV-related diarrhea

Oral administration of Saccharomyces boulardii reduces diarrhea related to the Human Immunodeficiency Virus.

Traveler’s diarrhea

Oral administration of Saccharomyces boulardii prevents traveler’s diarrhea.

Mechanism of action

The primary function of Saccharomyces boulardii is to replace the pathogenic flora of the intestine.

Saccharomyces boulardii acts in the digestive tract and restores the balance of the intestinal ecosystem.

Saccharomyces boulardii exerts a protective, preventive, and curative effect on the diarrhea of ​​various origins:

• Enterotoxigenic diarrhea due to Escherichia coli
• Colitis due to Clostridium difficile
• Digestive infestations due to Candida
• Intestinal amebiasis due to Entamoeba histolytica

The following mode of action can explain the effects observed in animal models:

• Inhibiting the effects or production of bacterial toxins, such as Escherichia coli heat-stable enterotoxin, cholera toxin, and Clostridium difficile cytotoxin.
• Reinforcing non-specific anti-infective defenses.
• Microbial antagonism to various pathogenic microorganisms such as Escherichia coli, Salmonella typhi, Shigella dysenteriae, and Candida albicans.
• Increased activity of intestinal disaccharidases.

Oral administration of parenteral is carried out as follows:

For diarrhea

Attack treatment:  on the first day, two sachets or two capsules (1 in the morning and 1 in the afternoon).

The attack treatment can continue on medical prescription if necessary for several days.

Maintenance treatment:  the following days, one sachet or one capsule per day until the symptoms disappear.

If vomiting occurs within an hour after taking medicine, repeat the administration.

Parenteral can be given to babies, children, and adults in the same dose.

Antibiotic-induced diarrhea (prevention and treatment)

Dosage:  up to 1 g per day, up to 4 capsules or 4 sachets per day.

Diarrhea after a T4 feeding tube

Dosage:  up to 2 g per day, up to 8 sachets per day.

Dlperenterol how to use is:

Mix the contents of the sachet in a liquid or food in the form of a puree, and in babies, pour the contents of the sachet over a puree or in a bottle. It must be ensured that the temperature is not too high (it must not exceed 50 ° C).

Swallow the capsule with a sip of liquid.

Parenteral can be taken at any time of the day. Administration before meals promotes faster action.

Due to the risk of contamination in the air, the sachets or capsules should not be opened in the patient’s room.

Side effects

The side effects that may occur are:

• Fever (systemic infections with Saccharomyces).
• Fungemia in critically ill or immunocompromised patients or patients with central venous catheters.
• Itching, hives, local or generalized rash, redness of the skin, and Quincke’s edema.
• Anaphylactic shock.
• Shortness of breath
• Swelling of the gastrointestinal tract.

Warnings and Contraindications

Because the risk of systemic colonization with Saccharomyces boulardii has not been evaluated so far, this drug should not be used in patients with weak immune defenses such as HIV, organ transplantation, leukemia, malignancies, radiotherapy, chemotherapy, cortisone treatment in long-term high doses.

Sufficient rehydration should be provided depending on the condition and age of the patient, as well as the severity of diarrhea.

Sporadic cases of fungemia with positive blood culture for Saccharomyces have been reported, mainly in patients with central venous catheters, critically ill patients, or immunocompromised patients.

In these cases, they have manifested most of the time due to fever.

In most of these cases, the course was favorable after discontinuation of Saccharomyces boulardii treatment, administration of antifungal therapy, and, if appropriate, removal of the catheter.

As with any drug containing live microorganisms, special care should be taken when handling the product in the presence of patients, mainly carriers of a central venous catheter and peripheral ones, even if these patients are not treated with Saccharomyces boulardii.

Healthcare professionals should wear gloves when handling probiotics during administration, dispose of them carefully and wash their hands immediately after use.

The product can also be taken with an antibiotic but not antifungal medicine.

Interactions

The active substance, Saccharomyces boulardii, is sensitive to antifungal medications. Therefore Perenterol cannot be used at the same time as these medications.

Since Perenterol is made from living cells, it should not be mixed with liquids or foods that are very hot (over 50 ° C), with ice, or with alcohol.

Saccharomyces boulardii can give false-positive results in microbiological stool tests.

About the author.

Dr. Cameron Troup MD

Dr. Cameron Troup,, MD is a family medicine specialist in Eastchester, NY and has been practicing for 25 years. He specializes in family medicine.

Perenterol® Junior

For all types of diarrhoea*.

