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Copyright O 1997 by Am. Col l . of GastroenterologyVol. 92, No. 5, 1997

Printed in U.S.A.

Practice guidelines

Guidelines for the Diagnosis and Management of Clostridiumdfficile-Associated Diarrhea and Colitis

Robert Feketv. M.D.

Guidelines for clinical practice are intended to suggestpreferable approaches to particular medical problems asestablished by interpretation and collation of scientifi-cally valid research, derived from extensive review ofpublished literature. When data are not available thatwill withstand objective scrutiny, a recommendationmay be made based on a consensus of experts. Guide-lines are intended to apply to the clinical situation for allphysicians without regard to specialty. Guidelines areintended to be flexible, not necessarily indicating theonly acceptable approach, and should be distinguishedfrom standards of care that are inflexible and rarelyviolated. Given the wide range of choices in any healthcare problem, the physician should select the course bestsuited to the individual patient and the clinical situationpresented. These guidelines are developed under theauspices of the American College of Gastroenterologyand its Practice Parameters Committee. These guide-lines are also approved by the governing boards ofAmerican College of Gastroenterology and Practice Pa-rameters Committee. Expert opinion is solicited fromthe outset for the document. Guidelines are reviewed indepth by the committee, with participation from expe-rienced clinicians and others in related fields. The finalrecommendations are based on the data available at thetime of the production of the document and may beupdated with pertinent scientific developments at a latertime. The following guidelines are intended for adultsand not for pediatric patients.

INTRODUCTION

Antibiotic-associated diarhea and colitis are imporrantand increasingly frequent complications of antibiotic ther-apy. While these occur most often in hospitals and nursinghomes, they also occur in the community. Antibiotic-asso-ciated dianhea is even more common; it is caused bv Clos-

tridium dfficile in only l5-207o of cases, and is of unknowncause in most of the remaining cases (1-3). The type ofantibiotic-associated diarrhea that is not caused by C. dffi-cile is relatively mild, self-limited, unassociated with intes-tinal lesions, is treatable with nonspecific supportive mea-sures and by discontinuation of antibiotics, and is alsoreferred to by a variety of terms such as simple, benign, orenigmatic antibiotic-associated diarrhea. In contrast, C. difficile associated diarrhea is usually associated with colitiscaused by the combined effects of toxins A and B producedby C. dfficile within the intestinal lumen and is a seriousand potentially life-threatening disease. C. dfficile, a spore-forming obligate anaerobic bacillus, is a component of thenormal fecal flora of many infants, and about 5% of healthyadults; it may be found in the stools of l07o or more ofhospitalized adults without diarrhea who have received an-tibiotics or cancer chemotherapeutic agents. C. dfficilecauses a spectrum of diarrheal syndromes that vary widelyin severity and merge with one another; they are also com-monly referred to by a variety of names, including C.dfficile diarrhea, C. dfficile colitis, antibiotic-associated C.dfficile colitis, and pseudomembranous colitis. Unless spec-ified otherwise, the general term "C. difiicile diarrhea" willbe used herein to refer to the entire spectrum ofthe diarrhealdiseases caused by this organism. The diarrheal illnesscaused by C. dfficile may and often does closely resemblethe more frequent benign or simple antibiotic diarrhea.Patients with antibiotic-associated diarrhea in which C. dfficile cannot be incriminated, which is true about 80o/a of thetime, are assumed to have the simple or benign diarrhea ofunknown cause.

C. dfficile diarrhea, colitis without pseudomembranes,and pseudomembranous colitis are toxin-mediated mucosalinflammatory processes that are usually characterized by thepresence of grossly or microscopically visible pseudomem-branes consisting of nodules or large plaques containingleukocytes, fibrin, mucus, and epithelial cells loosely ad-herent to the surface ofthe underlying inflamed and necroticmucosa. Almost all cases of antibiotic-associated colitis orpseudomembranous colitis are caused by both toxin A andRectivetl Oct. 10, 1996: accepted Jan. 28, 1997

740 FEKETY

B producing strains of C. dffici le. Most patients with C.dfficile diarrhea can be found to have gross and/or micro-scopic colitis with or without pseudomembranes if theyundergo a workup that includes colonoscopy with biopsies.When pseudomembranes are not evident in patients with C.diflicile diarrhea who have undergone colonoscopy, thediarrheal process may have resulted from a purely secretorydiarrhea without colonic inflammation. Because, for a va-riety of reasons, many if not most patients with antibiotic-associated diarrhea do not undergo endoscopy and biopsy,the general term "C. dfficile diarrhea" is used more andmore often when one of more laboratory tests for C. dfficileare positive and the organism is considered to be the causeof the diarrhea, and it is not certain whether or not colitisand/or pseudomembranes are present. C. dfficile diarrheawith colitis and pseudomembranes can lead to toxic dilationand/or perforation of the colon, dehydration, hypovolemia,shock, and death. Although pseudomembranous colitis waswell-recognized in the preantibiotic era (and was thought tobe caused by staphylococci), it is now uncommon to diag-nose it in a patient who has not received antibiotics and inwhom C. dfficile cannot be implicated. As many as 20Vo ofpatients with C. dfficile diarrhea do not develop symptomsuntil as long as 6-8 weeks after discontinuation of antibi-otic therapy. In addition, patients have developed C. dfficilediarrhea after the use of cancer chemotherapeutic agents,many of which have significant in vitro antibacterial activity(4-1) .

