The Spectrum of Pseudomembranous Enterocolitis and Antibiotic-Associated Diarrhea

REVIEW ARTICLE The Spectrum of Pseudomembranous Enterocolitis and Antibiotic-Associated Diarrhea

Brian W. Hurley, MD; Cuong C. Nguyen, MD

seudomembranous (entero)colitis is primarily caused by Clostridium difficile infection. The most common predisposing factor is prior use of antibiotics, including vancomycin and metronidazole, which themselves are therapy for C difficile colitis. Other risk factors have also been described. The presence of C difficile in the gastrointestinal tract leadsP to a spectrum of manifestations from the asymptomatic carrier state to fulminant colitis. Suc- cessful treatment of C difficile colitis requires prompt treatment with appropriate antibiotics, with- drawal of the suspected predisposing antibiotics, and, in rare cases, total colectomy. Preventive measures of adequate infection control and judicious use of antibiotics are necessary means in at- tempting to control the spread of C difficile infection. Attempts at making an effective human vaccine are currently under way. Arch Intern Med. 2002;162:2177-2184

HISTORICAL PERSPECTIVE uremic syndrome, ischemic cardiovascu- lar disease, Crohn disease, shigellosis, Preantibiotic Era severeinfection,ischemiccolitis,andHirsch- sprung disease.1 There is no definitive ex- The first reported case of pseudomembra- planation for how these conditions lead to nous enterocolitis (PMC) was reported by PMC, but it may be related to alterations J. M. Finney in association with William Os- in host defense mechanisms and enteric ler in 1893. They described a 22-year-old flora. Several postoperative cases were re- woman who underwent resection of gas- lated to hypotension and shock, suggest- tric tumors and developed postoperative di- ing an ischemic origin.4 arrhea. She died on the 15th postoperative day, and at autopsy, the small bowel Early Antibiotic Era (1950-1969) revealed diphtheritic membranes.1,2 In the preantibiotic era, PMC was rare. Only about During the dawn of the antibiotic era, PMC 4 cases were recognized annually at the became a common complication of anti- Mayo Clinic (Rochester, Minn).1,3 It was biotic use. Staphylococcus aureus, the prin- feared as a catastrophic complication of sur- cipal nosocomial pathogen at that time, gery because the diagnosis was only made was implicated as the agent responsible for at autopsy. this condition by Gram stains and cul- The most common clinical setting in tures of stools.1 Thus, vancomycin be- those cases not associated with antibiotic came the standard treatment. therapy was colonic, pelvic, or gastric sur- gery. Other risk factors include spinal frac- Established Antibiotic Era (1970s) ture, intestinal obstruction, colon carci- noma, leukemia, severe burns, shock, Because vancomycin therapy worked, the uremia, heavy metal poisoning, hemolytic- causative agent was not questioned until the middle to late 1970s. The use of clin- From the Division of Hospital Internal Medicine (Dr Hurley) and the Division damycin had become widespread during of Gastroenterology and Hepatology (Dr Nguyen), Mayo Clinic (Scottsdale), this period. A landmark study by Te- Scottsdale, Ariz. desco et al5 at the Barnes-Jewish Hospital

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Figure 3. Pseudomembranous colitis. Endoscopic en face view of colon wall demonstrating several pseudomembranes (arrows). (Courtesy of Jonathan Leighton, MD, Division of Gastroenterology, Mayo Clinic Scottsdale, Scottsdale, Ariz.) Figure 1. Microscopic pathologic appearance for a pseudomembrane in the colon. The pseudomembrane gives the appearance of a “volcanic eruption.” This appearance is classic for pseudomembranous colitis. (Courtesy of James Williams, MD, Department of Pathology, Mayo Clinic Scottsdale, Scottsdale, Ariz.) Other Pathogens Clostridium perfringens Staphylococcus aureus Candida albicans Antibiotic Specific