Perenterol ® Junior contains the medicinal yeast Saccharomyces boulardii and is an effective and well-tolerated product for the treatment of diarrhoea in children. Due to its variety of mechanisms of action, it is suitable for diarrhoea of various causes.

Reliable and the natural effect.

• * For acute cases and prevention (when travelling)
• Detoxifies the bowel and restores intestinal flora
• For children aged 2 years an over as self-medication; under 2 years of age after consulting a doctor.
• Covered by health insurance in infants and children up to the age of 12 years.
• Perenterol ® Junior is available on a fixed-rate basis; no additional payment.

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Home parenteral nutrition (HPN)

Traveling with parenteral nutrition

Until a few years ago, people being fed through parenteral nutrition, traveling was impossible and even after that meant a great challenge for quite some time. It’s no surprise that many affected are still scared to be away from their homes. It isn’t seldom that patients are fed parenterally for 30 years or longer and thereby never leave their home. Often, there is a lack of support and encouragement – and, not the least, a lack of practical experience.

"Once I finally hear the waves, feel the wind and the sun, I feel healthy. After all the planning and preparation, I am unbelievably thankful."

Planning your trip is key

More and more people who are dependent on parenteral nutrition are daring to meet the challenges coming along with traveling. Santra, Rhona, Rachel, Marek, Ratislav and Artur talk about the kinds of fears and obstacles they have overcome, experiences they have made, and tips they give others for their journeys. 

Regardless of where their travels take them, how far they travel, and whether they are gone for three or 30 days – all HPN globetrotters agree on one thing: thorough planning is key.

Rhona from England doesn’t spare any effort to visit the places she is longing for time and again. She admits that travel preparations take a great deal of energy:

“It is hard work and all kinds of organization is necessary to travel with HPN. But regardless: nothing is insurmountable. Besides, I know that brand new – and mostly wonderful – experiences are waiting for me.” Rhona from England

In her opinion, it is very important to get into contact with the HPN provider: “The advice and support that I receive are of inestimable value.” Furthermore, she finds it extremely helpful to talk about the entire trip from A to Z with a person of trust and at the same time consider even the smallest of details.

Well prepared

A good plan is half the journey

Parenteral nutrition radically changes your life – you might even wonder whether travelling will be a thing of the past. It doesn’t have to be! Your head may be swimming with questions about planning and logistical concerns, but don’t let that stop you – every question has an answer.

Whether for long-distance, day or weekend trips, make sure to clarify all questions in advance.

Consider the following when choosing your destination:

The climate

A temperate climate without high humidity

The hygiene standards

... adequate hygiene conditions.

The medical care

... access to an Home Parenteral Nutrition center.

The sanitary facilities

... accommodation with running water.

Refrigerator availability

... access to a refrigerator with constant temperature.

Have a pleasant trip

... lots of fun and relaxation!

A backpack against travel nerves

Your backpack might not be the flying carpet but it’s the next best thing because it makes traveling with HPN possible in the first place. To give you wings and not weigh you down, it should be light weight, made of innovative materials and have an intelligently designed interior.

• Make sure you’ve got your emergency kit, your medical certificate and a spare battery for your pump.
• Make sure that your backpack is clean and tidy in order to protect you against infection and potentially stressful situations.
• Be sure that the tube won’t easily bend or tangle during storage
• Check that the pump and the infusion work perfectly and that the HPN nutrition bag is properly filled.

Efforts that are definitely worth it

No doubt that traveling - whether by car, airplane or ferry - means also hassles and efforts. But there is a further phenomenon that all HPN travelers mention: the help and support they experience in every corner. And not just from medical professionals or service personnel. Whether it is the extra suitcase that can be checked in without additional costs, the hotel personnel who store the food already shipped before the guest arrives, or the host who antiseptically cleans the kitchen so that food can be prepared.

"For me, traveling means no longer being controlled by the circumstances surrounding my disease, but being able to live my life."

At the same time Santra confirms: "Of course, there are always moments where you have to deal with fear. For me, for example, it’s a nail-bite every time my bags with HPN disappear on the conveyor belt in the direction of the plane. After we arrive, I wait nervously for this small box whose contents keep me alive, and then I am incredibly relieved once it finally shows up." 

Also Rastislav from Slovakia is familiar with dicey situations. Once, he just couldn’t find his disinfection spray and was already prepared to find a pharmacist, when he eventually could retrieve the spray in his backpack. 

"HPN keeps me alive. But it also gives me the opportunity to meet people and to get to know other countries. This is wonderful because it gives me so much energy and joy."

Artur from Poland reports that he became nervous when his return flight from Portugal to Warsaw was suddenly cancelled and he wasn’t sure whether his supply of food would suffice until he got home. It did.