PATHOPHYSIOLOGY OF C. DIFFICILE DIARRHEA

C. difricile diarrhea is caused primarily by the elaborationwithin the intestinal lumen of both toxin A and toxin Bproduced by C. dfficile during its multiplication. Thesetoxins bind to the colonic mucosa and then exert theirdamaging effects upon it. Most toxigenic isolates produceboth toxins, but depending on whether they are obtainedfrom infants, healthy adults, the environment, or personswith antibiotic-associated diarrhea, about 5 to 25To of iso-lates of C. dfficile produce neither toxin A nor B, and do notcause colitis or diarrhea (5, 6, 8). Toxin A is a 308-kDaenterotoxin capable of causing extensive mucosal damage inexperimental animals; it is cytotoxic for certain cell lines inculture, a chemoattractant for neutrophils, and an activatorof macrophages and mast cells, causing them to producevarious inflammatory mediators (8). Toxin A causes actindisaggregation and intracellular calcium release, and alsoappears to damage neurons (3-6). Toxin B is a 270-kDacytotoxin that causes depolymerization of filamentous actin.Toxin B was first detected by virtue of its potent cytopathiceffects in cell culture monolayers, but because it was notcytotoxic for the colonic mucosa of various animal speciesit was originally considered of little importance in causingcolitis in humans. Recent evidence indicates toxin B dis-rupts the actin cytoskeleton, and is also a necrotizing en-terotoxin l0 times more Dotent than toxin A in causins

AJG - Vol. 92, No. 5, 1997

damage to human colonic mucosa in cell cultures (9). Itseems probable that both toxins are important in causingdiarrheal disease in humans. C. difricile rarely damages thecolon of patients by direct invasion, although it can occa-sionally do so (10), and it should be emphasized that thediarrhea the organism produces is caused by the effects oftoxins that are produced within the intestinal lumen andadhere to the mucosal surface (3-6).

EPIDEMIOLOGY OF C. DIFFICILE DIARRHEA

The frequency and incidence of C. dfficile diarrhea varieswidely not only geographically but within different institu-tions in the same area, and depends on patterns of antimi-crobial use, on antimicrobial resistance patterns of the prev-alent C. dfficile isolates, on epidemiologic factors favoringtransmission of the organism, on patients' risk factors, onclinicians index of suspicion, and especially on the fre-quency with which endoscopy and/or various laboratorytests for the presence of toxins A or B in stools are per-formed on patients with antibiotic-associated diarrhea (4-6,8, I 1). Ironically, as the frequency of postoperative woundinfections has declined over the past few decades, in nosmall measure because of the skill of surgeons and theirappropriate use of short-course perioperative antibiotic pro-phylaxis in high-risk patients, the frequency of C. dfficilediarrhea has markedly increased in hospitals in the UnitedStates, especially in the elderly (12). Almost every popularantimicrobial has been implicated in the causation of C.dfficile diarrhea, but ampicillin and other penicillin deriv-atives, cephalosporins and clindamycin, are implicated mostfrequently (l-6). Less frequently incriminated are erythro.mycin, aminoglycosides, fluoroquinolones, sulfamethox-azole-trimethoprim, and perhaps surprisingly, both vanco-mycin and metronidazole, which are the drugs of choice fortreatment of C. dfficile dianhea. Tetracyclines and chlor-amphenicol are now rarely implicated, but they were fre-quently implicated in what was diagnosed as staphylococcalenterocolitis in the early antibiotic era (1, 5, 13). C. dfficilediarrhea occurs both sporadically and in clusters or out-breaks in hospitals, nursing homes and chronic care facili-ties, but the frequency of the disease is very much lower inthe community. C. difficile canbe detected in the stools of5Vo or more of healthy adults, and even more frequently inthe stools of healthy infants (30-507a) and patients withoutdiarrhea in some hospitals and nursing homes (up to 307o).Infants who carry the organism rarely develop C. dfficilecolitis, and there is evidence suggesting the reason for thisapparent protection is that the toxins do not bind well to thecolonic mucosa because its binding sites are immature (3, 5,6). C. dfficile is widely distributed in the soil, water, andenvironment of patients with C. dfficile diarrhea (14). Insome hospitals and nursing homes, as many as 20-30Vo ormore of patients who have received antibiotics have beenfound to be asymptomatic carriers and shedders of theorganism into the environment. Consequently, spread of the

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organism to others there who have been treated with anti-biotics and are therefore susceptible to colonization by smallnumbers of C. dfficile spores may be frequent. Transmis-sion of the C. dfficile seems most often to be via the handsof hospital personnel, and also by contact with contaminatedsurfaces and fomites (11, 13).