Clostridium difficile ? ? Diarrhea and Colitis

20%

70%-80% Nonspecific Diarrhea

Figure 4. Categories, causes, and relative frequencies of antibiotic-associated diarrheas. (Reprinted from LaHatte et al4 with permission from WB Saunders Co.)

antistaphylococcal activity favored emergence of C difficile.4 Pseudo- membranous enterocolitis primarily affects the large bowel, but it can Figure 2. A surgical specimen of pseudomembrane formation in the colon. The plaques were yellowish rarely affect the small bowel. Since and raised and varied in size from 2 to 10 mm. The intervening mucosa was pinkish and hyperemic. the 1970s, C difficile has been rec- (Courtesy of James Williams, MD, Department of Pathology, Mayo Clinic Scottsdale, Scottsdale, Ariz.) ognized as the most common cause of PMC. Other causes of pseudo- in St Louis, Mo, implicated clinda- PSEUDOMEMBRANOUS membrane formation in the large mycin as a cause of PMC. It was the ENTEROCOLITIS and small bowel include early ische- first study to prospectively use en dos- mia, verotoxin-producing organ- copy to establish the diagnosis of PMC Pseudomembranous enterocolitis isms such as Escherichia coli, and in the setting of antibiotic-associ- occurred in the preantibiotic era. drug therapy with chlorprop- ated diarrhea. Among 200 patients There were risk factors other than amide, gold, and nonsteroidal anti- treated with clindamycin, 21% devel- antimicrobial therapy that were im- inflammatory agents. oped diarrhea and 10% developed portant in the development of PMC. Figure 1 demonstrates the his- PMC.1 Furthermore, S aureus could Staphylococcus aureus was impli- tologic changes associated with not be isolated from these patients. cated in the early antibiotic era as the PMC. Figure 2 illustrates the gross Subsequent studies of 8 stool speci- causative pathogen; however, later pathologic appearance of PMC. mens collected and tested 5 years later studies shifted the focus to C diffi- Figure 3 illustrates the appear- in Tedesco’s laboratory showed that cile. Reports of possible S aureus– ance of PMC on endoscopy. all contained C difficile and its cyto- related PMC in patients testing nega- pathic toxins.1 Meanwhile, animal tive for C difficile serve as reminders ANTIBIOTIC-ASSOCIATED studies and subsequent human stud- that this entity may indeed occur, al- DIARRHEA ies isolated C difficile and its toxins in beit rarely.4 One theory for this etio- almost all patients with endoscopic logic shift is that, with the advent of Most cases of antibiotic-associated di- evidence of PMC. newer antibiotics, more effective arrhea are categorized as nonspe-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Isolation Rates of 50 Pathogenesis of Clostridium difficile Infection Toxigenic Clostridium difficile 40 From the Stool of Various Subject , % Antibiotic Therapy 30 Populations* Alteration of Colonic Microflora 20 C difficile C difficile Exposure and Colonization Subject Population Positive, % 10 Clostridium difficile

