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PubMed2004

Outbreak of Clostridium difficile infection in a long-term care facility: association with gatifloxacin use.

To determine the cause of an increase in the rate of Clostridium difficile-associated diarrhea (CDAD) in a long-term care facility (LTCF), we analyzed CDAD cases among LTCF patients from October 2001 through June 2002. CDAD cases were identified from review of all enzyme immunoassays positive for C. difficile toxin A. The increase coincided with a formulary change from levofloxacin to gatifloxacin. We performed a case-control study in which we randomly selected control subjects from 612 LTCF admissions during this period. Although we examined a variety of risk factors, logistic regression analysis only demonstrated associations between CDAD and use of clindamycin (P=.005) and gatifloxacin, the latter being associated with an increasing risk of CDAD with increasing duration of gatifloxacin therapy (P<.0001). We concluded that an outbreak of CDAD in an LTCF was associated with a formulary change from levofloxacin to gatifloxacin. The rate of CDAD in the LTCF decreased after a change back to levofloxacin.

Case-Control Studies↗
PubMed1997

Effect of arginine on toxin production by Clostridium difficile in defined medium.

Twenty strains of Clostridium difficile were examined for the effect of arginine on toxin production in a defined medium. In three strains, the production of toxins A and B was greatly enhanced in the absence of arginine. These strains showed distinctively poorer growth in the absence of arginine in comparison with the remaining 17 strains, indicating that the presence of arginine is required for good growth among the three strains. From the present results, test strains were divided into two groups: a group in which arginine insufficiency caused distinctly poor growth and enhanced toxin production, and another group in which there was neither distinctly poor growth nor enhanced toxin production. The phenomenon is discussed in relation to the biosynthesis and catabolism of arginine.

Arginine↗
PubMed1996

Effect of Clostridium difficile toxin B on IgE receptor-mediated signal transduction in rat basophilic leukemia cells: inhibition of phospholipase D activation.

Antigen (Ag)-stimulated phospholipase D (PLD) activation and secretion were almost abolished by pretreatment of rat basophilic leukemia (RBL)-2H3 cells for 4 h with 5 ng/ml Clostridium difficile Toxin B which is known to inhibit Rho family proteins (Rho, Cdc42, Rac). The concentration-dependent inhibition of PLD activation was well correlated with the level of glucosylation of Rho family proteins. In streptolysin O-permeabilized RBL cells, Toxin B suppressed [3H] phosphatidylbutanol (PBut) formation in response to guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and phorbol 12-myristate 13-acetate (PMA) by 67 and 43%, respectively. The synergistic PLD activation by GTP gamma S and PMA was also reduced by Toxin B by 67%. These results suggest that the IgE receptor-coupled PLD activation is largely mediated by Rho proteins.

Animals↗
PubMed2001

[Clostridium difficile-associated diarrhea--a growing problem in geriatric care].

From 1994 to 1998 the incidence of Clostridium difficile-associated diarrhoea (CDAD) in the Department of Geriatric Medicine, Huddinge University Hospital increased from 0.5% to 2.2% of all admissions. Corresponding figures for the whole hospital were 0.3% and 0.6%, respectively. The increase in CDAD at the Department of Geriatric Medicine was parallel with a more than doubled consumption of antibiotics. All geriatric patients with CDAD had been treated with antibiotics before onset of diarrhoea. Out of the antibiotic prescriptions 48% were a cephalosporin (mainly cefuroxim). In a matched reference group of geriatric patients 51% had been treated with antibiotics during the hospital stay. The patients with CDAD spent 27 +/- 14 days in hospital as compared to 13 +/- 9 days (P < 0.05) in the reference population.

Aged↗
PubMed1995

Concurrence of Clostridium difficile toxin A enzyme-linked immunosorbent assay, fecal lactoferrin assay, and clinical criteria with C. difficile cytotoxin titer in two patient cohorts.

