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Background
This uncommon colitis is caused by Clostridium difficile toxin released into the gut. It is most commonly associated with antibiotic therapy which destroys or inhibits much of the normal bacterial flora of the gut, allowing overgrowth of the Clostridium species with release of the toxin. It is this toxin that is assayed in the most common laboratory tests.
OUTLINE
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Leukocytosis
PCR
PFGE
Restriction enzyme analysis
Toxin A immunoassay
Triage Micro C Difficile ImmunoassayGross Appearance and Clinical Variants Histopathological Features and Variants Differential Diagnosis Prognosis and Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Antibiotic associated colitis INCIDENCE
Clostridium difficile-associated diarrhoea in hospitalised patients.Al-Eidan FA, McElnay JC, Scott MG, Kearney MP.
Pharmacy Practice Research Group, School of Pharmacy, The Queen's University of Belfast, Northern Ireland.
J Clin Pharm Ther 2000 Apr;25(2):101-9 Abstract quote OBJECTIVE: The aim of the present study was to evaluate the incidence, risk factors and cost implications of Clostridium difficile-associated diarrhoea (CDAD) in hospitalized adult patients.
METHODS: Eighty-seven hospitalized adult patients, positively identified as having CDAD, were reviewed retrospectively to determine the risk factors and cost implications of CDAD.
RESULTS: The clinical manifestations, in addition to diarrhoea, included elevated temperature (= 37.8 degrees C; 42.5%), abdominal pain (63. 2%) and leucocytosis (=12 x 109 cells/l; 52.9%). Eight patients underwent endoscopy, and pseudomembranous colitis was confirmed in all of these patients. Nine patients died during their hospital stay. Cefotaxime and cefuroxime were the agents most commonly associated with CDAD. There was a significant difference (P < 0.001) between the sex distribution of CDAD patients and adult hospital patients (69% of CDAD patients were female vs. 52% of general adult hospital population). Significantly (P < 0.001) more patients with CDAD were admitted from the nursing home (NH) setting. The mean age of patients with CDAD admitted from NHs (n = 19) was older than those cases admitted from the community (n = 68) by 14 years (P < 0.001). The length of hospital stay was significantly (P < 0.001) longer for patients with CDAD (16.9 vs. 3.89 days). No differences (P = 0.306) were found in the response times for CDAD patients treated with either oral metronidazole (n = 39) or oral vancomycin (n = 48). The mean response time was, however, significantly longer in the CDAD patients admitted from NHs (4.2 days) compared with those admitted from the community (2.5 days), although the former patients were older and had significantly more comorbidity (P < 0.001). The mean cost per one treated-case of CDAD (bed, laboratory requests and treatment therapy) was calculated as pound2860.
CONCLUSION: Patients admitted from NHs are at increased risk of development of CDAD; receiving cefotaxime or cefuroxime axetil (oral form), being elderly and being female are risk factors for the development of CDAD. Treatment of CDAD with oral metronidazole or oral vancomycin gives rise to similar response times and efficacy.
Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study.Wistrom J, Norrby SR, Myhre EB, Eriksson S, Granstrom G, Lagergren L, Englund G, Nord CE, Svenungsson B.
Department of Infectious Diseases, University Hospital of Umea, Sweden.
J Antimicrob Chemother 2001 Jan;47(1):43-50 Abstract quote The frequency of antibiotic-associated diarrhoea (AAD) and Clostridium difficile-associated diarrhoea (CdAD) was prospectively determined in a population of 2462 patients recruited from five Swedish hospitals, including divisions for infectious diseases, orthopaedics, surgery, geriatrics, nephrology and internal medicine. AAD developed in 4.9% of the treated patients.
Faecal samples were obtained from 69% of patients with AAD and 55.4% were positive for C. difficile cytotoxin B. The frequency of AAD varied from 1.8 to 6.9% at the participating centres (P < 0.001). The frequency of AAD also varied considerably between medical disciplines and wards within different hospitals and was highest in the nephrology and geriatric units (6.7 and 7.1%, respectively). There was no difference in frequency of AAD when analysed with respect to gender or age. Medical interventions (laxative treatment, endoscopy and abdominal surgery) or presence of one concomitant disease (diabetes, malignancy, chronic renal disease and inflammatory bowel disease) did not significantly affect the frequency of AAD, whereas patients suffering from two or more of these illnesses had significantly (P = 0.001) higher frequencies of AAD. Patients treated with antibiotics for 3 days had a significantly (P = 0.009) lower frequency of AAD than those treated for longer periods.
Treatment with cephalosporins, clindamycin or broad-spectrum penicillins was associated with an increased risk of AAD. With specimens from one centre, 62.5% of tested patients with AAD and 33.8% of asymptomatic patients were positive for cytotoxin B. Although C. difficile cytotoxin B in stool samples was significantly associated with AAD (P = 0.003), the causal relationship with diarrhoea is not always evident.
Clostridium difficile cytotoxin B in adults with diarrhea: a comparison of patients treated or not treated with antibiotics prior to infection.Svenungsson B, Lagergren A, Lundberg A.
Division of Infectious Diseases, Department of Medicine and Immunology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.
Clin Microbiol Infect 2001 Aug;7(8):447-50 Abstract quote OBJECTIVE: To study the detection rate of Clostridium difficile cytotoxin B in stool specimens from adults with diarrhea as related to previous antimicrobial treatment.
METHODS: Stool specimens from 802 adult patients with diarrhea and 203 healthy controls were tested for C. difficile cytotoxin B using a cell cytotoxicity assay. Antibiotic susceptibility testing of C. difficile was performed with the E test.
RESULTS: Of 173 patients treated with antimicrobial medication within 5 weeks of onset of diarrhea, 60 (35%) were positive for C. difficile cytotoxin B (group A) compared to only 41 (7%) of 629 untreated patients (group B) and two of the 203 (1%) healthy controls. Compared to patients in group A, patients in group B possessed characteristics not usually connected with C. difficile disease. They were generally younger (median age 40 years vs. 73 years), had been hospitalized less frequently (10% vs. 67%), had more often travelled abroad within the previous 2 weeks (46% vs. 1%), and more often had multiple enteropathogens (41% vs. 3%). Minimal inhibitory concentrations for vancomycin, metronidazole and fucidic acid to C. difficile isolates ranged from 0.5 to 4 mg/L, from 0.125 to 256 mg/L and 0.25 to 4 mg/L, respectively.