CLINICAL MANIFESTATIONS OF C. DIFFICILEDIARRHEA

The typical manifestations of Clostridium dfficile diar-rhea are cramping abdominal pain, profuse diarrhea consist-ing of mucoid, greenish, foul-smelling, watery stools, lowgrade fever, and leukocytosis. These can start a few daysafter antibiotic therapy is begun or up to 8 weeks after itsdiscontinuation. Many patients with C. dfficile diarrheahave fever that exceeds 40'C and leukocytosis as high as50,000 per mm (3); in fact, leukemoid reactions in the rangeof 100,000 per mm3 have been reporled. It is not rare forpatients to have watery diarrhea similar to that seen in thebenign antibiotic diarrhea of unknown cause (l-6). Al-though colitis can occur throughout the colon, it is usuallymost severe in the distal colon and rectum. When patientsdevelop colitis localized to the cecum and right side of thecolon, they may have little or no diarrhea. lnstead, fever,marked right-sided lower abdominal pain and tenderness,marked leukocytosis, and decreased intestinal motility maybe the only clues to the disease. This presentation is not rarebut is especially serious, in part because diagnosis andtreatment may be delayed because of the lack of diarrhea,and seems to occur more frequently when antiperistalticagents or opiates have been given postoperatively. Unlessendoscopy or computerized tomography or other tests aredone and suggest the diagnosis and the need for specificantibiotic therapy, these patients may progress rapidly inseverity and require emergent abdominal laparotomy andsubtotal colectomy because of toxic megacolon or colonicperforation (15, 16). Other complications of C. dfficilediarrhea include dehydration, hypovolemia, hypoalbumine-mia, anasarca, electrolyte disturbance, shock, and a reactivearthrit is (4-6).

The differential diagnosis of C. difficile diarrhea includesbenign or simple antibiotic-associated diarrhea, acute andchronic diarrhea caused by other enteric pathogens, adversereactions to various medications other than antibiotics, isch-emic colitis, idiopathic inflammatory bowel diseases, andintra-abdominal sepsis.

DIAGNOSIS OF C. DIFFICILE DIARRHEA ANDCOLITIS

Ertdoscoltic diagnosi s

Guidelines for diagnosis are presented in Table 1. Thebest and most rapid way to establish the diagnosis of C.diffic'ile colitis is by endoscopy with biopsy of suspiciouslesions, but endoscopy is expensive and usually reserved fbr

CLOSTRIDIUM DIFFICILE-ASSOCIATEDDIARRHEAANDCOLITIS 141

TABLE I

P r a c t i c e G u i d e t i ne s fo r, - t ;;:; ::^: :o

s t r i d i u m d ffi c i t e D i a r r h e a t

l. The diagnosis should be suspected in anyone with dianhea who hasreceived antibiotics within the previous 2 months and/or whosediarrhea began 72 h or more after hospitalization.

2. When the diagnosis of C. dfficile diarrhea is suspected, a single stoolspecimen should be sent to the laboratory for testing for the presence

of C. difficile and/or its toxins.3. If the results of those tests are negative but diarrhea persists, one or

two additional stools can be sent for testins with the same ordifferent tests.

4. Endoscopy is reserved for special situations, such as when a rapiddiagnosis is needed and test results are delayed or the test is nothighly sensitive, or the patient has ileus and a stool is not available,or when other colonic diseases are in the differential.

special situations, such as when the patient is seriously illand the results of rapid but not highly sensitive noninvasivetests are negative or delayed and C. dfficile diarrhea isstrongly suspected, or when some other disease process thatcan be diagnosed by endoscopy is also being considered(2-6). Endoscopy is diagnostic when it demonstrates char-acteristic, raised, yellowish nodules or plaque-likepseudomembranes, often with skip areas of normal mucosa.The nodules are usually 2-10 mm in diameter, but in ad-vanced stages they are increased in number, enlarged, andcoalesced to form plaques or membranes that cover largesegments of the inflamed mucosa but are easily strippedfrom it (hence the term pseudomembrane). Nodules andsmall pseudomembranes are easily dislodged during theprocessing of biopsies. Microscopic examination of the le-sions shows epithelial necrosis, goblet cells distended withmucus, edema, and infiltration of the lamina propria withleukocytes, epithelial cells, fibrin, and mucin. The terms"summit lesions" or "volcano lesions" have been used todescr ibe these les ions (1,3,4) . Gross les ions may be socharacteristic to experienced endoscopists that biopsy is notneeded, but it is best to obtain a biopsy if there is doubtabout the diagnosis. When the colonic mucosa shows onlyerythema, friability, or edema without nodules orpseudomembranes, it is suggestive of the so-called nonspe-cific colitis or simple colitis that may be caused by C.dfficile as well as a variety of other conditions. Biopsy ofsuch lesions, even when small, may confirm the presence ofinflammation (colitis) along with pseudomembranes that arenot grossly apparent. In a study of 22 patients withpseudomembranous colitis, it was found that endoscopywith a rigid endoscope detected fewer cases of colitis thanwith a flexible sigmoidoscope (77 vs 9lVo), and thatcolonoscopy detected additional cases (97a of the total) notreached using flexible sigmoidoscopy (17).

