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Clostridium difficile is the most common cause of nosocomial infectious diarrhea that is usually treated adequately with standard treatment of metronidazole or vancomycin. Relapse or recurrent infection can occur in certain patients and this can be very difficult to treat.
We have fingerprinted Clostridium difficile isolates from patients with symptomatic recurrences of infection, using random amplified polymorphic DNA (RAPD). The medical records of 55/79 patients were examined, from whom multiple C. difficile-positive faeces were received during hospitalization at least five days, but no more than two months, apart. In 20 of these cases symptoms either did not recur (i.e., absent for at least three days between episodes), or were explainable by other causes, such as laxative administration. Of the remaining 35 patients, 27 sets of C. difficile isolates (23 pairs and four triplicates) were available for RAPD fingerprinting. Differing C. difficile DNA fingerprints (at least three major bands difference) were obtained for 15/27 patients, and hence at least 56% of the clinical recurrences of infection were in fact due to re-infection as opposed to relapse. Since we found that an endemic C. difficile clone was present in 18 out of 27 patients (67%) and accounted for 53% (31/58) of all isolates, it is probable that the majority of symptomatic recurrences are in fact re-infections, with either a different or the same C. difficile strain. We conclude that more attention must be given to preventing the re-infection of C. difficile symptomatic patients. Isolation of symptomatic individuals is the preferred option for the protection of other patients, but measures must be taken to ensure that further strain acquisition by the index cases does not occur.
A 47-year-old multiple trauma patient, experiencing a C. Difficile colitis with diarrhoea, developed diffuse oedema with peritoneal and pleural effusion due to global heart failure. Selenium deficiency, reported in trauma patients, may explain the occurrence of cardiomyopathy. The role of selenium in cardiac dysfunction and the various situations inducing a selenium deficiency are discussed.
A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence and outcome of infection with Clostridium difficile. The diagnosis was confirmed in 14 patients with diarrhea (15 episodes) at a median of 33 days after stem cell infusion. Five patients were neutropenic at the time of diagnosis. Every individual had adverse known risk factors such as recent or current use of antibiotic, corticosteroid and antiviral therapy, recent administration of myeloablative chemotherapy and numerous, prolonged periods of hospitalization. Diarrhea, frequently hemorrhagic, was the most common presenting feature along with fever, abdominal cramps and abdominal distention. Diagnosis was established by the stool-cytotoxin test. Response to standard treatment with oral vancomycin or metronidazole was prompt despite the presence of several adverse prognostic features in these patients. There was only one instance of relapse which was also treated successfully. Several transplant-related variables such as age, sex, underlying malignancy, myelo-ablative regimen, duration of neutropenia, and prophylactic use of oral ampicillin underwent statistical analysis but failed to be predictive of C. difficile infection in such a setting. Finally, C. difficile is not uncommon after autologous PBSCT and must be included in the differential diagnosis in any such patient with diarrhea.
Autologous peripheral blood progenitor cell (PBPC) transplant recipients frequently receive multiple antibiotics for neutropenic fever in addition to high-dose chemotherapy. Although there are many possible causes for diarrhea in this population, empiric therapy for possible C. difficile colitis is common in some centers. This study sought to define the frequency of diarrhea and of a positive C. difficile toxin assay in PBPC transplant recipients. Data were collected on 80 patients enrolled in a randomized trial of two different antibiotic regimens during PBPC transplant. Data included the presence or absence of diarrhea, all microbiologic studies performed during the transplant admission, and all antimicrobials administered during the transplant admission. Of 80 patients enrolled, 61 (76.3%) developed diarrhea. Only 3/61 (4.9%) had a positive C. difficile toxin assay. A total of 122 C. difficile toxin assays were performed; for each positive C. difficile assay, 41 stool samples were analyzed. Twenty courses of oral metronidazole (18/20 empiric) and 10 courses of oral vancomycin (8/10 empiric) were given. A total of 25 of 61 patients with diarrhea (41%) received therapy for possible C. difficile. Diarrhea is common during autologous PBPC transplant but a positive C. difficile assay is uncommon. The practice of empiric therapy for C. difficile in this population in a non-outbreak setting should be re-evaluated. Bone Marrow Transplantation (2000) 25, 67-69.