CONCLUSIONS: The detection rate of C. difficile cytotoxin B in patients with diarrhea, not associated with antibiotic treatment, is comparable to that in healthy control subjects. It probably merely reflects a carrier state without clinical significance.
GEOGRAPHY
Prevalence and Genetic Characterization of Toxin A Variant Strains of Clostridium difficile among Adults and Children with Diarrhea in France.Barbut F, Lalande V, Burghoffer B, Thien HV, Grimprel E, Petit JC.
Research Group on Clostridium difficile, Centre Hospitalo-Universitaire Saint-Antoine, Assistance Publique-Hopitaux de Paris, Universite Pierre et Marie Curie, Paris, France.
J Clin Microbiol 2002 Jun;40(6):2079-83 Abstract quote Toxin A variant strains (toxin A-negative, toxin B-positive strains) of Clostridium difficile have been reported to be responsible for diarrhea or pseudomembranous colitis in humans. These strains lack parts of the repeating sequences of the toxin A gene (tcdA) and are toxin A negative by commercial enzyme immunoassays (EIA).
Here, we report the prevalence of the toxin A variant strains in 334 patients with C. difficile-associated diarrhea in France. The repeating segment of the tcdA gene (1,200 bp) was amplified by PCR using the primers NK9 and NK11 (H. Kato et al., J. Clin. Microbiol. 36:2178-2182, 1998). In the case of amplified fragments of unexpected size, the entire tcdA gene was studied by PCRs A1, A2, and A3 (Rupnik et al., J. Clin. Microbiol. 36:2240-2247, 1998), and strains were characterized by serotyping, pulsed-field gel electrophoresis and PCR ribotyping. By PCR with primers NK9 and NK11, C. difficile variant strains were detected in 2.7% of patients. Several variant types were found. A deletion of approximately 1,700 bp was observed in six strains from five patients. These strains belonged to serotype F and were characterized by the same pulsotype and the same PCR ribotype. They were toxin A negative by EIA and exhibited an atypical cytopathic effect on MRC-5 cells.
Two other tcdA variant types that exhibited a positive result for toxin A by EIA were identified: one from serotype H with a longer amplified fragment (insertion of 200 bp) and one with a deletion of 600 bp. Diagnosis of C. difficile-associated diseases would have been missed in five patients (1.5%) by laboratories that screen the stools only for the presence of toxin A.
This result underlines the need for testing stool by the cytotoxicity assay in patients with a high suspicion of C. difficile-associated diarrhea but a negative immunoassay for toxin A.
TRANSMISSION
Low prevalence of nosocomial Clostridium difficile transmission, as determined by comparison of arbitrarily primed PCR and epidemiological data.Wullt M, Laurell MH.
Department of Infectious Diseases, University of Lund, University Hospital, Malmo, Sweden.
J Hosp Infect 1999 Dec;43(4):265-73 Abstract quote An increased prevalence of patients with C. difficile-associated diarrhoea in a hospital setting suggested the possible existence of an endemic occurrence.
A study was therefore designed to determine clonal relatedness among 173 isolates of C. difficile, collected consecutively during 1995 from 147 patients (89 inpatients and 58 outpatients) and to estimate the probability of nosocomial transmission. Arbitrarily primed PCR (AP-PCR) with three different primers, AP1, AP2 and CLD1, was used for fingerprinting and identified 21, 92 and 70 types, respectively. Overall DNA analysis of the combined AP-PCR data yielded 140 types, of which 130 were unique, whereas 10 types occurred repeatedly in 36 isolates from 33 patients; seven isolates were non-typeable by one of the primers.
Epidemiological data confirmed that in eight of the 33 patients there was a high probability of nosocomial transmission. Despite a high prevalence of C. difficile among hospitalized patients, a low frequency of nosocomial transmission was suggested by high resolution molecular typing of bacterial isolates in conjunction with traditional epidemiological methods.
DISEASE ASSOCIATIONS CHARACTERIZATION ANTIBIOTIC TREATMENT
Factors associated with nosocomial diarrhea and Clostridium difficile-associated disease on the adult wards of an urban tertiary care hospital.Schwaber MJ, Simhon A, Block C, Roval V, Ferderber N, Shapiro M.
Department of Clinical Microbiology and Infectious Diseases, Hadassah University Hospital, Jerusalem, Israel.
Eur J Clin Microbiol Infect Dis 2000 Jan;19(1):9-15 Abstract quote A prospective survey of the adult inpatient population of an urban tertiary care hospital was conducted to determine factors associated with the development of nosocomial diarrhea and the acquisition of Clostridium difficile-associated disease. During the 3-month survey, 98 patients with nosocomial diarrhea were enrolled, and 38 controls were recruited.
The controls were patients without diarrhea lying in beds adjacent to the affected patients. Factors significantly associated with nosocomial diarrhea were the administration of a special diet (P = 0.02) and receipt of a greater number of different antibiotics (P=0.02). Among the 98 patients with diarrhea, Clostridium difficile toxin B was identified in the stool of 13. Factors found to be associated with the presence of toxin B as compared to other causes of nosocomial diarrhea were a greater number of individual antibiotics used during hospitalization (P=0.02) and receipt of a cephalosporin (P=0.03) or, more specifically, a third-generation cephalosporin (P=0.02).
Among patients with nosocomial diarrhea, those who had toxin in their stool had a significantly higher total antibiotic burden (expressed as antibiotic days) than those with diarrhea due to other causes (P = 0.01).
COLLAGENOUS COLITIS
Synchronous occurrence of collagenous colitis and pseudomembranous colitis.Vesoulis Z, Lozanski G, Loiudice T.
Akron City Hospital, OH 44304, USA.
Can J Gastroenterol 2000 Apr;14(4):353-8 Abstract quote Synchronous collagenous and pseudomembranous colitis has not been previously reported. A 73-year-old woman presented with chronic watery diarrhea and abdominal cramping of six weeks' duration. Biopsies of the colon revealed findings of collagenous colitis involving the endoscopically normal right colon, and superimposed collagenous and pseudomembranous colitis involving the rectosigmoid colon.
Endoscopically, the left colon revealed discrete ulcerative plaques, and Clostridium difficile toxin A assay was positive. The patient partially responded to a three-week regimen of metronidazole, and symptoms resolved completely with subsequent steroid therapy. At follow-up endoscopy four months later, colon biopsies demonstrated persistence of subepithelial collagen but no pseudomembranes. The patient remained asymptomatic during this interval. Collagenous colitis has been reported in association with other inflammatory bowel diseases, including lymphocytic colitis, sprue and idiopathic inflammatory bowel disease.
