Primary prevention of Clostridium difficile infections with a specific probiotic combining Lactobacillus acidophilus, L. casei, and L. rhamnosus strains: assessing the evidence.

Clostridium difficile infection (CDI) has become the leading healthcare-associated infection and cause of outbreaks around the world. Although various innovative treatments have been developed, preventive strategies using multi-faceted infection control programmes have not been successful in reducing CDI rates. The major risk factor for CDI is the disruption of the normally protective gastrointestinal microbiota, typically by antibiotic use. Supplementation with specific probiotics has been effective in preventing various negative outcomes, including antibiotic-associated diarrhoea and CDI. However, a consensus of which probiotic strains might prevent CDI has not been reached and meta-analyses report high degrees of heterogeneity when studies of different probiotic products are pooled together. We searched the literature for probiotics with sufficient evidence to assess clinical efficacy for the prevention of CDI and focused on one specific probiotic formulation comprised of three lactobacilli strains (Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, Lactobacillus rhamnosus CLR2, Bio-K+) for its ability to prevent CDI in healthcare settings. A literature search on this probiotic formulation was conducted using electronic databases (PubMed, Google Scholar), abstracts from infectious disease and infection control meetings, and communications from the probiotic company. Supporting evidence was found for its mechanisms of action against CDI and that it has an excellent safety and tolerability profile. Evidence from randomized controlled trials and facility-level interventions that administer Bio-K+ show reduced incidence rates of CDI. This probiotic formulation may have a role in primary prevention of healthcare-associated CDI when administered to patients who receive antibiotics.

Is there a role for modified probiotics as beneficial microbes: a systematic review of the literature.

Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent and treat various diseases. Recent clinical research has focused on living strains of probiotics, but use in high-risk patients and potential adverse reactions including bacteremia has focused interest on alternatives to the use of live probiotics. We searched MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Alt Health Watch, Web of Science, Scopus, PubMed, from inception to February 14, 2017 for randomised controlled trials involving modified probiotic strains. The primary outcome was efficacy to prevent or treat disease and the secondary outcome was incidence of adverse events. A total of 40 trials were included (n=3,913): 14 trials (15 arms with modified probiotics and 20 control arms) for the prevention of diseases and 26 trials (29 arms with modified probiotics and 32 control arms) for treatment of various diseases. Modified microbes were compared to either placebo (44%), or the same living probiotic strain (39%) or to only standard therapies (17%). Modified microbes were not significantly more or less effective than the living probiotic in 86% of the preventive trials and 69% of the treatment trials. Modified probiotic strains were significantly more effective in 15% of the treatment trials. Incidence rates of adverse events were similar for modified and living probiotics and other control groups, but many trials did not collect adequate safety data. Although several types of modified probiotics showed significant efficacy over living strains of probiotics, firm conclusions could not be reached due to the limited number of trials using the same type of modified microbe (strain, daily dose and duration) for a specific disease indication. Further research may illuminate other strains of modified probiotics that may have potential as clinical biotherapeutics.

Probiotics and prevention of Clostridium difficile infection.

The role of probiotics as adjunctive measures in the prevention of Clostridium difficile infection (CDI) has been controversial. However, a growing body of evidence has suggested that they have a role in primary prevention of CDI. Elements of this controversy are reviewed and the proposed mechanisms of action, the value and cost effectiveness of probiotics are addressed with a focus on three agents, Saccharomyces boulardii, Lactobacillus rhamnosus GG and the combination of Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, Lactobacillus rhamnosus CLR2 (Bio-K+).

Weight loss intention, dietary behaviors, and barriers to dietary change in veterans with lower extremity amputations.

BACKGROUND: Obesity is thought to be highly prevalent in persons with lower extremity amputations (LEAs) and can impair physical and social functioning. OBJECTIVE: The aim of this study was to determine the prevalence of weight loss intention, weight loss strategies, dietary patterns, and barriers to making dietary changes, and their associations with body mass index (BMI, kg/m(2)), amputation characteristics, health status, and socioeconomic factors. METHODS: We conducted a cross-sectional study (n = 150) using data from a self-administered questionnaire. RESULTS: 43% of participants were obese and 48% were trying to lose weight; 83% of those trying to lose weight reported trying to "eat differently", but only 7% were following a comprehensive weight loss program involving dietary changes, physical activity, and behavioral counseling. 21% of participants reported ≥ 6 barriers to changing their eating habits (e.g., habit, too little money, stress/depression). Obesity was associated with younger age, lower physical health scores, hypertension, arthritis, and diabetes. Compared to those not trying to lose weight, a greater proportion of those trying to lose weight had a BMI ≥ 35 kg/m(2), age <55 years, higher physical and mental health scores, and more frequent consumption of vegetables, beans, chicken, and fish. CONCLUSIONS: Though over half of overweight and obese individuals with LEA were trying to lose weight, few reported following a comprehensive program to lose weight, which may indicate an unmet need for services for this group. To be effective, these programs will need to address the complex physical and mental health challenges that many of these individuals face.