The accurate and sensitive diagnosis of Clostridium difficile-related diarrhea, normally treated with vancomycin, has become increasingly important in light of the emergence of dangerous new strains of vancomycin-resistant enterococci. In order to improve the threshold for C. difficile diagnosis and treatment, a number of commonly used assays for the diagnosis of C. difficile diarrhea were examined. These included an enzyme-linked immunosorbent assay for C. difficile toxin A (ToxA), a CHO cell culture assay for fecal C. difficile (cyto)toxin B, and a lactoferrin latex agglutination assay for fecal lactoferrin (LFLA). We studied 722 fecal specimens submitted by physicians for C. difficile toxin testing at the Salem, Va., Veterans' Affairs Hospital and at the University of Virginia Medical Center in Charlottesville. Charts were reviewed from 123 Veterans' Hospital patients and 114 University of Virginia patients for clinical criteria indicative of C. difficile diarrhea. An increasing titer of CHO cell cytotoxicity was correlated with an increasing likelihood of ToxA positivity (5 to 90%), LFLA positivity (39 to 77%), and clinical agreement (28 to 85%). However, some data indicate that the CHO cell cytotoxicity assay may be nonspecific when positive only at low titers. When the CHO assay result is positive at high titers, it remains the best diagnostic tool. Yet, when it is positive at a low titer, careful interpretation of the results in conjunction with other assays and the clinical setting is warranted, especially in light of new drug-resistant strains of microorganisms.

Animals↗
PubMed2001

Evaluation of methods for detection of toxins in specimens of feces submitted for diagnosis of Clostridium difficile-associated diarrhea.

Clostridium difficile is the principal pathogen associated with hospital-acquired acute diarrheal disease. We have evaluated the performances of six approaches for diagnosis of C. difficile-associated diarrhea (CDAD). Consecutive stool specimens (n = 200) from 133 patients were examined by cytotoxin assay, by culture of C. difficile on cycloserine-cefoxitin-fructose agar, and by toxin detection using four rapid immunoassay systems (Oxoid Toxin A test, ImmunoCard Toxin A test, TechLab Tox A/B II test, and Premier Toxins A&B test). A diagnosis of CDAD was established for 35 (27%) patients (representing 29% of specimens). The adjusted sensitivity and specificity of the methods were, respectively, 98 and 99% for the cytotoxin assay, 54 and 99% for ImmunoCard, 50 and 98% for Oxoid, 79 and 98% for TechLab, 80 and 98% for Premier, and 57 and 100% for culture. The TechLab and Premier assays are acceptable tests for diagnosis of CDAD but are not equivalent to the cytotoxin assay.

Adult↗
PubMed1995

Diagnosis of Clostridium difficile associated diarrhea: comparison of three rapid methods employing different markers for detection.

Latex agglutination and the enzyme immunoassays Cytoclone (EIA-C) and VIDAS (EIA-V) were compared with a cytotoxicity assay for the diagnosis of Clostridium difficile associated diarrhea. Among patients with discrepant results, the cytotoxicity assay and clinical assessment were used to evaluate the performance of the latex agglutination and EIA tests. Clostridium difficile associated diarrhea was documented in 30/149 samples (20.1%) from 130 patients. All test results matched in 113 instances. Latex agglutination, EIA-C, and EIA-V yielded false positive results in 10, 4, and 7 samples and false negative results in 8, 9, and 14 samples, respectively. Latex agglutination demonstrated 87.8% efficiency compared with 91.3% for EIA-C and 85.7% for EIA-V and 3 min hands-on time compared with 4.5 min for EIA-V and 10 min for EIA-C. On the basis of these findings and given the fact that all rapid tests have their shortcomings, we believe that latex agglutination is the most practical method.

Biomarkers↗
PubMed1994

Management and control of a large outbreak of diarrhoea due to Clostridium difficile.

In the six-month period 1 November 1991 to 1 May 1992 175 patients developed diarrhoea due to Clostridium difficile in three hospitals in Manchester, UK. Most patients (90%) were over 60 years old and had been admitted to acute geriatric or medical wards with other illnesses. Infection is thought to have contributed to 17 deaths. Twenty-two patients relapsed clinically after antibiotic treatment. The outbreak began in one ward and affected 15 patients and two nurses. During the following months cases occurred on 34 wards. The pattern of spread suggested that a ward index case was followed by several secondary cases. Pyrolysis mass spectrometry showed that 79% of isolates of C. difficile belong to a single cluster and this putative outbreak strain also extensively colonizes the hospital environment. It was also responsible for a smaller outbreak in 1991 and many 'sporadic' cases in our hospitals before then. An outbreak control team was convened at an early stage and expert opinion co-opted. Infection control measures included: intensive education of staff; increased vigilance; strict enteric precautions; cohort nursing in a designated ward; rigorous cleaning procedures including emptying and 'deep' cleaning of wards where several cases had occurred; restriction of staff and patient movement; and restriction of antibiotic use. Subsequent to these measures there has been a substantial and sustained decrease in the number of new cases.

