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PubMed2005

Angiotensin II subtype 1 receptor blockade inhibits Clostridium difficile toxin A-induced intestinal secretion in a rabbit model.

Angiotensin II (ANG II) has been described in the regulation of intestinal secretion and absorption via angiotensin subtype 1 (AT(1)) and AT(2) receptors, respectively, in rats. We investigated the role that ANG II plays in the rabbit ileal-loop model of Clostridium difficile infection. Expression of AT(1), the more abundant ANG II receptor, was demonstrated in ileal loops, and an AT(1) receptor blocker, losartan, inhibited hypersecretion induced by C. difficile toxin A (mean volume : length ratio, 0.27+/-0.06 vs. 0.60+/-0.06 mL/cm in controls). Losartan also decreased production of ANG II in the ileum (0.48+/-0.06 vs. 0.87+/-0.12 pg/mg in controls), raising the possibility that ANG II may participate in a positive feedback loop involving the hypersecretory response. Our findings suggest that ANG II plays a significant role in the pathogenesis of C. difficile toxin-induced diarrhea.

Angiotensin II↗

PubMed1996

Pathogenesis of Clostridium difficile-associated diarrhoea.

Clostridium difficile is now regarded as a major enteric pathogen in hospitals and nursing-home facilities. The pathophysiology of this pathogen involves alterations of the indigenous colonic flora by antibiotics, ingestion of spores and colonization by C. difficile, followed by release of its toxins. Although most of the research on the intestinal effects of C. difficile had been focused on its enterotoxin or toxin A, recent results indicate that toxin B, the cytotoxin of C. difficile, is also active in human colon. The cloning and sequencing of the toxin A and toxin B gene and the identification of the GTP-binding protein Rho as their intracellular target represent major advances in our understanding of the mode of action of these toxins. An important characteristic of C. difficile infection is the dramatic inflammation seen in pseudomembranous colitis. Recent studies indicate that an interplay between lamina propria neuroimmune cells and intestinal epithelial cells may be central in pathogenesis of this toxin-mediated inflammatory response.

Bacterial Toxins↗

PubMed2004

The diagnostic yield of stool pathogen studies during relapses of inflammatory bowel disease.

GOALS: We sought to determine the yield of stool analysis for bacterial culture, ova and parasites, and Clostridium difficile toxin in suspected relapses of inflammatory bowel disease (IBD). BACKGROUND: The diagnostic yield of such stool studies has not been examined recently in the United States. STUDY: The medical records of consecutive IBD patients who underwent stool testing for relapses at our institution between July 1, 2000, and November 25, 2001, were abstracted for demographics, stool test results, recent antibiotic exposure, and hospitalization. RESULTS: Fifty-four patients were evaluated during 62 relapses with 99 stool samples. Twelve stool tests were positive. C. difficile accounted for the majority of positive tests (10/12). Of these, 9 (90%) were associated with antibiotic use in the prior month versus 10 (22%) in the C. difficile-negative group (P < 0.001). Hospitalization, prednisone use, or sulfasalazine use did not differ significantly with C. difficile status. Eight C. difficile-positive patients improved clinically with targeted antibiotic therapy. Two bacterial cultures (4%) were positive for Campylobacter jejuni and Plesiomonas shigelloides. CONCLUSION: Stool studies yielded a pathogen, mainly C. difficile, in 20% of the relapsing IBD patients. Antibiotic use was significantly associated with a positive C. difficile toxin. Toxin-positive patients improved clinically with targeted antibiotics.

Adult↗

PubMed2005

Generation of an erythromycin-sensitive derivative of Clostridium difficile strain 630 (630Deltaerm) and demonstration that the conjugative transposon Tn916DeltaE enters the genome of this strain at multiple sites.

Erythromycin resistance in Clostridium difficile strain 630 is conferred by a genetic element termed Tn5398 which contains two erm(B) genes: erm1(B) and erm2(B). An erythromycin-sensitive derivative of strain 630 (designated 630Deltaerm) was generated by spontaneous mutation after continuous subculture for 30 days. This strain had lost the erm2(B) gene from within Tn5398 but retained erm1(B). However, the strain could revert to erythromycin resistance at a frequency of 2.79 x 10(-8), although it still contained the deletion of erm2(B). The availability of C. difficile 630Deltaerm allowed the behaviour of Tn916DeltaE to be investigated in this strain. This element entered the genome at multiple sites indicating that it could be useful as an insertional mutagen.

