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PubMed1998

The diagnosis of Clostridium difficile-associated disease.

There are well-documented risk factors associated with the development of antibiotic-associated diarrhoea; knowledge of these and of the typical signs and symptoms should alert the clinician to the possibility of Clostridium difficile-associated diarrhoea (CDAD). It is therefore common practice in large general hospitals for clinicians to request, and for laboratories to include, investigations for C. difficile on in-patient stool specimens to confirm a diagnosis of CDAD. The laboratory methods used to investigate for CDAD are divided into two main categories: those that are aimed at detecting the presence of C. difficile or its products, and those that detect either of its two major toxins, A (enterotoxin) and B (cytotoxin). Within each of these broad strategies there are various rationales which are reviewed here.

Animals↗
PubMed2002

Clostridium difficile.

Clostridium difficile is the most commonly identified infective cause of antibiotic associated diarrhoea. Broad spectrum antibiotics, are most frequently incriminated, although short (<3 day) antibiotic courses cause fewer episodes. Gold standard cell-culture based cytotoxin assays have been compared to rapid immunoassays, which are less effective, especially since toxin A negative, toxin B positive strains have been shown to be truly virulent. Details of colonization and adherence mechanisms have been revealed, and clonal spread has been demonstrated. The mainstay of treatment of C. difficile infection remains metronidazole. Justified fears over resistance are leading to development of alternative therapeutic strategies. These include a toxin binding polymer and ongoing biotherapy research. An antibody rise to toxin A during an episode of C. difficile diarrhoea protects against recurrence, and trials are in progress to investigate immunization: a toxoid vaccine which is immunogenic and safe in healthy volunteers shows promise for the future.

Bacterial Toxins↗
PubMed2001

Nonfunctional gut? Try a probiotic food.

This month's Nutrition column discusses the problem of antibiotic-associated diarrhea. The overgrowth of the "good" bacteria, Clostridium difficile, can cause severe abdominal pain, fever, and diarrhea. This article examines the benefits of including probiotics in a meal plan when the use of antibiotics is medically indicated.

Anti-Bacterial Agents↗
PubMed2002

Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease.

OBJECTIVE: There is currently uncertainty as to the best treatment for patients with recurrent episodes of Clostridium difficile disease (RCDD). Our objective was to evaluate the success of treatment strategies in a cohort of 163 RCDD patients. METHODS: Data were used from patients who had participated in the placebo arm in two national referral clinical trials evaluating a new combination treatment. Patients with active RCCD were enrolled, prescribed either vancomycin or metronidazole, and randomized to either the investigational biological or a placebo. All patients were observed for at least 2 months for a subsequent episode of RCCD. RESULTS: Of the 163 cases, 44.8% recurred. A tapering course of vancomycin resulted in significantly fewer recurrences (31%, p = 0.01), as did pulsed dosing of vancomycin (14.3%, p = 0.02). A trend (p = 0.09) for a lower recurrence frequency was observed for high-dose (> or =2 g/day) vancomycin and low-dose (< or =1 g/day) metronidazole. Vancomycin was significantly more effective in clearing C. difficile culture and/or toxin by the end of therapy than metronidazole (89% vs 59%, respectively; p < 0.001). CONCLUSIONS: These data show that tapered or pulsed dosing regimens of vancomycin may result in a significantly better cure of RCDD. The persistence of C. difficile spores suggests that additional strategies to restore the normal colonic microflora may also be beneficial.

Adolescent↗
PubMed2002

gyrA and gyrB mutations are implicated in cross-resistance to Ciprofloxacin and moxifloxacin in Clostridium difficile.

A total of 198 nonrepetitive clinical strains of Clostridium difficile isolated from different French hospitals in 1991 (n = 100) and 1997 (n = 98) were screened for decreased susceptibility to fluoroquinolones by plating onto Wilkins-Chalgren agar containing 16 micro g of ciprofloxacin per ml. The frequency of decreased susceptibility was 7% (14 of 198) and was identical for the years 1991 and 1997. Serogroups C, H, D, A9, and K accounted for five, four, two, one, and one of the resistant strains, respectively, one strain being nontypeable. Arbitrarily primed PCR typing showed that all resistant strains had unique patterns except two serotype C strains, which could not be clearly distinguished. All isolates with decreased susceptibility carried a mutation either in gyrA (eight mutations, amino acid changes Asp71-->Val in one, Thr82-->Ile in six, and Ala118-->Thr in one) or in gyrB (six mutations, amino acid changes Asp426-->Asn in five and Arg447-->Leu in one). These changes are similar to those already described in other species except for Asp71-->Val, which is novel, and Ala118-->Thr, which is exceptional. Attempts to detect the topoisomerase IV parC gene by PCR amplification with universal parC primers or DNA-DNA hybridization under low-stringency conditions were unsuccessful. The susceptibilities of all resistant strains to ciprofloxacin and ethidium bromide were not affected by the addition of reserpine at 20 micro g/ml. In conclusion, decreased susceptibility to fluoroquinolones in C. difficile is rare in France and is associated with the occurrence of a gyrA or gyrB mutation.

