Probiotics for prevention of antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) occurs in approximately 25% of patients receiving antibiotics. Hospitalized patients with AAD are at increased risk for nosocomial infections and have a higher mortality. Probiotics are living microorganisms used to restore gut health by changing the intestinal microbiota. Several have been studied for the prevention of AAD. Five meta-analyses of trials of probiotics for the prevention of AAD have been performed. The results showed an overall reduction in the risk of AAD when probiotics were coadministered with antibiotics. McFarland conducted the largest meta-analysis to date analyzing 25 randomized controlled trials of probiotics for the prevention of AAD including 2810 subjects. More than half of the trials demonstrated efficacy of the probiotic. In particular, Lactobacillus GG, Saccharomyces boulardii, and the probiotic mixtures were effective. The Cochrane Database of Systematic Reviews published a review of the literature on the use of probiotics for the prevention of pediatric AAD, including 10 randomized trials testing 1986 children. The per protocol pooled analysis, but not the intent-to-treat analysis, showed that probiotics are effective for preventing AAD with the number needed to treat to prevent 1 case of diarrhea being 10. Lactobacillus GG, Bacillus coagulans, and S. boulardii appeared to be most effective. Probiotics are generally safe, however, they should be used with caution in patients who have compromise of either the immune system or the integrity of the intestinal mucosa, and in the presence of a central venous catheter.     

益生菌预防成人抗生素相关性腹泻的荟萃分析

目的:探讨益生菌的使用与成人抗生素相关性腹泻(AAD)的关联,分析益生菌预防AAD的有效性及安全性.方法:系统检索PubMed,Embase,CINAHL,AMED,the Cochrane database of SystematicReviews,the Cochrane Controlled TrialsRegister和中国期刊全文数据库(CNKI),检索时间跨度从1966-01/2012-04.我们只纳入随机对照试验,研究对象>18周岁,研究内容为服用抗生素的同时服用益生菌预防AAD.结果:本研究结果表明,RR=0.45,95%CI:0.29-0.69,P<0.001,益生菌可以显著降低服用抗生素后发生腹泻的机率.基于益生菌种类的亚组分析的结果(RR=0.42,95%CI:0.20-0.85,P=0.003)同样证明了益生菌预防AAD的有效性.结论:益生菌可以显著降低服用抗生素后发生成人AAD的机率.     

益生菌在防治老年人抗生素相关性腹泻中的应用与思考

益生菌是一类能使其宿主获益的活体微生物,应用广泛,但目前并没有大数据支持其临床应用。很多临床研究证实了不同益生菌防治抗生素相关性腹泻（AAD）的有效性,但基于近年的数据,回答益生菌是否可降低老年人AAD发生率的科学依据尚显薄弱。总的来说,益生菌有着非常好的安全记录,特定人群包括AAD患者使用益生菌将会获益,但需要个体化。     

Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease

CONTEXT: Antibiotic-associated diarrhea (AAD) is a common complication of most antibiotics and Clostridium difficile disease (CDD), which also is incited by antibiotics, is a leading cause of nosocomial outbreaks of diarrhea and colitis. The use of probiotics for these two related diseases remains controversial. OBJECTIVE: To compare the efficacy of probiotics for the prevention of AAD and the treatment of CDD based on the published randomized, controlled clinical trials. DATA SOURCES: PubMed, Medline, Google Scholar, NIH registry of clinical trials, metaRegister, and Cochrane Central Register of Controlled Trials were searched from 1977 to 2005, unrestricted by language. Secondary searches of reference lists, authors, reviews, commentaries, associated diseases, books, and meeting abstracts. STUDY SELECTION: Trials were included in which specific probiotics given to either prevent or treat the diseases of interest. Trials were required to be randomized, controlled, blinded efficacy trials in humans published in peer-reviewed journals. Trials that were excluded were pre-clinical, safety, Phase 1 studies in volunteers, reviews, duplicate reports, trials of unspecified probiotics, trials of prebiotics, not the disease being studied, or inconsistent outcome measures. Thirty-one of 180 screened studies (totally 3,164 subjects) met the inclusion and exclusion criteria. DATA EXTRACTION: One reviewer identified studies and abstracted data on sample size, population characteristics, treatments, and outcomes. DATA SYNTHESIS: From 25 randomized controlled trials (RCTs), probiotics significantly reduced the relative risk of AAD (RR = 0.43, 95% CI 0.31, 0.58, p < 0.001). From six randomized trials, probiotics had significant efficacy for CDD (RR = 0.59, 95% CI 0.41, 0.85, p = 0.005). CONCLUSION: A variety of different types of probiotics show promise as effective therapies for these two diseases. Using meta-analyses, three types of probiotics (Saccharomyces boulardii, Lactobacillus rhamnosus GG, and probiotic mixtures) significantly reduced the development of antibiotic-associated diarrhea. Only S. boulardii was effective for CDD.     