Patients Who Acquired Asymptomatic Release of Toxins

Pseudomembranous 95-100 0 Colonization A and B colitis <1 1-2 2-3 3-4 >4 Length of Hospital Stay, wk Hospital inpatients 20 CDAD Healthy adults 0-3 Figure 5. Rate of Clostridium difficile acquisition Figure 6. The pathogenesis of C difficile colitis Healthy neonates 25-80 as a function of hospital stay in weeks. Only 3 involves initiation of antibiotic therapy, which and infants (1%) of 323 patients whose hospital stays were alters the normal colonic flora. Note that less than 1 week acquired C difficile, whereas 10 colonization may occur before the initiation of *Reprinted from Linevsky and Kelly10 with (50%) of 20 patients hospitalized for more than antibiotic therapy. The patient either develops permission from Marcel Dekker. 4 weeks had positive stool cultures. (Data from asymptomatic colonization or expresses C Clabots et al.12) difficile–associated diarrhea (CDAD) and/or 8 4 colitis. (Modified from Kelly and LaMont with cific diarrhea (Figure 4). These are permission from the Annual Review of mild diarrhea episodes without a de- floors, telephones, call buttons, scales, Medicine.) finitive cause. They usually resolve shoes of hospital personnel, finger- with simple discontinuation of anti- nails, fingertips, and the underside of of acquisition was 13% up to 2 weeks biotic therapy. Alteration of colonic rings. Clostridium difficile can be cul- and 50% for those hospitalized for flora leading to impaired colonic car- tured in rooms of infected individu- more than 4 weeks (Figure 5).13 bohydrate metabolism may be the als up to 40 days after discharge. 6 cause in some cases.4 Approxi- Clostridium difficile infection is Pathogenesis mately 20% of cases of antibiotic- primarily a nosocomial infection. It associated diarrhea are due to C dif- causes approximately 3 million cases Development of C difficile–associ- ficile. Two percent to 3% of cases are of diarrhea and colitis annually in the ated diarrhea (CDAD) requires sev- due to other pathogens such as Clos- United States. Only about 20000 eral factors (Figure 6).8 The first 2 tridium perfringens, S aureus, and Can- cases annually are diagnosed in the factors are treatment with antimicro- dida albicans. Also, a few cases are cat- outpatient setting.8 Community- bials and colonization or acquisi- egorized as antibiotic specific. One acquired disease does occur, but the tion of C difficile. However, most example of this type would be the epidemiologic factors in this set- patients subsequently develop promotility adverse effect of eryth- ting are not fully understood. In a asymptomatic colonization rather romycin causing diarrhea. Another recent study, Riley et al9 suggested than frank CDAD. Therefore, other example is the malabsorption caused that the incidence in the commu- additional factors likely play a role in by large doses of neomycin.4 nity may be underestimated: this the development of CDAD. These may be owing to a lack of aware- may be related to host susceptibility CLOSTRIDIUM ness and investigation by physi- or immunity, the virulence of the par- DIFFICILE–RELATED cians of this organism as a cause of ticular C difficile strain, or the type SPECTRUM OF DISEASE community-acquired diarrhea. and timing of antimicrobial expo- Table 110 demonstrates the distri- sure.11 However, it is clear from mo- Description of Organism bution of C difficile from the stools lecular typing studies that even the and Epidemiology of various patient populations. Clos- most virulent of C difficile strains pro- tridium difficile can be isolated from duces asymptomatic colonization Clostridium difficile is a spore- up to 3% of healthy adults in the gen- more often than CDAD, and this find- forming, gram-positive bacillus. It was eral population and up to 80% of ing suggests that factors in addition given its name because it was diffi- healthy newborns and infants. In- to virulence are necessary for CDAD cult to grow in culture and isolate. It fants are exposed from nosocomial to occur.11,14 In the article by Shim et forms spores and thus can survive un- infection and not from maternal al,15 4 longitudinal studies revealed der harsh environmental conditions transmission. A review by Johnson that once asymptomatic coloniza- and withstand antibiotic therapy.6 In and Gerding11 revealed that the rate tion is established, these patients are his doctoral thesis in 1974, Hafitz7 of colonization was approximately at decreased risk for subsequent de- noted that C difficile survives well in 20% in patients who were hospital- velopment of CDAD.15 nature and is widely distributed in the ized for more than 1 week. A mi- Virtually every antibiotic has the environment. The organism is fre- nority of these patients were colo- potential to cause CDAD or colitis, quently transmitted by person-to- nized on admission. However, of including the antibiotics used to treat person contact. Therefore, strict hand those who were initially negative for the disorder itself (Table 2).16 Am- washing and contact and enteric pre- C difficile on admission, the risk of picillin, cephalosporins, and clinda- cautions are imperative measures in acquiring the organism increased in mycin are the most frequently impli- preventing the spread of the organ- direct proportion to the duration of cated antibiotics. Ampicillin and ism. It has been cultured from many the hospital stay.11 Another study by cephalosporins are prescribed more items including toilets, bedpans, Clabots et al12 showed that the rate frequently than clindamycin and

