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Diarrhées associées aux antibiotiques chez le sujet âgé
Abstract
Purpose. – Most of the antibiotic-associated diarrhea (AAD) cases result from a transient disturbance in the function of the normal intestinal flora and are spontaneously solved when discontinuing the antibacterial therapy. However, a mild diarrhea lasting several days may induce a dehydration or worsen a denutrition in frail elderly people.Current knowledge and key points. – The incidence of AAD varies between 5 and 25% depending on the concerned antibiotic. Only 10–20% of all AAD cases are caused by infection, especially with Clostridium difficile, for which advanced age is a major risk factor. The first biological exam to perform when severe AAD or in frail people is the detection of C. difficile toxins, especially in elderly patient treated with beta-lactam antibiotics. Nevertheless, other infectious organisms causing AAD may be considered, as Staphylococcus aureus when predominant in stool cultures from patients treated with fluoroquinolones or as Klebsiella oxytoca when isolated in bloody diarrhea from patients treated with ampicillin. Elevated fecal counts of Candida spp. found in patients treated with antibiotics is rather the consequence of therapy than the cause of AAD. The prevention of AAD is based on a rational antibiotic use to avoid endogenous selection of C. difficile and on the improvement of the hygiene measures to limit the exogenous transmission of the bacteria or related spores by spoiled hands.Future prospects. – Simultaneous prescription of non-pathogenic living organisms, capable of re-establishing the equilibrium of the intestinal flora, should be better described, especially in elderly people, because of its important economic impact.
... T he extensive utilization of antibiotics usually helps in promoting growth and preventing diarrhea (1,2). Nevertheless, intestinal pathogenic bacterial resistance and drug residues caused by the overuse of antibiotics are worthy of attention and need to be resolved (3,4). Researchers have been concerned about antibiotic substitutes that can improve growth performance and immune function without any biological harm. ...
Bacillus amyloliquefaciens is a nonpathogenic microorganism whose highly active amylase is widely isolated from soil and plants. TL106 is an isolate of Bacillus amyloliquefaciens isolated from cold- and disease-resistant Tibetan pigs in Linzhi, Tibet. Here, we report that TL106 not only could survive in acidic environments, high bile salt concentrations, and high-temperature conditions but also was resistant to antibiotics. It significantly improved the growth performance of weaned piglets, especially in the prevention of diarrhea. The crude fiber and crude ash digestibility in weaned piglets after TL106 administration was considerably higher than that in other groups. The results of 16S rRNA sequencing conveyed that TL106 stabilized gut microbiota that was disturbed by the weaning process with an increased level of Lachnospiraceae, Peptococcaceae.rc4_4, Erysipelotrichaceae.L7A_E11, and Mollicutes.RF39. Hence, this study proved that Bacillus amyloliquefaciens TL106 might be a candidate for antibiotics in Duroc×Landrace×Yorkshire weaned piglets.
IMPORTANCE Antibiotics are often used to promote animal growth and prevent diarrhea in weanling piglets. Nevertheless, intestinal pathogenic bacterial resistance and drug residues caused by antibiotic overuse are worthy of concern and demand an urgent solution. Bacillus amyloliquefaciens TL106 has been isolated from cold- and disease-resistant Tibetan pigs in Linzhi, Tibet. It significantly improved the growth performance, decreased diarrhea, increased the absorption of crude substances, and regulated the gut flora homeostasis in Duroc×Landrace×Yorkshire weaned piglets. As an antibiotic candidate, TL106 perfectly displayed its probiotic potential and pollution-free properties.
... Hence, studies performed on patients under chronic treatment with the antimicrobial neomycin revealed different histological changes in their mucosa, including severe villous atrophy [79,153]. AAD mainly appears in the shape of benign diarrhea, which may induce hypohydration or worsen malnutrition in the elderly [154]. However, in severe cases, AAD may result in pseudomembranous colitis or a toxic megacolon, leading to increased fatality rates [152]. ...
Despite being the most essential nutrient, water is commonly forgotten in the fields of pharmacy and nutrition. Hydration status is determined by water balance (the difference between water input and output). Hypohydration or negative water balance is affected by numerous factors, either internal (i.e., a lack of thirst sensation) or external (e.g., polypharmacy or chronic consumption of certain drugs). However, to date, research on the interaction between hydration status and drugs/excipients has been scarce. Drugs may trigger the appearance of hypohydration by means of the increase of water elimination through either diarrhea, urine or sweat; a decrease in thirst sensation or appetite; or the alteration of central thermoregulation. On the other hand, pharmaceutical excipients induce alterations in hydration status by decreasing the gastrointestinal transit time or increasing the gastrointestinal tract rate or intestinal permeability. In the present review, we evaluate studies that focus on the effects of drugs/excipients on hydration status. These studies support the aim of monitoring the hydration status in patients, mainly in those population segments with a higher risk, to avoid complications and associated pathologies, which are key axes in both pharmaceutical care and the field of nutrition.
... Antibiotics are widely used to treat diarrhea, but antibiotic use is considered a double-edged sword, as some problems have emerged with antibiotic usage, especially antibiotic resistance. Previous studies have shown that the misuse of antibiotics has become a serious problem, affecting microbial balance and increasing the incidence of antibiotic-associated diarrhea by 5 to 25% (Kaltenbach and Heitz, 2004). Probiotics are living microorganisms that not only improve the balance of intestinal microflora but also inhibit many pathogens (Food Agriculture Organization/World Health Organization [FAO/WHO], 2011). ...
The purpose of this study was to evaluate the antibacterial activity and safety of bacterias with probiotic potential isolated from free-ranging Tibetan yaks in high altitude regions of Tibet. For this purpose, one Leuconostoc pseudomesenteroides strain (named P1) and two Lactobacillus johnsonii and Lactobacillus mucosae strains (named LY1 and LY2), respectively, were isolated from fecal samples of Tibetan yaks. The antibacterial activity of the isolates was studied using Escherichia coli (E. coli ATCC 25922), Staphylococcus aureus (S. aureus ATCC 26112), and Salmonella enteritidis (S. enteritidis NCTC 13349) as indicator pathogens. The results showed that LY1 had high antibacterial efficacy against E. coli and S. enteritidis, while P1 had the most powerful bacteriostatic ability against S. aureus. PCR amplification showed that all the isolated strains were positive for Ent P2 (enterocin P-like bacteriocin) and exhibited a high tolerance to bile and low pH. Moreover, the safety of P1, LY1, and LY2 was determined through antibiotic resistance experiments, resistance gene testing, and hemolytic analysis while the antibacterial activity was assessed by in vitro and in vivo experiments. The LY2 strain was abandoned as a potential probiotic due to the detection of the vanA gene. The mice were fed from days 1 to 30 in six groups, the P1-1 (gavaged with P1 1 × 108 CFU/day), P1-2 (gavaged with P1 1 × 109 CFU/day), LY1-1 (gavaged with LY1 1 × 108 CFU/day), LY1-2 (gavaged with LY1 1 × 109 CFU/day), control (gavaged with an equal volume of vehicle), and blank control (gavaged with an equal volume of vehicle) groups. After 30 days, mice in the P1-1, P1-2, LY1-1, LY1-2, and control groups were intraperitoneal challenged with 1 × 108 CFU of E. coli (n = 10) in the abdomen. After 2 days of infection, the mice in the control group showed more severe damage in the liver, spleen and intestine than the mice in the P1-2 and LY1-2 groups. The mice in the P1-2 and LY1-2 groups had lower rates of diarrhea and mortality than other groups. In conclusion, bacteria with probiotic potential isolated from yaks may possibly be effective and safe antibacterial substances, providing a new treatment method to reduce the incidence of diarrhea associated with bacterial diseases in yaks.
... The incidence of AAD varies between 5% and 25% depending on the antibiotic concerned. 2 Staphylococcus aureus can infect a wide range of host systems, and is responsible for about 5-20% of nosocomial infections; 3 it is recognized as one of the most frequent causes of AAD. This species was first suspected to cause AAD in 1954. ...
The aim of this study was to investigate the in vitro and in vivo anti-staphylococcal activity of a lactic acid bacterial strain and its effect on the intestinal histological damage caused by Staphylococcus aureus infection.
Lactobacillus paracasei subsp. paracasei was isolated in our laboratory from breastfed newborn feces and identified phenotypically and genotypically. The strain was analyzed by spot-on-lawn and well diffusion assays for the production of bacteriocins against five antibiotic-resistant S. aureus strains isolated from the feces of hospitalized patients with antibiotic-associated diarrhea. The anti-staphylococcal activity of this strain was evaluated in fermented milk and in vivo using holoxenic rabbits.