Blotting, Southern↗

PubMed2003

Transcription and analysis of polymorphism in a cluster of genes encoding surface-associated proteins of Clostridium difficile.

Recent investigations of the Clostridium difficile genome have revealed the presence of a cluster of 17 genes, 11 of which encode proteins with similar two-domain structures, likely to be surface-anchored proteins. Two of these genes have been proven to encode proteins involved in cell adherence: slpA encodes the precursor of the two proteins of the S-layer, P36 and P47, whereas cwp66 encodes the Cwp66 adhesin. To gain further insight into the function of this cluster, we further focused on slpA, cwp66, and cwp84, the latter of which encodes a putative surface-associated protein with homology to numerous cysteine proteases. It displayed nonspecific proteolytic activity when expressed as a recombinant protein in Escherichia coli. Polymorphism of cwp66 and cwp84 genes was analyzed in 28 strains, and transcriptional organization of the three genes was explored by Northern blots. The slpA gene is strongly transcribed during the entire growth phase as a bicistronic transcript; cwp66 is transcribed only in the early exponential growth phase as a polycistronic transcript encompassing the two contiguous genes upstream. The putative proteins encoded by the cotranscribed genes have no significant homology with known proteins but may have a role in adherence. No correlation could be established between sequence patterns of Cwp66 and Cwp84 and virulence of the strains. The cwp84 gene is strongly transcribed as a monocistronic message. This feature, together with the highly conserved sequence pattern of cwp84, suggests a significant role in the physiopathology of C. difficile for the Cwp84 protease, potentially in the maturation of surface-associated adhesins encoded by the gene cluster.

Adult↗

PubMed1996

Genotyping of outbreak-related and sporadic isolates of Clostridium difficile belonging to serogroup C.

Serogroup C of Clostridium difficile is the serogroup most frequently related to outbreaks. Fifty-six toxigenic serogroup C isolates of C. difficile were genotyped by ribotyping PCR (ribo-PCR), random amplified polymorphic DNA (RAPD) assay, and pulsed-field gel electrophoresis (PFGE). Thirty-five of the 56 isolates were recovered from four unrelated outbreaks (Belgium, 1987, 1992, and 1995; France, 1992 to 1993) 7 derived from a spatiotemporal cluster in Cotonou, Benin (1992), and 14 were sporadic isolates. The serogroup C reference strain, also isolated during an outbreak (Belgium, 1983), was genotyped too. Ribo-PCR, the RAPD assay, and PFGE generated 2, 5, and 11 major genotypes, respectively. Combination of the three methods finally yielded 13 general types, although ribo-PCR did not play any role in enhancing resolution. Three general types were recovered from all the isolates from the five outbreaks and the cluster, with two types being predominant. The 14 sporadic serogroup C isolates were divided into 11 overall genotypes. These results indicate that genotyping methods, and more particularly the combination of the RAPD assay and PFGE, can resolve genetic diversity within toxigenic, serogroup C C. difficile strains. Also, this study suggests that outbreak-related serogroup C strains are limited to a few genetically stable and apparently very widely (internationally and intercontinentally) distributed genotypes.

Bacterial Typing Techniques↗

PubMed2003

Recent emergence of an epidemic clindamycin-resistant clone of Clostridium difficile among Polish patients with C. difficile-associated diarrhea.

Analysis of both the antibiotic resistance and the virulence characteristics of anaerobic human microbial pathogens is important in order to improve our understanding of a number of clinically significant infectious diseases, including Clostridium difficile-associated diarrhea (CDAD). We determined the presence of the clindamycin resistance-associated gene ermB and the ribotype of 33 C. difficile strains isolated from Polish patients suffering from CDAD. While all strains produced cytotoxin B (TcdB), enterotoxin A (TcdA) was produced by a subset of 15 strains only. The results showed that a single ermB-positive, TcdA(-)B(+) C. difficile strain with ribotype A has disseminated widely in the two Warsaw hospitals under investigation. Although different strains with the same phenotype were detected, the genotype A strain appeared to be the only one with a clear epidemic character. Apparently, enhanced local spread of CDAD-causing C. difficile may be restricted to a limited number of bacterial genotypes only.