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 carrier state, simple antibiotic- Table 2. Antibiotics Associated With Clostridium difficile Colitis and Diarrhea* associated diarrhea, PMC, and fulminant colitis. The basis for the vari- Antimicrobial Agents That Predispose to C difficile Diarrhea and Colitis able expression of disease may be Frequently Infrequently Rarely related to host immune factors and 8 Ampicillin and amoxicillin Tetracyclines Parenteral aminoglycosides virulence factors of the organism. Cephalosporins Sulfonamides Bacitracin The asymptomatic carrier state Clindamycin Erythromycin Metronidazole is the end result for most patients in- Chloramphenicol Vancomycin fected with C difficile. These pa- Trimethoprim Quinolones tients act as a silent reservoir of infection and probably perpetuate *Reprinted from Kelly and LaMont8 with permission from the Annual Review of Medicine. contamination of the hospital environment. Treatment of asymptomatic carriers with antibiotics does not eradicate the carrier state and is not recommended.8 Simple antibiotic-associated diarrhea is mild. As previously stated, C difficile accounts for only 20% of all cases of antibiotic-associated diarrhea. Obvious colitis and systemic symptoms are absent. Colitis without pseudomembrane formation is a more serious illness than simple antibiotic-associated diarrhea. Patients may present with malaise, abdominal pain, nausea, an- orexia, watery diarrhea, low-grade fe- ver, and a peripheral leukocytosis. En- doscopy reveals a nonspecific diffuse or patchy erythematous colitis with- 8 Figure 7. Acute toxic megacolon in a patient with fulminant pseudomembranous colitis. Note the out pseudomembranes. thickened and edematous bowel wall (arrow). Pseudomembranous enterocolitis is the characteristic manifesta- therefore cause a greater number of phils, lymphocytes, serum proteins, tion of full-blown C difficile colitis. cases of CDAD. However, clindamy- erythrocytes, and mucus. Toxin B is Sigmoidoscopic examination re- cin causes a greater percentage of primarily cytotoxic, causing the dis- veals the classic pseudomembranes— cases relative to its frequency of use. integration of filamentous actin and raised yellow plaques from 2 to 10 Symptoms can occur at any time dur- leading to the collapse of the micro- mm in diameter scattered over the co- ing antibiotic therapy and even up to filament cytoskeleton and cell round- lorectal mucosa.8 Patients with PMC 8 weeks after discontinuation of the ing. Clostridium difficile toxins also have a more serious illness than pa- antibiotic. However, most episodes of stimulate leukocyte chemotaxis in tients who have colitis without pseu- CDAD occur from days 4 through 9 vitro and up-regulate the production domembrane formation. Approxi- of antibiotic treatment.8 of cytokines and other inflammatory mately 20% of patients have more Clostridium difficile produces 2 mediators. These stimulatory effects proximal disease not detected on rou- toxins that are responsible for its may underlie the ability of C difficile tine flexible sigmoidoscopy. Pseudo- pathogenesis. Toxin A is a 308-kd toxins to elicit a profound colonic in- membranous enterocolitis may rarely protein and toxin B is a 250-kd pro- flammatory response, culminating in affect the small bowel. tein. Both toxins are high-molecular- PMC.6 Clostridium difficile also pro- Fulminant colitis occurs in only weight proteins and are heat labile. duces tissue degradative enzymes, 3% of patients with C difficile infec- They are separated by only a small which may play a minor role in the tion. Patients may exhibit severe area on the C difficile chromosome. pathogenesis. These include chon- abdominal pain and diarrhea, high Both toxins play a role in the patho- droitin 4-sulfatase, collagenase, and fevers, and a marked peripheral leu- genesis of CDAD and colitis and hyaluronidase.17 kocytosis. Diarrhea may be absent if share common intracellular mecha- ileus develops, and these patients are nisms of action as a result of their Clinical Features and at greatest risk to develop toxic homology. Nontoxigenic strains lack Complications of C difficile megacolon. A protein-losing enter- toxins A and B.1 Infection opathy may lead to hypoalbumin- Toxin A is primarily an entero- emia, which in turn can cause asci- toxin that causes excretion of fluid Clostridium difficile infection leads to tes. Complications may include from bowel. This fluid is profoundly a spectrum of disease. This spec- colonic perforation, toxic megaco- inflammatory, containing neutro- trum includes the asymptomatic lon, prolonged ileus, ascites, and

