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PubMed1992

Evaluation of a commercial enzyme immunoassay kit for the detection of Clostridium difficile toxin A.

A new enzyme immunoassay (EIA) kit developed for the rapid detection of Clostridium difficile toxin A in faecal specimens, Premier (Meridian Diagnostics), was evaluated using 101 faecal specimens. Sixty-nine specimens were positive for Clostridium difficile by isolation of the organism and by cytotoxicity in tissue culture. The EIA for toxin A was positive in 49 of these 69 cases. No specimen that was negative for cytotoxicity was positive by EIA. Eight of the 32 specimens negative by both EIA and cytotoxicity assay yielded Clostridium difficile by culture. In five of these cases the cytotoxigenic status of the isolate was determined, and four were positive. There was no direct relationship between cytotoxin titre and EIA reading.

Animals↗
PubMed1991

Transfer of Tn916 and Tn916 delta E into Clostridium difficile: demonstration of a hot-spot for these elements in the C. difficile genome.

The conjugative transposon Tn916 and a derivative Tn916 delta E was transferred from Bacillus subtilis into Clostridium difficile CD37 by filter mating. All the C. difficile transconjugants appeared to contain one copy of the transposon integrated into the same position in the genome. Transposition from the original site of integration was not observed. Like Tn916 the transferable tetracycline resistance determinant (Tc-CD) of C. difficile has a preferred site of integration in C. difficile and is homologous with Tn916 along the whole length of Tn916. However comparisons of the distribution of TaqI and Sau3AI sites in the homologous regions of the two elements did not demonstrate any hybridizing fragments in common.

Bacillus subtilis↗
PubMed1996

Definition of the single integration site of the pathogenicity locus in Clostridium difficile.

We determined the nucleotide sequence 3.8 kb upstream and 5.2 kb downstream of the toxin genes A and B of Clostridium difficile. Nine ORFs were discovered. Based on PCR-directed approaches, two were attributed to the pathogenicity locus (PaLoc). The other seven were found in every C. difficile isolate obtained from the human gastrointestinal tract, respectless of their toxinogenicity. The ORFs cdu1 and cdu2/2' upstream of the PaLoc displayed similarity to repressors of Gram-positive bacteria (cdu1), and to an Na+/H+ antiporter described for Enterococcus hirae (cdu2/2'). Downstream of the locus a putative ABC transporter (cdd2-4) was identified. With a set of three paired primers used in polymerase chain reactions we succeeded in delineating the PaLoc. Sequencing of the appropriate stretch of DNA in C. difficile VPI10463 and four additional toxinogenic strains proved a high conservation of the borders of the PaLoc in all these strains. Our data define the locus as a distinct genetic element. Comparing the sequences of five toxinogenic and five non-toxinogenic strains the integration site of the PaLoc was defined. This showed that a stretch of 115 bp found in non-toxinogenic strains is replaced by the 19-kb locus in toxinogenic strains. Analysis of the boundary sequences showed that the locus is obviously not a mobile genetic element by itself. Instead we propose that it is the independent pathogenic part of a more extended genetic element associated with virulence. The 115 bp of non-toxinogenic strains replaced by the locus in toxinogenic strains carry the putative transcription terminator of the cdu1, a predicted repressor protein. A possible polar effect of the loss of this terminator on transcription of the TcdABCDE genes is discussed. Such an effect would explain the unidirectional insertion of the PaLoc at a single site of the C. difficile genome and might give a rationale for the development of the disease which is induced after antibiotical treatment.

ATP-Binding Cassette Transporters↗
PubMed2004

Clostridium difficile colitis associated with valaciclovir.