Anti-Infective Agents↗
PubMed2002

Environmental response and autoregulation of Clostridium difficile TxeR, a sigma factor for toxin gene expression.

TxeR, a sigma factor that directs Clostridium difficile RNA polymerase to recognize the promoters of two major toxin genes, was shown to stimulate its own synthesis. Whether expressed in C. difficile, Clostridium perfringens, or Escherichia coli, TxeR stimulated transcription of fusions of the txeR promoter region to reporter genes. As is the case for the tox genes, txeR expression was responsive to the cellular growth phase and the constituents of the medium. That is, the level of expression in broth culture was low during the exponential growth phase, but rapidly increased as cells approached the stationary phase. In the presence of excess glucose, expression from the txeR promoter was repressed. The results support a model for toxin gene expression in which synthesis of TxeR is induced by specific environmental signals. The increased level of TxeR then permits high-level expression of the toxin genes. The study of txeR gene regulation in C. difficile was made possible by introduction of a mobilizable, replicative plasmid via conjugation with E. coli.

Bacterial Proteins↗
PubMed1991

Evaluation of cycloserine-cefoxitin-fructose agar and cycloserine-cefoxitin-fructose broth for recovery of Clostridium difficile from environmental sites.

Cycloserine-cefoxitin-fructose agar (CCFA) and cycloserine-cefoxitin-fructose broth (CCFB) containing either 500 or 250 micrograms of cycloserine per ml were compared for efficacy in the isolation of Clostridium difficile from hospital ward environmental sites. A RODAC imprint technique was used to inoculate prereduced CCFA. Moistened swabs were used to inoculate prereduced CCFB from environmental sites immediately adjacent to the RODAC sample sites. CCFA (6% positive) was significantly more sensitive than CCFB (3% positive; P less than 0.005), regardless of the cycloserine concentration. When the CCFA cycloserine concentration was decreased from 500 to 250 micrograms/ml, the overall rate of positive cultures rose from 4 to 17%. Medium containing 500 micrograms of cycloserine per ml may be too inhibitory to isolate many moderately sensitive strains of C. difficile from environmental sites. Regardless of the cycloserine concentration, the CCFA RODAC imprint technique is superior to the CCFB method.

Agar↗
PubMed1992

Comparison of five cultural procedures for isolation of Clostridium difficile from stools.

Several procedures have been described for the culture of Clostridium difficile from stool specimens. The goal of this study was to determine the effectiveness of five of these methods for the isolation of C. difficile from feces of patients suspected of having C. difficile-associated illness. A total of 564 stool specimens were cultured by using heat shock, ethanol treatment (ET), and direct plating on Carr-Scarborough cycloserine-cefoxitin-fructose agar (CCFA) with horse blood (C/S medium), BBL CCFA medium, and Remel C. difficile agar. Cytotoxin assays were performed on all specimens. A total of 113 specimens (20%) were positive for C. difficile by one or more methods. The numbers of positive cultures by using heat shock, ET, and direct plating on C/S medium, BBL CCFA medium, and Remel C. difficile agar were 79 (70%), 89 (79%), 91 (81%), 79 (70%), and 52 (46%), respectively. We concluded that ET and direct plating on C/S medium were the most effective procedures for isolating C. difficile from stool specimens and found significant variation in the performance of modified CCFA from different manufacturers.

Bacteriological Techniques↗
PubMed2005

Variability of Clostridium difficile surface proteins and specific serum antibody response in patients with Clostridium difficile-associated disease.

Pathogen attachment is a crucial early step in mucosal infections. This step is mediated by important virulence factors, such as surface proteins. Clostridium difficile surface proteins have been identified as (i) adhesins (the flagellar cap protein FliD; the flagellin FliC; and the cell wall protein Cwp 66 with a two domain-structure [Cw 66 N-terminal and Cwp 66 C-terminal domains]) and (ii) protease (the Cwp 84 protein). To address the roles of these proteins in the pathogenesis of Clostridium difficile and to identify vaccine antigen candidates, we analyzed the variability of the proteins and their immunogenicities in 17 patients with C. difficile-associated disease. PCR-restriction fragment length polymorphism analysis of amplified gene products revealed interstrain homogeneity with fliC and fliD, in contrast to cwp 66 genes. Immunoblot analysis showed that FliC and FliD were detected in the majority of isolates. The N-terminal domain of Cwp 66 and Cwp 84 were present in all strains tested, in contrast to the Cwp 66 C-terminal domain, the expression of which was heterogeneous. The 17 sera from the corresponding patients were analyzed by enzyme-linked immunosorbent assay to detect antibodies directed against these proteins. Many patients developed antibodies to FliC, FliD, Cwp 84, and the Cwp 66 C-terminal domain, but not to the Cwp 66 N-terminal domain. In conclusion, this study confirms the expression of these surface proteins of C. difficile during the course of the disease. In addition, the FliC, FliD, and Cwp 84 proteins appeared to be good potential vaccine candidates.