C. di.fficile-specific diagnoslic /csls

There is as yet no simple, inexpensive, rapid, sensitive,and specific test for diagnosing C. dfficile diarhea andcolitis. nor are all the available tests suitable for adootion bv

742 FEKETY

every laboratory (18). However, each laboratory shouldconsider providing one of the rapid, inexpensive tests andalso, if practical, a specific test for the presence of theorganism or its toxins. Many institutions provide an enzymeimmunoassay (EIA) test for rapid detection of toxin A or Band also a cell culture assay for toxin B, the cytotoxin.

Tissue culture tests for toxin B. The "Gold Standard"Iaboratory test for establishing the diagnosis of C. dfficilecolitis is still the demonstration in cell culture monolayers ofthe characteristic cytopathic effect of toxin B in filtrates ofdiarrheal stools. Specificity of the cytotoxicity is demon-strated by showing that it is prevented (neutralized) by useof antitoxin Io C. dfficile or Clostridium sordellii toxin (theutility of the latter reflects antigenic cross-reactivity) (1-6,18-21). There is no practical laboratory test available fordetecting toxin A in stools by means of its biological prop-erties. Cell culture tests to detect the specific cytopathiceffects of toxin B are positive in more than 90%a of patientswith pseudomembranous colitis (1-6). False negative re-sults in this as well as the other tests used for detecting thesetoxins may be caused by a number of factors: because of theinactivation of the heat and acid labile toxins during storageor transportation or by medications, because some cell linesused for this test are less sensitive than others to the cyto-pathic effect of the toxin (.2-6), and especially because oftesting stool specimens diluted in the laboratory. Therefore,it is important to recognize that a negative test for toxin Bin cell cultures does not rule oil C. dfficile as the cause ofthe diarrhea. If toxin B is detected in high titer, it is highlylikely that C. dfficile is the cause of the diarrhea, but thereis little conelation in individual patients between the heightof the toxin titer and the severity of the diarrheal disease. Itis not uncommon for patients who have responded to ap-propriate therapy for C. dfficile diarrhea to continue to havestools that test positive for toxin B or the organism for ashort time after discontinuation of otherwise successful ther-apy. Experience has shown that most of these patients willhave no furlher diarrhea and that it is not necessary toperform cultures or tests for the toxin on stools from patientswho no longer have diarrhea (5, 6, 18,22).

Enzl,me immunoassay tests Jbr toxin A and/or B. Thereare several commercially available EIA tests for detection oftoxins A and/or B of C. diff ici le in stools (l-3,5, 18-21).They are rapidly performed and relatively inexpensive whendone in batches, and they are probably the most widely usedlaboratory aids in the United States in diagnosing C. dfficilediarrhea. The EIA tests are more specific than they aresensitive. The sensitivity of the commercial EIA kits usedfor toxin A and B detection has varied widely when eval-uated in different laboratories using the same kits but dif-fering criteria for a positive endpoint. Whereas sensitivitieshave ranged from a low of about'707o to as high as 957o,specificity was generally very good. In most publishedreports, accuracy ofthese tests was evaluated on the basis ofprobable clinical diagnoses instead of upon diagnosesreached using both a cytotoxicity test for toxin B and en-

AJG - VoL 92. No. 5. 1997

doscopy, arguably the two most accurate and dependablediagnostic aids. On average, EIA tests for toxin A and/or Bfailed to detect about l07o (range 5 to 33Vo) or more of casesof C. dfficile diarrhea diagnosed clinically and by endos-copy with biopsy or by use of toxin B assays in cell cultures.Newer and allegedly better EIA tests (as well as other noveltests) are becoming available, but proper clinical studiesdocumenting their superiority have not yet been reported.Therefore, it should be emphasized that a negative EIA testfor toxins A or B does not rule out the diagnosis of C.dfficile colitis. Sensitivity is rarely improved by sendingmore than one stool on the same day for EIA testing, so thispractice is probably not cost-effective and should be dis-couraged. However, when an EIA test, or other rapid test, isreported negative, it may be then be worthwhile to sendanother stool the next day for testing by EIA or by differenttests, especially if the patient with antibiotic diarrhea ofunknown cause is critically ill or does not improve afterantibiotic therapy has been discontinued and supportivetherapy has been given. Alternatively, empiric therapy withmetronidazole may be given to seriously ill patients whenthe first test result is negative and other diagnostic tests arenot available or are in process.

Latex agglutination re.lt. Originally thought to detecttoxin A, this simple, rapid, and inexpensive immunologictest actually detects the presence of glutamate dehydroge-nase produced by C. dfficile, not toxin A (3, 4). Thisenzyme appears to play no role in the pathogenesis of C.dfficile diarrhea, but many clinicians and laboratory per-sonnel still incorrectly believe the latex agglutination testdetects toxin A. Nontoxigenic strains of C. difficile (whichdo not cause diarrhea) are also positive with the latex test.In addition, the latex agglutination test is nonspecific, be-cause several other organisms commonly found in stoolscan produce an antigen that cross-reacts with the antibodydirected against glutamate dehydrogenase produced by C.dfficile. Overall, the latex agglutination test is about assensitive as but not as specific as the EIA tests for the toxins(19-21,23). Comments in the previous section discourag-ing the practice of sending more than one diarrheal stool perday for EIA testing apply equally well to the latex aggluti-nation test.