BACKGROUND & AIMS: Recurrent C difficile -associated diarrhea (CDAD) is associated with a lack of protective immunity to C difficile toxins. A parenteral C difficile vaccine containing toxoid A and toxoid B was reported previously to be safe and immunogenic in healthy volunteers. Our aim was to examine whether the vaccine is also well tolerated and immunogenic in patients with recurrent CDAD. METHODS: Subjects received 4, 50-microg intramuscular inoculations of the C difficile vaccine over an 8-week period. Serum antitoxin antibodies were measured by ELISA, and toxin neutralizing activity was evaluated using the tissue culture cytotoxin assay. RESULTS: Three patients with multiple episodes of recurrent CDAD were vaccinated. Two of the 3 showed an increase in serum IgG antitoxin A antibodies (3-fold and 4-fold increases, respectively) and in serum IgG antitoxin B antibodies (52-fold and 20-fold, respectively). Both also developed cytotoxin neutralizing activity against toxin A and toxin B. Prior to vaccination, the subjects had required nearly continuous treatment with oral vancomycin for 7, 9, and 22 months, respectively, to treat recurrent episodes of CDAD. After vaccination, all 3 subjects discontinued treatment with oral vancomycin without any further recurrence. CONCLUSIONS: A C difficile toxoid vaccine induced immune responses to toxins A and B in patients with CDAD and was associated with resolution of recurrent diarrhea. The results of this study support the feasibility of active vaccination against C difficile and its toxins in high-risk individuals but must be validated in larger, randomized, controlled trials.
Clostridium difficile toxin B that is one of the largest cytotoxins (270 kDa) known acts on Rho subfamily proteins by monoglucosylation (Just, I., Selzer, J., Wilm, M., von Eichel-Streiber, C., Mann, M., and Aktories, K. (1995) Nature 375, 500-503). By deletion analysis we identified the enzyme and cytotoxic activity of the toxin to be located at the N terminus of the holotoxin. A 63-kDa fragment of toxin B covering the first 546 amino acid residues glucosylated Rho, Rac, and Cdc42, but not Ras, by using UDP-glucose as a cosubstrate. As known for the holotoxin, glucosylation by the toxin fragment was favored with the GDP-bound form of the low molecular mass GTPases. Microinjection of the toxin fragment into NIH-3T3 cells induced rounding up of cells and redistribution of the actin cytoskeleton. In contrast, a toxin fragment encompassing the first 516 amino acid residues was at least 1000-fold less active than toxin fragment 1-546 and cytotoxically inactive. The data give direct evidence for location of the enzyme activity of C. difficile toxin B at the N-terminal 546 amino acids residues and indicate a functionally and/or structurally important role of the region from amino acid residues 516 through 546 for enzyme and cytotoxic activities.
The epidemiology of Clostridium difficile-associated diarrhea (CDAD) in an endemic setting was investigated by use of DNA typing methods to determine the strain identity of C. difficile isolates. Two predominant toxigenic clones were found in the environment and accounted for 29.8% (type 1) and 15.5% (type 2) of CDAD cases, respectively. In endemic settings, the environment and cross-transmission may play a role in acquisition of CDAD.
An MLS resistance gene designated ermBZ, from a toxigenic Clostridium difficile strain (630) could be transferred between C. difficile strains, and to and from Bacillus subtilis. The intergeneric transfer occurred in the absence of any detectable plasmid DNA and the element responsible for gene transfer entered the recipient's chromosome, behaviour which is characteristic of a conjugative transposon. The element was designated Tn5398 and was found in six C. difficile strains. Tn5398 could be transferred to the non-toxigenic strain C. difficile CD37 which lacks the genes for toxins A and B. Transconjugants from both C. difficile and B. subtilis that had received the ermBZ gene also acquired a sequence of DNA that was homologous to the part of the toxin A gene that coded for the C-terminal repeat region.