Deciphering meta-analytic results: a mini-review of probiotics for the prevention of paediatric antibiotic-associated diarrhoea and Clostridium difficile infections.

Meta-analyses are used to evaluate pooled effects of a wide variety of investigational agents, but the interpretation of the results into clinical practices may be difficult. This mini-review offers a three-step process to enable healthcare providers to decipher pooled meta-analysis estimates into results that are useful for therapeutic decisions. As an example of how meta-analyses should be interpreted, a recent meta-analysis of probiotics for the prevention of paediatric antibiotic-associated diarrhoea (AAD) and the prevention of Clostridium difficile infections (CDI) will be used. First, the pooled results of this meta-analysis indicates a significant protective efficacy for AAD is found when the 16 different types of probiotics are combined (pooled relative risk (RR) = 0.43, 95% confidence interval (CI)=0.33-0.56) and also a significant reduction of paediatric CDI (pooled RR=0.34, 95%CI=0.16-0.74) was found pooling four different types of probiotics. Secondly, because the efficacy of probiotics is strain-specific, it is necessary to do a sensitivity analysis, restricting the meta-analysis to one specific strain. Two strains, Saccharomyces boulardii lyo and Lactobacillus rhamnosus GG showed significant efficacy for paediatric AAD when pooled (pooled RR for S. boulardii = 0.43, 95%CI=0.21-0.86 and pooled RR for L. rhamnosus GG = 0.44, 95%CI=0.20-0.95). Thirdly, if studies within probiotic types have different results, it is prudent to examine these studies individually to determine the reasons why non-significant differences in efficacy were found. By drilling down through these three analytic layers, physicians will be confident in recommending the correct probiotic strain to their patients.

Biotherapeutic agents in the treatment of infectious diarrhea.

Biotherapeutic agents offer unique advantages over traditional treatments for infectious diarrhea, and several have been shown to be effective (Table 4). These therapeutic microbial agents are most effective in types of infectious diseases that are associated with a disruption of the normal intestinal microecology (e.g., AAD, C. difficile disease). The impact of biotherapeutic agents on rotaviral diarrhea is of special clinical importance because this is the most common cause of pediatric diarrhea, and there is no defined treatment. Strong efforts need to be made to limit antibiotic exposure in children. Biotherapeutic agents offer a safe and effective nonantibiotic method of treating this important pathogen, especially after the withdrawal of a rotaviral vaccine from the market by the FDA. However, for many biotherapeutic agents, well-done, placebo-controlled trials still are lacking, and not all types of infectious diarrhea respond to these agents. Continued research in this innovative therapeutic area is warranted.

Beneficial microbes: health or hazard?

Normal microbial flora support the health of the host by diverse mechanisms. When antibiotics, stress, disease or medications disrupt normal microflora, the ability to ward off infection by pathogens is compromised. The use of beneficial microbes (also known as biotherapeutic agents, probiotics, synbiotics) has been shown to be an effective therapeutic agent for some diseases. Various types of diarrhoea (antibiotic-associated diarrhoea, Clostridium difficile disease, traveller's diarrhoea) are most responsive to these beneficial microbes. Serious risks associated with these microbes are largely theoretical at this point, but the risks need to be studied as the use of these beneficial microbes increases in popularity. Beneficial microbes are living organisms used as therapeutic agents to restore the health of the host in times when normal microflora have been disturbed. The efficacy to prevent or treat diarrhoea has been documented in multiple large, placebo-controlled, blinded clinical trials with only a few of these beneficial microbes. Risks of these beneficial microbes are limited, but potential risks have not been extensively studied in large numbers of patients.

The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii.

Recurrent Clostridium difficile disease (CDD) is a difficult clinical problem because antibiotic therapy often does not prevent further recurrences. In a previous study, the biotherapeutic agent Saccharomyces boulardii was used in combination with standard antibiotics and was found to be effective in reducing subsequent recurrences of CDD. In an effort to further refine a standard regimen, we tested patients receiving a regimen of a standard antibiotic for 10 days and then added either S. boulardii (1 g/day for 28 days) or placebo. A significant decrease in recurrences was observed only in patients treated with high-dose vancomycin (2 g/day) and S. boulardii (16.7%), compared with those who received high-dose vancomycin and placebo (50%; P=.05). No serious adverse reactions were observed in these patients. Comparison of data from this trial with data from previous studies indicates that recurrent CDD may respond to a short course of high-dose vancomycin or to longer courses of low-dose vancomycin when either is combined with S. boulardii.