Anti-Bacterial Agents↗

PubMed1997

Intravenous immunoglobulin therapy for severe Clostridium difficile colitis.

BACKGROUND: Many individuals have serum antibodies against Clostridium difficile toxins. Those with an impaired antitoxin response may be susceptible to recurrent, prolonged, or severe C difficile diarrhoea and colitis. AIMS: To examine whether treatment with intravenous immunoglobulin might be effective in patients with severe pseudomembranous colitis unresponsive to standard antimicrobial therapy. PATIENTS: Two patients with pseudomembranous colitis not responding to metronidazole and vancomycin were given normal pooled human immunoglobulin intravenously (200-300 mg/kg). METHODS: Antibodies against C difficile toxins were measured in nine immunoglobulin preparations by ELISA and by cytotoxin neutralisation assay. RESULTS: Both patients responded quickly as shown by resolution of diarrhoea, abdominal tenderness, and distension. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B by ELISA and neutralised the cytotoxic activity of C difficile toxins in vitro at IgG concentrations of 0.4-1.6 mg/ml. CONCLUSION: Passive immunotherapy with intravenous immunoglobulin may be a useful addition to antibiotic therapy for severe, refractory C difficile colitis. IgG antitoxin is present in standard immunoglobulin preparations and C difficile toxin neutralising activity is evident at IgG concentrations which are readily achieved in the serum by intravenous immunoglobulin administration.

Antibodies↗

PubMed2006

Evaluation of five enzyme immunoassays compared with the cytotoxicity assay for diagnosis of Clostridium difficile-associated diarrhea in dogs.

Clostridium difficile-associated-diarrhea (CDAD) is a nosocomial infection in dogs. Diagnosis of this infection is dependent on clinical signs of disease supported by laboratory detection of C. difficile toxins A or B, or both, in fecal specimens via enzyme-linked immunosorbent assay (ELISA). Unfortunately, to the authors' knowledge, commercially available ELISAs have not been validated in dogs to date. We evaluated 5 ELISAs done on 143 canine fecal specimens (100 diarrheic and 43 nondiarrheic dogs) and on 29 C. difficile isolates. The results of each ELISA were compared with the cytotoxin B tissue culture assay (CTA). Clostridium difficile was isolated from 23% of the fecal specimens. Eighteen of the 143 fecal specimens were toxin positive (15 diarrheic and 3 nondiarrheic dogs). On the basis of multiplex polymerase chain reaction (PCR) analysis for toxin-A and -B genes, 72% of the isolates were toxigenic. The carriage rate of toxigenic isolates in diarrheic dogs was higher than that in the nondiarrheic dogs; however, these differences were not statistically significant. A good correlation was found between CTA, PCR, and culture results. The ELISAs done on fecal specimens collected from diarrheic dogs had low sensitivity (7-33%). In contrast, ELISA for toxin A or B, or both, performed on toxigenic isolates had high sensitivity (93%). These results suggest that commercially available human ELISAs are inadequate for the diagnosis of canine C. difficile-associated diarrhea when tested on fecal specimens. In contrast, the Premier ToxinA/B and Techlab ToxinA/B ELISAs may be useful for the diagnosis of canine CDAD when used on toxigenic isolates.

Animals↗

PubMed1995

Apparent outbreaks of Clostridium difficile-associated diarrhea in horses in a veterinary medical teaching hospital.

Intestinal colonization with toxigenic strains of Clostridium difficile was documented in 9 of 10 horses with acute onset diarrhea in a veterinary medical teaching hospital, whereas a similar isolate was detected in only 1 of 23 other horses without diarrhea in the hospital. One horse with diarrhea was infected simultaneously with both C. difficile and Salmonella krefeld. Clostridium difficile was detected by fecal culture on selective medium, confirmed with a latex particle agglutination test, and identified as toxigenic by polymerase chain reaction amplification of toxin A and toxin B gene sequences. Using an arbitrarily-primed polymerase chain reaction, 6 distinct C. difficile isolates were detected in the feces of the 9 affected horses at the time of the outbreak of diarrhea.

Animals↗

PubMed1996

Antibiotic-associated diarrhoea, Clostridium difficile, and short-chain fatty acids.