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 3. Stool Test for Diagnosis of Clostridium difficile Infection*

Test Detects Advantages Disadvantages Cytotoxin assay Toxin B Standard highly sensitive and Requires tissue culture facility, takes specific 24-48 h Enzyme immunoassay Toxin A or B Fast (2-6 h), easy to perform, Not as sensitive as the cytotoxin high specificity assay Latex agglutination assay Bacterial enzyme (glutamate Fast, inexpensive, easy to Poor sensitivity and specificity dehydrogenase) perform Culture Toxigenic and nontoxigenic Sensitive, allows strain typing in Requires aerobic culture, not C difficile epidemics specific for toxin-producing bacteria, takes 2-5 d

*Reprinted from Kelly and LaMont8 with permission from the Annual Review of Medicine. even death. Endoscopy is usually not prudent owing to the risk of perfo- A B C ration, and exploratory laparotomy and total colectomy may become necessary interventions.8 Figure 7 is an upright abdominal plain film that demonstrates the complication of toxic megacolon.

Diagnosis

There are various methods and as- says available for the detection of C difficile infection. Table 38 compares and contrasts various methods used to diagnose C difficile infection. The cytotoxin assay is considered the standard for the diagnosis of C difficile infection (Figure 8).1 It detects toxin B, which is the primary cytotoxin. It has a sensitivity of 94% to 100% and a specificity of 97%.8 However, it re- Figure 8. Tissue culture assay for Clostridium difficile toxin. A, Normal primary human amnion cells; quires a tissue culture facility, which B, typical actinomorphic changes after application of stool containing C difficile toxin; and C, the is not widely available in most hos- tissue-cultured cells with the same specimen after neutralization with Clostridium sordellii antitoxin. pitals. It also takes 24 to 48 hours (Reprinted from Bartlett1 with permission from WB Saunders Co.) to perform. The method used most widely in the clinical setting to diag- Table 4. Clostridium difficile and Its Cytotoxin in Patients nose C difficile infection is the With Various Manifestations of C difficile Infection enzyme-linked immunosorbent assay (ELISA). It only takes 2 to 6 C difficile C difficile hours to perform. Characteristics Condition Culture, % Positive Cytotoxin, % Positive of this assay include a sensitivity Pseudomembranous colitis 95-100 95-100 of 85% with a specificity of 100%. Colitis without pseudomembranes 75-90 60-75 Antibiotic-associated diarrhea 20-40 15-30 The sensitivity of ELISA may be Hospitalized adults, asymptomatic 10-15 2 improved by serial testing. Healthy adults 0-3 0 Another diagnostic assay is the Healthy neonates and infants 30-80 25-50 latex agglutination assay. It does not detect any of the toxins produced by C difficile, but rather it detects a bac- genic and nontoxigenic strains. It is patients with various manifesta- terial enzyme, glutamate dehydro- highly sensitive and allows for strain tions of C difficile infection. genase. This enzyme is found in typing during epidemics. Its major Polymerase chain reaction can many other bacteria. Therefore, this disadvantage is that it takes 2 to 5 be used to diagnose C difficile infec- assay has poor specificity. It also has days to perform. It is also not spe- tion. Its sensitivity and specificity poor sensitivity. cific for toxin-producing bacteria. closely resemble those of ELISA. It Clostridium difficile can be cul- Table 41 compares the culture is not widely available in most hos- tured. The culture detects both toxi- method with the cytotoxin assay in pitals and clinical settings, likely be-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 agent, Synsorb Cd (SYNSORB Bio- Table 5. Treatment of Clostridium difficile−Induced Diarrhea and Colitis* tech Inc, Calgary, Alberta), is currently in phase 3 clinical trials for the Antimicrobial agents (only if symptoms are severe or persistent) treatment of recurrent C difficile in- Oral agent (preferred) Vancomycin: 125 mg, 4 times daily, 7-14 d fection when given for 25 days in Metronidazole: 250 mg, 3 times daily, 7-14 d combination therapy with metroni- Bacitracin: 25 000 U, 4 times daily, 7-14 d dazole. Synsorb Cd is a synthetic oli- Parenteral agent (to be used only until oral agents are tolerated) gosaccharide with bioadsorbent prop- Metronidazole: 500 mg, given intravenously every 6 h erties that selectively