益生菌在抗生素相关性腹泻和难辨梭状芽孢杆菌相关性腹泻预防中的作用

随着抗生素的广泛应用,抗生素相关性腹泻（AAD）和难辨梭状芽孢杆菌相关性腹泻（CDAD）在临床上日益受到重视。目前,益生菌治疗已成为预防AAD和CDAD的一种潜在手段,本文就益生菌在AAD和CDAD预防中的机制、有效性和安全性等方面作一综述。     

Probiotics and Prebiotics in Infants and Children

Probiotics and prebiotics have a major influence on gastrointestinal flora composition. This review analyses the relationship between this change in flora composition and health benefits in children. Literature databases were searched for relevant articles. Despite exhaustive research on the subject in different indications, such as prevention and treatment of acute gastroenteritis, antibiotic associated diarrhea (AAD), traveler's diarrhea, inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori, necrotizing enterocolitis, constipation, allergy and atopic dermatitis, colic and extraintestinal infections, reports of clear benefits for the use of prebiotics and probiotics in pediatric disorders remain scarce. The best evidence has been provided for the use of probiotics in acute gastroenteritis and in prevention of AAD. However, AAD in children is in general mild, and only seldom necessitates additional interventions. Overall, the duration of acute infectious diarrhea is reduced by approximately 24 hours. Evidence for clinically relevant benefit in all other indications (inflammatory bowel disease, irritable bowel syndrome, constipation, allergy) is weak to nonexistent. Selected probiotic strains given during late pregnancy and early infancy decrease atopic dermatitis. Adverse effects have very seldom been reported. Since the risk seems minimal to nonexistent, prebiotics and probiotics may be helpful in the prevention and treatment of some disorders in children, although the evidence for benefit is limited. The best evidence has been accumulated for some lactobacilli strains and for Saccharomyces boulardii in the reduction of the duration of acute diarrhea due to gastroenteritis and prevention of AAD.     

Probiotics and gastrointestinal diseases

There is increasing evidence indicating health benefits by consumption of foods containing microorganisms, i.e. probiotics. A number of clinical trials have been performed to evaluate the effects in the prevention and treatment of gastrointestinal diseases caused by pathogenic microorganisms or by disturbances in the normal microflora. Gastrointestinal infections caused by Helicobacter pylori, traveller's diarrhoea, rotavirus diarrhoea, antibiotic-associated diarrhoea (AAD) and Clostridium difficile-induced diarrhoea are conditions that have been studied. There are also studies performed on the preventive effect of probiotics on radiation-induced diarrhoea and diarrhoea in tube-fed patients. Inflammatory bowel disease and irritable bowel syndrome, two idiopathic conditions where alterations in the normal microflora have been implicated as responsible for initiation, are two further areas where the use of probiotics has been regarded as promising. The results from clinical studies have not been conclusive in that the effects of probiotics have been strain-dependent and different study designs have been used. Treatment of acute diarrhoea in children and prevention of AAD are the two most justified areas for the application of probiotics.     