The strain was able to produce a bacteriocin-like substance active against the staphylococcal strains. A reduction of 2 log in S. aureus cell numbers was registered in co-culture with L. paracasei in fermented milk. Administration of skimmed milk containing S. aureus (10(7) cells/ml) to healthy rabbits induced a persistent diarrheal state 5 days after the challenge. Dissection of the rabbits and consequent histological observations showed damage and an atrophy of the intestinal and colonic mucosae of the diarrheal rabbits; in contrast an arrest of the diarrhea concomitant with recovery of the intestinal villi and the colonic crypts was observed in the rabbits treated with L. paracasei-fermented milk. Furthermore, the diarrheal state persisted in spite of a decrease in the level of S. aureus cells in the feces of the rabbits receiving sterile milk; this was in contrast to the rabbits treated with L. paracasei-fermented milk, in which the decrease in the S. aureus fecal number was associated with the arrest of the diarrhea.
L. paracasei could act as a potential barrier to prevent S. aureus- associated injury and might exert its effect on the staphylococcal enterotoxins or their target.
Abstract Background Given the crucial role of gut microbiota in animal and human health, studies on modulating the intestinal microbiome for therapeutic purposes have grasped a significant attention, of which the role of fecal microbiota transplantation (FMT) has been emphasized. Methods In the current study, we evaluated the effect of FMT on gut functions in Escherichia coli (E. coli) infection by using mice model. Moreover, we also investigated the subsequently dependent variables of infection, i.e., body weight, mortality, intestinal histopathology, and the expression changes in tight junction proteins (TJPs). Results The FMT effectively decreased weight loss and mortality to a certain extent with the restoration of intestinal villi that resulted in high histological scores for jejunum tissue damage (p
The aim of this study was to evaluate the antibacterial potential of lactic acid bacteria (Weissella confuse, Pediococcus acidilactici, and Ligilactobacillus equi) isolated from healthy equine in Wuhan against Salmonella Typhimurium CVCC542-induced mice model on intestinal microflora. In previous studies, these isolated strains showed good probiotic potentials in vitro. In this study, fifty healthy mice were randomly divided into five groups, the blank control group, the control group, the Pediococcus acidilactici group (1 × 108 CFU/day), the Ligilactobacillus equi group (1 × 108 CFU/day), and the Weissella confuse group (1 × 108 CFU/day). The body weight in control group and Weissella confuse group showed significant decreased (P < 0.05, P < 0.01), while Pediococcus acidilactici group and Ligilactobacillus equi group showed good recovering after treatments. The lowest diarrhea rate was shown in Ligilactobacillus equi group after treatment. In histopathology, Ligilactobacillus equi group showed the least structural damage in duodenum, and all probiotic treatment groups showed less damage in cecum. The sequence data and optical transform unit showed that Pediococcus acidilactici group and Ligilactobacillus equi group had higher number than control group, while the diversity data showed that the control group and Weissella confuse group had lower diversity in cecum. Microbial community analysis showed increased abundance of Firmicutes, Bacteroidetes, uncultured_bacterium_f_Muribaculaceae, and Lactobacillus in treatment groups, while potential microbes that can induce intestinal diseases such as Verrucomicrobia, Akkermansia, and Lachnospiraceae_NK4A136_group decreased in the treatment groups. In conclusion, lactic acid bacteria isolated from the healthy horses could alleviate the infection of Salmonella and regulate intestinal flora.
To study enteropathogens, 100 fecal samples were collected from a Brazilian human immunodeficiency virus (HIV)-seropositive population, with or without diarrhea. Giardia lamblia and calicivirus were significantly associated with diarrhea as were severe immunosuppression and the presence of at least one enteropathogen. No sample was positive for rotavirus and only one asymptomatic individual carried the astrovirus. We concluded that there is a great diversity of pathogens and opportunistic infections in the studied population, with a high prevalence of mixed colonization/infection. Our findings pave the way for future molecular studies related to the expression of virulence factors and to the possibility of pathogen-pathogen interactions, especially between G. lamblia and calicivirus. These findings are relevant to the improvement of therapies and controlling diarrhea in the HIV-seropositive population.
Aim: Describe the most important physiological changes associated with aging, the characteristics of infections in these patients and the most common side effects and severe interactions with antimicrobials in older people. Material and methods: We conducted a literature review on the risks associated with the use of antibiotics in the elderly. The information was based on the update of the scientific evidence and information from the drug Sheets. The search was limited to the past 11 years, selected papers published in English, Spanish or French. We performed an electronic search of secondary sources (systematic reviews) and a manual search "ad hoc" basis of the literature retrieved, primary studies, reports of drug evaluation agencies, clinical practice guidelines and documents of Scientific Societies. Information sources: Pubmed, Embase, Iowa Drug Information Service (IDIS), WinSPIRS 5.00, Up to Date, The Cochrane Library®. Results: We identified 321 results, after eliminating those who did not meet inclusion criteria 52 papers in addition to the technical specifications of all mentioned antibiotics were included in the literature review. Conclusion: Older patients can acquire infections more frequently multi-resistant pathogens and suffer more serious complications of infections. The antibiotics is a group of drugs sensitive to the physiological changes induced by aging, which may influence the response to these and often requires dosage modifications to avoid poisoning and / or therapeutic failures. This paper provides information on these physiological changes and risks of antibiotics in the elderly, aspects necessary to choose a proper treatment.
The french population is growing older every year. As a result, the practice of medicine will continue to shift toward the care of elderly patients. Infections are a common problem in the elderly. The most common infections are urinary and respiratory tract infections. Whenever possible, clinicians should collect appropriate cultures before initiating antibiotic therapy. In practice, clinical and microbiological diagnosis of infection in the elderly are generally not well documented. Because the elderly appear to be at an increased risk for more severe complications of infection, it is usually appropriate to begin treatment with empiric antibiotics. Drug dosages and galenic forms should be appropriate for elderly patients and selected according to the suspected causative organism, the severity of infection, and potential drug interactions and toxicity. Adverse drug reactions, pharmacokinetic changes (renal dysfunction) and drug interactions are common in the elderly. The calculation of creatinine clearance is the most useful measure of renal function in elderly patients. Amoxicillin with clavulanic acid, cephalosporins and quinolones are the first-line antibiotics in the elderly.
Here, we evaluated the efficacy of probiotic interventions in prevention of antibiotic-associated diarrhoea (AAD) and Clostridium difficile diarrhoea (CDD) in older patients.
PubMed, Embase, CENTRAL, CINAHL, and Web of Science were comprehensively searched from their dates of inception to May 2014. Only randomised controlled trials reporting data on probiotics including Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus-alone or in combination-versus placebo or absence of treatment in older patients (age ≥65 years) were included. Risk ratios (RRs) for AAD and CDD relative to placebo or absence of treatment were estimated.
Six trials with a total of 3562 patients were included. Only one trial showed that Bacillus licheniformis was effective for preventing AAD in older patients. However, there was no preventive effect for AAD and CDD with Lactobacillus acidophilus (Florajen), Lactobacillus casei Shirota, Saccharomyces cerevisiae (boulardii) lyo, mixture of Lactobacillus acidophilus and Bifidobacterium bifidum (Cultech strains), and mixture of Lactobacillus acidophilus CUL60, CUL21, Bifidobacterium bifidum CUL20 and B. lactis CUL34.
Our findings indicate that probiotics may not reduce the risk of AAD and CDD in older patients. However, with current published data, it is difficult to draw concrete conclusions. To confirm these findings, sample sizes, multi-centre, double-blind studies that consider factors such as probiotic strains and types of antibiotics are required.
Copyright © 2015 Elsevier Ltd. All rights reserved.
In the UK, older people are particularly prone to developing community acquired pneumonia. The most common pathogen is the bacterium Streptococcus pneumoniae. In the environment, S. pnumoniae is a robust microbe that can adapt and survive in hostile conditions and in the human body. Antibiotic therapy targets the mechanisms and processes that bacteria use to metabolize, replicate and survive. However, the inappropriate use of antibiotics has allowed bacteria to become resistant to the actions of specific antibiotics, and this has led to difficulties in treating infections caused by S.pneumoniae. Although immunization is available, older people continue to die from pneumococcal pneumonia. Penicillin is still used as the main method of treatment against S. pneumoniae, but the threat of antibiotic resistance is increasing.
