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PubMed1993

Specific detection of toxigenic strains of Clostridium difficile in stool specimens.

Clostridium difficile is the infectious agent responsible for antibiotic-associated colitis. We report the use of the polymerase chain reaction technique to identify toxigenic strains of C. difficile in human stool specimens. A set of primers based on the nucleotide sequence of the toxin B gene, which amplified a 399-bp fragment from isolates producing toxin B, was designed. We examined 28 known toxigenic strains, which were all positive by this assay. DNAs from the nontoxigenic strains examined and from strains of Clostridium sordellii and C. bifermentans were not amplified with these primers. The sensitivity of this assay allowed us to identify as little as 10% toxigenic C. difficile cells in the presence of 90% nontoxigenic cells and to detect the toxin B gene in 1 pg of DNA from a toxigenic strain. DNAs extracted from 18 clinical stool specimens that were positive for toxin B by the tissue culture cytotoxicity assay were also positive by this assay. In addition, we detected toxin B sequences in DNA from 2 of 18 stool specimens that were negative for toxin B by the cytotoxicity assay. These two stool specimens were from patients who had a clinical pattern of colitis that was compatible with C. difficile causation. This rapid, sensitive assay will be useful for specific identification of toxigenic C. difficile and for revealing cases that are undetected by analysis of fecal samples for toxin B alone.

Bacterial Proteins↗
PubMed1994

Antibiotic-induced diarrhea: specificity of abdominal CT for the diagnosis of Clostridium difficile disease.

PURPOSE: To evaluate the specificity of abdominal computed tomography (CT) in the diagnosis of Clostridium difficile disease. MATERIALS AND METHODS: The authors retrospectively reviewed CT scans of 64 patients with C difficile disease and 30 control subjects with diarrhea and negative findings for C difficile disease at stool tests. RESULTS: Colon wall thickening (range, 4-22 mm; mean, 11.7 mm; median, 11 mm) was seen in 39 patients (61%) with C difficile disease. Other findings included focal colon wall thickening (n = 28) and pancolonic thickening (n = 11). Two patients had only right-sided and transverse colon involvement. CT-specific diagnostic features of C difficile disease, such as nodular haustral thickening or the accordion pattern, were present in 17% of patients. No colonic abnormality was detected in 25 patients (39%). Seven of the 30 (23%) control subjects had colon wall thickening. Six of those seven subjects were subsequently determined to have ischemic colitis. The sensitivity of CT in the detection of colon abnormalities in patients with C difficile disease was 85%, and the specificity was 48%. CONCLUSION: Specific CT features of C difficile disease are uncommon. A considerable number of patients (39%) with C difficile disease have normal abdominal CT scans.

Adult↗
PubMed2001

Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins.

Clostridium difficile, the major etiologic factor of antibiotic-associated diarrhea and colitis, mediates its effects by releasing two large protein exotoxins, toxins A and B. A major toxin effect is related to the disassembly of actin microfilaments, leading to impairment of tight junctions in human colonocytes. The mechanism of actin disaggregation involves monoglucosylation of the signaling proteins Rho A, Rac, and Cdc 42, which control stress fiber formation directly by toxins A and B. An important aspect of C. difficile infection is the acute necroinflammatory changes seen in patients with pseudomembranous colitis. The early mechanism of toxin-mediated inflammation involves toxin effects on cellular mitochondria, release of reactive oxygen species, and activation of mitogen-activated protein kinases and the transcription factor nuclear factor-kappaB. Injection of toxin A into animal intestine triggers secretion of fluid and intestinal inflammation characterized by epithelial cell destruction and neutrophil activation. A critical feature of C. difficile enterotoxicity is communication between enterocytes and lamina propria nerves, macrophages, and mast cells mediated via release of neuropeptides and proinflammatory cytokines.

Acute-Phase Proteins↗
PubMedDate not supplied

[Diarrhea associated with antibiotic therapy].