Aged↗
PubMed2000

Effects of Clostridium difficile toxins on epithelial cell barrier.

Clostridium difficile is the primary agent responsible for many patients with antibiotic-associated diarrhea and almost all patients with pseudomembranous colitis following antibiotic therapy. C. difficile infection is the most frequent form of colitis in hospitals and nursing homes and affects millions of patients in the United States and abroad. The first event in the pathogenesis of C. difficile infection involves alterations of the indigenous colonic microflora by antibiotics, followed by colonization with C. difficile. C. difficile causes diarrhea and colitis by releasing two high molecular weight protein exotoxins, toxin A and toxin B, with potent cytotoxic and enterotoxic properties. Evidence presented here indicates that C. difficile toxins compromise the epithelial cell barrier by at least two pathophysiologic pathways, one involving disaggregation of actin microfilaments in colonocytes via glucosylation of the Rho family of proteins leading to epithelial cell destruction and opening of the tight junctions, whereas the other appears to involve early release of proinflammatory cytokines from intestinal epithelial cells probably via activation of MAP kinases. We speculate that cytokines released from intestinal epithelial cells in response to toxin A exposure will diffuse into the lamina propria and activate macrophages, enteric nerves, and sensory neurons to release SP, CGRP, and NT, which, in turn, interact with immune and inflammatory cells and amplify the inflammatory response. Dissection of this inflammatory cascade may help us understand the pathophysiology of inflammatory diarrhea caused by this important pathogen.

Animals↗
PubMedDate not supplied

Clostridium difficile-associated disease. Implications for midwifery practice.

Clostridium difficile-associated disease (CDAD), a gastrointestinal infection with a wide range of manifestations whose primary symptom is diarrhea, occurs when antibiotic medications, or rarely other drugs or conditions, disrupt the normal colonic microflora, making it susceptible to the growth of toxigenic C difficile. It is a significant nosocomial infection and an increased incidence has been noted in recent years. Although infrequently seen in midwifery practices, it does occur and may increase with the growing usage of intrapartal antibiotics. Midwives may evaluate and treat a client with an initial episode of mild to moderate CDAD; they also may manage collaboratively or refer for medical management those clients with recurrent or severe disease. This article reviews the epidemiology, pathogenesis, clinical presentation, prevention, and midwifery management of initial and recurrent CDAD. The limitation in the use of oral vancomycin due to the emergence of vancomycin-resistant enterococcus, resulting in metronidazole becoming the primary agent for treatment of CDAD, and the implications of this in the treatment of CDAD during pregnancy and lactation are addressed.

Adult↗
PubMed2005

Prevalence of Clostridium difficile toxins A and B and Clostridium perfringens enterotoxin A in stool samples of patients with antibiotic-associated diarrhea.

BACKGROUND: Antibiotic-associated diarrhea (AAD) is a major nosocomial as well as a community health problem. Clostridium difficile toxins (CDT) can be detected in only 10-25% of patients with AAD. The role of Clostridium perfringens enterotoxin A (CPEnt) as a cause of AAD remains to be elucidated. We, therefore, prospectively investigated the prevalences of both CPEnt and CDT in stool samples of patients with AAD. MATERIALS AND METHODS: A total of 693 stool samples consecutively submitted to our department from patients with AAD were screened for CDT and CPEnt using commercially available enzyme-linked immunoassays (ELISA). C. difficile and C. perfringens were detected by standard culture techniques. In addition, samples being CPEnt positive and/ or harboring C. perfringens were screened for the CPEnt gene by duplex PCR. RESULTS: CDT was detected in 79 (11.4%) of 693 stool samples. Of these, 49 (62.0%) harbored C. difficile. In one (0.14%) of 693 samples, CPEnt could be detected by ELISA. This respective CPEnt-positive stool sample also harbored C. perfringens. 147 (21.2%) of all stool samples were culture positive for C. perfringens. We did not detect samples positive for both CPEnt and CDT. In five (3.4%) of 147 C. perfringens isolates, the CPEnt gene could be detected by duplex PCR. PCR was positive in two (40%) of the five stool samples harboring CPEnt gene-positive C. perfringens isolates. CONCLUSION: The present prospective study revealed a prevalence of CDT of 11.4%, whereas the prevalence of CPEnt was less than 1%. Routine screening of stool samples for CPEnt does not appear to be justified in patients with AAD.