Animals↗
PubMed1992

Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. A randomized, placebo-controlled trial.

OBJECTIVE: 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. DESIGN: Randomized, placebo-controlled, non-blinded trial. SETTING: Six hundred-bed regional referral Veterans Affairs Medical Center. PATIENTS: Thirty patients excreting C. difficile without diarrhea or abdominal symptoms. INTERVENTIONS: 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. MEASUREMENTS: Stool cultures were obtained during treatment and for 2 months after treatment. All C. difficile isolates were typed by restriction endonuclease analysis (REA). RESULTS: 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). CONCLUSIONS: 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.

Aged↗
PubMed1999

Roles of intracellular calcium and NF-kappa B in the Clostridium difficile toxin A-induced up-regulation and secretion of IL-8 from human monocytes.

Clostridium difficile causes an intense inflammatory colitis through the actions of two large exotoxins, toxin A and toxin B. IL-8 is believed to play an important role in the pathophysiology of C. difficile-mediated colitis, although the mechanism whereby the toxins up-regulate the release of IL-8 from target cells is not well understood. In this study, we investigated the mechanisms through which toxin A induces IL-8 secretion in human monocytes. We found that cellular uptake of toxin A is required for the up-regulation of IL-8, an effect that is not duplicated by a recombinant toxin fragment comprising the cell-binding domain alone. Toxin A induced IL-8 expression at the level of gene transcription and this effect occurred through a mechanism requiring intracellular calcium and calmodulin activation. Additionally, the effects of toxin A were inhibited by the protein tyrosine kinase inhibitor genistein, but were unaffected by inhibitors of protein kinase C and phosphatidylinositol-3 kinase. We determined that toxin A activates nuclear translocation of the transcription factors NF-kappa B and AP-1, but not NF-IL-6. NF-kappa B inhibitors blocked the ability of toxin A to induce IL-8 secretion, and supershift analysis indicated that the major isoform of NF-kappa B activated by the toxin is a p50-p65 heterodimer. This study is the first to identify intracellular signaling pathways and transcription factors involved in the C. difficile toxin-mediated up-regulation of IL-8 synthesis and release by target cells. This information should increase our understanding of the pathogenesis of C. difficile colitis and the nature of IL-8 gene regulation as well.

Bacterial Toxins↗
PubMed2001

The effect of tumour necrosis factor (TNF) inhibitors in Clostridium difficile toxin-induced paw oedema and neutrophil migration.

Clostridium difficile produces a potent enterotoxin and a cytotoxin, toxin A and toxin B, respectively. These toxins are associated with pseudomembranous colitis and antibiotic-associated diarrhoea. In the present study, we investigated the oedematogenic activity of both toxins, characterizing the time-course and dose-response of this pro-inflammatory event. We also explored the effects of two inhibitors of tumour necrosis factor (TNF) production, thalidomide and pentoxifylline, in neutrophil recruitment and the oedematogenic activity of these toxins. Subplantar injection of toxin A induced paw oedema with a maximal response at 1 microg, reaching a maximal value 9 hr after toxin A challenge (toxin A 1 microg:1.39+/-0.09 ml). Toxin B also showed a dose-dependent oedematogenic activity with a late peak at 24 hr and a maximal response at a dose of 0.1 microg (toxin B 0.1 microg:1.74+/-0.12 ml). Pentoxifylline, but not thalidomide, significantly reduced the oedema induced by Toxin A (pentoxifylline 135 mg/kg:60% of inhibition) and Toxin B (pentoxifylline 135 mg/kg:33.6% of inhibition). Both thalidomide and pentoxifylline were able to significantly reduce neutrophil influx into the peritoneal cavities of rats evoked with Toxin A (thalidomide 45 mg/kg: 53.1% of inhibition; pentoxifylline 45 mg/kg:47.1% of inhibition) and Toxin B (thalidomide 45 mg/kg:46.8% of inhibition; pentoxifylline 45 mg/kg:63.1% of inhibition). This study demonstrates the oedematogenic activities of both toxins with distinct potencies and time-courses. These data also show an inhibitory effect of pentoxifylline in toxin A and B-induced paw oedema. Furthermore, both pentoxifylline and thalidomide significantly inhibited the Clostridium difficile toxins-induced neutrophil migration.