This unique association of collagenous colitis with an endotoxigenic inflammatory bowel disease is presented with a review of related disease features.
HELICOBACTER ANTIBIOTIC THERAPY
Pseudomembranous colitis after eradication of Helicobacter pylori infection with a triple therapy.Harsch IA, Hahn EG, Konturek PC.
1st Department of Medicine, Friedrich-Alexander University, Erlangen-Nuremberg, Erlangen, Germany.
Med Sci Monit 2001 Jul-Aug;7(4):751-4 Abstract quote BACKGROUND: H.pylori (H.p.) infection of the gastric mucosa is causally related to chronic gastritis, peptic ulcer disease, MALT-lymphoma and gastric cancer. There is also an evidence for a link between the H.p.-infection and non-ulcer dyspepsia and even extragastric diseases. The number of patients treated against H.p. infection is expanding. Although in the last years the PPI-based triple therapies have been considered to be effective and safe, in some patients, however, severe side-effects may occur.
CASE REPORT: We report on a 86 year old female patient, who received a one-week triple eradication therapy (metronidazole 3x400 mg/die, clarithromycin 2x250 mg/die and omeprazole 2x20 mg/die) because of non-ulcer dyspepsia. A few days after the eradication treatment, she developed profuse watery and bloody diarrhea and abdominal pain with distention. In stool specimens Clostridium difficile toxin was detected. A colonoscopy showed typical features of antibiotic associated pseudomembranous colitis. Until now, only few reports concerning this complication have been published and the frequency of the complication in patients eradicated for H.p. is unknown.
The potential risk factors to develop this condition have not been clarified. Since the complication may be potentially lethal, this severe side-effect of the usually well-tolerated triple-therapy has to be considered in patients suffering from profuse diarrhea and abdominal pain after eradication therapy.
ULCERATIVE COLITIS
Ulcerative colitis complicating pseudomembranous colitis of the right colon.Wang A, Takeshima F, Ikeda M, Ohnita K, Furusu H, Isomoto H, Mizuta Y, Murase K, Murata I, Kohno S.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
J Gastroenterol 2002;37(4):309-12 Abstract quote A 65-year-old man in the remission stage of ulcerative colitis developed severe bloody diarrhea and high fever. He was treated with imipenem/cilastatin and clindamycin for infectious enterocolitis at a local hospital, but there was no improvement in his condition. Steroid pulse therapy was also ineffective.
Colonoscopy revealed pseudomembranous colitis extending from the ascending colon to the cecum, and Clostridium difficile toxin was positive in the feces. The administration of vancomycin in addition to oral steroids resulted in rapid improvement of the condition.
Total colonoscopy is recommended for precise diagnosis when patients with ulcerative colitis develop intractable diarrhea during or after antibiotic therapy.
VRE
Clostridium difficile and vancomycin-resistant enterococcus: the new nosocomial alliance.Poduval RD, Kamath RP, Corpuz M, Norkus EP, Pitchumoni CS.
Department of Medicine, Our Lady of Mercy Medical Center, Bronx, New York 10466, USA
Am J Gastroenterol 2000 Dec;95(12):3513-5 Abstract quote OBJECTIVES: The aims of this study were to determine the frequency of the association between Clostridium difficile (C. difficile) and vancomycin-resistant Enterococcus (VRE) and delineate the role of C. difficile coinfection as a predictor of VRE infection versus colonization and adverse outcome.
METHODS: Patients with both C. difficile colitis and VRE (CD/VRE) were compared to patients with VRE alone with regard to demographics, comorbidity, prior antibiotic therapy, and coinfection with methicillin-resistant Staphylococcus aureus and funguria. C. difficile as a predictor of VRE infection (VRE-I) versus colonization (VRE-C) and adverse outcome was also studied.
RESULTS: Eighty-nine patients with VRE infection or colonization were studied. This included 31 cases of VRE-I and 58 VRE-C. C. difficile was isolated in 17 (19.1%) of patients; of these C. difficile was isolated before VRE in 9 patients and after VRE in 8. The two groups did not differ in age, residence, or comorbidity. C. difficile coinfection was not predictive of VRE-I versus VRE-C, nor was it associated with increased length of stay or mortality. However, the mortality rates in both groups was high, around 30%. A significant association was noted between the use of vancomycin and metronidazole (before the isolation of VRE) and C. difficile coinfection (p = 0.03 and p = 0.001, respectively). A high incidence of nosocomial coinfection with methicillin-resistant Staphylococcus aureus, funguria, and gram-negative sepsis was noted in both groups; the association with funguria was statistically significant (p = 0.029).
CONCLUSIONS: In conclusion, C. difficile coinfection is common in patients with VRE infection or colonization and is significantly associated with other nosocomial dilemmas like funguria. This may result in the emergence of highly virulent pathogens including vancomycin-resistant C. difficile, posing new challenges in the management of nosocomial diarrheas.
Yield of vancomycin-resistant enterococci and multidrug-resistant Enterobacteriaceae from stools submitted for Clostridium difficile testing compared to results from a focused surveillance program.Hacek DM, Bednarz P, Noskin GA, Zembower T, Peterson LR.
Department of Pathology, Clinical Microbiology Division, Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Clin Microbiol 2001 Mar;39(3):1152-4 Abstract quote It has been suggested that a method of performing surveillance for vancomycin-resistant enterococci (VRE) is to screen specimens submitted for Clostridium difficile testing. We compared this approach to our focused surveillance program of high-risk units during October 1997 to compare the yield of VRE and multidrug-resistant Enterobacteriaceae (MDRE) with both methods.
Of the stools submitted for C. difficile testing, 14% were positive for VRE or MDRE, whereas rectal swabs from routine surveillance yielded 11% VRE- or MDRE-positive results. Although stools submitted for C. difficile testing resulted in a higher percentage of positive cultures, 14 VRE- and 2 MDRE-positive patients from our high-risk population were missed because many patients had no stool submitted for C. difficile testing.
Therefore, while screening stools submitted for C. difficile testing cannot replace our focused surveillance program, it appears advantageous to assess these stools at various intervals to detect new patient reservoirs of drug-resistant organisms that may benefit from routine surveillance cultures.