Diarrhoea is a common side effect of antibiotics. Different mechanisms are involved in antibiotic associated diarrhea (AAD): a direct toxic effect of antibiotic on digestive mucosa, an alteration of metabolic functions of the intestinal microbiota (decrease of carbohydrates fermentation, accumulation of biliary salts) or the emergence and overgrowth of a bacterial pathogen. An infectious etiology is involved in less than 25 % of the cases. Clostridium difficile infection (CDI) is the leading causes of AAD. C. difficile is currently responsible for 10 to 20 % of cases of AAD and for virtually all cases of pseudomembranous colitis (PMC). The first step in development of the infection is a disruption of the normal colonic flora, mainly caused by antibiotics. The reduction of the protective microflora allows C. difficile to overgrow and to produce two enterotoxic and cytotoxic toxins (TcdA and TcdB). All antibiotics may predispose to CDI but antibiotics with higher risk for infection include cephalosporins, ampicillin, amoxicillin, clindamycin and, more recently, fluoroquinolones. Risk factors for CDI also include age >65 years and previous hospitalization. Other pathogens involved in AAD include K. oxytoca, C. perfringens, S. aureus or Candida spp. However their respective frequency and physiopathology still remain unclear.
The french population is growing older every year. As a result, the practice of medicine will continue to shift toward the care of elderly patients. Infections are a common problem in the elderly. The most common infections are urinary and respiratory tract infections. Whenever possible, clinicians should collect appropriate cultures before initiating antibiotic therapy. In practice, clinical and microbiological diagnosis of infection in the elderly are generally not well documented. Because the elderly appear to be at an increased risk for more severe complications of infection, it is usually appropriate to begin treatment with empiric antibiotics. Drug dosages and galenic forms should be appropriate for elderly patients and selected according to the suspected causative organism, the severity of infection, and potential drug interactions and toxicity. Adverse drug reactions, pharmacokinetic changes (renal dysfunction) and drug interactions are common in the elderly. The calculation of creatinine clearance is the most useful measure of renal function in elderly patients. Amoxicillin with clavulanic acid, cephalosporins and quinolones are the first-line antibiotics in the elderly.
In December, 2005 the NIH/Center for Disease Control's (CDC) newsletter MMWR reported that in the past Clostridium difficile-associated diseases which usually affected hospital patients, are now appearing in cases of relatively healthy adults, including some who have not even been exposed to a hospital. In the same month The New England Journal of Medicine printed an early edition with several reports suggesting that not only is the rate of disease associated with C. difficile increasing, but a previously uncommon strain of C. difficile has been found. The new found strain of C. difficile has variations in toxin genes and is more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of Antibiotic Associated Diarrhea (AAD), specifically C. difficile diseases (CDD), and Clostridium Difficile-Associated Diarrhea (CDAD). Bacteria are constantly mutating to become resistant to antibiotics. These more virulent toxin producing C. difficile infections include CDAD, C. difficile-associated colitis or pseudomembranous colitis (CDAC). This latter can progress to toxic megacolon (TM). CDAC is increasing in frequency and severity. C. difficile also accounts for an unknown but increasing percentage of community acquired diarrhea. Fluoroquinolones, especially C-8-methoxy fluoroquinolones like moxifloxacin and gatifloxacin have been incriminated in CDAD epidemics in different health care facilities. This article describes the methods of prevention, early diagnosis and prompt aggressive treatment which are critical in managing CDAD/CDAC. A very important method of controlling outbreaks of C. difficile-associated disease must be interventions on the prevention and use of antimicrobial agents implicated as risk factors for the disease. These interventions have been shown to be cost effective and successful in improving antibiotic prescribing to hospital inpatients. These interventions have also been shown to reduce antimicrobial resistance or hospital acquired infections. Guidelines to prevent and curtail AAD, and CDAD epidemics are presented in this article for this new era of virulent nosocomial and community acquired bacterial resistant infections.
Antibiotic associated diarrhea (AAD) is a frequently encountered adverse event following antibiotic administration. Evidence suggests that probiotics may be beneficial in preventing and decreasing the severity of AAD.
Adult patients who were prescribed antibiotics for 3-14 days were enrolled from eight Canadian centers. Study treatment was randomized at a 1 : 1 ratio of BIO-K+CL1285( (®) ) or placebo and was administered within 24 h of initiation to 5 days after termination of antibiotherapy. Patients were followed for 21 days after last dose of study treatment. The primary outcome was severity and incidence of AAD. Severity was measured by the total number of days with diarrhea and incidence was defined as the number of patients with at least one day with diarrhea over the total number of patients enrolled in the study.
216 patients were randomized to BIO-K+ and 221 to placebo. The mean (SD) number of days with diarrhea was 1.19. (3.20) days for the placebo and 0.67 (2.05) days for BIO-K+CL1285( (®) ) (p = 0.040). Adjusted multivariate linear regression results showed that the duration of diarrhea for BIO-K+CL1285 (®)vs. placebo was reduced by 51.5% (b[SE] = 0.515 [0.256], p = 0.045). The incidence of diarrhea was 21.8% for the BIO-K+ and 29.4% for the placebo group (OR = 0.667, p = 0.067). Multivariate logistic regression, showed that the adjusted odds ratio of AAD in patients receiving BIO-K+ vs. placebo was 0.627 (p = 0.037). Study treatment was well tolerated.
BIO-K+ is effective for preventing and reducing the severity of AAD in patients receiving antibiotic therapy in a hospital setting.
This work aimed to evaluate the antibiotic susceptibility of 63 Lactobacillus rhamnosus strains isolated from Parmigiano Reggiano cheese, of Lactobacillus GG and of the type strain L. rhamnosus DSM 20021. Antimicrobial susceptibility was determined by the disc diffusion method on 41 antibiotics. Inhibition zone diameter was carefully measured and the results ( the mean of four determinations) were expressed in terms of resistance or susceptibility. All the strains isolated from cheese showed resistance to six antibiotics (cefixime, vancomycin, neomycin, enoxacin, pefloxacin and sulphamethoxazole plus trimethoprim). The strain DSM 20021(T) was resistant to nine antibiotics ( the previous six plus cephalexin, bacitracin and lincomycin), while the commercial strain L. GG showed resistance to eighteen antibiotics. A high strain-specific resistance to different antibiotics was ascertained in Lactobacillus rhamnosus isolated from cheese. The results obtained in this study confirm that antibiotic resistance is a very important feature in the selection of potentially probiotic lactic acid bacteria.
To study enteropathogens, 100 fecal samples were collected from a Brazilian human immunodeficiency virus (HIV)-seropositive population, with or without diarrhea. Giardia lamblia and calicivirus were significantly associated with diarrhea as were severe immunosuppression and the presence of at least one enteropathogen. No sample was positive for rotavirus and only one asymptomatic individual carried the astrovirus. We concluded that there is a great diversity of pathogens and opportunistic infections in the studied population, with a high prevalence of mixed colonization/infection. Our findings pave the way for future molecular studies related to the expression of virulence factors and to the possibility of pathogen-pathogen interactions, especially between G. lamblia and calicivirus. These findings are relevant to the improvement of therapies and controlling diarrhea in the HIV-seropositive population.
Candida is the most frequently encountered fungal infection of the gastrointestinal tract after antibiotic exposure. The pathogenesis of Candida probably varies with each species. The speciation of fecal Candida after antibiotic use is not well investigated. One hundred and eleven fecal samples negative for Clostridium difficile toxin and for other enteric pathogens formed the basis of our investigation. The diarrheic samples came from patients receiving antibiotics in a hospital setting. In addition, samples from 30 age-matched healthy participants who did not receive antibiotics and did not have diarrhea were also studied. Initially, a Gram stain identification for yeasts was performed for each fecal sample, then each sample was cultured on Sabouraud's dextrose agar. Candida was isolated as pure growth (>10(5) cfu/ml) from the stools of 32 (28.8%) patients. The identification of the yeast was done based upon a combination of morphological, physiological and biochemical criteria. The predominant isolates were C. tropicalis (n=16), C. albicans (n=14) and C. krusei (n=2). Candida isolated from healthy participants (n=4) was sparse and therefore not speciated. Different Candida spp. may play an important role in precipitating antibiotic-associated diarrhea.
Stools from a patient with antibiotic-associated colitis and cecal contents from a hamster with clindamycin-induced enterocolitis were compared in a cytotoxicity assay to determine common properties. Both specimens produced actinomorphic changes in human amnion cells at 10(-7) dilutions. The toxin was acid labile, heat labile, nonether extractable, non-dialyzable, and produced maximum activity at 60% with ammonium sulfate precipitation. Cytotoxicity was neutralized with clostridial antitoxin but not with equine serum. Clostridium difficile was recovered in high concentrations in specimens from both the hamster and patients. The supernatants of these C. difficile strains produced cytoxic effects which were also neutralized by clostridial antitoxins. These results indicate that clindamycin-induced enterocolitis in hamsters is a model of human disease and implicate toxin-producing clostridia as responsible agents.