Both the EIA and latex agglutination tests are simple,rapid, and inexpensive if they are performed in batches andquantity, but neither one is as reliable and sensitive asdesired. Unfortunately, clinicians are often unaware of thespecific test used for detecting C. difficile or its toxins intheir Iaboratory and of their important differences in sensi-tivity and interpretation, in part because such results arecommonly reported simply as a positive or negative "C.

dfficile test" without specifying the test used. A few labo-ratories have begun to use both the EIA and the latexagglutination tests, reserving the performance of the latterfor specimens that are negative by the EIA. This strategyappears to improve sensitivity and to decrease specificity,but many clinicians would conclude this errs in the right

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144 FEKETY

Tasls 2

Practice Guidelines .for Treatment of Cktstridium dfficile Diarrhea or

Colitis

1. Antibiotics should be discontinued if possible.

2. Nonspecific supportive therapy should be given, and is often all that

is needed in treatment. Specific antibiotics should not be given

rout inely.3. When the diagnosis of C. dfficile diarrhea is confirmed and specific

therapy is indicated, metronidazole given orally is preferred.

4. If the diagnosis of C. dfficile diarrhea is highly likely and the patient

is seriously ill, metronidazole may be given empirically before the

diagnosis is definitely established.

5. Vancomycin given orally is reserved for therapy of C. dfficile'

associated diarrhea until one or more of the following conditions are

present:(a) The patient has failed to respond to metronidazole.(b) The patient's organism is resistant to metronidazole.(c) The patient is unable to tolerate metronidazole, or is allergic to it,

or is being treated with ethanol containing solutions.(d) The patient is either pregnant or a child under the age of l0 years

of age.(e) The patient is critically ill because of C. dfficile-associated

diarrhea or colitis.(i) There is evidence suggesting the diarrhea is caused by

Sl t t nh| I t ,C)CC U S OU re t t \ .

diarrhea, or in the early detection of complications of C.

dfficile diarrhea. However, because it is expensive, CT is

reserved for special situations (30, 31). Radionuclide scansmay detect evidence of colonic inflammation rapidly, but

the findings are nonspecific, expensive, time-consuming.

and not always readily available.

TREATMENT OF ANTIBIOTIC-ASSOCIATEDDIARRHEA/COLITIS

Nonspecific supportive the rapy

Guidelines for treatment are presented in Table 2. When

appropriate diagnostic measures are in progress, but the

diagnosis of C. dfficile diarrhea has not yet been establishedand the patient is not seriously ill, nonspecific supportive

therapy should be given and is often all that is needed for

resolution of diarrhea, even when it is caused by C. dfficile.Nonspecific therapy may have the additional benefit of

reducing the likelihood of a relapse, as compared to specific

antibiotic therapy. Supportive therapy usually consists of

replacement therapy with fluids and electrolytes. If possible,

antibiotics given to treat an infection should either be dis-

continued or switched to alternate appropriate antibiotics.The administration of antiperistaltic and opiate drugs should

be avoided, because they may mask the patient's symptomsand also cause pooling of toxin-laden fluids within the colon(2, 4). Some patients with C. dfficile diarrhea have wors-

ened after being given antiperistaltics or opiates, but thismay have been coincidental (32), since many patients with

the disease have been given antiperistaltics without any

adverse consequences.

AJG Vol. 92. l,,lo. 5, 1997

Sp e cific antimicrobial the rapv

When appropriate diagnostic tests have been performed

and the diagnosis of C. dfficile dianhea is likely or con-

firmed, or the patient is a nonpregnant adult or a child over

l0 yr of age who is worsening or has not responded to

supportive therapy given for 2 or 3 days, specific antimi-

crobial therapy may be initiated. Metronidazole, vancomy-

cin, teicoplanin (which is not available in the United States),

and, less often, bacitracin have been used to treat C. dfficilediarrhea because these antimicrobials inhibit growth and

toxin production by C. dfficile. Metronidazole and vanco-

mycin are by far used most often in the United States.Therapy given by the oral route is always preferred, because

C. dfficile diarrhea is not caused by tissue invasion, and the

toxins produced by the organism within the intestinal lumen

cause diarrhea only after binding to specific receptors on thecolonic mucosa. C. dfficile diarrheal syndromes usuallyrespond well to oral therapy with either metronidazole orvancomycin if therapy is started early enough, but the re-

sponse is sometimes less good when metronidazole or van-comycin are given to patients who are critically ill with thedisease ( l -6) .