PATHOGENESIS CHARACTERIZATION TOXIN
Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor.Mani N, Dupuy B.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02211, USA.
Proc Natl Acad Sci U S A 2001 May 8;98(10):5844-9 Abstract quote Clostridium difficile, a causative agent of antibiotic-associated diarrhea and its potentially lethal form, pseudomembranous colitis, produces two large protein toxins that are responsible for the cellular damage associated with the disease.
The level of toxin production appears to be critical for determining the severity of the disease, but the mechanism by which toxin synthesis is regulated is unknown. The product of a gene, txeR, that lies just upstream of the tox gene cluster was shown to be needed for tox gene expression in vivo and to activate promoter-specific transcription of the tox genes in vitro in conjunction with RNA polymerases from C. difficile, Bacillus subtilis, or Escherichia coli. TxeR was shown to function as an alternative sigma factor for RNA polymerase.
Because homologs of TxeR regulate synthesis of toxins and a bacteriocin in other Clostridium species, TxeR appears to be a prototype for a novel mode of regulation of toxin genes.
LABORATORY/RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC
Evaluating the CT diagnosis of Clostridium difficile colitis: should CT guide therapy?Kirkpatrick ID, Greenberg HM.
Department of Radiology, University of Manitoba, Health Sciences Centre, 820 Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada.
AJR Am J Roentgenol 2001 Mar;176(3):635-9 Abstract quote OBJECTIVE: The purpose of this study was to further characterize the CT findings of Clostridium difficile colitis and to provide for the first time a diagnostic sensitivity, specificity, positive predictive value, and negative predictive value to help clinicians decide whether antibiotic treatment is warranted on the basis of CT findings while awaiting stool test results (which may take as long as 48 hr).
MATERIALS AND METHODS: A retrospective review covering a 4-year period was performed of the charts and CT scans of 54 symptomatic patients with stool test results positive for C. difficile and of a control group of 56 patients with antibiotic-associated diarrhea with stool test results negative for C. difficile.
RESULTS: At our institution, C. difficile colitis was explicitly diagnosed at CT in these patients with a sensitivity of 52%, specificity of 93%, positive predictive value of 88%, and negative predictive value of 67%. The sensitivity can be raised to 70% with no change in specificity with more rigid adherence to diagnostic criteria of colon wall thickening of greater than 4 mm combined with any one or more findings of pericolonic stranding, colon wall nodularity, the "accordion" sign, or otherwise unexplained ascites.
CONCLUSION: Although routine CT screening of antibiotic-associated diarrhea is not advocated, the 88% positive predictive value of a diagnosis of C. difficile colitis in those who are scanned may merit consideration of treatment by clinicians on the basis of the CT results alone.
Toxic megacolon: role of CT in evaluation and detection of complications.Imbriaco M, Balthazar EJ.
Department of Radiology and National Research Council, University Federico, Naples, Italy.
Clin Imaging 2001 Sep-Oct;25(5):349-54 Abstract quote The purpose of this study is to determine the role of CT in the evaluation and in detecting complications in patients with toxic megacolon. A retrospective analysis of CT findings of 18 consecutive patients with toxic megacolon was performed.
Underlying etiology included 12 patients with pseudomembranous colitis (PC), four patients with ulcerative colitis and two patients with cytomegalovirus colitis. Eleven patients were HIV+. CT features, correlation with severity of disease and development of complications were analyzed. Colonic dilatation with intraluminal air and/or fluid with a distorted colonic contour or an ahaustral pattern was seen in all patients. In four patients (22%), CT depicted complications-two colonic perforations and two septic thrombosis of the portal system. Six patients died (33%), three of whom had the above complications. The presence and degree of submucosal edema (accordion sign, target sign), wall thickening, degree of dilatation, nodular contour and ascites did not correlate with clinical outcome.
Two thirds of patients with toxic megacolon had PC as the underlying etiology. CT was helpful in depicting diffuse colitis, and it was instrumental in detecting life-threatening abdominal complications, contributing to the management of these patients. CT abnormalities cannot be used to predict the clinical outcome unless complications develop.
LABORATORY MARKERS LEUKOCYTOSIS
Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea.Bulusu M, Narayan S, Shetler K, Triadafilopoulos G.
Gastroenterology Section, Palo Alto Veterans Affairs Health Care System, California 94304, USA.
Am J Gastroenterol 2000 Nov;95(11):3137-41 Abstract quote 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.
PCR
Diagnosis and monitoring of Clostridium difficile infections with the polymerase chain reaction.Kuhl SJ, Tang YJ, Navarro L, Gumerlock PH, Silva J Jr.
Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento
Clin Infect Dis 1993 Jun;16 Suppl 4:S234-8 Abstract quote Toxigenic Clostridium difficile is the etiologic agent of pseudomembranous colitis.
We have developed an assay system for the rapid direct detection of toxigenic C. difficile in human stool samples. After DNA extraction, polymerase chain reaction (PCR) amplification is undertaken with primers targeting specific sequences in the C. difficile 16S rRNA gene.
Next, toxigenic strains of C. difficile are distinguished from nontoxigenic strains by PCR amplification of toxin A and/or B gene sequences. This study included 12 patients with C. difficile colitis, seven of whom had clinical relapses after discontinuation of vancomycin therapy.
We detected toxigenic C. difficile in stools from four (57%) of these seven patients before relapse--at a time when no toxin B was detectable in stools and results of anaerobic culture were negative. The PCR assay is 100-fold more sensitive than anaerobic culture methods. The course of the infection in one patient (both during and after therapy) was monitored by the PCR technique. The multigene analysis approach permitted the detection of colonization with a nontoxigenic strain when this patient's relapses had cleared. This clinically applicable assay allows earlier detection of infection with toxigenic C. difficile. The result is more timely therapeutic intervention.
Laboratory diagnosis of toxigenic Clostridium difficile by polymerase chain reaction: presence of toxin genes and their stable expression in toxigenic isolates from Japanese individuals.Karasawa T, Nojiri T, Hayashi Y, Maegawa T, Yamakawa K, Wang XM, Nakamura S.
Department of Bacteriology, School of Medicine, Kanazawa University, Japan.
J Gastroenterol 1999 Feb;34(1):41-5 Abstract quote Clostridium difficile causes pseudomembranous colitis and antibiotic-associated diarrhea. The definitive diagnosis of C. difficile infection is finally accomplished by the isolation of toxigenic C. difficile. However, only a small number of Japanese clinical laboratories are able to reach a definitive diagnosis of C. difficile infection, probably because simple reliable assays for toxins in the isolates are not available.