OBJECTIVE: To report a case of Clostridium difficile colitis associated with valaciclovir treatment. CASE SUMMARY: A 73-year-old man with lumbar herpes-zoster started valaciclovir 1 g tid. After three days he began vomiting and developed diarrhea, three to four stools per day. Symptoms worsened over the following days and he was admitted. Valaciclovir was stopped and fluid and electrolyte replacement was started. He continued 6 days later with diarrhea of 7 to 13 stools per day and a stool test for diagnosis of C. difficile infection was performed with a positive result. The patient received oral metronidazole (500 mg/t.i.d. for 10 days) and rapid improvement and eventual resolution of his diarrhea was observed after 3 days of therapy. DISCUSSION: Although no conclusive reports of this reaction exist, we think this is a case of C difficile colitis that appeared three days after valaciclovir was initiated. Colitis improved with metronidazole. Other causes of diarrhea were excluded, such as diabetes mellitus, renal failure, intestinal surgery and intestinal obstruction. Infection was confirmed by a positive test for C. difficile. The application of Naranjo's algorithm asserts the reaction as 'probable'. CONCLUSIONS: Valaciclovir-associated C. difficile colitis, although rare, can have severe consequences for the patient's health. It should be included as a possible adverse effect of valaciclovir treatment by health professionals.

Acyclovir↗
PubMed1994

Characterization of six murine monoclonal antibodies specific for toxin B of Clostridium difficile.

Six murine hybridoma cell lines producing monoclonal antibodies (MAbs) specific for Toxin B of Clostridium difficile have been generated from toxin-immunized female RBF/DnJ mice. All six antibodies were reactive in Western blots with a > 200-kD protein in the supernatants of the toxigenic strain 10463 and were unreactive with similarly prepared material from the nontoxigenic strain 2037. Polyclonal antisera from rabbits immunized with Toxin B reacted on Western blots primarily with Toxin B, a 40-kD and a 55-kD band with a minor set of triplet bands at approximately 100 kD. None of the MAbs reacted in a direct EIA with purified Toxin A from C. difficile but two MAbs reacted weakly with a trypsin-sensitive band (> 200 kD) in Western blots of C. sordellii. Polyclonal antisera developed against Toxin B reacted strongly with supernatants from C. sordellii, C. bifermentans, and the nontoxigenic strain 2037. Toxin B-specific antisera was unreactive with supernatants from C. perfringens or purified Toxin A from C. difficile in direct EIA. Toxin B-specific MAbs linked to an affinity column were able to deplete bacterial supernatant of cytotoxigenic activity.

Animals↗
PubMed1997

Recurrent Clostridium difficile diarrhea: characteristics of and risk factors for patients enrolled in a prospective, randomized, double-blinded trial.

Recurrent Clostridium difficile diarrhea (RCDD) occurs in 20% of patients after they have received standard antibiotic treatment with vancomycin or metronidazole, but the reasons for the recurrences are largely unknown. Patients receiving vancomycin or metronidazole for active C. difficile diarrhea (CDD) were referred to our study centers for treatment and a 2-month follow-up as part of a randomized placebo-controlled trial. Sixty patients had RCDD (median number of episodes, 3.0; range, 2-9 episodes) and 64 were having their first episode of CDD. Patients with RCDD had more-severe abdominal pain and were more likely to have fever but initially responded well to antibiotic therapy. Data on sequential episodes showed no progression in disease severity. Five factors were associated with a higher risk of RCDD: the number of previous CDD episodes, onset of the initial disease in the spring, exposure to additional antibiotics for treatment of other infections, infection with immunoblot type 1 or 2 strains of C. difficile, and female gender. These factors may help to identify patients who are more likely to develop RCDD and require careful medical supervision.

Adult↗
PubMed2001

PCR ribotyping of clinically important Clostridium difficile strains from Hungary.

Isolates of Clostridium difficile from different hospital wards at the University Hospital of Szeged in Hungary were typed by PCR amplification of rRNA intergenic spacer regions (PCR ribotyping). A total of 15 different ribotypes was detected among the 65 isolates tested. The predominant type, PCR ribotype 087, accounted for 39% of all isolates, in contrast with an international typing study where ribotype 001 was the most common. Two non-toxigenic C. difficile strains were found to exhibit the same pattern, which was distinct from those of all the ribotypes described previously, suggesting that this is a new type.

Animals↗
PubMed2002

Linkage between toxin production and purine biosynthesis in Clostridium difficile.

