Does gastrointestinal Candida albicans prevent ubiquinone absorption?

Ubiquinones (coenzyme Qs (CoQ)) are essential for oxidative phosphorylation in yeasts and humans, although the isomers present in each are different. The human coenzyme Q, CoQ10, is administered orally for the treatment of heart disease and other disorders. Some patients, however, require much higher doses than others to attain a therapeutic CoQ10 blood level. We propose that one possible explanation for this variability is Candida colonization of the GI tract. Many common medical treatments including antibiotics and anti-hyperchlorhydric agents increase the risk of GI tract Candida colonization. Subsequent uptake and utilization of supplemental CoQ10 by the yeast could diminish availability for the human subject. Data from one patient and an in vitro pilot study using two pathogenic strains of C. albicans support this hypothesis. If C. albicans in the GI tract can hinder availability and interfere with therapeutic effects of CoQ10, it could be of clinical significance for large numbers of 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.

Possible interaction between warfarin and Lycium barbarum L.

OBJECTIVE: To describe a patient who was stabilized on warfarin and developed an elevated international normalized ratio (INR) after drinking a concentrated Chinese herbal tea. Additionally, to determine the effect of the tea on CYP2C9, the isoenzyme responsible for the metabolism of S-warfarin. CASE SUMMARY: An elevated INR of 4.1 was observed in a 61-year-old Chinese woman, previously stabilized on anticoagulation therapy (INR 2-3). With no changes in her other medications or lifestyle, a review of her dietary habits revealed four days of drinking a concentrated Chinese herbal tea made from Lycium barbarum L. fruits (3-4 glasses daily) prior to her clinic visit Warfarin was withheld for one day and then resumed at a lower weekly dose. She discontinued the tea, while maintaining consistency with medications and dietary habits. A follow-up INR seven days later was 2.4, and seven subsequent INR values were in the 2.0-2.5 range. DISCUSSION: L barbarum L. (family Solanaceae) is a commonly used Chinese herb considered to have a tonic effect on various organs. Any impact of an herbal product on the metabolism of S-warfarin, the enantiomer responsible for most of the anticoagulant activity, could alter the INR values. An herbal-drug interaction was suspected in this case. In vitro evaluation showed inhibition of S-warfarin metabolism by CYP2C9 by the tea of L. barbarum L.; however, the inhibition observed was weak, with a dissociation constant (Ki) value of 3.4 mg/mL, suggesting that the observed interaction may be caused by factors other than the CYP450 system. CONCLUSIONS: There is a potential herbal-drug interaction between warfarin and L. barbarum L., based on an increased INRvalue noted with concurrent use. Thus, combination of L. barbarum L. and warfarin should be avoided. Vigilance is needed with other herbal combinations taken with drugs of narrow therapeutic indices.

Probiotics: "living drugs".

The uses, mechanisms of action, and safety of probiotics are discussed. Probiotics are live microorganisms or microbial mixtures administered to improve the patient's microbial balance, particularly the environment of the gastrointestinal tract and the vagina. The yeast Saccharomyces boulardii and the bacterium Lactobacillus rhamnosus, strain GG, have shown efficacy in clinical trials for the prevention of antimicrobial-associated diarrhea. Other probiotics that have demonstrated at least some promise as prophylaxis for this type of diarrhea are Lactobacillus acidophilus, Bifidobacterium longum, and Enterococcus faecium. The use of S. boulardii as an adjunctive treatment to therapy with metronidazole or vancomycin has been found in controlled studies to decrease further recurrences of Clostridium difficile-associated disease. Other gastrointestinal disorders for which probiotics have been studied include traveler's diarrhea, acute infantile diarrhea, and acute diarrhea in adults. Several Lactobacillus species given in yogurt or in tablet or suppository form have shown clinical efficacy as a treatment for vaginal infections. Lactobacillus strains have also been examined as a treatment for urinary-tract infections. Putative mechanisms of action of probiotics include production of pathogen-inhibitory substances, inhibition of pathogen attachment, inhibition of the action of microbial toxins, stimulation of immunoglobulin A, and trophic effects on intestinal mucosa. The available probiotics are considered nonpathogenic, but even benign microorganisms can be infective when a patient is severely debilitated or immunosuppressed. Probiotics have demonstrated an ability to prevent and treat some infections. Effective use of probiotics could decrease patients' exposure to antimicrobials. Additional controlled studies are needed to clearly define the safety and efficacy of these agents.