In this study, we examined the compatibility of a polymerase chain reaction (PCR) assay and tissue culture assay to identify toxigenic C. difficile, in toxigenic and nontoxigenic C. difficile isolates from Japanese patients and healthy carriers. The specificity of PCR primers was demonstrated by restriction endonuclease digestion and seminested PCR in C. difficile VPI 10463 strain. No PCR product was amplified in the eight other clostridial species used to check the specificity of the PCR assay. The detection limit was 10(3) cells. Both toxin A and toxin B genes (the genes encoding the major virulence factors of C. difficile) were detected in 58 toxigenic C. difficile isolates, which showed a wide range of cytotoxic activity in tissue culture assays. Neither of the toxin genes was carried by 40 nontoxigenic strains of C. difficile.
The results of this study strongly suggest that a definitive diagnosis of C. difficile infection can be accomplished by PCR detection of the toxin genes rather than by tissue culture assay of isolates.
PFGE
Molecular fingerprinting of Clostridium difficile isolates: pulsed-field gel electrophoresis versus amplified fragment length polymorphism.Klaassen CH, van Haren HA, Horrevorts AM.
Department of Medical Microbiology and Regional Public Health Laboratory, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.
J Clin Microbiol 2002 Jan;40(1):101-4 Abstract quote Two molecular fingerprinting techniques, pulsed-field gel electrophoresis (PFGE) and amplified fragment length polymorphism (AFLP), were used to investigate the epidemiological relatedness among Clostridium difficile isolates from suspected outbreaks in three general hospitals.
Analysis by PFGE yielded inconclusive data as a result of extensive DNA degradation. Although this degradation could be prevented to a certain extent by the inclusion of thiourea in the electrophoresis buffer, the weak DNA banding patterns obtained in this way were still far from optimal. AFLP data were obtained by using fluorescently labeled PCR primers and analysis on an ABI PRISM automated DNA analysis platform. AFLP analysis yielded high resolution and highly reproducible DNA fingerprinting patterns from which the epidemiological relatedness among the isolates could easily be determined. AFLP results could be readily obtained within 24 h, whereas 3 to 4 days were routinely required to complete the lengthy PFGE protocol.
AFLP clearly proved to be a much more fail-safe fingerprinting method for C. difficile isolates, especially for those isolates for which a standard PFGE procedure yielded inconclusive results due to DNA degradation.
RESTRICTION ENZYME ANALYSIS
Relapse versus reinfection with Clostridium difficile.O'Neill GL, Beaman MH, Riley TV.
Department of Microbiology, University of Western Australia, Nedlands.
Epidemiol Infect 1991 Dec;107(3):627-35 Abstract quote Relapse of Clostridium difficile-associated diarrhoea occurs in 15-20% of patients; however, whether relapse is due to an endogenous source of the organism or reinfection from the environment remains unclear.
Restriction enzyme analysis (REA) of chromosomal DNA was used to type multiple isolates from ten patients who had experienced apparent relapses. More than half the relapses were due to infection with a new strain of C. difficile. The remaining patients were infected with the same strain, but whether this strain was acquired from the environment or from endogenous sources could not be determined. Relapses with a different strain of C. difficile could occur if an individual harboured more than one strain in their gastrointestinal tract.
To investigate this possibility ten other patients were assessed for carriage of multiple strains. Ten colonies from a primary culture plate from each patient were typed by REA and tested for their ability to produce cytotoxin. All isolates from the same patient were identical by both methods, indicating that multiple carriage of strains may be a rare event.
TOXIN A IMMUNOASSAY
How to detect Clostridium difficile variant strains in a routine laboratory.Rupnik M.
Department of Biology, University of Ljubljana, Slovenia.
Clin Microbiol Infect 2001 Aug;7(8):417-20 Abstract quote Toxin A-negative, toxin B-positive strains (A-/B+) are the best studied examples of Clostridium difficile variant strains. In addition, there are some other groups of variant C. difficile strains that produce both toxins (A+/B+) or are non-cytotoxic (A-/B-) but differ from the reference strain VPI 10463 in their toxin genes.
Here we describe two simple methods (amplification of the tcdA gene and amplification of the binary toxin gene cdtA) which can be used in rapid screening for variant C. difficile strains in collections or in routine laboratories.
Fatal pseudomembranous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay.Johnson S, Kent SA, O'Leary KJ, Merrigan MM, Sambol SP, Peterson LR, Gerding DN.
Medical Service, Veterans Affairs Chicago Health Care System-Lakeside, 333 East Huron Street, Chicago, IL 60611, USA.
Ann Intern Med 2001 Sep 18;135(6):434-8 Abstract quote BACKGROUND: Many clinical laboratories use toxin A immunoassays to test for Clostridium difficile.
OBJECTIVE: To describe the clinical course of a patient infected with a toxin variant strain of C. difficile that was not detected by toxin A immunoassay; to genetically characterize this strain; and to estimate the number of laboratories that use only toxin A immunoassays.
DESIGN: Case report, molecular investigation, and laboratory survey.
SETTING: Tertiary care hospital in Chicago, Illinois.
PATIENT: An 86-year-old man.
MEASUREMENTS: Restriction endonuclease analysis, polymerase chain reaction, and survey of regional clinical laboratories.
RESULTS: An elderly hospitalized man died of advanced pseudomembranous colitis. Four stool specimens submitted over a 2-month period had tested negative on toxin A immunoassay, but a strain of C. difficile with a 1.8-kb deletion of the toxin A gene was recovered from each specimen. This strain, identified as restriction endonuclease analysis type CF4, is closely related to a widely disseminated variant, toxinotype VIII. Toxin A immunoassay was the only test being performed for detection of C. difficile at 31 of 67 (46%) regional clinical laboratories.
CONCLUSIONS: Toxin A variant strains of C. difficile cause serious disease and are undetectable in clinical laboratories that use only toxin A immunoassays for C. difficile testing.
Failure of single-toxin assays to detect clostridium difficile infection in pediatric inflammatory bowel disease.Markowitz JE, Brown KA, Mamula P, Drott HR, Piccoli DA, Baldassano RN.
Divisions of Gastroenterology & Nutrition and Clinical Laboratories, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
Am J Gastroenterol 2001 Sep;96(9):2688-90 Abstract quote 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.