The production of toxins A and B by Clostridium difficile was greatly enhanced under biotin-limited conditions, in which a 140-kDa protein was expressed strongly. Gene cloning revealed that this protein was a homologue of formylglycinamidine ribonucleotide synthetase (FGAM synthetase, EC 6.3.5.3), which is known as PurL in Escherichia coli and catalyses the fourth step of the de novo purine biosynthesis pathway. This enzyme consisted of a single polypeptide, although FGAM synthetases of gram-positive bacteria usually consist of two subunits. Inhibition of the enzymic activity of C. difficile PurL by O-diazoacetyl-L-serine (azaserine) resulted in enhanced toxin B production even in biotin-sufficient conditions. In contrast, blockade of the preceding step of the PurL catalysing step by sulfamethoxazole inhibited toxin B production almost completely. These results suggest that accumulation of formylglycinamide ribonucleotide (FGAR), a substrate of FGAM synthetase, enhances toxin production by C difficile and depletion of FGAR reduces toxin production.

Amino Acid Sequence↗
PubMed2000

Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea.

OBJECTIVES: Clostridium difficile is the etiological agent of antibiotic-associated diarrhea and pseudomembranous colitis and is a leading cause of nosocomial diarrhea. The objective of the study was to examine if leukocytosis could be a harbinger and surrogate marker of C. difficile infection in hospitalized patients. METHODS: We retrospectively examined the medical records of 70 hospitalized patients who presented with diarrhea of variable severity and who underwent stool examination for enteric pathogens, including C. difficile. We specifically recorded the white blood cell count and the pattern and severity of leukocytosis in two groups of patients--those who were C. difficile-positive and those who were negative. RESULTS: Leukocytosis was common in C. difficile-positive patients, compared to in C. difficile-negative patients (mean 15,800/mm3 vs 7700/mm3, p < 0.01). Review of the 35 C. difficile-positive patients revealed three patterns: Pattern A) sudden WBC increase coinciding with the onset of symptoms suggestive of C. difficile; Pattern B) unexplained leukocytosis preceding the appearance of C. difficile-related diarrhea and serving as a harbinger of the infection; and Pattern C) worsening of pre-existing leukocytosis as a surrogate marker of C. difficile infection. Treatment with metronidazole led to amelioration of symptoms and normalization of the leukocyte count in all cases. CONCLUSIONS: Infection with C. difficile should be considered in the differential diagnosis of sudden onset of leukocytosis in hospitalized patients previously or concurrently treated with antibiotics. Doing so may obviate the need for expensive and time-consuming tests for other etiologies.

Clostridioides difficile↗
PubMed2006

Clostridium difficile lacks detectable superantigen activity.

Clostridium difficile colitis causes striking leukocytosis. We examined the possibility that toxins A or B, or other nontoxin products of C. difficile, act as superantigens, thereby stimulating leukocytosis. Our results failed to show major histocompatibility complex class II-dependent T lymphocyte proliferation, the hallmark of superantigen activity. Elevated white blood cell counts in C. difficile colitis are probably due to increased generation of cytokines such as interleukin-6 (IL-6) or IL-8.

Animals↗
PubMed1990

In vitro activity of LY 264826 compared with that of vancomycin against 100 clinical isolates each of methicillin-resistant Staphylococcus aureus and Clostridium difficile.

The in vitro activity of LY 264826, a new glycopeptide antibiotic, was compared with that of vancomycin against 100 strains each of methicillin-resistant Staphylococcus aureus and Clostridium difficile. LY 264826 was more active, by weight, than vancomycin against the isolates tested. The human serum protein binding of LY 264826 was 15.3% (range, 9.8 to 21.8%).

Anti-Bacterial Agents↗
PubMed2004

The host cell chaperone Hsp90 is necessary for cytotoxic action of the binary iota-like toxins.

The heat shock protein Hsp90 is essential for uptake of the binary actin ADP-ribosylating toxins Clostridium perfringens iota-toxin and Clostridium difficile transferase into eukaryotic cells. Inhibition of Hsp90 by its specific inhibitor radicicol delayed intoxication of Vero cells by these toxins. A common Hsp90-dependent mechanism for their translocation is discussed.

ADP Ribose Transferases↗
PubMed2004

Characterization of toxin A-negative, toxin B-positive Clostridium difficile isolates from outbreaks in different countries by amplified fragment length polymorphism and PCR ribotyping.