"For too long I believed that I couldn’t travel anymore. But then I dared to do it – and it was the best decision I have ever made."

Marek, who travels with his family and by no means wants to miss these experiences, is also familiar with such situations. He knows all too well that the “path to freedom”, as he calls it, is neither risk-free nor effortless. “But it’s one thing for me: indispensable. Because when we take this path, we are rewarded incredibly.”

"The vacations with my family are infinitely precious moments. I hope that they remain present in my children’s memories for some time."

If things do end up becoming tricky... 

“By no means rush around trying to manage everything at once,” suggests Rhona. “Instead, handle one thing after the other – calmly and focused.”

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Perenterol Uses, Dosage, Side Effects, Food Interaction and all others data.

Perenterol is a fungus which can provoke allergic reactions. Perenterol is used in allergenic testing.

Table Of contents

• Side Effect
• Precautions
• Interactions
• Uses during Pregnancy
• Uses during Breastfeeding
• Accute Overdose
• Food Interaction
• Volume of Distribution
• Interaction With other Medicine
• Contradiction

Perenterol is an extract from Perenterol used in allergy testing.

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You find simplified version here Perenterol

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A Guide to Traveling During Fertility Treatment

Sep 20, 2022

Alto Pharmacy

Traveling during fertility treatment may feel overwhelming, but it’s definitely doable. While the fertility journey involves many moving parts, careful planning and coordination with your care team can help you take a trip without impacting your treatment. Use the suggestions below to prepare for your travels. 

Advanced preparation is important when traveling with any medication . Given the complex and time-sensitive nature of fertility treatment, the planning process involves a few more steps.

First, consult your doctor about your plans and make sure your intended travel dates don’t conflict with your treatment. In vitro fertilization (IVF) requires very thorough travel planning, since it entails multiple in-person doctor’s appointments and a very carefully timed egg retrieval. Other treatments such as intrauterine insemination (IUI) may leave more room for flexibility.

Regardless of your specific treatment plan, make sure you are up to date on vaccines and be sure to monitor health-related travel alerts. The CDC advises that women who intend to conceive consult their physician before traveling to a destination with potential exposure to the Zika virus.

Lastly, make sure that you have more than enough of your fertility medication(s) and supplies on hand. Aim for several additional days’ worth. Needles used to inject medications require a prescription in some states, so bring extra to avoid unnecessary hassle.

If you are traveling near an Alto location , same-day delivery of fertility medications and supplies may be available.

Pack your medications and supplies in a carry-on

When traveling by plane, it’s always best to pack important medications and supplies in your carry-on rather than in a checked bag. Bring everything you need to safely administer your medications, including syringes, needles, alcohol swabs, hand sanitizer, gauze, and a sharps disposal container.

While the U.S. Transportation Security Administration (TSA)’s current limit on liquids, gels, and creams in a carry-on is 3.4 ounces (100 milliliters), there are exceptions for medications . Bringing needles onto a plane is acceptable when accompanied by injectable medications.

Give yourself extra time to allow for additional screening of these items. The following tips may help you get through security as efficiently as possible.

Inform the TSA officer that you are carrying more than 3.4 ounces of liquid medication before your screening process begins, if applicable.

Bring a copy of your prescription(s) with you.

Keep all medications and supplies in their original packaging.

Put your medications and supplies in a separate, clear bag, as they will need to be separated from the rest of your belongings.

Store your medications at the appropriate temperature

Refrigeration is essential with many fertility medications. (At Alto, we ensure that medications are held at the right temperature before you receive them and guide you on safe at-home storage.)

Many people use frozen gel packs and insulated medication bags to store fertility medications at an appropriate temperature while traveling. (This approach is particularly useful for air travel.) As you finalize your travel plans, verify that your hotel or other accommodation offers access to a refrigerator or mini fridge.

Choose a flexible and reliable pharmacy partner

Fertility treatment can be stressful, let alone traveling during the process, but we’ll be with you every step of the way. We offer free, same-day delivery of medication and supplies right to your doorstep, and our dedicated fertility team is here to answer any questions you may have before your trip.

Interested in learning more about how Alto can support your fertility treatment? Request a price quote online or reach out through secure in-app messaging or by phone at 1-800-874-5881.

This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition.

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• Perenterol travel

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Was ist es und wofür wird es verwendet?

Was müssen sie vor dem gebrauch beachten, wie wird es angewendet, was sind mögliche nebenwirkungen, wie soll es aufbewahrt werden, weitere informationen.