Anti-Bacterial Agents↗
PubMed1991

Production of monoclonal antibody to Clostridium difficile toxin A which neutralizes enterotoxicity but not haemagglutination activity.

Nine monoclonal antibodies (mAb) to Clostridium difficile toxin A were produced. The isotype of one mAb (37B5) was IgG2b, kappa, and that of the other eight mAbs was IgM, kappa. Immunoblot analysis after non-denatured PAGE showed that with the exception of one mAb (112G6) all mAbs gave a positive reaction with the 540 kDa band of toxin A. Immunoblot analysis showed that four mAbs (2E15, 3B4, 37B5 and 49C4) gave a positive reaction with the 240 kDa major band of toxin A. In neutralisation tests with these mAbs for enterotoxicity, mouse lethality, haemagglutination activity and cytotoxicity, 37B5 neutralised enterotoxicity in a rabbit ileal loop response test but did not neutralise any other biological activities. None of the other eight mAbs showed any neutralising activities at all.

Animals↗
PubMed2001

Comparison of Tn5397 from Clostridium difficile, Tn916 from Enterococcus faecalis and the CW459tet(M) element from Clostridium perfringens shows that they have similar conjugation regions but different insertion and excision modules.

Comparative analysis of the conjugative transposons Tn5397 from Clostridium difficile and Tn916 from Enterococcus faecalis, and the CW459tet(M) element from Clostridium perfringens, has revealed that these tetracycline-resistance elements are closely related. All three elements contain the tet(M) resistance gene and have sequence similarity throughout their central region. However, they have very different integration/excision modules. Instead of the int and xis genes that are found in Tn916, Tn5397 has a large resolvase gene, tndX. The C. perfringens element encodes the putative Int459 protein, which is a member of the integrase family of site-specific recombinases but is not closely related to Int from Tn916. Based on these studies it is concluded that the clostridial elements have a modular genetic organization and were derived independently from distinct mobile genetic elements.

Base Sequence↗
PubMed1995

Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein.

BACKGROUND & AIMS: Goblet cells secrete a combination of trefoil peptides and mucin glycoproteins to form a continuous gel on the mucosal surface. The functional effects of these products remain uncertain. METHODS: Trefoil peptides and/or mucin glycoproteins were added to Transwell monolayers of the human colonic cancer-derived T84 cell line. Intact monolayers permitted penetration of < 4% of the inert marker [3H]mannitol at 4 hours. Exposure to the toxic lectin phytohemagglutinin (1 mg/mL), oleic acid (8 mmol/L) and taurocholic acid (12 mmol/L), or Clostridium difficile toxin A (0.7 microgram/mL) resulted in loss of barrier function with 36%, 62%, and 45% of [3H]mannitol penetration, respectively. RESULTS: Addition of recombinant human intestinal trefoil factor in physiological concentrations (1-5 micrograms/microL) resulted in attenuation of the damage to monolayer integrity by up to 52%. Protection was enhanced (up to 95%) by the copresence of human colonic mucin glycoproteins. Similar effects were observed when rat intestinal trefoil factor or human spasmolysin, another human trefoil peptide, were added alone or in the presence of human mucin glycoproteins. Conversely, mucin glycoproteins isolated from the rat colon or stomach facilitated protection when added with human spasmolysin or human intestinal trefoil factor. CONCLUSIONS: Trefoil peptides and mucin glycoproteins protect gastrointestinal mucosa from a variety of insults.

Bacterial Toxins↗
PubMed2003

A 5-year study of the bacterial pathogens associated with acute diarrhoea on the island of Crete, Greece, and their resistance to antibiotics.