The amoxicillin-clavulanate combination (Augmentin) frequently induces gastric complaints and diarrhea by an unknown mechanism. The aim of this study was to assess the effects of two orally therapeutic regimens of amoxicillin-clavulanate on small bowel motility in human beings. Duodeno-jejunal manometric recordings were performed in six healthy subjects treated in a cross-over double-blind study with placebo; amoxicillin-clavulanate, 1 g plus 250 mg per os every 12 h for 3 days; or amoxicillin-clavulanate, 1 g plus 250 mg per os every 12 h on day 3 only (1-day regimen). Recordings were all performed on day 3 during a diurnal fasting period, a fed state after a standard dinner, and a nocturnal fasting period. Amoxicillin-clavulanate did not affect the motility of the small intestine during the diurnal fast or the fed state. During the nocturnal fast, amoxicillin-clavulanate significantly increased the motility index of the nonpropagated contractions and tended to increase the duration and the amplitude of the propagated contractions. The same digestive motor effect was already observed on the first day of treatment (1-day regimen). This study demonstrates that the oral administration of a therapeutic regimen of amoxicillin-clavulanate is associated, in most cases, with the occurrence of small intestinal motor disturbances.
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.
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.
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).
The prophylactic use of S. boulardii given with a beta-lactam antibiotic resulted in a significant reduction of AAD with no serious adverse reactions.
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.
Enzyme immunoassays (EIAs) based on monoclonal antibodies for the detection of Clostridium difficile toxins have recently been developed for clinical use. The aim of this study was to compare three commercially available EIAs, two for toxin A (Premier C. difficile Toxin A; Meridian, Osi, Elancourt, France; and Vidas C. difficile Toxin A; bioMérieux, Marcy l'Etoile, France) and one for toxins A and B (Cytoclone A + B EIA; Cambridge Biotech Corp., Codiapharm, Evian, France), with a cytotoxicity assay and toxigenic culture for the diagnosis of C. difficile-associated diarrhea (CDAD). The study was performed with 285 fresh stools from 285 patients with suspected CDAD. In case of disagreement, the tests were repeated on a frozen aliquot of the same stool sample, and the patient's chart was reviewed. CDAD diagnosis was established in 55 cases (incidence, 19.3%). The sensitivities and specificities of the methods were, respectively, 92.7 and 100% for the cytotoxicity assay, 96.4 and 99.1% for toxigenic culture, 75.5 and 97.8% for Cytoclone, 65.4 and 99.6% for Premier, and 65.4 and 100% for Vidas. The results were uninterpretable in 3.2% of cases with Cytoclone, 0.3% with Premier, and 2.5% with Vidas. We conclude that the cytotoxicity assay and toxigenic culture remain the best methods for the diagnosis of CDAD even though they lack standardization and require 48 to 96 h to obtain the result. Despite their rapidity and simplicity, EIAs are not sensitive enough to be relied on as the sole laboratory test.
Although Clostridium difficile is the main agent responsible for nosocomial diarrhea in adults, its prevalence in stool cultures sent to hospital microbiology laboratories is not clearly established.
To determine the prevalence of C difficile in inpatient stools sent to hospital microbiology laboratories and to assess the relationship between serotypes and toxigenicity of the strains isolated and the clinical data.
From January 18, 1993, to July 31, 1993, the presence of C difficile was systematically investigated in a case-control study on 3921 stool samples sent for stool culture to 11 French hospital microbiology laboratories. The prevalence of C difficile in this population (cases) was compared with that of a group of 229 random hospital controls matched for age, department, and length of stay (controls). Stool culture from controls was requested by the laboratory although not prescribed by the clinical staff. Serotype and toxigenesis of the strains isolated were compared.
The overall prevalence of C difficile in the cases was twice the prevalence in the controls (9.7% vs 4.8%; P < .001) and was approximately 4 times as high in diarrheal stools (ie, soft or liquid) as in normally formed stools from controls (11.5% vs 3.3%; P < .001). The strains isolated from diarrheal stools were more frequently toxigenic than those isolated from normally formed stools. Serogroup D was never toxigenic, and its proportion was statistically greater in the controls than in the cases (45% vs 18%; chi 2 = 5.2; P < .05). Conversely, serogroup C was isolated only from the cases. Clostridium difficile was mainly found in older patients ( > 65 years), suffering from a severe disabling disease, who had been treated with antibiotics and hospitalized for more than 1 week in long-stay wards or in intensive care.
This multicenter period prevalence study clearly supports the hypothesis of a common role of C difficile in infectious diarrhea in hospitalized patients. Disease associated with C difficile should therefore be systematically evaluated in diarrheal stools from inpatients.
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.
Only 10%–20% of all cases of antibiotic-associated diarrhea (AAD) are caused by infection with Clostridium difficile. Other infectious organisms causing AAD include Clostridium perfringens, Staphylococcus aureus, Klebsiella oxytoca, Candida species, and Salmonella species. Most of the clinically mild AAD cases are due to functional disturbances of intestinal carbohydrate or bile acid
metabolism, to allergic and toxic effects of antibiotics on intestinal mucosa, or to pharmacological effects on motility.
Saccharomyces boulardii and Enterococcus SF68 can reduce the risk of developing AAD. Patients receiving antibiotic treatment should avoid food containing high amounts
of poorly absorbable carbohydrates. Mild cases of AAD that may or may not be caused by C. difficile can be resolved by discontinuation of antibiotic therapy and by dietary carbohydrate reduction. Only severe AAD caused by
C. difficile requires specific antibiotic treatment.
Staphylococcus aureus was isolated as the predominant or only isolate from cultures of stools of 60 patients over 2 years in a university hospital, leading to the collection of 114 isolates. Diarrhea was observed in 90% of the patients. Ninety-eight percent of the patients had received antibiotics in the month before the diarrhea. Ninety-two percent of the S. aureus isolates were methicillin resistant. S. aureus was encountered with antibiotic-associated diarrhea among 47 quite elderly patients affected or not affected by a gastrointestinal disease. Among the antimicrobial treatments, cessation of the previous therapy when possible or rapid application of oral vancomycin therapy was the most appropriate. Analysis of total DNA by pulsed-field gel electrophoresis revealed 27 different SmaI pulsotypes distributed in 15 clusters. The pulsotypes never differed for related isolates from a single patient, even if they originated from patients with bacteremia. S. aureus was not isolated as the predominant isolate in cultures of stools of 57 patients who received an antimicrobial treatment for more than 5 days without diarrhea. Occurence of production of both enterotoxin A and the bicomponent leucotoxin LukE-LukD by the S. aureus isolates was significantly different from that by random isolates. The results strongly suggest that when predominant in stool samples, S. aureus should be considered a possible etiologic agent for some cases of antibiotic-associated diarrhea.
Clostridium perfringens type A isolates producing enterotoxin (CPE) are an important cause of food poisoning and non-food-borne human gastrointestinal
(GI) diseases, including antibiotic-associated diarrhea (AAD). Recent studies suggest thatC. perfringens type A food poisoning is caused by C. perfringens isolates carrying a chromosomal cpe gene, while CPE-associated non-food-borne GI diseases, such as AAD, are caused by plasmid cpe isolates. Those putative relationships, obtained predominantly with European isolates, were tested in the current study by
examining 34 cpe-positive,C. perfringens fecal isolates from North American cases of food poisoning or AAD. These North American disease isolates were all classified
as type A using a multiplex PCR assay. Furthermore, restriction fragment length polymorphism and pulsed-field gel electrophoresis
genotyping analyses showed the North American AAD isolates included in this collection all have a plasmid cpegene, but the North American food poisoning isolates all carry a chromosomal cpe gene. Western blotting demonstrated CPE expression by nearly all of these disease isolates, confirming their virulence potential.
These findings with North American isolates provide important new evidence that, regardless of geographic origin or date of
isolation, plasmid cpe isolates cause most CPE-associated AAD cases and chromosomal cpe isolates cause most C. perfringens type A food poisoning cases. These findings hold importance for the development of assays for distinguishing cases of CPE-associated
food-borne and non-food-borne human GI illnesses and also identify potential epidemiologic tools for determining the reservoirs
for these illnesses.
Infection with fluoroquinolone-resistant strains of salmonella is rare, as is nosocomial salmonella infection. We describe the first recognized outbreak of fluoroquinolone-resistant salmonella infections in the United States, which occurred in two nursing homes and one hospital in Oregon.
We interviewed medical staff and reviewed patients' charts and death certificates. In Nursing Home A we conducted a case-control study. Patients were defined as residents of the nursing home from whom fluoroquinolone-resistant Salmonella enterica serotype Schwarzengrund was isolated between February 1996 and December 1998. Controls were residents with similar medical conditions whose cultures did not yield salmonella. We compared isolates using pulsed-field gel electrophoresis and sequence analysis. We reviewed pharmacy records to compare the use of fluoroquinolone among several nursing homes.