Antibiotics and Clostridium difficile diarrhea in the ambulatory care setting.

OBJECTIVE: The goal of this study was to determine the prevalence of Clostridium difficile diarrhea (CDD) and the risk for CDD associated with different oral antibiotics commonly used in the ambulatory care setting. METHODS: The prevalence of CDD was determined for enrollees in 4 UnitedHealth Group-affiliated health plans between January 1, 1992, and December 31, 1994. Cases were identified based on the presence of an inpatient or outpatient claim with a primary diagnosis of diarrhea, a pharmacy claim for a prescription drug used to treat CDD, or a physician or facility claim for the C. difficile toxin test, and were confirmed using full-text medical records. Within a retrospective cohort design, periods of risk for CDD were defined on the basis of duration of antibiotic therapy. To control for potential selection bias created by heterogeneous rates of C. difficile testing and to limit confounding due to multiple antibiotic exposures, we used a nested case-control design, restricting eligibility to subjects who underwent screening for C. difficile and who had been exposed to only 1 antibiotic risk period with a single antibiotic. RESULTS: The global prevalence of CDD in 358,389 ambulatory care enrollees was 12 per 100,000 person-years. In the nested case-control study, after controlling for other risk factors, 2 antibiotics demonstrated an increased association with CDD: cephalexin (odds ratio [OR] = 7.5, 95% CI = 1.8 to 34.7) and cefixime (OR = 6.4, 95% CI = 1.2 to 39.0). CONCLUSIONS: Although CDD is thought to occur primarily in hospitalized patients, it was found to be present in an ambulatory care population, but at a low frequency. In this population, it appeared to be associated with 2 cephalosporins but not with other types of antibiotics usually linked with nosocomial CDD. Because the frequency of C. difficile testing was shown to be more common with high-risk antibiotics, CDD may be underdiagnosed in the ambulatory care setting.

Behaviour of Saccharomyces boulardii in recurrent Clostridium difficile disease patients.

BACKGROUND: Despite recent interest in therapeutic microorganisms taken orally, little is known about the pharmacodynamics of these agents in a target population of patients with disease. The present study reports the stool concentrations of Saccharomyces boulardii in a patient population with Clostridium difficile disease (CDD) and correlates stool concentrations with efficacy. METHODS: Patients with recurrent CDD all received a 10-day standard antibiotic regimen together with 28 days of S. boulardii or placebo. Stool samples were collected from patients at various time points and assayed for S. boulardii. RESULTS: The mean concentration of S. boulardii of patients who recurred was 2.5 x 104 CFU/g compared to 1 x 106 CFU/g in patients that did not recur (P=0.02). Patients with low yeast concentrations in their stools (<104/g) recurred more often (14/15, 93%) compared with patients with higher levels (19/35, 54%, P=0.007). Clearance of S. boulardii was rapid; only 4% had positive stools 3 days after stopping dosing. CONCLUSIONS: After chronic dosing of S. boulardii, patients with low stool concentrations had a higher likelihood of recurrence of CDD. Stool concentrations were also lower during periods of diarrhoea. These results show the importance of characterizing the dynamics of a therapeutic microorganism in patients with disease, as kinetic studies in healthy volunteers may not give a true reflection of the disturbed microecology in the disease state.

Pseudomembranous colitis: causes and cures.

Clostridium difficile is the most common nosocomial pathogen of the gastrointestinal tract and has increased in frequency over time. Typical symptoms of C. difficile infection include diarrhea, which is usually nonbloody, or colitis associated with severe abdominal pain, fever and/or gross or occult blood in the stools. Pseudomembranous colitis (PMC), the severest form of this disease, occurs as a result of a severe inflammatory response to the C. difficile toxins. This review focuses on PMC, as this severe form is associated with the greatest medical concern. Diagnosis rests on detection of C. difficile in the stool, either by culture, tissue culture assay for cytotoxin B or detection of antigens in the stool by rapid enzyme immunoassays. Oral therapy with metronidazole 250 mg 4 times a day for 10 days is the recommended first-line therapy. Vancomycin is also effective, but its use must be limited to decrease the development of vancomycin-resistant organisms such as enterococci. Vancomycin (125-500 mg 4 times a day for 10 days) should be limited to those who cannot tolerate or have not responded to metronidazole, or when metronidazole use is contraindicated, as in the first trimester of pregnancy. A therapeutic response within a few days is usual. Recurrence of symptoms after antibiotics occurs in 20% of cases and is associated with persistence of C. difficile in the stools. Further recurrences then become more likely. Therapy with antibiotics in a pulsed or tapered regimen is often effective as are efforts to normalize the fecal flora. The yeast Saccharomyces boulardii has been proven in controlled trials to reduce recurrences when given as an adjunct to antibiotic therapy. Careful hand washing and environmental decontamination are necessary to prevent epidemics.