TRIAGE MICRO C IMMUNOASSAY
Clinical usefulness of components of the Triage immunoassay, enzyme immunoassay for toxins A and B, and cytotoxin B tissue culture assay for the diagnosis of Clostridium difficile diarrhea.Massey V, Gregson DB, Chagla AH, Storey M, John MA, Hussain Z.
Department of Clinical Microbiology and Infection Control, London Health Sciences Centre, 307 C Westminster Tower, 800 Commissioner's Rd, London, Ontario, Canada, N6A 4G5.
Am J Clin Pathol 2003 Jan;119(1):45-9 Abstract quote We studied 557 nonduplicate fresh stool specimens from adult patients clinically suspected of having Clostridium difficile-associated diarrhea. All samples were tested in parallel with an in-house cytotoxin B tissue culture assay (CTA), the C DIFFICILE TOX A/B II test (TA/B; TechLab, Blacksburg, VA), and the Triage Micro C DIFFICILE Panel (Biosite Diagnostics, San Diego, CA).
The Triage device detects toxin A (TA) and glutamate dehydrogenase (GDH) simultaneously. Of the specimens, 350 were negative and 95 were positive for all markers. Another 112 specimens yielded discrepant results. The CTA found 143 positive specimens. Results of the components of the Triage and TA/B were compared separately with those of CTA. GDH was the most sensitive but least specific marker, whereas TA and TA/B were less sensitive but highly specific.
Because of these attributes and a quick turnaround time, GDH would be the best screening test for C difficile-associated diarrhea. CTA detected the highest number of cases of C difficile-associated diarrhea and would be most useful as a confirmatory test for GDH-positive and TA-negative specimens.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS EXTRACOLONIC SITES
Extracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature.Jacobs A, Barnard K, Fishel R, Gradon JD.
Johns Hopkins University School of Medicine, Baltimore MD, USA.
Medicine (Baltimore) 2001 Mar;80(2):88-101 Abstract quote Clostridium difficile is most commonly associated with colonic infection. It may, however, also cause disease in a variety of other organ systems. Small bowel involvement is often associated with previous surgical procedures on the small intestine and is associated with a significant mortality rate (4 of 7 patients).
When associated with bacteremia, the infection is, as expected, frequently polymicrobial in association with usual colonic flora. The mortality rate among patients with C. difficile bacteremia is 2 of 10 reported patients. Visceral abscess formation involves mainly the spleen, with 1 reported case of pancreatic abscess formation. Frequently these abscesses are only recognized weeks to months after the onset of diarrhea or other colonic symptoms. C. difficile-related reactive arthritis is frequently polyarticular in nature and is not related to the patient's underlying HLA-B27 status. Fever is not universally present. The most commonly involved joints are the knee and wrist (involved in 18 of 36 cases). Reactive arthritis begins an average of 11.3 days after the onset of diarrhea and is a prolonged illness, taking an average of 68 days to resolve.
Other entities, such as cellulitis, necrotizing fasciitis, osteomyelitis, and prosthetic device infections, can also occur. Localized skin and bone infections frequently follow traumatic injury, implying the implantation of either environmental or the patient's own C. difficile spores with the subsequent development of clinical infection. It is noteworthy that except for cases involving the small intestine and reactive arthritis, most of the cases of extracolonic C. difficile disease do not appear to be strongly related to previous antibiotic exposure. The reason for this is unclear.
We hope that clinicians will become more aware of these extracolonic manifestations of infection, so that they may be recognized and treated promptly and appropriately. Such early diagnosis may also serve to prevent extensive and perhaps unnecessary patient evaluations, thus improving resource utilization and shortening length of hospital stay.
FULMINANT
Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications.Dallal RM, Harbrecht BG, Boujoukas AJ, Sirio CA, Farkas LM, Lee KK, Simmons RL.
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Ann Surg 2002 Mar;235(3):363-72 Abstract quote OBJECTIVE: To review the epidemiology and characteristics of patients who died or underwent colectomy secondary to fulminant Clostridium difficile colitis.
SUMMARY BACKGROUND DATA: In patients with C. difficile colitis, a progressive, systemic inflammatory state may develop that is unresponsive to medical therapy; it may progress to colectomy or death.
METHODS: The authors reviewed 2,334 hospitalized patients with C. difficile colitis from January 1989 to December 2000. Sixty-four patients died or underwent colectomy for pathologically proven C. difficile colitis.
RESULTS: In 2000, the incidence of C. difficile colitis in hospitalized patients increased from a baseline of 0.68% to 1.2%, and the incidence of patients with C. difficile colitis in whom life-threatening symptoms developed increased from 1.6% to 3.2%. Forty-four patients required a colectomy and 20 others died directly from C. difficile colitis. Twenty-two percent had a prior history of C. difficile colitis. A recent surgical procedure and immunosuppression were common predisposing conditions. Lung transplant patients were 46 times more likely to have C. difficile colitis and eight times more likely to have severe disease. Abdominal computed tomography scan correctly diagnosed all patients, whereas 12.5% of toxin assays and 10% of endoscopies were falsely negative. Patients undergoing colectomy for C. difficile colitis had an overall death rate of 57%. Significant predictors of death after colectomy were preoperative vasopressor requirements and age.
CONCLUSIONS: C. difficile colitis is a significant and increasing cause of death. Surgical treatment of C. difficile colitis has a high death rate once the fulminant expression of the disease is present.
PSEUDOOBSTRUCTION
Pseudomembranous colitis without diarrhea presenting clinically as acute intestinal pseudo-obstruction.Sheikh RA, Yasmeen S, Pauly MP, Trudeau WL.
Division of Gastroenterology/Hepatology, San Joaquin General Hospital, Stockton, CA95201, USA.
J Gastroenterol 2001 Sep;36(9):629-32 Abstract quote Pseudomembranous colitis usually presents with diarrhea in a clinical setting of recent antibiotic use. It is uncommon to see it as a cause of obstipation and colonic pseudo-obstruction.
We report an unusual case of an elderly woman with hypertension, congestive heart failure, chronic obstructive pulmonary disease, chronic renal insufficiency, and diabetes mellitus, who was admitted with fever, abdominal pain, and distension without diarrhea. She presented with decreased stool frequency and obstipation. She did not respond to conservative management.
Colonoscopy revealed a picture of pseudomembranous colitis, and Clostridium difficile toxin was positive. She responded well to metronidazole therapy.