The authors suggest rational procedures to prevent the antibiotic associated diarrhea (AAD) Clostridium difficile positive or not, considering its high cost (both to stay in Hospital and for specific therapy). Twenty-four cases of diarrhea starting during antibiotic therapy and until one month from its interruption was assessed. Twelve (50%) was found Clostridium difficile (+); 12 (50%) was Clostridium difficile (-); no case of pseudomembranous colitis was found. Two hospitalized patients shared the room with others suffering from diarrhea Clostridium difficile (+) developing the same illness although precautions were used both by physicians and by nursing staff. Four patients had diarrhea after domiciliary antibiotic therapy. Vancomycin (1-2 g/die p.o.) was effective therapy in patients with important diarrhea (more than 10 withdrawals in a day). Two cases with moderate diarrhea (less than 6 withdrawals in a day) Clostridium difficile (+) recovered without antibiotic therapy. The authors propose: a) rational antibiotic use; b) isolation of affected patients; c) sanitary measures in dejections treatment.

Adolescent↗
PubMed1993

[Prevalence of Clostridium difficile and toxin A in feces of HIV infected patients].

Patients with AIDS are immunodeficient, receive multiple antibiotic treatments, occasionally anti-cancer chemotherapy and are often hospitalised; thus they are susceptible to develop a Clostridium difficile infection. The aim of this study was to evaluate the role of C. difficile in diarrhoea in this patient population. Therefore, C. difficile and toxin A which plays a major role in pathogenicity were examined in faecal samples of HIV infected patients. Between January 1991 and June 1992, 102 stool samples from 67 patients were studied. Ninety p. cent of these patients were hospitalised (length > 3 days), 80% had a diagnosis of AIDS stage IV, and 66% had diarrhoea. Nineteen point four p. cent of the patients were carriers of C. difficile. Different associations were found: 1) presence of non toxigenic strains and absence of toxin A in stool samples (6 patients), 2) presence of toxigenic strains and absence of toxin A in stool samples (6 patients), 3) presence of toxigenic strains and toxin A in stool samples (2 patients). None of the patients developed a colitis or pseudomembranous colitis. The carrier rate was identical to those found in other hospitalised populations without AIDS. The prevalence of C. difficile diarrhoea or colitis is low. In this study, AIDS patients do not seem to constitute a risk group for C. difficile intestinal pathology. However, carriers of C. difficile were subjected to strict hygiene rules to prevent nosocomial spread.

AIDS-Related Opportunistic Infections↗
PubMed1998

Guidelines for optimal surveillance of Clostridium difficile infection in hospitals.

The availability of surveillance data on C. difficile infection in hospitals in England and Wales is being jeopardised by the trend not to culture the organism for diagnostic purposes. NHS trust laboratories that no longer have the ability to isolate C. difficile cannot investigate putative outbreaks or monitor antimicrobial susceptibilities. These laboratories may now need to rely on their local public health laboratory for such investigations. Recent recommendations from the Department of Health(DH)/PHLS have highlighted the need for culture in outbreak investigations, for surveillance purposes, and for monitoring antimicrobial susceptibilities. It is important, therefore, that NHS diagnostic laboratories and public health laboratories, in particular, retain the ability to isolate C. difficile. A cost-effective approach is described that will facilitate surveillance by typing of strains and also enable their antimicrobial susceptibilities to be monitored.

Bacterial Typing Techniques↗
PubMed1992

Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding.

Clostridium difficile toxin A, a 308-kilodalton protein exotoxin, is the principal causative agent of antibiotic-associated, C. difficile-induced colitis. In the current study, the prevalence of specific human serum and secretory antibody to toxin A and the possible protective effect of secretory, intestinal anti-toxin A antibody are examined. Serum (n = 35), colonic aspirates (n = 35), and duodenal aspirates (n = 20) were collected from adults at diagnostic endoscopy. Patients with evidence of colitis or a history of recent antibiotic use were excluded from the study. Specific serum immunoglobulin (Ig) A and IgG antitoxin A antibodies were detected in 60% and 57% of subjects, respectively, by enzyme-linked immunosorbent assay. Fifty-seven percent of colonic aspirates contained IgA antitoxin, whereas only 10% of duodenal aspirates were positive (P = 0.002). Binding of toxin A to its intestinal receptor was studied using [3H]toxin A and purified rabbit ileal brush border membranes. Toxin A binding was significantly inhibited by colonic aspirates with high IgA anti-toxin A antibody levels (0.503 +/- 0.055 pmol toxin A bound per milligram of brush border membrane protein, mean +/- SE) in comparison with antitoxin A-negative aspirates (0.778 +/- 0.089 pmol; P = 0.02) and control (0.766 +/- 0.004 pmol; P = 0.03). In the current study, a specific intestinal secretory IgA antibody response to C. difficile toxin A in humans is reported. This antibody response is more evident in the colon, the site of C. difficile infection, than in the upper intestinal tract. Our data suggest that human colonic IgA antitoxin may protect against C. difficile colitis by inhibiting the binding of toxin A to its intestinal epithelial cell receptor.