Recurrent Clostridium difficile disease: epidemiology and clinical characteristics.

OBJECTIVE: To describe the epidemiology, diagnosis, risk factors, patient impact, and treatment strategies for recurrent Clostridium difficile-associated disease (CDAD). DESIGN: Data were collected as part of a blinded, placebo-controlled clinical trial testing a new combination treatment for recurrent CDAD. Retrospective data regarding prior CDAD episodes were collected from interviews and medical-chart review. Prospective data on the current CDAD episode, risk factors, and recurrence rates were collected during a 2-month follow-up. SETTINGS: National referral study. PARTICIPANTS: Patients with recurrent CDAD. INTERVENTIONS: Treatment with a 10-day course of low-dose (500 mg/d) or high-dose (2 g/d) vancomycin or metronidazole (1 g/d). RESULTS: Recurrent CDAD was found to have a lengthy course involving multiple episodes of diarrhea, abdominal cramping, nausea, and fever. CDAD may recur over several years despite frequent treatment with antibiotics. Recurrence rates were similar regardless of the choice or dose of antibiotic. Recurrent CDAD is not a trivial disease: patients may have multiple episodes (as many as 14), may require hospitalization, and the mean lifetime cost of direct medical care was $10,970 per patient. Fortunately, the disease does not become progressively more severe as the number of episodes increase. Two risk factors predictive for recurrent CDAD were found: increasing age and a decreased quality-of-life score at enrollment. CONCLUSIONS: Recurrent CDAD is a persistent disease that may result in prolonged hospital stays, additional medical costs, and rare serious complications.

Microecologic approaches for traveler's diarrhea, antibiotic-associated diarrhea, and acute pediatric diarrhea.

Bacterial and viral diarrhea remain important causes of morbidity and mortality throughout the world. Current concerns with medical costs, increasing frequency of antibiotic resistance, and overuse of antibiotics in general have redirected therapeutic approaches for diarrhea from traditional drugs to the use of living therapeutic organisms. Awareness of the important role of normal flora in the microecology of the intestines in fighting infection, along with the recent availability of well-controlled clinical trials for these agents, has brought microecologic therapies to the forefront of clinical practice.

[Risk factor for antibiotic-associated diarrhea. A review of the literature]. / Facteurs de risque de la diarrhée associée aux antibiotiques. Une revue de la littérature.

Antibiotic associated diarrhea (AAD) is a common adverse reaction to most types of antibiotics with frequencies ranging from 5-39%, depending upon the specific type of antibiotic and the presence of other risk factors. The pathogenesis of antibiotic associated diarrhea is mediated through the disruption of the normal flora and overgrowth of pathogens or through metabolic imbalances. Beside risk factors associated with the type and duration of antibiotic therapy, host factors include the extremes of age (< 6 years or > 65 years), severe underlying disease, presence of other chronic intestinal conditions, immunosuppression, prior history of AAD and exposures during recent hospitalizations (surgery, nasogastric tube feeding). Factors which have not been significantly associated with antibiotic associated diarrhea include gender, dose or route of the inciting antibiotic and inflammatory bowel disease. The clinical impact of AAD is reflected by potential severity of the illness (PMC), possible consequences of the disruption in the treatment of the primary infection, higher medical costs, increased hospital stays and increased rates of morbidity and mortality. The key to decreasing these consequences is prompt diagnosis followed by effective treatment and institution of control measures and preventive treatments in patients at risk.

Epidemiology, risk factors and treatments for antibiotic-associated diarrhea.

Antibiotic-associated diarrhea (AAD) is a common complication of antibiotics and recent findings on the epidemiology, etiologies and treatment strategies are reviewed. Rates of AAD vary from 5 to 39% depending upon the specific type of antibiotic. The severity of AAD may include uncomplicated diarrhea, colitis or pseudomembranous colitis. The pathogenesis of AAD may be mediated through the disruption of the normal flora and overgrowth of pathogens or through metabolic imbalances. The impact of AAD is reflected by increased hospital stays, higher medical costs and increased rates of comorbidity. The key to decreasing these consequences is prompt diagnosis followed by effective treatment and institution of control measures.