Zulassungsinhaber

Zambon Switzerland Ltd

Medikamente mit gleichem Wirkstoff

• Gebrauchsinformation

Perenterol travel ist ein Antidiarrhoikum und enthält als Wirksubstanz einen Hefepilz (Saccharomyces boulardii). Es dient zur Behandlung von Reisedurchfall. Es ermöglicht die Wiederherstellung der Darmflora und die Linderung des Durchfalls .

Perenterol travel reguliert und normalisiert die Darmtätigkeit.

In verschiedenen Untersuchungen konnte eine hemmende Wirkung auf die Entwicklung verschiedener schädlicher Bakterien und Candida albicans festgestellt werden.

Die Hefe Saccharomyces boulardii ist gegenüber Antibiotika resistent und wirkt in lebender Form im Darminnern. Sie wird nicht vom Körper aufgenommen.

Was sollte dazu beachtet werden?

Bei Durchfallerkrankungen soll der Patient/die Patientin (speziell Kinder und ältere Personen) genügend Flüssigkeit zu sich nehmen. Wenn die Krankheit länger als 2–3 Tage dauert, sollte der Arzt/die Ärztin konsultiert werden. Bei Säuglingen kann eine Durchfallerkrankung wegen des Flüssigkeits- und des Salzverlustes rasch, schon nach einem Tag, bedrohlich werden. Konsultieren Sie deshalb Ihren Arzt/Ihre Ärztin rechtzeitig.

Wann darf Perenterol travel nicht angewendet werden?

Bei Überempfindlichkeit gegenüber dem Präparat. Hefeallergie, insbesondere gegen Saccharomyces boulardii.

Perenterol travel darf nicht bei Patienten mit schwerer Immunschwäche (z.B. HIV-Infektionen , Organtransplantation, Leukämie , bösartige fortgeschrittene Tumore, Bestrahlung, Chemotherapie, langzeitig hochdosierte Kortisonbehandlung) verwendet werden.

Patienten mit einem Zentralvenenkatheter (z.B. Port-A-cath) dürfen Perenterol travel wegen Infektionsgefahr mit Saccharomyces boulardii nicht verwenden.

Wann ist bei der Einnahme von Perenterol travel Vorsicht geboten?

Da Perenterol travel aus lebenden Zellen besteht, darf das Präparat nicht mit einer zu heissen (über 50 °C), eiskalten oder alkoholhaltigen Flüssigkeit oder Speise gemischt werden.

Im Weiteren sind die in Perenterol travel enthaltenen Hefepilze empfindlich auf pilzhemmende Arzneimittel (Antimykotika). Sollte Ihnen Ihr Arzt/Ihre Ärztin solche Arzneimittel verschrieben haben, müssen Sie auf die Einnahme von Perenterol travel verzichten, weil es dann wirkungslos wird.

Informieren Sie Ihren Arzt, Apotheker oder Drogisten bzw. Ihre Ärztin, Apothekerin oder Drogistin, wenn Sie

• an anderen Krankheiten leiden,
• Allergien haben oder
• andere Arzneimittel (auch selbst gekaufte!) einnehmen!

Darf Perenterol travel während einer Schwangerschaft oder in der Stillzeit eingenommen werden?

Es bestehen keine Bedenken gegen eine Anwendung von Perenterol travel während der Schwangerschaft oder in der Stillzeit.

Das Präparat wird oral eingenommen.

Anfangsdosierung: am 1. Tag 2 Kapseln (1 am Morgen und 1 am Abend) einnehmen.

Weitere Dosierung: an den folgenden Tagen: 1 Kapsel täglich, bis keine Krankheitssymptome mehr auftreten, einnehmen.

Auf ärztlichen Rat kann die Anfangsdosierung (2 Kapseln täglich) wenn nötig während mehreren Tagen durchgeführt werden bzw. erhöht werden.

Im Falle von Erbrechen innerhalb von 1 Stunde nach der Arzneimittelgabe muss die Einnahme wiederholt werden.

Perenterol travel kann Säuglingen, Kindern und Erwachsenen in gleicher Dosierung verabreicht werden.

Die Kapsel mit etwas Flüssigkeit schlucken.

Für Säuglinge: den Inhalt einer Kapsel über den Brei streuen oder in die Flasche geben. Achten Sie darauf, dass die Nahrung nicht zu heiss ist (nicht über 50 °C).

Perenterol travel kann zu jeder Tageszeit eingenommen werden. Wenn Sie einen schnellen Wirkungseintritt erzielen wollen, können Sie das Präparat vor dem Essen einnehmen.

Sie können Perenterol travel auch zusammen mit einem Antibiotikum zu jeder Zeit einnehmen, jedoch nicht zusammen mit einem Antimykotikum.