Adult↗
PubMed1998

Low rate of Clostridium difficile colonization in ambulatory and hospitalized HIV-infected patients in a hospital unit: a prospective survey.

OBJECTIVE: To determine the frequency of Clostridium difficile carriage in HIV-infected in- and out-patients, and to assess the role of this carriage in nosocomial transmission of C. difficile. PATIENTS AND METHODS: Prospective study in a university hospital. Forty-five consecutive HIV-infected out-patients and 120 hospitalized patients (52 HIV and 68 non HIV-infected-patients) were studied. During the period of hospitalization, 44 patients (24 HIV and 20 non-HIV-infected patients) with a negative culture within 48 h of admission were followed weekly for fecal carriage. Clostridium difficile culture and latex agglutination were performed on the fecal samples of each patient. In the case of positive culture and/or latex agglutination, C. difficile toxin assays were performed by microtitre cytotoxicity method. RESULTS: Out-patients: one patient was a carrier and one patient with diarrhoea was infected with a toxigenic strain (2/45, 4.5%, 95% CI = 1-17). Eighty percent of the HIV-infected out-patients had received antimicrobial agents previously. In-patients: in the first 48 h, five asymptomatic patients were carriers (three non-HIV and two HIV-infected patients). Among 20 patients who complained of diarrhoea, one HIV-infected patient had only a positive latex agglutination and one HIV-infected patient was infected with a toxigenic strain. Overall, 7/120 (5.8%, 95% CI = 2-10) patients were infected or colonized with C. difficile. During the hospitalization (743 patient-days), none of the 44 patients acquired C. difficile. CONCLUSION: This study suggests that in this given unit, C. difficile carriage is low, at least with single room accommodation, and in the absence of clusters of cases. This carriage is not different in HIV and non-HIV infected patients despite treatment with multiple antibiotics, and is not different in patients managed in different care environments. The systematic identification of C. difficile carriers for isolation and prophylactic treatment is not useful under these circumstances.

Ambulatory Care↗
PubMed2003

Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea.

Clostridium difficile is the main infectious cause of colitis in hospital inpatients. The incidence is increasing, and it is associated with significant mortality, morbidity, and increased length of stay. The main risk factor is use of broad-spectrum antibiotics, and antibiotic restriction is the most effective control measure. We carried out a retrospective case-control study to investigate whether use of proton pump inhibitors (PPI) was an additional risk factor. PPI use within the preceding eight weeks was associated with an increased risk of C. difficile diarrhoea (odds ratio 2.5, 95% CI 1.5-4.2). Reduction of unnecessary PPI use may be an additional strategy to reduce the incidence of this infection.

Achlorhydria↗
PubMed2005

An epidemic, toxin gene-variant strain of Clostridium difficile.

BACKGROUND: Recent reports suggest that the rate and severity of Clostridium difficile-associated disease in the United States are increasing and that the increase may be associated with the emergence of a new strain of C. difficile with increased virulence, resistance, or both. METHODS: A total of 187 C. difficile isolates were collected from eight health care facilities in six states (Georgia, Illinois, Maine, New Jersey, Oregon, and Pennsylvania) in which outbreaks of C. difficile-associated disease had occurred between 2000 and 2003. The isolates were characterized by restriction-endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and toxinotyping, and the results were compared with those from a database of more than 6000 isolates obtained before 2001. The polymerase chain reaction was used to detect the recently described binary toxin CDT and a deletion in the pathogenicity locus gene, tcdC, that might result in increased production of toxins A and B. RESULTS: Isolates that belonged to one REA group (BI) and had the same PFGE type (NAP1) were identified in specimens collected from patients at all eight facilities and accounted for at least half of the isolates from five facilities. REA group BI, which was first identified in 1984, was uncommon among isolates from the historic database (14 cases). Both historic and current (obtained since 2001) BI/NAP1 isolates were of toxinotype III, were positive for the binary toxin CDT, and contained an 18-bp tcdC deletion. Resistance to gatifloxacin and moxifloxacin was more common in current BI/NAP1 isolates than in non-BI/NAP1 isolates (100 percent vs. 42 percent, P<0.001), whereas the rate of resistance to clindamycin was the same in the two groups (79 percent). All of the current but none of the historic BI/NAP1 isolates were resistant to gatifloxacin and moxifloxacin (P<0.001). CONCLUSIONS: A previously uncommon strain of C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease.