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.

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.

Pharmaceutical probiotics for the treatment of anaerobic and other infections.

Pharmaceutical probiotics have been used as alternative treatments or preventative therapies for a variety of clinical diseases. The overuse of antibiotics and emergence of multiple-antibiotic resistant pathogens has refocused clinical attention on the field of probiotics. Anaerobic infections which seem to respond well to probiotics are infections which involve the disruption of normal microbial flora. Gastrointestinal infections (travelers' diarrhea, antibiotic-associated diarrhea,Clostridium difficile disease, rotavirus diarrhea) have been studied using the following pharmaceutical probiotics:Saccharomyces boulardii, Lactobacillus casei GG, Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Streptococcus thermophilus and Enterococcus faecium. Vaginitis has been experimentally studied using L. acidophilus and L. casei GG. The efficacy, safety and mechanisms of action of these various probiotics are reviewed. Requirements for drug approval are similar for biologic probiotics and new drug entities and these requirements involve preclinical tolerability studies, pharmacokinetic studies and large, well-controlled blinded clinical trials.

Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial.

Recurrent Clostridium difficile diarrhea (RCDD) occurs in 20% of patients after they have received standard antibiotic treatment with vancomycin or metronidazole, but the reasons for the recurrences are largely unknown. Patients receiving vancomycin or metronidazole for active C. difficile diarrhea (CDD) were referred to our study centers for treatment and a 2-month follow-up as part of a randomized placebo-controlled trial. Sixty patients had RCDD (median number of episodes, 3.0; range, 2-9 episodes) and 64 were having their first episode of CDD. Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well to antibiotic therapy. Data on sequential episodes showed no progression in disease severity. Five factors were associated with a higher risk of RCDD: the number of previous CDD episodes, onset of the initial disease in the spring, exposure to additional antibiotics for treatment of other infections, infection with immunoblot type 1 or 2 strains of C. difficile, and female gender. These factors may help to identify patients who are more likely to develop RCDD and require careful medical supervision.

Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections.

OBJECTIVE: To evaluate the potential of biotherapeutic agents (microorganisms with therapeutic properties) for the prevention and/or treatment of selected intestinal and vaginal infections. DATA SOURCES: The MEDLINE database was searched for all relevant articles published between 1966 and September 1995. Search terms used were biotherapeutic agent, probiotic, Lactobacillus, Saccharomyces, Bifidobacterium, Candida, gastrointestinal- system, vaginitis, vaginosis-bacterial, and related terms. The bibliographies of obtained articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All placebo-controlled human studies on biotherapeutic agents were reviewed. English-language open trials, case series and reports, and animal studies were reviewed only if they were especially relevant to providing information on the potential efficacy, adverse effects, or mechanisms of action of these agents. DATA SYNTHESIS: Placebo-controlled studies have shown that biotherapeutic agents have been used successfully to prevent antibiotic-associated diarrhea (Lactobacillus caseiGG, bifidobacterium longum, B longum with L acidophilus, and Saccharomyces boulardii), to prevent acute infantile diarrhea (Bifidobacterium bifidum with Streptococcus thermophilus), to treat recurrent Clostridium difficile disease (S boulardii), and to treat various other diarrheal illnesses (Enterococcus faecium SF68, L caseiGG, and S boulardii). There is also evidence for Lactobacillus acidophilus in the prevention of candidal vaginitis. Few adverse effects have been reported. However, many of the studies tested only small numbers of patients or volunteers. CONCLUSIONS: There is now evidence that administration of selected microorganisms is beneficial in the prevention and treatment of certain intestinal and, possibly, treatment of vaginal infections. In an effort to decrease the reliance on antimicrobials, the time has come to carefully explore the therapeutic applications of biotherapeutic agents.

Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo.

OBJECTIVES: To determine the safety and efficacy of a new preventive agent for antibiotic-associated diarrhea (AAD) in patients receiving at least one beta-lactam antibiotic. METHODS: A double-blinded, placebo-controlled, parallel group study was performed in a high-risk group of hospitalized patients receiving a new prescription for a beta-lactam antibiotic and having no acute diarrhea on enrollment. Lyophilized Saccharomyces boulardii or placebo (1 g/day) was given within 72 h of the start of the antibiotic(s) and continued until 3 days after the antibiotic was discontinued, after which the patients were followed for 7 wk. RESULTS: Of the 193 eligible patients, significantly fewer, 7/97 (7.2%), patients receiving S. boulardii developed AAD compared with 14/96 (14.6%) on placebo (p = 0.02). The efficacy of S. boulardii for the prevention of AAD was 51%. Using a multivariate model to adjust for two independent risk factors for AAD (age and days of cephalosporin use), the adjusted relative risk was significantly protective for S. boulardii (RR = 0.29, 95% CI = 0.08, 0.98). CONCLUSION: The prophylactic use of S. boulardii given with a beta-lactam antibiotic resulted in a significant reduction of AAD with no serious adverse reactions.

A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease.

OBJECTIVE--To determine the safety and efficacy of a new combination treatment for patients with Clostridium difficile-associated disease (CDD). The treatment combines the yeast Saccharomyces boulardii with an antibiotic (vancomycin hydrochloride or metronidazole). DESIGN--A double-blind, randomized, placebo-controlled, parallel-group intervention study in patients with active CDD. Patients received standard antibiotics and S boulardii or placebo for 4 weeks, and were followed up for an additional 4 weeks after therapy. Effectiveness was determined by comparing the recurrence of CDD in the two groups using multivariate analysis to control for other risk factors for CDD. SETTING--National referral study of ambulatory or hospitalized patients from three main study coordinating centers. PATIENTS--A total of 124 eligible consenting adult patients, including 64 who were enrolled with an initial episode of CDD, and 60 who had a history of at least one prior CDD episode. Patients who were immunosuppressed due to acquired immunodeficiency syndrome or cancer chemotherapy within 3 months were not eligible. INTERVENTION--Treatment with oral S boulardii (1 g/d for 4 weeks) or placebo in combination with a standard antibiotic. MAIN OUTCOME MEASURE--Recurrence of active CDD. RESULTS--A history of CDD episodes dramatically increased the likelihood of further recurrences. Multivariate analysis revealed that patients treated with S boulardii and standard antibiotics had a significantly lower relative risk (RR) of CDD recurrence (RR, 0.43; 95% confidence interval, 0.20 to 0.97) compared with placebo and standard antibiotics. The efficacy of S boulardii was significant (recurrence rate 34.6%, compared with 64.7% on placebo; P = .04) in patients with recurrent CDD, but not in patients with initial CDD (recurrence rate 19.3% compared with 24.2% on placebo; P = .86). There were no serious adverse reactions associated with S boulardii. CONCLUSIONS--The combination of standard antibiotics and S boulardii was shown to be an effective and safe therapy for these patients with recurrent CDD; no benefit of S boulardii was demonstrated for those with an initial episode of CDD.

Recovery and elimination of the biotherapeutic agent, Saccharomyces boulardii, in healthy human volunteers.

Saccharomyces boulardii (Sb) is a nonpathogenic yeast used to treat intestinal illnesses such as pseudomembranous colitis and antibiotic associated diarrhea. The behavior of this biotherapeutic agent in humans was determined (1) in investigating the effect of dose on the steady-state level and recovery and (2) in quantitating the effect of ampicillin on the recovery and elimination profile. As the Sb dose increased, the mean steady-state concentration of Sb increased significantly. The percentage recovery was dose independent. When a single Sb dose was administered 24 hr after beginning a course of ampicillin, there was a significant increase (P < 0.01) in both the area under the concentration versus time curve and the maximum fecal concentration compared to values obtained without ampicillin. Ampicillin increased steady-state recovery of the drug about twofold (P < 0.05) and steady-state levels about 2.4 times (P < 0.01). These studies have shown that there is a relationship between the dose and the amount of Sb recovered and that perturbation of the GI flora by ampicillin increases steady-state levels of Sb.

Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients.

To determine whether strain-specific differences in immunoblot type, enterotoxin production, or cytotoxin production correlated with clinical presentation of Clostridium difficile infection, we evaluated isolates obtained from 428 prospectively studied hospitalized patients. Of 99 isolates available for immunoblot typing, 61 were recovered from asymptomatic carriers and 38 were from patients with C. difficile-associated diarrhea. Of 17 immunoblot types, the seven types comprising the majority of isolates (82 of 99; 83%) were variably associated with disease. Neither the presence of cytotoxin in the stool nor the production of cytotoxin or enterotoxin by isolates in vitro was significantly different for symptomatic versus asymptomatic patients. Selected host factors were more predictive of symptomatic disease than was the specific infecting C. difficile strain. These results suggest that variations in the clinical severity of C. difficile infection in different patients are not solely strain-specific phenomena related to immunoblot type or to the production of cytotoxin or enterotoxin.

Influence of antibiotics on the recovery and kinetics of Saccharomyces boulardii in rats.

Saccharomyces boulardii (SB) is a yeast that is used for the prevention and treatment of antibiotic-associated diarrhea and for the treatment of pseudomembranous colitis. Since SB will most commonly be used when the bacterial flora of the gastrointestinal tract have been disrupted by antibiotic treatment, the influence of different antibiotics on the kinetics and recovery of SB in feces was investigated in rats. Following a single oral dose, SB concentrations in feces were measured for periods of 1 to 6 days. Although SB is eliminated exclusively in the feces, less than 3% of the dose is recovered as viable yeast. When rats were treated with neomycin, which is active against gram-negative aerobic bacteria but not against anaerobes, no change was observed in recovery of SB when compared with recovery from untreated rats. Also, there was no change in the rate at which SB concentrations declined in feces. In contrast, treatment with clindamycin and the broad-spectrum antibiotic ampicillin, which are active against anaerobes, produced an increase in the recovery of SB of up to seven times that of controls and slowed the rate of decline of SB concentration in the feces. This antibiotic effect on SB disposition was also found when SB was administered in multiple doses. An eightfold increase in the steady-state output of SB was observed from ampicillin-treated animals. Analysis of the recovery and kinetic data showed that the primary effect of these antibiotics was to reduce the destruction of SB, probably in the cecum and colon.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of Clostridium difficile induced mortality as a function of the dose and the viability of the Saccharomyces boulardii used as a preventative agent in gnotobiotic mice.

The ability of viable and nonviable Saccharomyces boulardii to protect gnotobiotic mice from Clostridium difficile induced mortality was tested. With the exception of irradiated S. boulardii, which retained some activity, only viable yeast protected the mice from lethality. The survival of C. difficile infected mice was dependent on the dose of the yeast provided in the drinking water.

Prevention of further recurrences of Clostridium difficile colitis with Saccharomyces boulardii.

A patient with six documented episodes of recurrent Clostridium difficile colitis over an eight-month period is described. Relapses of colitis occurred despite treatment with vancomycin, metronidazole, bacitracin, and cholestyramine. Each recurrence appeared to begin successively closer to the end of the previous course of treatment. Four episodes were sufficiently severe to require hospitalization for rehydration. Saccharomyces boulardii, a nonpathogenic yeast, was begun prior to discontinuing vancomycin therapy for the last recurrence and was continued for three months. Serial stool cultures and assays for C. difficile showed persistence of the organism but rapid reduction of high titers of cytotoxin. No further recurrences of diarrhea or colitis were encountered while the patient was taking Saccharomyces boulardii and for 18 months of follow-up after the yeast was discontinued.