BACKGROUND: It has been hypothesized that Clostridium difficile and decreased colonic production of short-chain fatty acids (SCFAs) cause the development of antibiotic-associated diarrhoea. We therefore wanted to investigate the effects of an intensive and uniform antibiotic therapy on faecal SCFAs concentrations. C. difficile, and extent of diarrhoea. METHODS: Fifteen liver-transplanted patients who received oral bowel flora suppression therapy (6.3 g cefuroxime, 0.6 g tobramycin, and 0.5 g nystatin three times daily) were studied for 12 days before and 12 days after discontinuation of therapy. RESULTS: Thirteen of the 15 patients (87%) developed diarrhoea. Colonic fermentation was negligible in all patients, judged by very low levels of faecal SCFAs (< 10 mmol/l). Diarrhoea lessened as suppression therapy proceeded despite continuous low levels of SCFAs. Initial stool frequency of 4.1 +/- 0.6 and viscosity of 2.5 +/- 0.2 per day (on a scale of 1-3; mean +/- SE) decreased to 2.2 +/- 0.5 (p = 0.0009) and 1.6 +/- 0.2 (p = 0.003) per day, respectively, just before cessation of suppression therapy. Both SCFAs and stool habits normalized within days after discontinuation of antibiotics. Only a few samples from 2 patients were culture-positive for C. difficile during therapy, whereas 9 of the 15 patients (60%) became culture-positive (6 cytotoxin-positive) after cessation of suppression therapy at a time when none had diarrhoea. CONCLUSIONS: Intensive treatment with antibiotics directed against the colonic flora resulted in diarrhoea in the vast majority of patients, but the diarrhoea was self-limiting despite continual antibiotic treatment and very low faecal concentrations of SCFAs. C. difficile was not associated with antibiotic-associated diarrhoea but was a common finding after treatment with antibiotics was stopped at the time when diarrhoea had ceased.

Adult↗

PubMed2006

Clostridium difficile ribotype 027, toxinotype III, the Netherlands.

Outbreaks due to Clostridium difficile polymerase chain reaction (PCR) ribotype 027, toxinotype III, were detected in 7 hospitals in the Netherlands from April 2005 to February 2006. One hospital experienced at the same time a second outbreak due to a toxin A-negative C. difficile PCR ribotype 017 toxinotype VIII strain. The outbreaks are difficult to control.

Clostridioides difficile↗

PubMed2000

[Pediatric nosocomial diarrhea].

Nosocomial diarrhea are an important cause of childhood morbidity and mortality. Rotavirus has been recognized as the most important cause of nosocomial gastroenteritidis particularly in infants during winter months. Nosocomial diarrhea are also, caused by bacterial pathogen like Clostridium difficile, Salmonella, Shigella, Campylobacter. Clostridium difficile toxin assay should be considered for patients who are receiving antibiotics. Modifications of hygiene procedures and preventive measures are necessary in order to reduce nosocomial infection.

Adenoviridae Infections↗

PubMed1992

[Evaluation of the immunoenzyme test (Elisa) in detecting Clostiridium difficile toxin A in fecal samples].

Currently, the method of choice in diagnosis of Clostridium difficile-associated intestinal diseases is the detection of toxin B in fecal specimens. This method is long (72 h) and can be realized in laboratories which have tissue culture facilities. Commercial agglutination test have been evaluated but they lack in specificity. An immunoenzymatic test has been recently commercialized for detection of toxin A. We have compared the results of this assay on 275 fecal specimens from patients suspected of having Clostridium difficile-associated intestinal diseases with the results obtained with the cytotoxicity test and the culture. Of the 275 fecal specimens, 58 were positive in cytotoxicity and 53 in Elisa. The overall sensitivity and specificity of the Elisa compared with cytotoxicity were 89.5% and 99.0% respectively. The immunoenzymatic test detecting Clostridium difficile toxin A is an easy test to perform in 2 h 15; it displays a good correlation with detection of toxin B and can be very useful in daily laboratory diagnosis.

Bacterial Toxins↗

PubMed2005

[Antibiotic associated diarrhea and Clostridium difficile associated diarrhea in the elderly].