ADP Ribose Transferases↗
PubMed1997

Prevalence of and risk factors for Clostridium difficile colonization at admission to an infectious diseases ward.

A study of 240 consecutive admissions to a single hospital ward over a 6-month period was conducted to determine the prevalence of and risk factors for Clostridium difficile colonization at admission. The prevalence rate of C. difficile colonization at admission was 13.3%. Seventy-four percent of the patients admitted to the ward were infected with human immunodeficiency virus (HIV). Multivariate analysis identified three risk factors for C. difficile colonization: clindamycin use (adjusted odds ratio [OR], 9.4; P < .001), penicillin use (adjusted OR, 3.9; P = .018), and a history of cytomegalovirus infection (adjusted OR, 4.2; P = .02). C. difficile colonization at admission to our infectious diseases ward was common. Antibiotic treatments received before admission were the main risk factors for C. difficile colonization. HIV infection per se was not associated with C. difficile colonization. It is interesting that there was an association between C. difficile colonization and a history of cytomegalovirus infection.

AIDS-Related Opportunistic Infections↗
PubMed2006

New variants of the tet(M) gene in Clostridium difficile clinical isolates harbouring Tn916-like elements.

OBJECTIVES: To detect Tn916-like elements in Clostridium difficile clinical isolates from different time periods and to analyse the genetic structure of these elements, in particular the tet(M) region. METHODS: Ninety C. difficile clinical isolates were examined by PCR assays for tet(M) and int, which are markers for the Tn916 family of elements. Positive isolates were typed by PCR-ribotyping, and tetracycline MIC values were evaluated by Etest. The genetic organization of the Tn916 elements was investigated by PCR mapping and hybridization assays. The tet(M) region of eight selected C. difficile isolates was sequenced. RESULTS: Nineteen isolates were tet(M)/int positive and the majority (12/19) belonged to PCR-ribotype R, previously found to be predominant in clinical strains of more recent isolation. Eleven isolates were tetracycline resistant, three inducibly resistant and five susceptible. Fifty-eight per cent of the C. difficile isolates harboured one Tn916 element and 42% harboured two. Most isolates showed elements with a genetic organization very similar to that of Enterococcus faecalis DS16 Tn916. Sequence analysis highlighted variations in the leader peptide and six tet(M) variants were identified, five of which have never been described before. CONCLUSIONS: C. difficile isolates harbouring Tn916-like elements have mainly been isolated since 1997, suggesting a recent circulation of these elements among C. difficile strains in Italian hospitals. Molecular analysis of these Tn916-like elements showed that they may have different genetic structures and carry new tet(M) alleles.

Bacterial Proteins↗
PubMed2001

Colonisation and transmission of Clostridium difficile in healthy individuals examined by PCR ribotyping and pulsed-field gel electrophoresis.

Healthy adults who had not been exposed to antimicrobial agents for the preceding 4 weeks were examined for intestinal carriage of Clostridium difficile. The 1234 individuals examined were composed of seven groups: three classes of university students, hospital workers at two hospitals, employees of a company and self-defence force personnel at a local station. Overall, 94 (7.6%) individuals were positive for C. difficile by faecal culture but carriage rates among the study groups ranged from 4.2% to 15.3%. Typing by PCR ribotyping and pulsed-field gel electrophoresis demonstrated clusters of carriers colonised by a single type in each of three groups, indicating that cross-transmission of C. difficile can occur in community settings. Follow-up culture was performed on 38 C. difficile-positive individuals and C. difficile was isolated again from 12 (32%) of them 5-7 months after the initial culture; six (50%) of these 12 individuals had a new strain on repeat culture. Two or more family members were C. difficile-positive in five of 22 families examined. C. difficile with an identical type was isolated from persons within a family in only one family. These results suggest that intestinal carriage by healthy adults may play a role as a reservoir for community-acquired C. difficile-associated diarrhoea, but that cross-transmission of C. difficile does not occur frequently among family members at home.