Clinical Clostridium difficile isolates of patients with diarrhea or pseudomembranous colitis usually produce both toxin A and toxin B, but an increasing number of reports mention infections due to toxin A-negative, toxin B-positive (A(-)/B(+)) strains. Thirty-nine clinical toxin A(-)/B(+) isolates, and 12 other unrelated isolates were obtained from Canada, the United States, Poland, the United Kingdom, France, Japan, and The Netherlands. The isolates were investigated by high-resolution genetic fingerprinting by use of amplified fragment length polymorphism (AFLP) and two well-described PCR ribotyping methods. Furthermore, the toxin profile and clindamycin resistance were determined. Reference strains of C. difficile representing 30 known serogroups were also included in the analysis. AFLP discriminated 29 types among the reference strains, whereas the two PCR ribotyping methods distinguished 25 and 26 types. The discriminatory power of AFLP and PCR ribotyping among 12 different unrelated isolates was similar. Typing of 39 toxin A(-)/B(+) isolates revealed 2 AFLP types and 2 and 3 PCR ribotypes. Of 39 toxin A(-)/B(+) isolates, 37 had PCR ribotype 017/20 and AFLP type 20 (95%). A deletion of 1.8 kb was seen in 38 isolates, and 1 isolate had a deletion of approximately 1.7 kb in the tcdA gene, which encodes toxin A. Clindamycin resistance encoded by the erm(B) gene was found in 33 of 39 toxin A(-)/B(+) isolates, and in 2 of the 12 unrelated isolates (P < 0.001, chi-square test). We conclude that clindamycin-resistant C. difficile toxin A(-)/B(+) strain (PCR ribotype 017/20, AFLP type 20, serogroup F) has a clonal worldwide spread.

Bacterial Proteins↗
PubMed1994

Neutrophil recruitment in Clostridium difficile toxin A enteritis in the rabbit.

Neutrophil infiltration is a prominent feature of Clostridium difficile-associated enteritis and colitis. The aim of this study was to examine the importance of neutrophil recruitment and neutrophil-mediated tissue damage in C. difficile toxin A-induced enteritis. Competitive binding experiments using purified 3H-toxin A demonstrated the presence of a single class of medium affinity receptors on rabbit neutrophils (Kd 7 x 10(-8) M). Pertussis toxin and the nonhydrolyzable GTP analog GTPgamma S both inhibited 3H-toxin A binding (by 56 and 65%, respectively), indicating that the rabbit neutrophil toxin A receptor is G protein linked. Toxin A elicited a dose-dependent (25-200 micrograms/ml) stimulation of neutrophil migration in vitro, and this functional effect was also pertussis toxin sensitive (69% inhibition). Treatment of neutrophils with R15.7, a blocking monoclonal antibody to the leuocyte adhesion molecule CD18, inhibited toxin A-stimulated neutrophil migration by 85% in vitro. Pretreatment of rabbits with R15.7 also prevented neutrophil infiltration of toxin A-exposed ileal loops in vivo as determined by histologic examination and by ileal tissue myeloperoxidase levels. Furthermore, R15.7 effected a substantial inhibition of fluid secretion (by 65%), mannitol permeability (by 66%), and histologic damage in toxin A-exposed ileal loops. Anti-CD18 (R15.7) had no inhibitory effect on cholera toxin enterotoxicity. These data demonstrate that C. difficile toxin A is a proinflammatory toxin whose enterotoxic effects are substantially dependent upon neutrophil recruitment.

Animals↗
PubMed2001

[Antagonistic activity of Lactobacillus bacteria strains against anaerobic gastrointestinal tract pathogens (Helicobacter pylori, Campylobacter coli, Campylobacter jejuni, Clostridium difficile)].