益生菌制剂预防老年患者抗生素相关性腹泻

背景: 抗生素相关性腹泻(AAD)是临床应用抗生素的常见并发症。目前益生菌制剂用于AAD的治疗已得到广泛认可,但其是否可用于预防AAD仍存在争议。目的: 研究成年和老年住院患者的AAD发生率,以及益生菌制剂对老年患者AAD的预防作用。方法: 根据入选标准连续纳入同期接受抗生素治疗的成年和老年住院患者,后者随机分为两组,分别予地衣芽孢杆菌1.5×10~9 cfu/d干预至停用抗生素后1周或不予干预。分析各组抗生素使用情况和AAD发生率。结果: 成年组与老年未干预组间、老年干预组与未干预组间抗生素使用情况均无明显差异。成年组AAD发生率明显低于老年未干预组(10.6%对27.4%,P=0.001),老年干预组亦明显低于老年未干预组(13.6%对27.4%,P=0.01),差异均有统计学意义。结论: 老年患者为AAD高发人群,益生菌制剂与抗生素同时应用可有效减低老年住院患者的AAD发生率,可作为AAD预防措施应用于临床。     

Probiotics in the prevention and treatment of gastrointestinal infections

Probiotics have been studied in a variety of GI infections, and are an appealing concept given their favorable safety profiles. Several placebo-controlled trials indicated that lactobacilli have a suppressive effect on H pylori infection. Although some studies reported improvement in H pylori eradication, others failed to confirm this. Controlled trials support the use of Lactobacillus GG and S boulardii for the prevention of AAD, and have demonstrated the effectiveness of S boulardii as adjunctive therapy for RCDAD. Several placebo-controlled trials showed a reduction in the severity and duration of acute diarrhea in children with use of Lactobacillus GG. Studies of probiotics for the prevention of traveler's diarrhea yielded conflicting results, and their routine use cannot be recommended in this setting. Preliminary evidence suggests a potential role for reducing secondary pancreatic infections, although conclusive evidence is not available at this time. Additional clinical trials are indicated to define the role of probiotics further before wide-spread use can be recommended.     

Temporal variations at the onset of spontaneous acute aortic dissection

There have only been a few studies of the chronobiological occurrence of acute aortic dissection (AAD), and most were international and multicentered. The aim of the present study, conducted at only one center, was to determine the most frequent daily, monthly, and seasonal occurrences of AAD. The study population included 204 patients (66.5% male) treated at our institute between January 1, 1998 and January 1, 2004. A significantly higher frequency of AAD occurred from 6:00 AM to 12:00 noon, compared with other time periods (P < 0.001). The results showed a significant circadian variation in AAD (P < 0.001) with a peak between 9:00 AM and 10:00 AM. No significant variation was found for the day of the week; however, AAD occurred most frequently on Wednesday and Monday. The frequency of AAD was found to be significantly higher during winter versus other seasons (P < 0.001). The analysis of monthly variations of the onset of AAD confirmed a peak in February (12.9%) and in January (12.3%). Similar to other cardiovascular diseases, AAD exhibits significant circadian and seasonal/monthly variations. Our findings indicate that the prevention of AAD, especially during the aforementioned vulnerable periods, is possible by adequate tailoring of the treatment of hypertension, which is the main AAD predisposing factor.     