During a 5-year period (1995-1999) a total of 7090 stool samples obtained from patients with acute diarrhoea, mostly community-acquired, were examined for bacterial pathogens, in the Greek island of Crete. One or more enteric pathogens were isolated from 987 patients (14%). Salmonella enterica were the most commonly isolated bacteria (6%), followed by Campylobacter spp. (4.2%), and enteropathogenic Escherichia coli (EPEC) (1.8%). Yersinia enterocolitica (0.6%), Shigella spp. (0.3%), and Aeromonas hydrophila (0.04%), were less frequently isolated. Clostridium difficile was isolated from 65 out of 451 diarrhoeal specimens examined (14.4%). Toxin B was detected in all cases. No verotoxigenic E. coli strains were identified. Resistance to ampicillin was observed in 31.5% of the Salmonella, 58.3% of the Shigella and 31.5% of the EPEC isolates. Resistance to trimethoprim-sulfamethoxazole was observed in 4.4% of the Salmonella, 30.5% of the Shigella, and 18.5% of the EPEC isolates. High percentages of resistance to quinolones (44.5% to norfloxacin, and 40.5% to ciprofloxacin), were found among Campylobacter isolates, while resistance to erythromycin was observed in 14.9% of them. With the present study we continue the surveillance of bacterial pathogens associated with diarrhoeal disease on the island of Crete.

Acute Disease↗
PubMed2003

Restriction of third generation cephalosporin use reduces the incidence of Clostridium difficile-associated diarrhoea in hospitalised patients.

Third generation cephalosporin antibiotics (3GC) have become the antibiotics of choice in many hospitals in recent years for the treatment of infections such as community-acquired pneumonia. However, increased use of 3GCs has also been associated with a rise in the occurrence of antibiotic-associated diarrhoea due to Clostridium difficile, as well as an increase in the prevalence of antibiotic resistant organisms such as methicillin resistant Staphylococcus aureus, vancomycin resistant entrococci, and extended-spectrum beta-lactamase-producing gram negative bacilli. In Western Australia, greater use of 3GCs was shown to correlate with more Clostridium difficile-associated diarrhoea (CDAD) in a large acute care teaching hospital during the 1980s. During the 1990s, the use of 3GCs in this hospital remained high and, at the end of 1998, a policy was introduced to prevent the use of ceftriaxone (the only 3GC in use) without prior approval. This resulted in a decline in 3GC use and a 50 per cent reduction in the incidence of CDAD during 1999 and 2000. To strengthen these observations, the impact of the 3GC policy on the occurrence of CDAD was analysed using time-series intervention analysis that showed a statistically significant decrease in the occurrence of CDAD during the post-intervention period after controlling for exogenous factors. Thus, changes in antibiotic prescribing practices can influence the incidence of CDAD and, potentially, antibiotic resistant pathogens.

Cephalosporins↗
PubMed1991

Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y.

Clostridium difficile causes pseudomembranous colitis in humans. The enterotoxin (i.e., toxin A) from this organism is believed to be responsible for the initial intestinal pathology associated with this disease. Previous work shows that this toxin binds to carbohydrates that contain Gal alpha 1-3Gal beta 1-4GlcNAc. However, this carbohydrate is not present on normal human cells. Therefore, this study was undertaken to identify potential receptors for toxin A that do exist on human intestinal epithelium. Using enzyme-linked immunosorbent assay, affinity chromatography, and altered migration in an electric field, we assayed the binding of toxin A to purified carbohydrates and glycoproteins. We found that toxin A bound to the carbohydrate antigens designated I, X, and Y. Each of these carbohydrates exist on the intestinal epithelium of humans.

Animals↗
PubMed2005

Antibiotic-associated diarrhoea: an overlooked aetiology?

Sixty-three faeces samples from hospital in-patients with probable antibiotic-associated diarrhoea (AAD) are investigated. All samples are examined for routine bacterial enteric pathogens, pus cells, red blood cells and parasites. The samples are also screened for Clostridium difficile cytotoxin B (CDT), C. perfringens enterotoxin and Candida spp. (by microscopy and quantitative culture). Faecal samples from two control groups (healthy volunteers and community samples from GP patients) are also screened. A possible pathogen was found in 71% of AAD cases. Candida spp. overgrowth was the most common (44.4%), followed by CDT (34.9%) and Clostridium perfringens enterotoxin (9.5%). There was good agreement between the significant Gram films and quantitative Candida spp. culture (kappa=0.683). Clinical information revealed the majority of patients were on multiple antibiotic regimes, receiving 'high risk' antibiotics. Of community samples, 21% were positive for Clostridium perfringens enterotoxin, indicating that C. perfringens is a problem in the community, not necessarily associated with antibiotic use. The results suggest that quantitative Candida spp. culture should be performed on all specimens requesting AAD investigations.

Adult↗