Animals↗
PubMed2002

Faecal lactoferrin assay as an adjunct to Clostridium difficile diarrhoea.

Inflammation is the hallmark of Clostridium difficile associated diarrhoea and lactoferrin is produced by inflammatory cells. The aim of this study was to find out whether faecal lactoferrin latex agglutination (FLLA) assay done simultaneously with Clostridium difficile toxin (CDT) assay would help in the diagnosis of C. difficile infection in paediatric patients. One hundred and fifty faecal samples were obtained from paediatric group of patients. Both FLLA and CDT assays were done in conjunction on these samples. The data were expressed by descriptive statistics. One hundred and nineteen patients received antibiotics while 31 did not receive it. Of the former group 89 (74.8%) had diarrhoea while 30 (25.2%) did not have it. No significant relationship (p=0.287) was seen between antibiotic usage and occurrence of diarrhoea. However, CDT positivity was seen to be influenced by prior antibiotic usage as 51 (42.9%) patients receiving antibiotics were CDT positive when compared to 4 (7.3%) of those who did not receive antibiotics (p=0.002). A highly statistically significant (p<0.001) relationship was seen between CDT and FLLA positivity. FLLA appears to be an useful adjunct for C. difficile associated intestinal diseases in children when both the tests are done simultaneously and when other enteropathogens causing inflammatory diarrhoeas are ruled out.

Bacterial Toxins↗
PubMed1994

Clostridium difficile diarrhea: pathogenesis, epidemiology, and treatment.

Clostridium difficile, the bacterium responsible for antibiotic-associated diarrhea and colitis, has become a significant cause of morbidity and prolonged hospital stays, largely because of the increasing use of broad-spectrum antibiotics. This gram-positive organism, which can lay dormant in its spore form in the environment for extended periods of time, proliferates in the colon when the normal colonic flora is compromised by antibiotic use. C. difficile produces intestinal inflammation and diarrhea through the elaboration of two protein exotoxins, toxin A and toxin B. The spectrum of clinical manifestations ranges from mild diarrhea that resolves with the cessation of the offending antibiotic, to fulminant pseudomembranous colitis complicated by megacolon and perforation. Our ability to meet the challenge offered by this organism has been enhanced by the development of new diagnostic modalities as well as the development of new therapeutic regimens. Through further investigation of the structure and function of toxins A and B and further study of the interaction of C. difficile with the normal colonic flora, advances will continue to be made in the prevention and treatment of antibiotic-associated colitis.

Anti-Bacterial Agents↗
PubMed1994

Evaluation of an oligonucleotide probe and an immunological test for direct detection of toxigenic Clostridium difficile in stool samples.

A 33 basepair oligonucleotide probe, designed from the sequence of the Clostridium difficile toxin B gene, was evaluated for its ability to detect toxigenic Clostridium difficile directly in stool samples, without culture or DNA isolation. Two different labelling techniques were investigated: radiolabelling and digoxigenin-labelling. One hundred ninety-six stools were tested, with a good correlation (96%) obtained between the oligonucleotide probe and the gold standard, the cytotoxicity tissue culture assay. The sensitivity and specificity were 83% and 100%, respectively. In parallel, a new commercially available enzyme immunoassay for the detection of Clostridium difficile toxin A in stool specimens was investigated. In 162 samples tested, a sensitivity of 80% and a specificity of 98% were obtained.

Animals↗
PubMedDate not supplied

Fecal leukocytes in stool specimens submitted for Clostridium difficile toxin assay.

To determine their diagnostic utility, fecal leukocytes were sought by methylene blue stain in 502 consecutive stool specimens submitted for Clostridium difficile toxin assay. In addition, the stability of fecal leukocytes was assessed by daily examination of 23 stool specimens stored at 4 degrees C and room temperature. The sensitivity, specificity, and positive and negative predictive values of fecal leukocytes in predicting C. difficile toxin assay results were 28%, 92%, 27%, and 93%, respectively. At 4 degrees C, fecal leukocytes retained morphology for a minimum of 3 days. Leukocytes survived as long in stool specimens containing either C. difficile toxin or an enteric pathogen as they did in stool specimens with neither finding. We conclude that testing stool specimens for fecal leukocytes is not useful for predicting the presence of C. difficile toxin, because 72% of stool specimens positive for C. difficile toxin are negative for fecal leukocytes despite their stability.

Adolescent↗