Antibiotic associated diarrhea (AAD) is a common complication when antibiotics are used and is frequent in the elderly. It has an impact on the length of hospital stay and increases the comorbidity. Together with the type of antibiotic that is given, the length of antibiotical treatment and the combination of antibiotics is more predictive for the evolution of diarrhea when compared to the total given dose. Mostly AAD is benign, but an infection with C. difficile should always be excluded. C. difficile-enterocolitis is frequent among residents in nursing homes and in hospitalised patients. The clinical presentation varies from asymptomatic colonisation tot severe debilitating disease. A rapid diagnosis can be performed by detection of C. difficile toxin by an enzyme-linked immunoassay. Oral metronidazole and oral vancomycine are equally effective in the therapy. In relapsing infection an extended tapering regimen is sometimes necessary.

Aged↗

PubMed1991

Positive role of Clostridium difficile infection in diarrhea in infants and children.

A retrospective review of children with Clostridium difficile infection and diarrhea identified 43 patients. Fifteen (35%) had immunoglobulins below the normal range for age, and typified those with transient hypogammaglobulinemia of infancy, because all increased their levels over the following 12 months. The age of those with hypogammaglobulinemia was significantly younger (p less than 0.01), averaging 18.8 months, than those with normal immunoglobulins who had a mean age of 4.6 yr. The number with recurrent C. difficile infection was significantly greater (p less than 0.001) in the hypogammaglobulinemic group than in those with normal immunoglobulins (46% vs 18%). Eleven children were identified who had C. difficile toxin in the stool after antibiotic therapy, but who had no diarrhea at the time of study. All had normal immunoglobulins. Control patients (20 without and 40 with diarrhea) had no evidence of C. difficile infection, and all but three had normal immunoglobulins. Three (7%) of those with diarrhea had IgA deficiency, and all had a diagnosis of milk protein allergy. These data suggest that immunoglobulin values be obtained in infants and children who have problematic C. difficile diarrhea in order to identify disorders of immunoglobulin synthesis which may be the underlying cause of repeated upper respiratory disease requiring antibiotic usage.

Adolescent↗

PubMed1998

[Clostridium difficile outbreak in surgical wards].

OBJECTIVE: To evaluate the clinical consequences of a hospital outbreak of Clostridium difficile infections in the Netherlands. DESIGN: Descriptive. SETTING: Diakonessen Hospital Utrecht, the Netherlands. METHODS: In the period from 1 August 1995 to 1 September 1996 C. difficile infections were recorded (gastrointestinal symptoms after use of antibiotics and findings at C. difficile toxin assay in faeces, or sigmoidoscopy). The monthly incidence of infections increased to 5 patients in December 1995; at that time strict hygienic measures were implemented and perioperative antimicrobial prophylaxis was adjusted. Data on the clinical course were collected retrospectively from the records of the patients involved. RESULTS: In 20 patients, admitted for various reasons to the surgical wards, hospital stay was complicated by a C. difficile infection. The mean age was 70 years. Eleven patients presented with diarrhoea, eight patients had nausea and vomiting as well. Diagnosis was confirmed by C. difficile toxin determination in most patients (n = 15). Despite antibiotic treatment in 19 patients, recurrences were seen in five patients (25%) and five patients died (25%). The monthly incidence declined to 0-1 per month. CONCLUSION: C. difficile infections in surgical patients carry a significant morbidity and mortality. Preventive hygienic measures are important to control spread of the infection.

Aged↗

PubMed2002

One-step cloning and expression of Clostridium difficile toxin B gene (tcdB).

The toxin genes of Clostridium difficile have been previously cloned by reconstructing the entire gene in a series of steps in sequence using several cloned fragments. Amplification of a 7.9 kb fragment corresponding to the toxin B gene (tcdB) was obtained with EXPAND Long Template PCR system. The amplified fragment was inserted into the E. coli expression vector pBAD and cloned into competent E. coli TOP 10 cells. tcdB gene sequences representing the complete toxin gene were detected in 3/120 (2.5%) clones analyzed. Culture filtrates of 2/3 clones were found to have cytotoxic activity in human lung fibroblasts. The recombinant protein expressed in E. coli was identified as toxin B by Western immunoblot analysis using C. sordellii antitoxin. This rapid cloning method may be useful in determining the role that individual genes in the pathogenicity locus (PaLoc) play in the virulence of C. difficile. Our results also suggest that the activity of toxin B is independent of other genes in the PaLoc.

Bacterial Proteins↗