SEPSIS
Recurrent pseudomembranous colitis as a cause of recurrent severe sepsis.Eckel F, Huber W, Weiss W, Lersch C.
II. Medical Dept, Klinikum rechts der Isar, TU Munchen.
Z Gastroenterol 2002 Apr;40(4):255-8 Abstract quote Clostridium difficile (C. difficile) colitis accounts for nearly 15-20 % of antibiotic-associated diarrhea. Manifestations include asymptomatic carriage, self-limited diarrhea, and pseudomembranous colitis, which is sometimes life-threatening.
Despite effective therapy with metronidazole and vancomycin relapse rates are 15-33 %. Although colitis is seen in critically ill patients treated with combinations of broad-spectrum antibiotics, reports describing severe sepsis as a result of C. difficile infection are limited. We describe the case of recurrent severe sepsis due to recurrent local intestinal C. difficile infection as the only identifiable etiology. The mechanism of severe sepsis may be a derangement of the gastrointestinal barrier function. This could result in absorption of microbes or endotoxin or activation of inflammatory cascades in the submucosa of the intestine or liver. In general, for successful treatment of C. difficile infections other than anticlostridial antibiotics should be discontinuated.
However, in the present case bacterial translocation from the intestine is an attractive explanation for severe sepsis and therefore additional antibiotics had been administered.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL The summit lesion is the earliest lesion with punctate necrosis of the surface epithelium and overlying accumulation of fibrin, polys, mucous and necrotic epithelial cells
The lamina propria adjoining the area of necrosis has an infiltrate of polys and eosinophils
Later lesions develop necrosis of superficial crypts with a heavier infiltrate of polys and a plaquelike pseudomembrane of polys, fibrin and cellular debris which is plastered against the mucosal surface
Hallmark of most lesions is their involvement of the superficial mucosa onlyDeep denuding ulcerations may rarely occur
VARIANTS
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES COLLAGENOUS COLITIS
Pseudomembranous collagenous colitis.
Yuan S, Reyes V, Bronner MP.
Am J Surg Pathol. 2003 Oct;27(10):1375-9. Abstract quote
SUMMARY: The classic clinical and histologic features of collagenous colitis are well characterized; however, the acute or neutrophilic inflammatory changes that may accompany this entity are less well established. In this report of 10 patients, we describe the first series of pseudomembranous collagenous colitis. Because superimposed Clostridium difficile infection was only demonstrated in one patient and no other causes of pseudomembranous colitis were evident in the remaining nine patients, we conclude that pseudomembranes are part of the spectrum of collagenous colitis itself.
This case series illustrates the importance of searching for collagenous colitis in the evaluation of pseudomembranous colitis. At the same time, superimposed infectious or ischemic etiologies need to be excluded clinically in any patient with superimposed pseudomembranes.
The existence of pseudomembranes in collagenous colitis also lends support to the hypothesis that toxin- and/or ischemia-mediated injury may be involved in the pathogenesis of collagenous colitis.INFECTIOUS COLITIS ISCHEMIC COLITIS
Can ischemic colitis be differentiated from C difficile colitis in biopsy specimens?
Dignan CR, Greenson JK.
Department of Pathology, University of Michigan Hospitals, Ann Arbor 48109-0054, USA.
Am J Surg Pathol 1997 Jun;21(6):706-10 Abstract quote Pseudomembranous colitis is often caused by Clostridium difficile; however, it may also be due to ischemia.
To determine if any histologic features could be used to differentiate C difficile from ischemia, 49 biopsies of pseudomembranous colitis (25 from patients with C difficile colitis and 24 from patients with ischemic colitis) were coded, randomized, and evaluated for the presence of numerous variables, including the amount and distribution of mucosal necrosis, lamina propria hyalinization, and atrophic "micro-crypts." Hyalinization of the lamina propria was seen in 19 cases of ischemia but not in C difficile colitis (p < 0.0001). Atrophic-appearing micro-crypts were seen in 18 ischemic cases and 6 C difficile cases (p < 0.0006). Lamina propria hemorrhage, full-thickness mucosal necrosis, and a diffuse microscopic distribution of pseudomembranes were significantly more common in ischemia than C difficile.
Endoscopic examination identified pseudomembranes significantly more often with C difficile than ischemia, while the endoscopic appearance of masses or polyps was seen exclusively in cases of ischemia.
The presence of a hyalinized lamina propria appeared to be a specific and sensitive marker for ischemia in colon biopsies with pseudomembranes. The presence of atrophic micro-crypts, lamina propria hemorrhage, full-thickness mucosal necrosis, diffuse involvement of all the surface of all biopsies by pseudomembranes, and the endoscopic impression of a localized process, polyp, or mass were also markers of ischemia, while the endoscopic identification of diffuse pseudomembranes favored the diagnosis of C difficile.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS TREATMENT GENERAL
Clostridium difficile-associated diseases. The clinical courses of 18 fatal cases.Siemann M, Koch-Dorfler M, Rabenhorst G.
Pathologisch-Bakteriologisches Institut, Stadtisches Krankenhaus Kiel, Germany.
Intensive Care Med 2000 Apr;26(4):416-21 Abstract quote OBJECTIVE: Severe cases of Clostridium difficile-associated diseases with sepsis seem to be rare, as are case reports about the pathogen involved and sepsis. Our objective was to investigate the frequency and the clinical courses of severe cases of C. difficile-associated diseases with a fatal outcome in our hospital.
SETTING: Teaching hospital of the University of Kiel (650 beds).
DESIGN: We reviewed retrospectively all deceased patients' charts who had prior histological or microbiological evidence of C. difficile-associated diarrhea (CDAD) and revised the available histological specimens of the autopsies.
PATIENTS: Over a 4-year period (November 1994-October 1998) we diagnosed 304 cases of C. difficile-associated diseases in our hospital.
RESULTS: Eighteen of our cases with C. difficile-associated diseases had a fatal outcome. C. difficile was not likely to be the cause of death in two of the cases. Four of the fatal infections were community-acquired and the reason for admission to the hospital. CDAD is most prevalent in elderly patients with multiple or severe underlying diseases and tends to be overlooked. Sepsis was diagnosed in 15 of our 18 patients with C. difficile-associated diseases.
CONCLUSION: Our study shows that severe cases of CDAD or cases with C. difficile-associated sepsis are probably not rare. Routine testing of fecal specimens for the presence of C. difficile toxins should be considered not only in nosocomial gastrointestinal infections but also in community-acquired gastrointestinal infections of elderly people.