Eleven patients with fluoroquinolone-resistant salmonellosis were identified at two nursing homes. The index patient had been hospitalized in the Philippines and had probably acquired the infection there. Transmission was probably direct (from patient to patient) or through contact with contaminated surfaces. Treatment with fluoroquinolones during the six months before a culture was obtained was associated with a significant risk of salmonella infection (4 of 5 patients had taken fluoroquinolones, as compared with 2 of 13 controls; odds ratio, 22.0; 95 percent confidence interval, 1.06 to 1177). The patients were not significantly more likely than the controls to have taken other antibiotics. More fluoroquinolones were used at Nursing Home A than at similar nursing homes in Oregon. The isolates from the outbreak had similar patterns on pulsed-field gel electrophoresis and the same gyrA mutations. The isolates from the outbreak were also similar to the only previous isolate of fluoroquinolone-resistant salmonella in the United States, which came from a patient in New York who had been transferred from a hospital in the Philippines.
We describe a prolonged nosocomial outbreak of infection with fluoroquinolone-resistant S. enterica serotype Schwarzengrund. More such outbreaks are likely in institutional settings, particularly those in which there is heavy use of antimicrobial agents.
To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics.
Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups.
Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics.
Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P<0.001) for the yeast and 0.34 (0.19 to 0.61; P<0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P<0.001) in favour of active treatment over placebo.
The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.
Consecutively to the few number of private room, poor financial support and particularities of the patients in such units, health care workers of long term care units considered as difficult the respect of isolation policy. However physicians are more and more often constrained to institute isolation practice as multiresistant bacteria tend to become endemic in those units. In May 1996 a salmonella outbreak occurred in two long term care units in Nancy. We have studied the working's conditions of health care workers during this period, using a retrospective questionnaire. After analysis we have proposed a set of measures which could improve ergonomic aspects of isolation practices. A better organisation should decrease health care worker's workload. The propositions reported in this work could be useful to other long stay care units which are confronted with same problems.
Background:
Although Clostridium difficile is the main agent responsible for nosocomial diarrhea in adults, its prevalence in stool cultures sent to hospital microbiology laboratories is not clearly established.Objectives:
To determine the prevalence of C difficile in inpatient stools sent to hospital microbiology laboratories and to assess the relationship between serotypes and toxigenicity of the strains isolated and the clinical data.Methods:
From January 18, 1993, to July 31, 1993, the presence of C difficile was systematically investigated in a case-control study on 3921 stool samples sent for stool culture to 11 French hospital microbiology laboratories. The prevalence of C difficile in this population (cases) was compared with that of a group of 229 random hospital controls matched for age, department, and length of stay (controls). Stool culture from controls was requested by the laboratory although not prescribed by the clinical staff. Serotype and toxigenesis of the strains isolated were compared.Results:
The overall prevalence of C difficile in the cases was twice the prevalence in the controls (9.7% vs 4.8%; P<.001) and was approximately 4 times as high in diarrheal stools (ie, soft or liquid) as in normally formed stools from controls (11.5% vs 3.3%; P<.001). The strains isolated from diarrheal stools were more frequently toxigenic than those isolated from normally formed stools. Serogroup D was never toxigenic, and its proportion was statistically greater in the controls than in the cases (45% vs 18%; χ2=5.2;P<.05). Conversely, serogroup C was isolated only from the cases. Clostridium difficile was mainly found in older patients (>65 years), suffering from a severe disabling disease, who had been treated with antibiotics and hospitalized for more than 1 week in long-stay wards or in intensive care.Conclusions:
This multicenter period prevalence study clearly supports the hypothesis of a common role of C difficile in infectious diarrhea in hospitalized patients. Disease associated with C difficile should therefore be systematically evaluated in diarrheal stools from inpatients.Arch Intern Med. 1996;156:1449-1454
Clostridium difficile is the major identifiable cause of antibiotic-associated diarrhoea in the UK. The aim of this study was to employ traditional culture, toxin detection and a novel typing method to determine the level of C. difficile colonization and disease in a population of elderly patients and to investigatetheassociationbetweenstrainsinthepatientsandtheirenvironment.Threehundredand ninety patients between 62 and 101 years of age admitted to a geriatric unit in the Royal Victoria Hospital(RVH),Edinburgh,wereinvestigatedforthepresenceofC.difficile.C.difficilewascultured from 100 (26%) patients using pre-reduced cycloserine-cefoxitin egg yolk agar, and toxin(s) was detectedinthefaecesof34ofthesepatientsusingtheTechlabELISAtestkitforthedetectionofC. difficile toxins A and/or B. Toxin(s) was detected in a further 18 patients from whom no C. difficile wasdetected inculture. Ofthe patients inwhomC.difficilewasdetected, 49% haddiarrhoea,with thehighestproportionofpatientswithdiarrhoeabeingbothculture-andtoxin-positiveforC.difficile. Environmental sampling of the patient environment yielded C. difficile from 14% of samples. The organism wasmostfrequentlyisolatedfromfloors,sluice-rooms andtoilet areas.Thevariationinthe molecularmassoftheC.difficileS-layerproteinswasexploitedasthebasisofanoveltypingmethod for C. difficile. Isolates from patients in the RVH were given a four-digit ‘S-type’ number based on their S-layer protein profile. A total of seven S-types were identified, with one type, toxigenic S-type 5236, accounting for 73% of all clinical isolates and 91% of environmental isolates.
5 cases of acute transient colitis associated with the ingestion of ampicillin, an ampicillin derivative, and penicillin are discussed. The clinical presentation, course, and radiographic and sigmoidoscopic findings are distinct from those in pseudomembranous colitis. The colonic changes may be related to an allergic reaction in the intestine which results primarily in transient ischaemia. The presenting symptom is blood diarrhoea, and barium enema is the most productive diagnostic examination.
To compare the efficacy of vancomycin and metronidazole for eradication of asymptomatic Clostridium difficile fecal excretion as a means of controlling nosocomial outbreaks of C. difficile diarrhea.
Randomized, placebo-controlled, non-blinded trial.
Six hundred-bed regional referral Veterans Affairs Medical Center.
Thirty patients excreting C. difficile without diarrhea or abdominal symptoms.
All patients were randomized to receive 10 days of oral vancomycin, 125 mg four times daily; metronidazole, 500 mg twice daily; or placebo, three times daily.
Stool cultures were obtained during treatment and for 2 months after treatment. All C. difficile isolates were typed by restriction endonuclease analysis (REA).
Clostridium difficile organisms were not detected during and immediately after treatment in 9 of 10 patients treated with vancomycin compared with 3 of 10 patients treated with metronidazole (P = 0.02) and 2 of 10 patients in the placebo group (P = 0.005). The fecal vancomycin concentration was 1406 +/- 1164 micrograms/g feces, but metronidazole was not detectable in 9 of 10 patients. Eight of the nine evaluable patients who had negative stool cultures after treatment with vancomycin began to excrete C. difficile again 20 +/- 8 days after completing treatment. Three of these patients received additional antibiotics before C. difficile excretion recurred, and five acquired new C. difficile REA strains. Four of six patients who received only vancomycin before C. difficile excretion recurred were culture-positive at the end of the study compared with one of nine patients who received only placebo (P = 0.047).
Asymptomatic fecal excretion of C. difficile is transient in most patients, and treatment with metronidazole is not effective. Although treatment with vancomycin is temporarily effective, it is associated with a significantly higher rate of C. difficile carriage 2 months after treatment and is not recommended.
The part that candida plays in antibiotic-associated diarrhoea was investigated in 24 elderly inpatients (mean age 74 years) who tested negative for Clostridium difficile toxin and other intestinal pathogens. 7 had intestinal overgrowth of Candida species (greater than or equal to 10(5) cfu/ml). None of the 24 matched, antibiotic-treated controls without diarrhoea had candida overgrowth. All 5 patients with diarrhoea and candida overgrowth treated with oral nystatin responded with resolution of diarrhoea and lowering of faecal counts to less than 10(4) cfu/ml within 7 days of start of antifungal therapy despite continuation of antibacterial therapy. In the other 2 patients with candida overgrowth, the diarrhoea subsided spontaneously and faecal candida counts returned to normal (less than 10(4) cfu/ml) after antibacterial agents were withdrawn. In patients without candida overgrowth, diarrhoea persisted until antibiotics were withdrawn, at a mean of 16 days after study entry.