Meta-analysis of probiotics for the prevention of traveler's diarrhea

BACKGROUND: Traveler's diarrhea (TD) is a common health complaint among travelers. Rates of TD can range from 5% to 50%, depending on the destination. The use of probiotics for this disease remains controversial. The objective of this study was to compare the efficacy of probiotics for the prevention of TD based on published randomized, controlled clinical trials. METHODS: PubMed, Google Scholar, metaRegister, NIH registry of clinical trials and Cochrane Central Register of Controlled Trials were searched from 1977 to 2005, unrestricted by language. Secondary searches of reference lists, authors, reviews, commentaries, associated diseases, books and meeting abstracts. Inclusion criteria included: randomization, controlled, blinded, efficacy trials, in humans, peer-reviewed journals. Exclusion criteria were: pre-clinical, safety, phase 1 studies in volunteers, reviews, duplicate reports, trials of unspecified probiotics, trials of prebiotics, and inconsistent outcome measures. RESULTS: Twelve of 940 screened studies met the inclusion and exclusion criteria. The pooled relative risk indicates that probiotics significantly prevent TD (RR=0.85, 95% CI 0.79,0.91, p<0.001). CONCLUSION: Several probiotics (Saccharomyces boulardii and a mixture of Lactobacillus acidophilus and Bifidobacterium bifidum) had significant efficacy. No serious adverse reactions were reported in the 12 trials. Probiotics may offer a safe and effective method to prevent TD.     

Comparison of pediatric and adult antibiotic-associated diarrhea and Clostridium difficile infections

Antibiotic-associated diarrhea(AAD) and Clostridum difficile infections(CDI) have been well studied for adult cases, but not as well in the pediatric population. Whether the disease process or response to treatments differs between pediatric and adult patients is an important clinical concern when following global guidelines based largely on adult patients. A systematic review of the literature using databases Pub Med(June 3, 1978-2015) was conducted to compare AAD and CDI in pediatric and adult populations and determine significant differences and similarities that might impact clinical decisions. In general, pediatric AAD and CDI have a more rapid onset of symptoms, a shorter duration of disease and fewer CDI complications(required surgeries and extended hospitalizations) than in adults. Children experience more community-associated CDI and are associated with smaller outbreaks than adult cases of CDI. The ribotype NAP1/027/BI is more common in adults than children. Children and adults share some similar risk factors, but adults have more complex risk factor profiles associated with more co-morbidities, types of disruptive factors and a wider range of exposures to C. difficile in the healthcare environment. The treatment of pediatric and adult AAD is similar(discontinuing or switching the inciting antibiotic), but other treatment strategies for AAD have not been established. Pediatric CDI responds better to metronidazole, while adult CDI responds better to vancomycin. Recurrent CDI is not commonly reported for children. Prevention for both pediatric and adult AAD and CDI relies upon integrated infection control programs, antibiotic stewardship and may include the use of adjunctive probiotics. Clinical presentation of pediatric AAD and CDI are different than adult AAD and CDI symptoms. These differences should be taken into account when rating severity of disease and prescribing antibiotics.     

Probiotics for Prevention of Atopy and Food Hypersensitivity in Early Childhood: A PRISMA-Compliant Systematic Review and Meta-Analysis of Randomized Controlled Trials

Most studies investigated probiotics on food hypersensitivity, not on oral food challenge confirmed food allergy in children. The authors systematically reviewed the literature to investigate whether probiotic supplementation prenatally and/or postnatally could reduce the risk of atopy and food hypersensitivity in young children.PubMed, Embase, the Cochrane Central Register of Controlled Trials, and 4 main Chinese literature databases (Wan Fang, VIP, China National Knowledge Infrastructure, and SinoMed) were searched for randomized controlled trials regarding the effect of probiotics on the prevention of allergy in children. The last search was conducted on July 11, 2015.Seventeen trials involving 2947 infants were included. The first follow-up studies were analyzed. Pooled analysis indicated that probiotics administered prenatally and postnatally could reduce the risk of atopy (relative risk [RR] 0.78; 95% confidence interval [CI] 0.66–0.92; I² = 0%), especially when administered prenatally to pregnant mother and postnatally to child (RR 0.71; 95% CI 0.57–0.89; I² = 0%), and the risk of food hypersensitivity (RR 0.77; 95% CI 0.61–0.98; I² = 0%). When probiotics were administered either only prenatally or only postnatally, no effects of probiotics on atopy and food hypersensitivity were observed.Probiotics administered prenatally and postnatally appears to be a feasible way to prevent atopy and food hypersensitivity in young children. The long-term effects of probiotics, however, remain to be defined in the follow-up of existing trials. Still, studies on probiotics and confirmed food allergy, rather than surrogate measure of food hypersensitivity, are warranted.     