binds toxin A. There has been considerable 1 *Modified from Bartlett with permission from WB Saunders Co. controversy regarding whether metronidazole or vancomycin should be used for initial therapy. Prospective Table 6. Approach to Management of Recurrent Clostridium difficile Colitis* randomized studies reveal no differ- ence in initial response rates to met- First relapse ronidazole and vancomycin.20 Previ- Confirm diagnosis ous exposure to vancomycin given Symptomatic treatment if symptoms are mild 10- to 14-d course of metronidazole or vancomycin orally and intravenously has been Second relapse proven to be a risk for the develop- Confirm diagnosis ment of vancomycin-resistant Entero- Vancomycin taper coccus.6 The cost of vancomycin and 125 mg every6hfor7d metronidazole at Mayo Clinic 125 mg every 12 h for 7 d Scottsdale’s pharmacy (as of January 125 mg/d for 7 d 2002) for a 10-day course is $215.33 125 mg every other day for 7 d 125 mg every3dfor7d and $15.97, respectively. For these Further relapse reasons, metronidazole is recom- Saccharomyces boulardii in combination with metronidazole or vancomycin, or mended as the drug of choice for Vancomycin in tapering dose (as specified above) plus cholestyramine, 4 g twice daily, or CDAD. Oral vancomycin treatment Vancomycin, 125 mg 4 times daily, and rifampin, 600 mg twice daily for 7 days, or should be reserved for patients with Intravenous immunoglobulin, or Therapy with microorganisms metronidazole intolerance, for patients who do not respond to metro- *Modified from Linevsky and Kelly10 with permission from Marcel Dekker. nidazole, for patients with severe or fulminant colitis, and, perhaps, for patients who are immunocompro- cause of increased costs compared agent that is less frequently associ- mised.6 However, there is little clini- with ELISA. Its use today is primar- ated with CDAD should be made. cal evidence, even in these circum- ily as a research tool. However, a Other nonspecific measures include stances, that oral vancomycin is group of investigators18 from Spain supportive measures, such as correc- superior. recently developed a rapid detection of fluid losses and electrolyte ab- tion method for toxigenic C diffi- normalities. One should avoid anti- Immunity cile from stool samples by a nested peristaltic agents and place infected polymerase chain reaction of the patients on enteric isolation precau- Are there natural protective antibod- toxin B gene. It takes only a few tions.1 ies against C difficile? Kelly21 found hours to perform and has a sensi- Oral agents used for first-line higher levels of serum IgG antibody tivity and specificity of 96% and therapy include vancomycin, met- against C difficile toxins in patients 100%, respectively. Thus, the clini- ronidazole, and bacitracin. Table 51 with mild, self-limiting diarrhea than cal use of polymerase chain reac- outlines the various first-line treat- in patients with more severe diar- tion may soon become more wide- ment regimens. Metronidazole given rhea requiring specific therapy. More- spread. intravenously can be used to treat pa- over, the appearance of neutralizing tients who cannot tolerate an oral serum antibodies correlated with reso- Treatment agent. Intravenous administration of lution of the diarrhea. Two further vancomycin is not efficacious in the studies have reported low serum IgG The treatment of symptomatic C dif- treatment of C difficile infection. antibody levels against toxin A in pa- ficile infection should begin with non- A first or initial relapse should tients with prolonged, relapsing specific measures. The most impor- be treated with a second course of the CDAD, and one also showed that fe- tant of these is the discontinuation of initial antibiotic regimen used for first- cal IgA antitoxin levels were re- the offending antibiotic, whenever line therapy. Of patients treated for a duced in this patient population.21 possible. Discontinuation of antibi- first episode of CDAD, 15% to 20% Thus, there is considerable, albeit in- otic therapy may not be realistic for will have a relapse.8 There are many conclusive, evidence that an inad- patients who are receiving therapy for different regimens used with vary- equate humoral response to C diffi- a life-threatening illness. However, ing degrees of success to treat mul- cile infection predisposes to severe or consideration of a change to another tiple relapses (Table 6).19 Anew prolonged CDAD.21