Halten Sie sich an die in dieser Packungsbeilage angegebene oder vom Arzt/der Ärztin verschriebene Dosierung. Wenn Sie glauben, das Medikament wirke zu schwach oder zu stark, sprechen Sie mit Ihrem Arzt, Apotheker oder Drogisten bzw. mit Ihrer Ärztin, Apothekerin oder Drogistin.

Aus dem Magazin

Der Mythos der gesunden Bräune: Welche Auswirkungen hat die Sonnenexposition auf die Haut?

Welche Behandlungsmethoden gibt es bei Schlafapnoe?

Selten treten nach Einnahme von Perenterol travel Blähungen auf und in sehr seltenen Fällen Verstopfung .

Sehr selten können allergische Hautreaktionen wie Juckreiz, Hautausschläge oder Nesselfieber , Atemnot, anaphylaktische Reaktionen und anaphylaktischer Schock auftreten.

In sehr seltenen Fällen wurde bei schwerkranken oder immungeschwächten Patienten oder bei Patienten mit Zentralvenenkathetern das Eindringen der Hefepilze ins Blut (Fungämie) und Einzelfälle von schweren Blutinfektionen (Sepsis) beobachtet, wobei auch Fieber auftreten kann.

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt, Apotheker oder Drogisten bzw. Ihre Ärztin, Apothekerin oder Drogistin. Dies gilt insbesondere auch für Nebenwirkungen, die nicht in dieser Packungsbeilage angegeben sind.

Das Arzneimittel darf nur bis zu dem auf dem Behälter mit «EXP» bezeichneten Datum verwendet werden.

Lagerungshinweis

Nicht über 30 °C lagern und für Kinder unzugänglich aufbewahren.

Weitere Hinweise

Weitere Auskünfte erteilt Ihnen Ihr Arzt, Apotheker oder Drogist bzw. Ihre Ärztin, Apothekerin oder Drogistin. Diese Personen verfügen über die ausführliche Fachinformation.

Was ist in Perenterol travel enthalten?

1 Kapsel enthält: 250 mg Saccharomyces boulardii lyophilisiert (250 mg Hefe), entsprechend mind. 2 Milliarden lebensfähiger Zellen.

Hilfsstoffe

1 Kapsel enthält: 32,5 mg Lactose und Hilfsstoffe.

Zulassungsnummer

60114 (Swissmedic).

Wo erhalten Sie Perenterol travel? Welche Packungen sind erhältlich?

In Apotheken und Drogerien, ohne ärztliche Verschreibung.

Packungen zu 8 und 12 Kapseln.

Zulassungsinhaberin

Zambon Schweiz AG, 6814 Cadempino

Diese Packungsbeilage wurde im Februar 2021 letztmals durch die Arzneimittelbehörde (Swissmedic) geprüft.

• Medikamente

Ähnliche Medikamente

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This is automatic translated text

Components:

Medically reviewed by Oliinyk Elizabeth Ivanovna, PharmD. Last updated on 22.03.2022

Attention! Information on this page is intended only for medical professionals! Information is collected in open sources and may contain significant errors! Be careful and double-check all the information on this page!

Top 20 medicines with the same components:.

Treatment of acute infectious diarrhea of adults and children.

Prevention and treatment of antibiotic-associated colitis and diarrhea.

Addition to Vancomycin/Metronidazole: Prevention of recurrence of Clostridium difficile diseases.

Prevention of tube-feeding-associated diarrhea.

Treatment of irritable bowel syndrome.

Capsule: 1 or 2 caps, once or twice daily. The caps have to be swallowed with a mouthful of liquid.

Sachet: 1 or 2 sachets, given once or twice.

The contents of the sachet should be mixed with water or another liquid or food. It should not be poured on or mixed with very cold or very hot liquids or food, or alcoholic drinks.

Hypersensitivity to the active

Probiotics contain different types of micro-organisms such as yeast ( Perenterol ) and bacteria (such as lactobacillus, bifidobacterium). Micro-organisms (flora) are naturally found in the stomach/intestines/vagina. Some conditions (such as antibiotic use, travel) can change the normal balance of bacteria/yeast. Probiotics are used to improve digestion and restore normal flora.

Probiotics have been used to treat bowel problems (such as diarrhea, irritable bowel), eczema, vaginal yeast infections, lactose intolerance, and urinary tract infections.

Probiotics are available in foods (such as yogurt, milk, juices, soy beverages) and as dietary supplements (capsules, tablets, powders). Different products have different uses. Check the label for information on uses for your particular product.