Probiotics for gastrointestinal disorders: Proposed recommendations for children of the Asia-Pacific region

Recommendations for probiotics are available in several regions. This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Epidemiology and clinical patterns of intestinal diseases in Asia-Pacific countries were discussed. Evidence-based recommendations and randomized controlled trials in the region were revised. Cultural aspects,health management issues and economic factors were also considered. Final recommendations were approved by applying the Likert scale and rated using the GRADE system. Saccharomyces boulardii CNCM I-745(Sb) and Lactobacillus rhamnosus GG(LGG) were strongly recommended as adjunct treatment to oral rehydration therapy for gastroenteritis. Lactobacillus reuteri could also be considered. Probiotics may be considered for prevention of(with the indicated strains): antibiotic-associated diarrhea(LGG or Sb); Clostridium difficile-induced diarrhea(Sb); nosocomial diarrhea(LGG); infantile colic(L reuteri) and as adjunct treatment of Helicobacter pylori(Sb and others). Specific probiotics with a history of safe use in preterm and term infants may be considered in infants for prevention of necrotizing enterocolitis. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological,socioeconomical and health system conditions,similar recommendations apply well to Asia pacific countries. These need to be validated with local randomized-controlled trials.     

D-dimer as a Biomarker for Acute Aortic Dissection: A Systematic Review and Meta-analysis

To perform a meta-analysis and examine the use of D-dimer levels for diagnosing acute aortic dissection (AAD).Medline, Cochrane, EMBASE, and Google Scholar were searched until April 23, 2014, using the following search terms: biomarker, acute aortic dissection, diagnosis, and D-dimer. Inclusion criteria were diagnosis of acute aortic dissection, D-dimer levels obtained, 2-armed study. Outcome measures were the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer level for the diagnosis of AAD. Sensitivity analysis was performed using the leave-one-out approach.Of 34 articles identified, 5 met the inclusion criteria and were included in the analysis. The age of participants was similar between treatments within studies. The number of AAD patients ranged from 16 to 107 (total = 274), and the number of control group patients ranged from 32 to 206 (total = 469). The pooled sensitivity of D-dimer levels in AAD patients was 94.5% (95% confidence interval [CI] 78.1%–98.8%, P < 0.001), and the specificity was 69.1% (95% CI 43.7%–86.5%, P = 0.136). The pooled area under the receiver-operating characteristic curve for D-dimer levels in AAD patients was 0.916 (95% CI 0.863–0.970, P < 0.001). The direction and magnitude of the combined estimates did not change markedly with the exclusion of individual studies, indicating the meta-analysis had good reliability.D-dimer levels are best used for ruling out AAD in patients with low likelihood of the disease.     