Antagonistic activity of Lactobacillus strains has been known for some time. This property is connected with production of many active substances by lactobacilli e.g., organic acids and bacteriocin-like substances which interfere with other indigenous microorganisms inhabiting the same ecological niche, including also anaerobic gastrointestinal tract pathogens. Growing interest of clinical medicine in finding new approaches to treatment and prevention of common inflammatory infections of the digestive tract resulted in studies on a possible usage of lactic acid bacteria. Last years, several in vitro and in vivo experiments on antagonism of different Lactobacillus strains against Helicobacter pylori and Clostridium difficile were performed. These observations had been done on already established, well known probiotic Lactobacillus strains. We tested antibacterial activities of Lactobacillus strains isolated from human digestive tract. As indicator bacteria, four species known as anaerobic bacterial etiologic agents of gastroenteric infections: Helicobacter pylori, Campylobacter jejuni, C. coli and Clostridium difficile were used. Some of them were obtained from international collections, others were clinical isolates from specimens taken from patients with different defined gastrointestinal infections. We used a slab method of testing inhibitory activity described in details previously. Following conclusions were drawn from our study: All tested human Lactobacillus strains were able to inhibit the growth of all strains of anaerobic human gastrointestinal pathogens used in this study. Inhibitory activities of tested Lactobacillus strains against Helicobacter pylori, Campylobacter spp., and Clostridium difficile as measured by comparing mean diameters of the inhibition zones were similar. Differences in susceptibility of individual indicator strains of Campylobacter spp. and Clostridium difficile to inhibitory activity of Lactobacillus strains were small. A similar mechanism of inhibition of anaerobic bacteria by lactobacilli is postulated.

Campylobacter coli↗
PubMed1993

Clostridium difficile infection is a treatable cause of diarrhea in patients with advanced human immunodeficiency virus infection: a study of seven consecutive patients admitted from 1986 to 1992 to a university teaching hospital.

Of 427 human immunodeficiency virus-seropositive patients admitted to the Robert Wood Johnson University Hospital from January 1986 through August 1992, seven had Clostridium difficile enteric infection documented by the presence of cytotoxin B in the stool, without other enteric infection. All seven patients had AIDS, and all had recently received antibiotics. These patients had a severe clinical presentation of C. difficile infection. All patients had profound watery diarrhea, with a mean of 20 +/- 14 (SD) bowel movements per day. Four had fever > 38.5 degrees C, and another had hypothermia. Three patients had borderline hypotension, and another was orthostatic. The mean pulse was 119 +/- 26 (SD) beats/min. Five patients had abdominal pain and tenderness. Two had occult blood in the stool. Four had metabolic derangements such as hyponatremia, hypokalemia, or prerenal azotemia. Three of four patients undergoing abdominal roentgenography had radiographic findings consistent with severe colitis of colonic dilation, mural thumbprinting, or mural thickening. Sigmoidoscopic findings ranged from diffuse erythema to prominent pseudomembranes. During a mean interval of 14.3 +/- 6.2 (SD) days before institution of specific antibiotic therapy, the diarrhea spontaneously resolved in only one of the seven patients. In the others, the diarrhea resolved on average 7.3 +/- 4.0 (SD) days after instituting antibiotic therapy. During a mean follow-up of 4.4 +/- 6.3 (SD) months, only two patients redeveloped diarrhea. Both patients had recurrent C. difficile colitis; the symptoms again rapidly resolved after repeat antibiotic therapy. We conclude that in patients with AIDS C. difficile may present as a severe enteric infection with profound diarrhea due to immunosuppression, that the diarrhea may be prolonged and not remit spontaneously, and that the diarrhea usually rapidly resolves with specific antibiotic therapy.

AIDS-Related Opportunistic Infections↗
PubMed2003

Development of an integrative vector for the expression of antisense RNA in Clostridium difficile.

A method was developed to use the conjugative transposon Tn916 as a vector for introducing recombinant DNA into Clostridium difficile. This was used to introduce antisense RNA for the adhesin encoding gene cwp66 into C. difficile 79-685. RT-PCR demonstrated that cwp66 specific antisense RNA was produced. However, there was no statistically significant difference in the protein expression or in the adherence of recombinant C. difficile strains. This may be due to the amount of transcripts of the wild-type (sense) cwp66 outnumbering the antisense transcripts or secondary structures present within the cwp66 mRNA. Unlike in other strains of C. difficile, where Tn916 inserts into the genome at highly preferred sites, in C. difficile 79-685, it integrates into multiple sites opening up the possibility of using Tn916 as a mutagen in this strain.

Adhesins, Bacterial↗