A controlled study comparing therapy of C. dffiicile di'arrhea with either metronidazole given orally in a dose of

250 mg four times per day or vancomycin in a dose of 500mg four times per day for 10 days showed that the onlystatistically significant difference between them was thatvancomycin was more costly (33). The duration of diarrheaand the frequency of side effects, posttreatment relapses,and carriage of the organism in convalescence were not

significantly different. All 52 patients given vancomycin

were cured, but 2 of 42 patients failed to respond to met-ronidazole (a difference that was not statistically signifi-cant), and were cured when therapy was changed to vanco-mycin, a fact that has led some investigators to prefer

vancomycin when the patient is critically ill. Interestingly,34 (22.87o) of the 149 patients in this study responded to

supportive therapy alone within a 48- to 72-h observationperiod while the diagnosis was being established, and didnot require therapy with either vancomycin or metronida-

zole. Specific oral therapy with metronidazole or vancomy-

cin is usually given for only 7 to 10 days, unless the i l lnessis severe or the diarrhea is slow to resolve (1,2, 4,33).Patients who require therapy for more than l0 days oftenhave severe colitis, or a delay in diagnosis and treatment of

colitis, or an underlying condition predisposing to diarrhea,such as lactose intolerance, irritable bowel disease, diabeticenteropathy, or diarrhea due to an adverse reaction to med-

ications or diet.Metronidazole given intravenousll, has been used to treat

pseudomembranous colitis in patients who are unable totake it orally. The reported results have been good, althoughtreatment failures have occurred. A possible explanation for

treatment failures when metronidazole is given intrave-

nously is that the stool concentrations achieved are usually

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AJG - May 1997

lower than those required for inhibition of the organism invitro (34). Even though stool concentrations are also lowwhen metronidazole is given orally (34,35), such therapy isusually successful, and this paradox is as yet unexplained.Nonetheless, the oral route is preferred when it can be usedbecause a wealth of clinical experience indicates it is highlyefficacious.

Oral metronidazole (Flagyl) is prefercedfor therapy of C.dfficile diarrhea. An expert committee of hospital infec-tion control practitioners has recently recommended thatmetronidazole is preferred for specific or empiric antimi-crobial treatment of C. dfficile diarrhea, and their recom-mendation has been widely adopted in the United States(36). One of the main reasons for their recommendation wastheir desire to curtail the use of vancomycin because of fearthat its use will encourage the spread of vancomycin-resis-tant enterococci (VRE), and ultimately the emergence andspread of vancomycin-resistant staphylococci, whereas met-ronidazole will not. Other reasons included were that met-ronidazole is much less expensive than vancomycin, that itis well-tolerated when given orally for short periods, andthat it is as effective as vancomycin for most patients (33).Although metronidazole has not been approved by the Foodand Drug Administration specifically for treatment of C.dfficile diarrhea, it has been approved by the FDA for thetreatment of serious infections caused by susceptible anaer-obic bacteria such as C. dfficile.

A few caveats concerning the preference for metronida-zole are in order, because use of vancomycin for treatmentof C. dfficile diarrhea is justified in special circumstances.Although metronidazole is usually well-tolerated, it has anunpleasant metallic taste and may also cause nausea, vom-iting, diarrhea, abdominal pain, pruritus, erythematousrashes, headache, confusion, dizziness, and reversible neu-tropenia, and additional patients may become allergic to it.Patients taking oral metronidazole should be cautionedagainst drinking alcoholic beverages because this mightresult in disulfiram (Antabuse)-like reactions. Also, rareisofates of C. dfficile are resistant to metronidazole in vitro,although there is little evidence that resistance is responsiblefor treatment failures. At the University of Michigan Hos-pitals, 6 (.3Vo) of 200 isolates of C. dfficile obrained frompatients and tested in vitro over the period from 1980 to1990 were resistant to metronidazole at concentrations rang-ing from 16 to 128 p,g/ml, whereas all were highly suscep-tible to vancomycin (37). Because metronidazole is a car-cinogen, mutagenic in some animal species and in vitro,crosses the placental barrier and is fetotoxic for pregnantmice, it should be used during pregnancy only if clearlyneeded. Similarly, because the safety of metronidazole forchildren has not been proven, many prefer not to use it fortreatment of children unless necessary.

For treatment of adults with C. dfficile diarrhea, metro-nidazole is usually given orally in a dosage of 250-500 mgfour times per day or 500-750 mg three times per day for7-10 days; for children, a dosage of 35-50 mgkg/24 h

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS 145

TaeI-e 3Practice Guidelines for Management of Relapses

1. Reconfirm the diagnosis.2. Discontinue medications that may be contributing to the diarrhea, and

treat the patient with nonspecific supportive therapy.3. If specific therapy is needed, treat the patient with a standard course

of metronidazole given orally for 7 to l0 days, or with vancomycin,as in the Treatment Guidelines (Table 2).

4. When possible, avoid treating (minor) infections with antibiotics forthe next 2 months after treatment of a relapse.

5. No treatment available in the United States has been proven toprevent recurrences. If the patient has suffered from multiplerecurrences, consider using one of the following antimicrobialregimens with or without one of the other therapeutic measures as anadjunct. These are not presented in an order of preference.(a) Oral metronidazole (or vancomycin, as in Table 3).(b) Specific therapy with vancomycin or metronidazole given orally

fbr I to 2 months, either intermittently (sucb as every other dayor week) or with gradual tapering, with or without adiunctivetherapy with an oral anion-binding regimen such ascholestyramine or colestipol begun near the end of antimicrobialtherapy and gradually tapered.