Clostridium difficile causes pseudomembranous colitis and is responsible for 20% to 25% of cases of postantibiotic diarrhea. In an earlier study, nursing-home patients with C. difficile infection were noted to have a high mortality rate. Because most of these infected patients had been treated with antibiotics, it was not clear whether this high mortality rate was associated with C. difficile infection or simply with antibiotic treatment. A prospective study was carried out to determine the rate of postantibiotic C. difficile colonization and risk factors for infection in patients in a 233-bed long-term care facility, as well as to determine whether C. difficile infection is associated with increased mortality. During a six-month period 150 courses of antibiotics were prescribed for 108 patients. Stool specimens were collected from 36 (33%) patients following the first course of antibiotic treatment, and 12 (33%) were infected with C. difficile. Risk factors for infection included ward location and stool incontinence. Age, body-mass index less than or equal to 18 kg/m2, and diagnoses of dementia and pressure scores tended to be associated with infection, but not significantly. Early mortality rates did not differ, but 12-month mortality for the infected patients was higher (83% vs 50%, P = .05). Therefore, we conclude that postantibiotic C. difficile infection serves as a marker of death in nursing-home patients, one that can be differentiated from the risk of antibiotic treatment alone. This increased death rate may be related in part to clinically unrecognized pseudomembranous colitis or, alternatively, to absorption of C. difficile toxins or even endotoxin from the gut lumen into the systemic circulation.
Saccharomyces boulardii, a nonpathogenic yeast, has been widely used in Europe to prevent antibiotic-associated diarrhea (AAD). We performed a prospective double-blind controlled study to investigate AAD in hospitalized patients and to evaluate the effect of S. boulardii, a living yeast, given in capsule form concurrently with antibiotics. Over 23 mo, 180 patients completed the study. Of the patients receiving placebo, 22% experienced diarrhea compared with 9.5% of patients receiving S. boulardii (p = 0.038). Risk factors found to be associated with AAD were multiple antibiotic combinations (containing clindamycin, cephalosporins, or trimethoprim-sulfamethoxazole) and tube feeding. Clostridium difficile, an anaerobe found in the stools of most patients with pseudomembranous colitis, was variably associated with AAD. We evaluated the role of C. difficile in AAD in the study population and found no significant association between the presence of C. difficile or cytotoxin with AAD. Approximately 33% of the patients without diarrhea harbored at least one C. difficile-positive stool and nearly 50% of these patients had detectable cytotoxin. Similar values were obtained in patients with diarrhea. Of C. difficile-positive patients, 31% (5/16) on placebo developed diarrhea compared with 9.4% (3/32) on S. boulardii; this difference was not statistically significant (p = 0.07). There were no discernable adverse effects of yeast administration. We conclude that S. boulardii reduces the incidence of antibiotic-associated diarrhea in hospitalized patients.
Clostridium perfringens has recently been shown to be associated with antibiotic-associated diarrhoea. We describe here the clinical features and
management of an outbreak of diarrhoea in a Geriatric Unit. Ten cases were due to enterotoxigenic C. perfnngens and in these cases there was a highly significant correlation with recent antibiotic administration (P=0.0001). The importance of early recognition of C. perfringens as a cause of infective diarrhoea in the elderly is stressed.
An apparent outbreak of Clostridium difficile diarrhoea on the chronic hospital ward of a long-term care facility prompted an investigation lasting seven months. Approximately a third of patients had stools that were positive for C difficile by either toxin or culture. Attempts to eradicate the infection by simultaneously treating all toxin-positive patients with metronidazole, limiting antibiotic use, and implementing enteric isolation were unsuccessful. New cases were both nosocomially acquired and imported into the facility. Of the C difficile toxin-positive patients, 34% had diarrhoea and 19/49 (38%) died during the study period. C difficile is not routinely sought by most clinical microbiology laboratories and may therefore be endemic in many long-term care facilities for the elderly.
101 patients with Clostridium-difficile-associated diarrhoea or colitis were prospectively randomised to 10-day oral courses of metronidazole, 250 mg four times a day, or vancomycin, 500 mg four times a day. 7 did not complete the protocol and were dropped from analysis. Pseudomembranous colitis (PMC) was diagnosed after endoscopy in 33 patients. Of the remaining patients without PMC, 38 had both C difficile culture and cytotoxin and 23 had only culture evidence of C difficile. 52 evaluable patients received vancomycin and 42 received metronidazole. There were two treatment failures with metronidazole and none with vancomycin (p = 0.20); and two relapses with metronidazole versus six with vancomycin (p = 0.17). Treatment in 1 patient in each group was discontinued because of drug intolerance. Response and relapse rates of the 33 patients with PMC were no different from those of the remaining patients. Pharmacy cost for the dosage used was $387.48 to $520.00 for vancomycin and $11.84 for metronidazole. Metronidazole and vancomycin have equivalent efficacy and relapse rates and are tolerated to a similar extent by patients with C-difficile-related diarrhoea and colitis, but metronidazole is considerably more economical.
Free Clostridium perfringens enterotoxin was detected in the stools of 11 patients with diarrhoea. All had high faecal counts of enterotoxigenic strains of C perfringens, mostly of serotypes not commonly associated with food poisoning. 10 of these 11 patients had severe or prolonged diarrhoea which had developed after antibiotic treatment. Enterotoxigenic C perfringens appears to be one of the causes of antibiotic-associated diarrhoea.
It has been difficult to document the postulated sequence of events that begins with the selection of drug-resistant organisms in animals fed subtherapeutic amounts of antimicrobials and ends with clinically important infections in human beings. In early 1983 we identified 18 persons in four Midwestern states who were infected with Salmonella newport that was resistant to ampicillin, carbenicillin, and tetracycline and characterized by a 38-kilobase R plasmid. Twelve of these patients had been taking penicillin derivatives for medical problems other than diarrhea in the 24 to 48 hours before the onset of salmonellosis. Eleven patients were hospitalized for salmonellosis for an average of eight days, and one had a fatal nosocomial infection. We compared plasmid profiles of all human (six-state area) and animal (United States) S. newport isolates over an 18-month period and examined selected records of meat distribution. The results indicated that the patients had been infected before they took antimicrobials, by eating hamburger originating from South Dakota beef cattle fed subtherapeutic chlortetracycline for growth promotion. This study demonstrates that antimicrobial-resistant organisms of animal origin cause serious human illness, and emphasizes the need for more prudent use of antimicrobials in both human beings and animals.
Mild or severe episodes of diarrhoea are the main side effects of antibiotic therapy. The major form of intestinal disorders is pseudomembranous colitis due to Cl. difficile. Among ecological means for control of these diarrhoea, which result from disruption of the intestinal ecosystem, several non-pathogenic microorganisms can be used in order to establish a new equilibrium; among the available microorganisms, S. boulardii is a non-pathogenic yeast, which has given rise to many experimental and clinical studies. Moreover, results of an in vitro study of susceptibilities to antibiotics of the available microorganisms are reported; for S. boulardii, these in vitro data confirm the bases of persistence of the organism in the gut during antibiotic therapy. Besides these in vitro data, experimental studies in animal models (gnotobiotic mice and hamsters with Cl. difficile colitis) have confirmed the potential effectiveness of S. boulardii in preventing the pathogenic effect of toxins A and B and in decreasing numbers of Cl. difficile colonies in the gut. Similarly, in intensive care unit patients, controlled prospective studies have shown that administration of S. boulardii prevented diarrhoea, pseudo-membranous colitis and intestinal translocation of gram-negative bacilli when combined with selective digestive decontamination.
We examined the enterotoxicity of a Klebsiella oxytoca cytotoxin which is produced by K. oxytoca OK-1, a strain from a patient with antibiotic-associated hemorrhagic colitis. Injection of the cytotoxin into ligated ileal and colonic loops in rabbits caused the accumulation of fluid in the loops. The fluid was bloody in the ileal loops but not in the colonic ones. Histological examination revealed intense mucosal hemorrhage with erosion in the ileum, whereas no microscopic change was noted in the colon. The fluid accumulation was shown to be a dose-dependent response in both ileal and colonic loops. The amounts of the cytotoxin required for maximal fluid accumulation in ileal and colonic loops were 60 and 10 micrograms, respectively. Fluid accumulation was first noticeable in ileal loops 12 h and in colonic ones 5 h after the injection of these doses of the cytotoxin and then proceeded with time. When K. oxytoca OK-1, a cytotoxin-producing strain, was inoculated into the loops at doses of 1 x 10(8) and 5 x 10(9) CFU, similar fluid accumulation was observed. However, inoculation of K. oxytoca ATCC 13182, a non-cytotoxin-producing strain, at the same doses did not cause any change. These results suggest that the cytotoxin-producing strain of K. oxytoca is the causative organism of antibiotic-associated hemorrhagic colitis and that the toxin is the factor responsible for pathogenesis.