Treatment and prevention of antibiotic associated diarrhea.Bergogne-Berezin E.
Microbiology Department, University Paris 7, 100 bis rue du Cherche-Midi, 75006 Paris, France
Int J Antimicrob Agents 2000 Dec;16(4):521-6 Abstract quote Mild or severe episodes of antibiotic-associated diarrhea (AAD) are common side effects of antibiotic therapy. The incidence of AAD differs with the antibiotic and varies from 5 to 25%. The major form of intestinal disorders is the pseudomembranous colitis associated with Clostridium difficile which occurs in 10-20% of all AAD.
In most cases of AAD discontinuation or replacement of the inciting antibiotic by another drug with lower AAD risk can be effective. For more severe cases involving C. difficile, the treatment of diarrhea requires an antibiotic treatment, with glycopeptides (vancomycin) or metronidazole. Another approach to AAD treatment or prevention is based on the use of non-pathogenic living organisms, capable of re-establishing the equilibrium of the intestinal ecosystem.
Several organisms have been used in treatment or prophylaxis of AAD such as selected strains of Lactobacillus acidophilus, L. bulgaricus, Bifidobacterium longum, and Enterococcus faecium. Another biotherapeutic agent, a non-pathogenic yeast, Saccharomyces boulardii has been used. In animal models of C. difficile colitis initiated by clindamycin, animals treated with S. boulardii (at end of vancomycin therapy) had a significant decrease in C. difficile colony-forming units, and of toxin B production. In several clinical randomised trials (versus placebo), S. boulardii has demonstrated its effectiveness by decreasing significantly the occurrence of C. difficile colitis and preventing the pathogenic effects of toxins A and B of C. difficile. It has been shown to be a safe and effective therapy in relapses of C. difficile colitis. A good response has been seen in children with AAD, treated by S. boulardii only.
In ICUs prevention of AAD remains based on limitation of antibiotic overuse and spread of C. difficile or other agents of AAD should be prevented by improved hygiene measures (single rooms, private bathrooms for patients, use of gloves and hand washing for personnel). In addition the increasing use of biotherapeutic agents such as S. boulardii should permit the prevention of the major side effect of antibiotics, i.e. AAD in at risk patients.
METRONIDAZOLE
Intravenous metronidazole for the treatment of Clostridium difficile colitis.Friedenberg F, Fernandez A, Kaul V, Niami P, Levine GM.
Division of Gastroenterology and Nutrition, Albert Einstein Medical Center, Philadelphia, PA 19141, USA.
Dis Colon Rectum 2001 Aug;44(8):1176-80 Abstract quote PURPOSE: Severe Clostridium difficile colitis may produce abdominal distention and ileus, precluding oral antibiotic therapy. Stimulated by several case reports in which intravenous metronidazole was used, we reviewed our experience.
METHODS: Using pharmacy and microbiology laboratory records, we retrospectively identified patients with C. difficile colitis who received intravenous metronidazole as initial monotherapy. To be included, patients had to fulfill the following criteria: 1) at least six doses (equivalent to two days of therapy) of intravenous metronidazole were administered, 2) no other potential cause for colitis was found, and 3) the diagnosis of C. difficile colitis was firmly established. For eligible patients, five clinical parameters were assessed before and after intravenous metronidazole.
RESULTS: Our patient group (n = 10) received an average of 13.7 (range, 6-24) doses of intravenous metronidazole as initial therapy for C. difficile colitis. All received a dose of 500 mg three times daily. The majority of patients with vomiting, fever, and/or abdominal pain present at the beginning of therapy had resolution with intravenous metronidazole. Only one patient developed a symptom (vomiting) while on therapy; however, this eventually resolved when oral metronidazole was instituted. No patient required colectomy for refractory colitis or developed toxic megacolon. No patient, including those on prolonged courses, developed toxicity related to intravenous metronidazole such as peripheral neuropathy.
CONCLUSIONS: Intravenous metronidazole may be effective therapy in patients with C. difficile colitis. A randomized, prospective study appears warranted.
VANCOMYCIN
Decompressive colonoscopy with intracolonic vancomycin administration for the treatment of severe pseudomembranous colitis.Shetler K, Nieuwenhuis R, Wren SM, Triadafilopoulos G.
Sections of Gastroenterology and Gastroenterology Division, Stanford University School of Medicine, Stanford, California, USA.
Surg Endosc 2001 Jul;15(7):653-9 Abstract quote BACKGROUND: We explored the potential of early decompressive colonoscopy with intracolonic vancomycin administration as an adjunctive therapy for severe pseudomembranous Clostridium difficile colitis with ileus and toxic megacolon.
METHODS: We reviewed the symptoms, signs, laboratory tests, radiographic findings, and outcomes from the medical records of seven patients who experienced eight episodes of severe pseudomembranous colitis with ileus and toxic megacolon. All seven patients underwent decompressive colonoscopy with intracolonic perfusion of vancomycin.
RESULTS: Fever, abdominal pain, diarrhea, abdominal distention, and tenderness were present in all patients. Five of seven patients were comatose, obtunded, or confused, and six of the seven required ventilatory support. The white blood cell count was greater than 16,000 in seven cases (six patients). Colonoscopy showed left-side pseudomembranous colitis in one patient, right-side colitis in one patient, and diffuse pseudomembranous pancolitis in five patients. Two patients were discharged with improvement. Five patients had numerous medical problems leading to their death. Complete resolution of pseudomembranous colitis occurred in four patients. One patient had a partial response, and two patients failed therapy.
CONCLUSION: Colonoscopic decompression and intracolonic vancomycin administration in the management of severe, acute, pseudomembranous colitis associated with ileus and toxic megacolon is feasible, safe, and effective in approximately 57% to 71% of cases.
Intracolonic use of vancomycin for treatment of clostridium difficile colitis in a patient with a diverted colon: report of a case.
Nathanson DR, Sheahan M, Chao L, Wallack MK.
Department of Surgery, Metropolitan Hospital Center, New York Medical College, NY, USA.
Dis Colon Rectum 2001 Dec;44(12):1871-2 Abstract quote Clostridium difficile-associated pseudomembranous colitis (PMC) is a common affliction of postoperative patients. Risk factors include antibiotic therapy, recent surgery, and hospitalization (1,2,3).
We present a case of PMC in a diverted colon and its treatment using vancomycin enemas.
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Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
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