Some diet supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details regarding the particular brand you use.

The FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.

How to use Perenterol

Follow all directions on the product package. Refer to the label directions for your specific product to see if the dose should be swallowed whole, chewed, sprinkled onto food or mixed with liquid. If you are uncertain about any of the information, consult your doctor or pharmacist.

Some probiotic products may contain live bacteria (such as bifidobacteria). Antibiotics may prevent these products from working well. Take any product containing live bacteria at least 2 to 3 hours before or after taking antibiotics. Follow the directions for your specific product.

If you are taking this product for diarrhea due to antibiotics, do not use it if you have a high fever or for more than 2 days, unless directed by your doctor. You may have a serious problem that requires medical treatment.

If your condition persists or worsens, or if you think you may have a serious medical problem, seek immediate medical attention.

The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring.

To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval.

Some medications that may interact with certain probiotics include: antibiotics, antifungals (such as clotrimazole, ketoconazole, griseofulvin, nystatin).

This document does not contain all possible drug interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems.

Vision may be temporarily blurred when this product is first used. Also, minor burning/stinging/irritation may temporarily occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

If your doctor has directed you to use this medication, remember that he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if any of these unlikely but serious side effects occur: eye pain, change in vision, continued eye redness/irritation.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Each capsule/sachet contains lyophilized Perenterol 282.5 mg corresponding to yeast 250 mg and lactose 32.5 mg.

References:

• https://www.drugs.com/search.php?searchterm=perenterol
• https://pubmed.ncbi.nlm.nih.gov/?term=perenterol

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Exploring the Charms of Samara Oblast: A Comprehensive Travel Guide

Samara Oblast, a region nestled in the heart of Russia, is a hidden gem waiting to be discovered by travelers seeking a unique blend of culture, nature, and history. Encompassing picturesque landscapes, vibrant cities, and a rich cultural heritage, Samara Oblast offers an array of experiences for all types of adventurers. In this comprehensive travel guide, we’ll explore everything you need to know about Samara Oblast, including the best time to visit, must-see places, exciting activities, transportation options, dining experiences, accommodation choices, famous street markets, and essential travel tips to make your journey truly unforgettable.

About Samara Oblast: Geography: Samara Oblast is located in the southeastern part of European Russia. It boasts diverse landscapes, including the Volga River, dense forests, rolling hills, and vast steppes.

Culture: The region’s culture is a fusion of Russian traditions and the heritage of the many ethnic groups residing there. Samara is known for its distinct folklore, music, and festivals.

Best Time to Visit Samara Oblast: Summer (June to August): Summer is the ideal time to visit Samara Oblast. The weather is warm, nature is in full bloom, and outdoor activities are at their peak.

Spring (May and early June) and Autumn (September): Spring and autumn offer pleasant weather, making it an excellent time to explore the region with fewer crowds.

Winter (December to February): Winter in Samara Oblast is perfect for those who enjoy snow activities like skiing and ice skating. The snow-covered landscapes are enchanting.

Places to Visit in Samara Oblast: Samara: The city of Samara, the regional capital, is known for its vibrant cultural scene. Don’t miss the Samara Art Museum, the beautiful embankment along the Volga River, and the historic center.

Zhigulevsk: This charming town is famous for its namesake Zhigulev beer. Visit the Zhigulevskye Hills and explore the local brewery to learn about the beer-making process.

Tolyatti: Tolyatti is one of Russia’s major industrial cities and offers a glimpse into modern urban life. Explore the city’s parks and the impressive Tolyatti Avtovaz automobile factory.

Volga River: The Volga River, one of Russia’s most famous waterways, flows through Samara Oblast. Enjoy a river cruise to appreciate the scenic beauty and historical sites along its banks.

Things to Do in Samara Oblast: Outdoor Adventures: Explore the region’s diverse natural landscapes through activities like hiking, camping, fishing, and birdwatching.

Cultural Festivals: Samara Oblast hosts numerous festivals and events throughout the year, celebrating music, dance, and local traditions. Check the event calendar to plan your visit accordingly.

Volga River Activities: Enjoy boat tours, fishing, and water sports on the Volga River, a central part of Samara Oblast’s identity.

Hot Air Ballooning: Get a unique perspective of the region’s landscapes by taking a hot air balloon ride, offering breathtaking views.

How to Get Around Samara Oblast: Domestic Flights: Samara’s Kurumoch International Airport connects the region to other Russian cities. Domestic flights are the most efficient way to travel.

Trains and Buses: Samara Oblast is well-connected by train and bus networks, making it easy to travel to cities and towns within the region.