(c) Oral vancomycin plus rifampin.(d) Oral yogurt, Lactobacillus preparations, or Lactobacillus GG.(e) Saccharomyces boulardii (500 mg orally twice daily), if available,

may be given for I month, if the patient is notimmunocompromi.sed, beginning 4 days before a lO-day course ofspecific antibiotic therapy has been completed.

(f) Human immune globulin by intravenous infusion, for patients withdocumented deficiencie".

divided into three doses has been used. If metronidazole isused intravenously for treating patients who are critically illand/or unable to tolerate oral medications, it can be used ina dosage of 500-750 mg three or four times per day. Asstated earlier, metronidazole given intravenously for treat-ment of C. dfficile diarrhea is probably not as reliable aseither metronidazole or vancomycin given orally. Metroni-dazole should be used via the intravenous route for treat-ment of C. dfficile diarrhea only when it is not possible totreat via the oral route, and never for reasons of conve-nience. When metronidazole is used intravenously to treatC. dfficile diarrhea, consideration should also be given tothe simultaneous use of vancomycin enterally, as discussedbelow.

Indications for treatment with vancomycin. Vancomycinstill has a role in the management of C. dfficile diarrhea,although it is a much smaller one than was the case beforethe recommendation that metronidazole is preferred fortherapy of C. dfficile diarrhea. Because vancomycin ispoorly absorbed systemically when given orally, effectiveconcentrations are easily achieved in stools and serioussystemic side effects are rare (2-6). Nevertheless. vanco-mycin should not be used for treatment of C. dfficile diar-rhea unless the patient is unable to tolerate metronidazole, orbecause of the other indications outlined the Practice Guide-lines in Table 3.

It should be pointed out here that pseudomembranousenterocolitis was a well-recognized clinical comolication of

146 FEKETY

surgery in the preantibiotic and early antibiotic era, that it

was commonly attributed to toxin-producing, antibiotic-resistant S. aureus, and that it was treatable with oral van-comycin. Some investigators have retrospectively ques-

tioned the role of staphylococci in the cause of thoseillnesses (1), and suggested they were actually caused by C.dfficile, whose importance in this syndrome was not estab-lished unti l about 1978 (1, l3). Staphylococcal enterocolit isbecame very much less frequent in the 1960s after theintroduction and use of vancomycin and semi-synthetic pen-

icillinase-resistant B-lactam antimicrobials for treatingstaphylococcal infections. However, there is a considerablebody of evidence suggesting that staphylococci can indeedcause diarrhea and colitis after the use of antimicrobials.Before the antibiotic era, many patients diagnosed withstaphylococcal enterocolitis had extensive inflammatory le-sions in the colon at postmortem examination, and often inthe i leum, jejunum, and stomach as well (13). These find-ings are not characteristic of C. dfficile diarrhea, althoughileitis has occasionally been documented in patients with it,

especially if they have an ileostomy (38). After recognitionin the late 1970s of the important and unquestionably dom-inant role of C. dfficile in the causation of antibiotic-associated pseudomembranous colitis, little attention wasgiven to S. aureus as an etiologic agent of antibiotic-asso-ciated diarrhea or colitis. However, there is no question thatdiarrhea can be caused by S. aureus. For example, diarrheais common in patients with the toxic shock syndrome causedby inf-ection with enterotoxigenic staphylococci, often thesite is one that is minor and hard to detect (39). Morealarming is that methicillin-resistant S. aureus enteritis hasbeen reported within the past few years as an importantcause of antibiotic-associated enteritis in Japan in patientswith negative studies for C. dfficile and its toxins (13, 40).Ifthese reports are confirmed outside ofJapan, then enteritiscaused by methicillin-resistant S. aureus and methicillin-sensitive S. aureus, organisms that are resistant to metroni-dazole, may emerge as an important complication of anti-biotic use elsewhere, including in the United States. Suchcases would most likely be recognized when patients withantibiotic-associated diarrhea presumed to be caused C.dfficile failed to respond to treatment with metronidazole.Staphylococci may already cause more nosocomial diarrheaor colitis in the United States and other countries than isappreciated, in part because selective culture media andother tests needed to implicate this organism are neitherwidely available nor often used for patients with nosocomialantibiotic diarrhea. Finally, in 1978, three patients inhospitals in the United States were reporled to havepseudomembranous colitis, which was well documented in

two of them, and good laboratory studies failed to detect C.difficile and its toxins in their stools, but were positive for S.aureus and a unique cytotoxin similar to one produced bytheir staphylococci ln vitro (41). Therefore, it is possible thatthe preference fbr metronidazole in treatment of C. difficilediarrhea may be associated in the future with a resurgence of

AJG - Vol. 92, No. 5, 1997

diarrhea and enterocolitis caused by staphylococci. Theseissues are discussed in greater detail elsewhere (13).