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Kyne et al22 found no evidence of immune protection against colo- Table 7. Practice Guidelines for Prevention of Clostridium difficile Diarrhea* nization by C difficile. However, after colonization, there was an asso- Limit the use of antimicrobial drugs. Wash hands between contact with all patients. ciation between a systemic immune Use enteric (stool) isolation precautions for patients with C difficile diarrhea. response to toxin A, as evidenced by Wear gloves when contacting patients with C difficile diarrhea or their environment. increased serum concentrations of Disinfect objects contaminated with C difficile with sodium hypochlorite, alkaline glutaraldehyde, IgG antibody against toxin A, and the or ethylene oxide. asymptomatic carrier state. Educate the medical, nursing, and other appropriate staff members about the disease and its epidemiology. Passive Vaccination *Reprinted from Fekety32 with permission from Elsevier Science Publishing, New York, NY. Kelly21 gave 5 children with recurrent CDAD, who had low serum val- ues of IgG antitoxin A, pooled in- similar preparations. Although im- REFERENCES travenous human gamma globulin. munization against C difficile tox- Their gastrointestinal tract symp- ins may reduce symptomatic dis- toms resolved after treatment, and ease, there is no evidence indicating 1. Bartlett JG. Pseudomembranous enterocolitis and antibiotic-associated colitis. In: Feldman M, Schar- there was clearance of C difficile that it will directly influence intes- schmidt BF, Sleisenger MH, eds. Sleisenger & toxin from their stools. A case re- tinal colonization rates. Fordtran’s Gastrointestinal and Liver Disease: port by Kelly21 noted successful Pathophysiology/Diagnosis/Management. 6th ed. treatment of 2 patients with the use Prevention Vol 2. Philadelphia, Pa: WB Saunders Co; 1998: 1633-1647. of gamma globulin as an adjunct to 2. Finney JM. Gastro-enterostomy for cicatrizing ul- vancomycin and metronidazole for Because there is no effective com- cer of the pylorus. Bull Johns Hopkins Hosp. 1893; fulminant colitis. The patients were mercially available human vaccine, 4:53. able to avoid surgical intervention. adequate infection control mea- 3. Penner A, Bernheim A. Acute postoperative en- Animal studies demonstrated sures are absolutely necessary in terocolitis; study on pathologic nature of shock. Arch Pathol. 1939;27:966-983. efficacy of oral anti–C difficile bo- controlling the spread of C difficile 4. LaHatte LJ, Tedesco FJ, Schuman BM. Antibiotic- 32 vine immunoglobulin concentrate. infection. Table 7 outlines an associated injury to the gut. In: Haubrich WS, Previous studies demonstrated pro- effective practice guideline for the Schaffner F, Berk JE, eds. Bockus Gastroenterol- tection from other bacteria with oral prevention of C difficile infection. ogy. 5th ed. Vol 2. Philadelphia, Pa: WB Saun- ders Co; 1995:1657-1671. administration of hyperimmune 5. Tedesco FJ, Barton RW, Alpers DH. Clindamycin- 23,24 globulin. An anti-clostridium im- SUMMARY associated colitis: a prospective study. Ann In- mune concentrate has been success- tern Med. 1974;81:429-433. fully produced from cows immu- Pseudomembranous enterocolitis is 6. LaMont JT, Kelly CP. Bacterial infections of the nized against C difficile. Clinical primarily caused by C difficile infec- colon. In: Yamada T, ed. Textbook of Gastroen- terology. 