Pseudomembranous colitis associated with antibiotic therapy is almost always due to an overgrowth of Clostridium difficile. If untreated, pseudomembranous colitis can lead to severe diarrhea, hypovolemic shock, toxic dilatation of the colon, cecal perforation, hemorrhage, and death. However, C difficile-associated colitis can mimic the more common "benign" antibiotic-associated diarrhea that is not caused by C difficile. An algorithm for diagnosis management of hospitalized patients with antibiotic diarrhea and C difficile colitis is presented in this review. Diagnosis depends on sigmoidoscopy and/or stool tests for C difficile toxins in all patients with antibiotic-associated diarrhea. If the results of these tests are positive, either metronidazole or vancomycin is recommended for treatment of mild illness, and vancomycin is recommended for treatment of severe illness. Oral therapy is always preferred because it is more reliable. In patients with recurrent or relapsing colitis, treatment with either metronidazole or vancomycin is effective for that episode, but novel approaches, such as the oral or rectal introduction of competing nonpathogenic organisms, may prove to be more successful in prevention of relapses.
Nosocomial diarrhea is a common problem in hospitals, but the epidemiology, causes, and consequences of infectious and iatrogenic nosocomial diarrhea are rarely documented in follow-up or surveillance studies of nosocomial infections. The objective of this study was to describe the epidemiology of nosocomial diarrhea in a cohort study of hospitalized patients.
The setting was a general medicine ward with a total of 30 beds in private or semiprivate rooms in a county hospital. A prospective cohort study of all consenting patients in the study ward was performed during an 11-month period. Patients were interviewed and cultures were obtained to check for stool pathogens within 48 hours of admission, and patients were followed up during their stay in the study ward. Data from medical notes, laboratory tests, antibiotic logs, and patient interviews were collected daily.
Among the 382 eligible patients, nosocomial diarrhea developed in 126 (32.9%): 37 cases were of infectious origin, 57 were iatrogenic, and 32 were of unknown origin. The most common causes of nosocomial diarrhea were Clostridium difficile and antibiotic therapy. Multivariate analysis revealed four risk factors for infectious nosocomial diarrhea: age, length of stay, number of antibiotics, and nasogastric tube feedings. Multivariate analysis also revealed four risk factors for iatrogenic nosocomial diarrhea: number of antibiotics, current gastrointestinal conditions, current renal conditions, and recent surgery. Comorbidity associated with nosocomial diarrhea included increased risk of acquiring another type of nosocomial infection, increased risk of death, and increased length of stay.
Nosocomial diarrhea was found to be common and associated with an additional burden of comorbidity. Analyses indicated different risk factors, depending on the etiology of nosocomial diarrhea (infectious or iatrogenic). Further studies are recommended to document the epidemiology and cost analysis of nosocomial diarrhea in other hospital populations.
We conducted a prospective, randomized study to compare the efficacy of oral fusidic acid, oral metronidazole, oral vancomycin,
and oral teicoplanin for the treatment of Clostridium difficile—associated diarrhea. Treatment resulted in clinical cure for 94% of the patients who were treated with vancomycin, 96% of
those treated with teicoplanin, 93% of those treated with fusidic acid, and 94% of those treated with metronidazole. Clinical
symptoms recurred in 16% of patients treated with vancomycin, 7% of those treated with teicoplanin, 28% of those treated with
fusidic acid, and 16% of those treated with metronidazole. There was asymptomatic carriage of C. difficile toxin in 13% of patients treated with vancomycin,4% of those treated with teicoplanin, 24% of those treated with fusidicacid,
and 16% of those treated with metronidazole. No adverse effectsrelated to therapy with vancomycin or teicoplanin were observed.
Considering the costs of treatment, our findings suggest that metronidazole is the drug of choice for C. difficile—associated diarrhea and that glycopeptides should be reserved for patients who cannot tolerate metronidazole or who do not
respond to treatment with this drug.
We examined the clinical features of 14 men (mean age 72 years) with postoperative enteritis caused by methicillin-resistant Staphylococcus aureus (MRSA). The patients had all undergone surgery for the treatment of digestive diseases and had received antibiotic prophylaxis consisting of an extended-spectrum cephem. Diarrhea appeared a mean of 3.3 days postoperatively and lasted for 5 days on average. In severe cases organ insufficiency was involved. Coagulate-positive staphylococci were the predominant organisms isolated from watery diarrhea. In 13 of 14 patients, coagulase type II isolates producing enterotoxins A, C and toxic shock syndrome toxin-1 (TSST-1) with enterotoxin A, C, and 1st genes were isolated. These strains were sensitive to vancomycin and arbekacin; however, they were highly resistant to many other antibiotics. We also investigated the effects of a glucocorticoid hormone and gamma globulin on production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) obtained from healthy volunteers. TNF-alpha and IL-2 production was enhanced by TSST-1 and the supernatant of Iscove-modified dulbecco medium, in which coagulase type II isolates producing enterotoxins A, C and TSST-1 with enterotoxin A, C were cultured for 24 h. Both glucocorticoid hormone and gamma globulin suppressed TNF-alpha and IL-2 production, thus suggesting that these drugs may be effective in treating postoperative MRSA enteritis.
Diarrhoea is a common side effect of antibiotic therapy, especially in the elderly. Saccharomyces boulardii is a non-pathogenic yeast which has been demonstrated to reduce the frequency of diarrhoea in patients due to a variety of causes. We set out to assess its role in preventing antibiotic-related diarrhoea. Consecutive patients over the age of 65 admitted to medical wards, and who were being prescribed antibiotics, were randomized to receive either S. boulardii 113 g twice daily or placebo for as long as they received antibiotics. Bowel habit was monitored using a record of interdefaecatory intervals (IDI) and stool form graded 1-4 (hard to liquid). Stool samples were tested every fourth day for Clostridium difficile toxin. Of the 72 patients randomized, 69 completed the study. There was no difference in sex, age, duration of antibiotic use, length of hospital stay, IDI, stool form, the proportion of patients receiving laxatives, the number of patients experiencing watery stools (seven vs. five), or the presence of C. difficile toxin (five vs. three). No side effects were attributable to S. boulardii. There was no evidence that the concomitant use of S. boulardii with antibiotics alters patients' bowel habits or prevents the appearance of C. difficile toxin in the stool. Thus, S. boulardii cannot be recommended as a 'natural' way to prevent antibiotic-related diarrhoea. This highlights the need for proper evaluation of probiotics before their unrestricted use in medical practice.
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.
Mild or severe episodes of antibiotic-associated diarrhea (AAD) are common side effects of antibiotic therapy. The incidence of AAD differs with the antibiotic and varies from 5 to 25%. The major form of intestinal disorders is the pseudomembranous colitis associated with Clostridium difficile which occurs in 10-20% of all AAD. In most cases of AAD discontinuation or replacement of the inciting antibiotic by another drug with lower AAD risk can be effective. For more severe cases involving C. difficile, the treatment of diarrhea requires an antibiotic treatment, with glycopeptides (vancomycin) or metronidazole. Another approach to AAD treatment or prevention is based on the use of non-pathogenic living organisms, capable of re-establishing the equilibrium of the intestinal ecosystem. Several organisms have been used in treatment or prophylaxis of AAD such as selected strains of Lactobacillus acidophilus, L. bulgaricus, Bifidobacterium longum, and Enterococcus faecium. Another biotherapeutic agent, a non-pathogenic yeast, Saccharomyces boulardii has been used. In animal models of C. difficile colitis initiated by clindamycin, animals treated with S. boulardii (at end of vancomycin therapy) had a significant decrease in C. difficile colony-forming units, and of toxin B production. In several clinical randomised trials (versus placebo), S. boulardii has demonstrated its effectiveness by decreasing significantly the occurrence of C. difficile colitis and preventing the pathogenic effects of toxins A and B of C. difficile. It has been shown to be a safe and effective therapy in relapses of C. difficile colitis. A good response has been seen in children with AAD, treated by S. boulardii only. In ICUs prevention of AAD remains based on limitation of antibiotic overuse and spread of C. difficile or other agents of AAD should be prevented by improved hygiene measures (single rooms, private bathrooms for patients, use of gloves and hand washing for personnel). In addition the increasing use of biotherapeutic agents such as S. boulardii should permit the prevention of the major side effect of antibiotics, i.e. AAD in at risk patients.