Adolescent↗
PubMed2006

Construction and analysis of chromosomal Clostridium difficile mutants.

Clostridium difficile is an emerging nosocomial pathogen of increasing importance and virulence but our ability to study the molecular mechanisms underlying the pathogenesis of C. difficile-associated disease has been limited because of a lack of tools for its genetic manipulation. We have now developed a reproducible method for the targeted insertional inactivation of chromosomal C. difficile genes. The approach relies on the observation that an Escherichia coli-Clostridium perfringens shuttle vector is unstable in C. difficile and can be used as a form of conditional lethal vector to deliver gene constructs to the chromosome. We have used this methodology to insertionally inactivate two putative response regulator genes, rgaR and rgbR, which encode proteins with similarity to the toxin gene regulator, VirR, from C. perfringens. Transcriptomic analysis demonstrated that the C. difficile RgaR protein positively regulated four genes, including a putative agrBD operon. The RgaR protein was also purified and shown to bind specifically to sites that contained two consensus VirR boxes located just upstream of the putative promoters of these genes. The development of this methodology will significantly enhance our ability to use molecular approaches to develop a greater understanding of the ability of C. difficile to cause disease.

Amino Acid Sequence↗
PubMed2001

Failure of single-toxin assays to detect clostridium difficile infection in pediatric inflammatory bowel disease.

OBJECTIVES: The aims of this retrospective study were 1) to determine the ability of single-toxin assays for Clostridium difficile to detect infection among pediatric patients with inflammatory bowel disease (IBD) and 2) to determine the toxin assays routinely used by pediatric tertiary care hospitals in the United States. METHODS: Stool specimens from patients with IBD (submitted from January, 1996, to August, 1999) were evaluated for the presence of C. difficile toxin A and toxin B. Toxin profile (toxin A alone, toxin B alone, toxin A and B together) was compared in positive specimens. A phone interview was conducted with representatives from laboratories in 22 pediatric hospitals to investigate which toxin assays were routinely used. RESULTS: A total of 697 specimens were submitted from 284 IBD patients. In all, 81 IBD patients (28.5%) had at least one documented infection. Toxin A assay failed to identify 41.5% of C. difficile infections. Toxin B assay failed to detect 34.9% of C. difficile infections. Toxin profile changed in 55% of patients with multiple infections. Of the hospitals surveyed, 59% did not test for both toxins. CONCLUSIONS: Single-toxin assays for C. difficile fail to detect a significant percentage of infections. The toxins identified during one infection are not predictive of the toxins identified in subsequent infections. Despite this, many pediatric hospitals do not routinely use both toxin assays to diagnose C. difficile infection. When infection is suspected, assays for C. difficile toxin A and toxin B should be requested.

Adolescent↗
PubMed2000

Production of actin-specific ADP-ribosyltransferase (binary toxin) by strains of Clostridium difficile.

In addition to the two large clostridial cytotoxins (TcdA and TcdB) certain strains of Clostridium difficile produce an actin-specific ADP-ribosyltransferase, or binary toxin. PCR reactions were developed to detect genes encoding the enzymatic (cdtA) and binding (cdtB) components of the binary toxin and 170 representative strains were tested to assess the prevalence of the toxin. Positive PCR results (n=59) were confirmed by immunoblotting and ADP-ribosyltransferase assay. PCR ribotype and toxinotype (restriction fragment length polymorphism analysis of genes for TcdA and TcdB) correlated with possession of binary toxin genes. All strains with cdtA and cdtB belonged to toxin-variable toxinotypes and five toxin-producing groups of strains have been described according to the presence or absence of TcdA, TcdB and binary toxin. Result indicate that ca. 6.4% of toxigenic isolates of C. difficile referred to the Anaerobe Reference Unit from UK hospitals have cdtA and cdtB genes.

ADP Ribose Transferases↗
PubMed2005

Effect of antibiotic treatment on growth of and toxin production by Clostridium difficile in the cecal contents of mice.

In mice, subcutaneous administration of antibiotics that disrupt the anaerobic microflora (i.e., clindamycin, piperacillin-tazobactam, and ceftriaxone) facilitated in vitro growth of and toxin production by Clostridium difficile in cecal contents, whereas antibiotics that cause minimal disruption of the anaerobic microflora (i.e., levofloxacin, cefepime, and aztreonam) did not.

Animals↗