We conducted a prospective observational study on the medical management and health service resource utilization associated with the hospital care of patients with community-acquired lower respiratory tract infection. Between January 1994 and June 1995, 28 such patients developed Clostridium difficile-associated diarrhoea; these 28 patients were matched with 56 age-matched patients, who were used as a control group in a comparative study. Progress during the first week after admission was similar as measured by fever days and pathology or radiology use. The use of iv cephalosporins (g/day) during the first week was greater in the group who developed C. difficile-associated diarrhoea than in controls. The length of hospital stay was 36.4 +/- 21.6 days in patients with C. difficile-associated diarrhoea compared with 19.8 +/- 13.3 days in controls. Cases also required more pathological and radiological tests and greater use of antimicrobials and other drugs; however, if pathology and radiology use was calculated per day of patient stay there was no difference between the two groups. When antimicrobial use was compared, controlling for the time taken until found to be C. difficile toxin positive, patients with C. difficile infection received more iv cefuroxime as well as more total cephalosporins, beta-lactams and macrolides measured in g/day. Interestingly, in this study we could not show an increased mortality associated with C. difficile diarrhoea despite obvious evidence of morbidity. The development of C. difficile-associated diarrhoea substantially increases health care resource utilization for individual patients who are admitted to hospital with lower respiratory tract infection.
Clostridium difficile is a nosocomial pathogen that causes a range of chronic intestinal diseases, usually as a result of antimicrobial therapy. Macrolide-lincosamide-streptogramin B (MLS) resistance in C. difficile is encoded by the Erm B resistance determinant, which is thought to be located on a conjugative transposon, Tn5398. The 9630 bp Tn5398 element has been cloned and completely sequenced and its insertion site determined. Analysis of the resultant data reveals that Tn5398 is not a classical conjugative transposon but appears to be a mobilizable non-conjugative element. It does not carry any transposase or site-specific recombinase genes, nor any genes likely to be involved in conjugation. Furthermore, using PCR analysis it has been shown that isolates of C. difficile obtained from different geographical locations exhibit heterogeneity in the genetic arrangement of both Tn5398 and their Erm B determinants. These results indicate that genetic exchange and recombination between these determinants occurs in the clinical and natural environment.
Toxins A and B of Clostridium difficile are responsible for pseudomembranous colitis, a disease that afflicts a substantial number of hospitalized patients treated with antibiotics. A major effect of these proteins is the disruption of the actin cytoskeleton. Recently, I. Just, G. Fritz, K. Aktories, M. Giry, M. R. Popoff, P. Boquet, S. Hegenbarth, and C. von Eichel-Streiber (J. Biol. Chem. 269:10706-10712, 1994) implicated Rho proteins as cellular targets of C. difficile toxin B, since pretreatment of cells or purified Rho with toxin prevented subsequent ADP-ribosylation of Rho by exoenzyme C3. Moreover, they showed that overexpression of Rho proteins in cells suppressed cell rounding normally associated with exposure of cells to C. difficile toxin B. Here we expand these findings by showing directly that Rho proteins are covalently modified by both C. difficile toxins A and B. In addition, we demonstrate that the stability of toxin-modified Rho in NIH 3T3 cells is dramatically reduced. Finally, we show that C. difficile toxins A and B do not have similar effects on the closely related Rac and CDC42 GTP-binding proteins.