Diarrhea that occurs in hospitalized patients is frequent and may be due to infectious or noninfectious causes. In adults with nosocomial diarrhea, the most commonly detected agent is Clostridium difficile; in children, rotaviruses are predominant. Various studies have shown that bacterial enteric pathogens (e.g. Salmonella spp., Shigella spp., Campylobacter spp...) or parasites are common causes of community-acquired diarrhea but rarely cause nosocomial enteritis. Stool cultures for these pathogens and ova and parasite examination should not be performed in patients hospitalized for more than three days unless there are plausible clinical or epidemiological reasons to do so. In contrast, C. difficile toxins assay (and rotavirus screening in children) should be primarily requested. The detection of C. difficile toxin B by stool cytotoxicity assay remains the 'gold standard'. Identification of toxin A (or A + B) can also be performed by immuno-enzymatic (ELISA) tests: results may be obtained in three hours. Electronic microscopy is the standard method for rotavirus diagnosis but tests using latex agglutination or immuno-enzymatic assay are now available. Various typing methods have been developed and may be routinely used in epidemiological investigations.
Clostridium difficile causes 300 000 to 3 000 000 cases of diarrhea and colitis in the United States every year. Antibiotics most frequently associated with the infection are clindamycin, ampicillin, amoxicillin, and cephalosporins, but all antibiotics may predispose patients to C difficile infection. The clinical presentation varies from asymptomatic colonization to mild diarrhea to severe debilitating disease, with high fever, severe abdominal pain, paralytic ileus, colonic dilation (or megacolon), or even perforation. The most sensitive and specific test available for diagnosis of C difficile infection is a tissue culture assay for the cytotoxicity of toxin B. However, this test takes 1 to 3 days to complete and requires tissue culture facilities. Detection of C difficile toxin by means of enzyme-linked immunoassay is more rapid and inexpensive. A minority of patients may require more than 1 stool assay to detect toxin. Oral metronidazole or oral vancomycin hydrochloride for 10 to 14 days are equally effective at resolving clinical symptoms; oral metronidazole is preferred in most cases because of lowered cost and less selective pressure for vancomycin-resistant organisms. Approximately 15% of patients experience relapse after initial therapy and require retreatment, sometimes with an extended, tapering regimen. Immunity appears to be incomplete and predominantly mediated by serum IgG to toxin A. Measures for preventing the spread of the pathogen, appropriate diagnostic testing, and treatment may avert morbidity and mortality due to C difficile-associated diarrhea.
To assess the efficacy of Lactobacillus GG in preventing antibiotic-associated diarrhea (AAD) in adults and, secondarily, to assess the effect of coadministered Lactobacillus GG on the number of tests performed to determine the cause of diarrhea.
In this prospective, randomized, double-blind, placebo-controlled trial conducted from July 1998 to October 1999, 302 hospitalized patients receiving antibiotics were randomized to receive Lactobacillus GG, 20 x 10(9) CFU/d, or placebo for 14 days. Subjects recorded the number of stools and their consistency daily for 21 days. The primary outcome was the proportion of patients who developed diarrhea in the first 21 days after enrollment. Weekly telephone follow-up was also performed. Results were analyzed in an intention-to-treat fashion.
Diarrhea developed in 39 (29.3%) of 133 patients randomized to receive Lactobacillus GG and in 40 (29.9%) of 134 patients randomized to receive placebo (P=.93). No additional difference in the rate of occurrence of diarrhea was found between treatment and placebo patients in a subgroup analysis of those treated with beta-lactam vs non-beta-lactam antibiotics. Too few patients had stool cultures, additional laboratory tests for diarrhea, or a positive diagnosis of Clostridium difficile infection to assess between-group differences.
Lactobacillus GG in a dose of 20 x 10(9) CFU/d did not reduce the rate of occurrence of diarrhea in this sample of 267 adult patients taking antibiotics initially administered in the hospital setting.
To quantitatively assess the role of Candida species in antibiotic-associated diarrhea (AAD), stool samples from a total of 395 patients and control subjects were cultured
in differential isolation medium: 98 patients had AAD, 93 patients were taking antibiotics but did not have diarrhea (A+D−), 97 patients were not taking antibiotics but had diarrhea (A−D+), and 107 patients were control subjects (A−D−). In addition, secreted aspartyl proteinase (Sap) production was tested. In AAD patients, Candida positivity (77/98) and Candida overgrowth (62/98) were not different from that among A+D− patients (75/93 [P=.860] and 52/93 [P=.375], respectively). Candida overgrowth among A−D+ patients (40/97, P=.003) was less frequent than among AAD patients, but Candida positivity was not different (80/97, P=.612). In control subjects, Candida positivity and overgrowth were less common than in all other groups. Production of Sap did not differ between patients with
AAD and control subjects (P=.568 and P=.590, respectively). Data indicate that elevated Candida counts are a result of antibiotic treatment or diarrhea rather than a cause of AAD
Infectious diarrhea is an important disease in the elderly. Some basic principles have been outlined, as follows. In the elderly: Infectious diarrhea is an underappreciated health problem. There is a higher mortality rate and case-fatality rate compared with younger persons. Infectious diarrhea is most often associated with group settings (e.g., nursing homes and skilled nursing facilities) or antibiotic use. Infectious diarrhea may be associated with abnormal immune function (i.e., immunosenescence). Certain bacterial infections are commoner (e.g., C. difficile, E. coli O157:H7, and Salmonella). Some infections behave differently (e.g., Salmonella). Prompt and adequate rehydration measures are crucial. The institution of appropriate contact isolation and infection control measures is crucial in group settings.
Clostridium difficile is responsible for 15-25% of cases of antibiotic-associated diarrhea (AAD) and for virtually all cases of antibiotic-associated pseudomembranous colitis (PMC). This anaerobic bacterium has been identified as the leading cause of nosocomial infectious diarrhea in adults and can be responsible for large outbreaks. Nosocomial C. difficile infection results in an increased length of stay in hospital ranging from 8 to 21 days. Risk factors for C. difficile-associated diarrhea include antimicrobial therapy, older age (>65 years), antineoplastic chemotherapy and length of hospital stay. Other interventions with high risk associations are enemas, nasogastric tubes, gastrointestinal surgery and antiperistaltic drugs. Prospective studies have shown that nosocomial transmission of C. difficile is frequent but often remains asymptomatic. Patients can be contaminated from environmental surfaces, shared instrumentation, hospital personnel hands and infected roommates. Once an outbreak starts, C. difficile may be spread rapidly throughout the hospital environment where spores may persist for months. Measures that are effective in reducing incidence of C. difficile infections and cross-infection include: (i) an accurate and rapid diagnosis, (ii) appropriate treatment, (iii) implementation of enteric precautions for symptomatic patients, (iv) reinforcement of hand-washing, (v) daily environmental disinfection, and (vi) a restrictive antibiotic policy. C. difficile is a common cause of infectious diarrhea and should be therefore systematically investigated in patients with nosocomial diarrhea.
A retrospective study of 45 patients with Clostridium difficile infection over a 4-year period in a department of Internal Medicine.
Mean age was 79 years; sex-ratio (F/M)=1.5; 38% of the patients had neurological or severe psychiatric disorders; 20% had a neoplastic disease. Ninety-three percent of cases had received one or more antibiotics before onset of diarrhea, prescribed mainly for a pulmonary infection. Amoxicillin clavulanic acid and cephalosporins were the most frequently used treatments, respectively in 48% and 40% of cases. For 25 patients (56%) Clostridium difficile-associated diarrhea was considered as a nosocomial infection, and as community-acquired diarrhea in 20 cases (44%). Treatment included isolation of the patient as soon as bacteriological diagnosis was known and specific therapy was instituted by metronidazole or vancomycin for a mean of 18 days. The addition of Saccharomyces boulardii was used in of cases. The clinical course was rapidly favorable for 80% of patients. Five patients died with complications of severe colitis in 2 cases. Mean hospital stay was 49 days (annual mean of the department=10 days).
Clostridium difficile diarrhea concerns above all elderly patients with one or more underlying pathologies. Amoxicillin clavulanic acid and third-generation cephalosporins are the most frequently prescribed antibiotics in these cases and have the highest correlation with this infectious complication. This medical problem requires greater knowledge as it causes significant morbidity and increases the risk of prolonged hospital stays.
Antimicrobial agents are among the most frequently prescribed medications in long-term-care facilities (LTCFs). Therefore, it is not surprising that Clostridium difficile colonization and C. difficile-associated diarrhea (CDAD) occur commonly in elderly LTCF residents. C. difficile has been identified as the most common cause of non-epidemic acute diarrheal illness in nursing homes, and outbreaks of CDAD in LTCFs have also been recognized. This position paper reviews the epidemiology and clinical features of CDAD in elderly residents of LTCFs and, using available evidence, provides recommendations for the management of C. difficile in this setting.