3rd ed. Vol 2. Philadelphia, Pa: Lippin- studies are under way to determine tion. There are risk factors other than cott Williams & Wilkins; 1999:1945-1964. whether anti–C difficile bovine im- antibiotics and C difficile, which have 7. Hafitz S. Clostridium difficile and Its Toxins [PhD munoglobulin concentrate is effec- historically been associated with the dissertation]. Leeds, England: University of Leeds; tive in the prevention and treat- development of PMC. Most cases of 1974. ment of C difficile infection.21,25 antibiotic-associated diarrhea do not 8. Kelly CP, LaMont JT. Clostridium difficile infection. Ann Rev Med. 1998;49:375-390. have a definitive cause. Clostridium 9. Riley TV, Cooper M, Bell B, Golledge CL. Com- Active Vaccination difficile accounts for only about 20% munity-acquired Clostridium difficile–asso- of all cases of antibiotic-associated ciated diarrhea. Clin Infect Dis. 1995;20(suppl 2): Several animal studies demon- diarrhea. Infection with C difficile S263-S265. 10. Linevsky JK, Kelly CP. Clostridium difficile coli- strated efficacy of parenteral immu- leads to a spectrum of disease, from tis. In: LaMont JT, ed. Gastrointestinal Infec- 26-28 nization. Oral or mucosal im- the asymptomatic carrier state to ful- tions: Diagnosis and Management. New York, NY: munization, as used for cholera minant colitis. Vaccination is not yet Marcel Dekker; 1997:293-325. toxin, is an alternative approach cur- available. Therefore, strict hand 11. Johnson S, Gerding DN. Clostridium difficile– rently under investigation.21,29 A washing, enteric precautions, and ju- associated diarrhea. Clin Infect Dis. 1998;26:1027- 1034. study in hamsters indicated that a dicious use of antibiotics are im- 12. Clabots CR, Johnson S, Olson MM, Peterson LR, combination of parenteral and mu- perative and remain the most effec- Gerding DN. Acquisition of Clostridium difficile by cosal (intranasal) immunization ap- tive means of preventing the spread hospitalized patients: evidence for colonized new pears to provide the best protec- of the organism and disease. admissions as a source of infection. J Infect Dis. tion against C difficile disease.21,30 1992;166:561-567. 13. Kelly CP, Pothoulakis C, Vavva F, et al. Anti– Formalin-inactivated culture fil- Accepted for publication February 13, Clostridium difficile bovine immunoglobulin con- trate from toxigenic C difficile as well 2002. centrate inhibits cytotoxicity and enterotoxicity of as purified and inactivated toxins Corresponding author and re- C difficile toxins. Antimicrob Agents Chemother. have been used to immunize ani- prints: Brian W. Hurley, MD, Divi- 1996;40:373-379. 21,25-28,31 14. Johnson S, Clabots CR, Linn FV, Olson MM, Pe- mals with good effect. These sion of Hospital Internal Medicine, terson LR, Gerding DN. Nosocomial Clostridium studies may provide the impetus for Mayo Clinic, 13400 E Shea Blvd, difficile colonisation and disease. Lancet. 1990; further human investigation using Scottsdale, AZ 85259. 336:97-100.

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CME from JAMA/Archives will be suspended between July and December 2002. Beginning in early 2003, we will offer a new online CME program that will provide many enhancements: • Article-specific questions • Hypertext links from questions to the relevant content • Online CME questionnaire • Printable CME certificates and ability to access total CME credits We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in early 2003.

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