Rental Cars: Renting a car is a convenient option for exploring Samara Oblast, especially if you plan to visit remote areas. Ensure you have the necessary documentation and insurance.

Local Transport: Cities like Samara and Tolyatti have public transportation systems, including trams, buses, and trolleybuses, making it easy to get around.

Where to Eat in Samara Oblast: Russian Cuisine: Sample traditional Russian dishes like borscht, pelmeni, and shashlik at local restaurants.

Local Specialties: Try regional dishes such as Samara-style kholodets (jellied meat) and the famous “Zhigulevskoe” beer.

International Cuisine: Samara Oblast also offers a variety of international cuisine, including Italian, Chinese, and European restaurants.

Famous Street Stalls in Samara Oblast: While street food culture may not be as prevalent in Samara Oblast as in larger cities, you can find local stalls offering traditional Russian and street food snacks in some areas.

Where to Stay in Samara Oblast: Hotels: Samara Oblast offers a range of hotels, from luxury to budget-friendly. Some popular options include the Renaissance Samara Hotel and the Hotel Ibis Samara.

Guesthouses and Homestays: For a more immersive and personal experience, consider staying in guesthouses or homestays in smaller towns and villages.

Camping and Eco-Lodges: If you prefer a more adventurous and nature-focused experience, consider camping or staying in eco-lodges near national parks and outdoor destinations.

Travel Tips for Samara Oblast: Visa Requirements: Ensure you have the necessary visa to enter Russia. Visa regulations can be strict, so check well in advance of your trip.

Language Barrier: English may not be widely spoken, so it’s helpful to learn some basic Russian phrases or have a translation app handy.

Weather Preparation: Depending on the season of your visit, pack accordingly. Winters can be very cold, so bring warm clothing.

Respect Local Customs: Russian culture values politeness and respect. Be courteous to the locals and follow cultural norms.

Wildlife Awareness: When exploring nature, be aware of the local wildlife, including bears. Take precautions and follow local advice to ensure your safety.

Conclusion: Samara Oblast, with its diverse landscapes, rich culture, and unique experiences, promises an unforgettable journey for travelers seeking an off-the-beaten-path adventure in Russia. Whether you’re captivated by the natural beauty, cultural festivals, or outdoor activities, Samara Oblast has something for every type of traveler. By following the travel tips provided in this guide, you can make the most of your visit to this enchanting region, whether you come in the summer, winter, or any other season. Samara Oblast is a destination where lasting memories are waiting to be created.

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Syzran city, Russia

The city of Samara oblast .

Syzran - Overview

Syzran is a city located in the Samara region of Russia, at the foot of the Volga Uplands, on the right bank of the Volga River (Saratov water reservoir), at the mouth of the Syzranka River, 172 km west of Samara (by road) and 896 km south-east of Moscow.

The population of Syzran is about 163,000 (2022), the area - 117 sq. km.

The phone code - +7 8464, the postal codes - 446000-446031.

Syzran city coat of arms

Syzran city map, Russia

Syzran city latest news and posts from our blog:.

15 February, 2020 / Syzran - the view from above .

History of Syzran

Syzran was founded as a fortress in 1683. It was named after the Syzran River (today, it is called Syzranka). Russian kingdom was expanding eastward, and, to ensure the safety of trade routes and to protect borders, it was necessary to build fortresses. However, the military function of the fortress soon came to naught and trade became the basis for development of the town.

In the 18th century, Syzran became a major trade center of the region. In 1780, the Russian Empress Catherine II gave the town its coat of arms - a black bull in a golden field - for success in livestock and grain trade. In the last third of the 19th century, Syzran was connected to the railway network of the Russian Empire.

At the turn of the 19th-20th centuries, milling was the main industry in Syzran. The town took 4th place in the Russian grain processing, after Nizhny Novgorod, Saratov and Samara.

More Historical Facts…

In July 1906, as a result of a fire, about 5,500 buildings burned down, most of the town was destroyed. After the fire, the local merchants built a lot of stone mansions for their families and social needs. New churches were built with the money collected by the town residents. Today, these buildings are architectural monuments, many of them have been restored in recent years.

During the Soviet regime, the structure of industrial production of Syzran changed because of the discovery of large deposits of oil. Syzran became known informally as the “Second Baku.” No coincidence that the city is literally entangled by oil and gas pipelines, main pipelines.

During the Second World War, the industrial potential of the city increased by 4-5 times at the expense of the evacuated plants. About 39,000 people from Syzran fought on the fronts of the war, 11,300 people died in the fighting.

In the postwar period, petrochemical, chemical, power, light, wood processing, food processing, machinery industries were developed in the city.