益生菌对炎症性肠病诱导缓解、维持治疗和贮袋炎作用系统评价

目的 评价益生菌对炎症性肠病缓解、维持治疗和贮袋炎的作用。方法 检索MEDLINE，EMBASE，the Cochrane Con—trolled Trials Register，OVID，BIOSIS和中国生物科技数据库，两位作者独立选取和炎症性肠病缓解率、复发率以及副作用相关的，对比益生菌治疗和非益生菌治疗的随机对照试验，使用Rev Man4．2．10软件统计分析，同时做亚组分析和敏感性分析。结果21项随机对照试验中共有1515例患者符合入选标准：4项研究评估了缓解率，14项研究评估了复发率，3项研究同时评估了缓解率和复发率。通过荟萃分析，炎症性肠病的总体缓解率相对危险度（relativerisk，RR）为1．05（95％CI=0．84—1．31），克罗恩病的缓解率RR0．85（95％CI=0．64—1．13），溃疡性结肠炎的缓解率RR1．18（95％CI=0．87—1．58）；贮袋炎临床复发率RR0．24（95％CI=0．12—0．48），克罗恩病临床复发率RR1．11（95％CI=0．69—1．80）；内镜复发率的RR1．08（95％CI=0．67—1．74）；益生菌与安慰剂比较，炎症性肠病的复发率RR0．51（95％CI=0．29—0．92）；益生菌与5-氨基水杨酸比较，溃疡性结肠炎的复发率RR0．96（95％CI=0．76—1．19）。结论 溃疡性结肠炎患者使用益生菌作为缓解治疗具有和5-氨基水杨酸相同的效果并优于安慰剂，但在炎症性肠病的诱导缓解中无额外益处。     

Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce antibiotic-associated diarrhea

AIM: To investigate the effect of Lactobacillus-containing commercially available probiotic formulations in Germany during antibiotic treatment with an analysis of cost-efficiency.METHODS: In an observational study, we analyzed the frequency of bowel movements from 258 patients with infections in a primary care hospital in western Germany; 107 of the patients were offered a probiotic drink containing at least 10 billion cultures of Lactobacillus casei DN 114001 b.i.d. The economic analysis was based on the costs of patient isolation vs preventive intake of probiotics. In a second pilot study, two commercially available probiotic drinks with different Lactobacillus casei strains were directly compared in 60 patients in a randomized controlled fashion.RESULTS: In the first study, the incidence of antibiotic-associated diarrhea (AAD) was significantly reduced in the intervention group (6.5% vs 28.4%), and the duration of AAD in days was significantly shorter (1.7 ± 1.1 vs 3.1 ± 2.1). Higher age and creatinine and lower albumin were identified as risk factors for AAD. Ampicillin was the antibiotic with the highest rate of AAD (50%) and with the greatest AAD reduction in the probiotic group (4.2%, relative risk reduction 92%). The economic analysis showed a cost advantage of nearly 60000 €/year in a department of this size. The second study confirmed the preventive effect of the drink with Lactobacillus casei {"type":"entrez-nucleotide","attrs":{"text":"DN114001","term_id":"59807791","term_text":"DN114001"}}DN114001; however, there were no advantages found for the other tested probiotic drink containing Lactobacillus casei Shirota.CONCLUSION: In contrast to a drink containing Lactobacillus casei Shirota, a commercially available probiotic drink containing Lactobacillus casei DN 114001 cost-efficiently reduces the prevalence of AAD during antibiotic treatment.     

Re-elevation of d-dimer as a predictor of re-dissection and venous thromboembolism after Stanford type B acute aortic dissection

D-dimer measurement is a useful complementary initial diagnostic marker in patients with acute aortic dissection (AAD). However, it has not been clarified whether serial measurements of D-dimer are useful during in-hospital management of Stanford type B AAD. We studied 30 patients who were admitted with diagnosis of Stanford type B AAD and treated conservatively. D-dimer was serially measured on admission and then every 5 days during hospitalization. Patients were divided into two groups according to the presence or absence of re-elevation of D-dimer during hospitalization, in which D-dimer transition were biphasic and latter peak >10.0 μg/ml. Re-elevation of D-dimer was observed in 17 patients. There were no differences in atherosclerotic risk factors, blood pressure on admission, D-dimer level on admission, extent of AAD, and false lumen patency. Patients with re-elevation of D-dimer showed higher incidence of re-dissection and/or venous thromboembolism (VTE). Peak D-dimer level in patients with re-dissection and/or VTE was significantly higher than that without these complications (p = 0.005). In conclusion, serial measurements of D-dimer are useful for early detection of re-dissection or VTE in patients with Stanford type B AAD, which may contribute to the prevention of disastrous consequences such as pulmonary embolism and extension of AAD.