Clostridium difficile has been recognized as the most important enteric pathogen of nosocomial antibiotic-associated diarrhea (CDAD) in adults from industrialized countries. The importance of C. difficile as a cause of diarrhea in ambulatory patients appears underestimated or under-recognized. Since the 1980's, outbreaks of CDAD have been increasingly reported, but there are few data available in Argentina. We developed a retrospective study to provide some information about CDAD in our country. From July 1998 to November 1999, a total of 245 fecal specimens from hospitalized and some ambulatory patients were tested in order to confirm the diagnosis of CDAD. C. difficile cytotoxin (toxin B) was identified by detecting its cytopathic effect on monolayers of McCoy culture cells. For culture and isolation of C. difficile, stool samples were prepared by ethanol shock prior to plating onto a selective medium which contained blood, cefoxitin and fructose. Of the 245 samples, 14 (5.8%) were identified as positive by the cell cytotoxicity assay. Using the criteria of isolation of cytotoxigenic C. difficile positivity increased to 6.5% (16 samples). Thirteen of the positive results were from hospitalized patients (81.3%) and 3 (18.7%) from outpatients. The mean age of inpatients was 72.9 years (ranging from 47 to 88). All patients had received 2 or more antimicrobial agents (most of them beta-lactams) 2 months before the appearance of diarrhea. There was one patient who had received only chemotherapy. The prevalence of CDAD in this study was less than in others previously reported. This difference may be due to the fact that not all general practitioners include testing for C. difficile when the patient with diarrhea had previously received antibiotics. More educational programs should be directed to all physicians, concerning the role of C. difficile as an important enteric pathogen in patients who have undergone treatment with antimicrobial or chemotherapeutic agents.
Pseudomembranous colitis is the classical and most dramatic manifestation of Clostridium difficile infection. Surgery is required for patients with perforation and for those who fail to respond to medical treatment. This is a report of a patient with severe pseudomembranous inflammation confined to the left colon, which was successfully treated by surgical resection.
Two cases of pseudomembranous colitis in patients with renal failure are presented. Both patients were treated with antibiotics. Clinical course, bacteriologic examination of feces, and endoscopy of the colon plays an important role in the diagnosis of this complication. No gut endoscopy was performed in both patients due to severe disease course. Pseudomembranous colitis was diagnosed by clinical symptoms and bacteriologic examination of feces out of which C. difficile was isolated. Teicoplanin-a drug of a known efficiency in the treatment of C. difficile infection-was given and vancomycin was used in the second patient. We would like to stress that renal failure predisposes to the a development of pseudomembranous colitis. An emphasis is also on the dose adjustments of drugs in renal failure.
The causes and clinical manifestations of Clostridium difficile infection in children are described in this report. The studies were performed on three children aged up to 3 years. Risk factors as well as possible diagnostic and therapeutic procedures are discussed.
Two variations of an egg yolk agar base medium containing cycloserine, cefoxitin, and fructose (CCFA), one with 250 micrograms and other with 500 micrograms of cycloserine/ml of agar medium were compared to study the effect of the cycloserine concentration on recovery of Clostridium difficile from stool samples. In addition, the role of prior anaerobic reduction of these media in the detection of Clostridium difficile-associated diarrhea (CDAD) was tested. Each medium was studied over a two-month period, with outcome compared between the testing periods and to historical data from our institution. Clinical correlation of test results was performed. The use of the originally described formulation of CCFA with 500 microgram of cycloserine/ml of agar combined with 4 h of anaerobic reduction prior to specimen inoculation increased the rate of isolation of toxigenic Clostridium difficile from clinical specimens from 6 to 17% (p < 0.001). Combining direct detection of stool toxin and properly performed culture for toxigenic Clostridium difficile enhances the potential for diagnosis of CDAD. For optimal performance the culture medium should contain the originally proposed cycloserine concentration of 500 microgram/ml of agar and should be anaerobically reduced at least 4 h prior to specimen inoculation.
The prevalence of enteropathogenic bacteria over a three-year period was 3.1% in an urban population in Germany. Nontyphoidal Salmonella spp. (1.8% prevalence) represented 59.3% of all positive isolates, followed by Campylobacter spp., which constituted 22.1% of such isolates. Clostridium difficile toxin was detected in 5.6% of samples submitted specifically for detection of cytotoxigenic C. difficile. The seasonal distribution showed an increase of Salmonella, Shigella and Aeromonas/Plesiomonas isolates in the post-holiday season, partly due to returning travelers. An epidemic five-fold increase of Salmonella enteritidis isolates was found over the three-year-period. Enteropathogenic bacteria such as Salmonella, Campylobacter and cytotoxigenic C. difficile were common etiologic agents of gastrointestinal tract infections in patients with AIDS. We conclude that travelers and HIV-infected subjects are especially prone to infection with enteropathogenic bacteria; preventive measures to control the Salmonella enteritidis epidemic are essential.