Syzran views

Apartment buildings in Syzran

Author: Aleksandr Proreshkin

Syzran architecture

Author: Anton Patisson

Administration of Syzran

Syzran - Features

The entire historic center of Syzran is a single urban ensemble, it has been well-preserved to this day. The city stretches along the Volga River from north to south for 17 km.

The climate is temperate continental, the average temperature in February is minus 9.7 degrees Celsius, in July - plus 20.5 degrees.

Urban transport is represented mainly by buses. Also the city has a bus station, river port and river cargo port.

The main sectors of the local economy are heavy industry, light and food industry, construction, transportation, small business, trade. Syzran refinery plays an important role in the city’s economy. Annually, the refinery processes about 6.5 million tons (47.5 million barrels) of oil.

Attractions of Syzran

Fortunately Syzran preserved the unique look of the 19th century trading town standing on the Volga. There are more than 140 monuments of history, culture and architecture in the city.

Syzran Museum of Local Lore. The museum is a modern cultural center of the Samara region that has collections of coins, photographs, icons, rare books, and archaeological finds. Dostoyevsky Street, 34/10, opening hours: 10:00-18:00.

The Museum of the Icon Painting School. Syzran has an icon-painting school. A.A.Bochkarev (1866-1934) was its brightest representative. The school has a workshop of artists, where you can even order to make an icon. Sovetskaya Street, 9.

Syzran Exhibition Hall. It is located in an old mansion of the public figure and merchant M.V.Chernukhin. The building is a monument of wooden architecture of regional importance. You can buy souvenirs and paintings made by the local artists here. Sverdlova Street, 2.

Syzran Kremlin . It stands on the Kremlin hill, at the confluence of the Volga, Syzranka, and Krymza rivers, at the very beginning of Sovetskaya Street. It is the only kremlin in the Samara region. Unfortunately only Spasskaya Tower (1683) is preserved till nowadays. It houses a museum of the Kremlin. On this territory you can also find Church of the Nativity of Christ (1717).

Syzran places

Syzran Drama Theater

Sterlyadkin Mansion - Syzran registry office

Syzran railway station

Other sights

Kazan Cathedral . The cathedral was built in 1872. This monumental building with a bell tower can be seen from the Kremlin hill. Dostoyevsky Street, 17.

Holy Ascension Monastery. The monastery was founded in 1685, two years after the foundation of Syzran fortress. The only preserved building is Church of the Assumption (1738). Monastyrskaya Street, 2.

Syzran Drama Theater named after A. Tolstoy was opened by a local merchant in 1870. Sovetskaya Street, 92.

Sovetskaya Street. It is the main street of the historic city center, an urban ensemble performed in a variety of architectural styles. Today, this street is the center of business, cultural, social and administrative life of Syzran.

Sterlyadkin Mansion. It was built by the miller Sterlyadkin in Art Nouveau style in the 1910s. Today, the building houses a registry office. Sovetskaya Street, 66.

Syzran Hydro Power Plant . This power plant standing on the Syzranka River was the first hydro power plant in the Volga region (1929).

Syzran Arboretum. It is located in the southern outskirts of the city, on the Saratov highway. The area of the arboretum is 8 hectares; more than 100 species of plants grow there.

The Manor of the Princes Gagarin . This manor with a unique park and a preserved church is located in Zaborovka village.

Racheysky forest . To the west of Syzran, almost on the border with the Ulyanovsk region, there is a unique forest. It is spread over an area of 10 thousand hectares in the valleys and slopes of the Volga Upland, attracting people with its freshness and beauty of the landscape, purity of springs, and diversity of plants. Staraya Racheyka village.

The Graveyard of Ichthyosaurs. This unique natural monument is located deep underground in the vicinity of the village of Novokashpirsky. The fossil collection is stored in the Samara Regional History Museum of P.V. Alabin.

“Syzran Tomato”. It is a regional festival held every August. Tomatos were brought here by merchants from Astrakhan centuries ago. The local climate and fertile black earth soil were the main reasons for rich harvests.

“Silver Trumpets of the Volga region”. It is an international festival of wind instruments, the main musical event of Syzran held in August. Ensembles, orchestras and soloists from France, Italy, Russia and other countries participate in the festival, concerts are held on the streets of the city.

Syzran city of Russia photos

Sights of syzran.

Syzran Kremlin - Spasskaya Tower

Author: Nefedov Igor

Kazan Cathedral in Syzran

Syzran Exhibition Hall

Churches in Syzran

Ilinskaya Church in Syzran

Holy Ascension Monastery in Syzran

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