When therapy with vancomycin for C. dfficile diarrhea isjustified, it is usually given orally in a dosage of either 125mg four times per day for 7-10 days, or 500 mg four timesper day if the patient is critically ill or has impending ileus,

colonic dilation, or perforation. These regimens seemedequally effective in reported studies (4,22). For infants andchildren, an oral dose of 5OOmg/1.73 m (2) every 6 h hasbeen used. Vancomycin should not be given intravenouslyas the sole therapy for C. dfficile diarrhea, since effectiveconcentrations within the colonic lumen are not reliablyachieved when it is given in this way. If patients cannot betreated orally with vancomycin, or they have paralytic ileus,and the patient is to be treated by the instillation of the drugby perfusion via a tube or pigtail catheter directly into thececum or ileostomy, 200 or 500 mg vancomycin in 500 ml(400 or 1000 pgiml) given up to four times per day can beused, if tolerated. Another regimen that has been used in thissetting consists of giving vancomycin intracolonically (2000

mg followed by 100 mg every 4 h and 100 mg after eachstool) via a pigtail catheter positioned during colonoscopy(42). Reconstituted solutions containing vancomycin mustbe diluted with at least 100 ml of diluent per 500 mgvancomycin.

Alternative therapies. Bacitracin (43), teicoplanin (44),

or nonabsorbable anion binding resins (45) such as cho-lestyramine or colestipol may be given orally for treatmentof mild C. dfficile diarrhea (4), but these agents are neitheras reliable nor as rapidly effective as metronidazole orvancomycin. Anion binding resins bind toxin B of C. dffi-cile, but experience suggests their capacity to do this islimited and probably inadequate in severe cases. They mayalso bind vancomycin and thereby diminish its efficacy, andcan cause severe constipation and intestinal obstructiononce diarrhea has resolved. Neither teicoplanin nor bacitra-cin for oral administration are readily available in the UnitedStates. It should be cautioned that teicoplanin has a propen-

sity similar to that of vancomycin for encouraging thespread of vancomycin-resistant enterococci, and that theclinical response to bacitracin is slower and less certain thanit is with vancomycin, possibly because some isolates areresistant to bacitracin (37).

MANAGEMENT OF RELAPSES OR RECURRENCESOF C. DIFFICILE DIARRHEA OR COLITIS

Guidelines for management of relapses are presented inTable 3. Relapses (recunences) of diarrhea or colitis arerecognized when there is a return of symptoms, signs andpositive diagnostic tests a few weeks to months after dis-continuation of successful antibiotic therapy for C. dfficilediarrhea. Because the patients had previously responded,these occurrences should not be thought of as treatmentfailures. Relapses occur in about 15-357o of patients, with amean fiequency of about 207o (4, 22, 23). Because C.

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AJG - May 1997

dfficile diarrhea and colitis have markedly increased infrequency in hospitals in the United States since lgg4 (11,46), so has the frequency of encountering patients withrecurrent or relapsing C. dfficile diarrhea. Relapsing C.dfficile diarrhea is a serious, difficult, and still unsolvedmanagement problem, especially when patients have expe_rienced three or more episodes (47). However, it is impor_tant to remember is that it is rarely difficult to treat eachrecurrence successfully using standard therapy with metro_nidazole (or vancomycin); what is still difficult to accom-plish is the prevention of further recurrences.

Recurrences may be caused either by persistence of theoriginal strain of C. dfficile or by reinfection with the sameor a different strain. Some strains seem more likely thanothers to cause recurrences (47), whereas strains that arenontoxigenic never do so. Recurrences usually begin withthe retum of diarrhea 2 wk to 2 months after successfulantimicrobial therapy of an episode of C. dfficile diarrhea.Recurrences are characterizedby the return of typical symp-toms and signs of C. dfficile diarrhea, positive assays for C.dfficile toxins in stools, and cultures that yield vancomycinand metronidazole susceptible strains of C. dfficite. Theliequency of recurrences does not seem to be influenced bythe specific nature of the original inciting antibiotic, bywhether metronidazole or vancomycin was used for treat-ment of the initial episode, or by the dosage or duration oftreatment with vancomycin or metronidazole. In some re_ports, recurrences occurred more often in patients whosestool cultures remain positive after successful antibiotictherapy for C. dfficile diarrhea, bur not in others (29,47).Ineither case, because there is no way to reliably eradicate theC. dfficile carrier state, there is no good reason to obtainstool cultures to determine whether a patient is at high riskfor a relapse. Relapses appear to be less likely to occur if thefirst episode was treated only with supportive therapy. Someunfortunate patients have experienced many recurrences;more than 6 episodes is not unusual and more than 20 isalleged to be the record, each after a course of apparentlysuccessful treatment. Fortunately, patients can be reassuredthat recurrences do nol have a tendency to become progres-sively more severe (47), even though they may cause moreand more concern with each episode.

Many different treatments have been used in an attempt toprevent recurrences, and most experts have their own fa-vorite regimen. However, no specific treatment regimencommercially available in the United States has beenproven in properly controlled, double blinded, randomizedstudies to prevent multiple recurrences or relapses ofC.difficile diarrhea. Standard antibiotic therapy should beused to treat relapses and is usually successful, even if itdoes not prevent further recurrences (47). Metronidazoleseems to be as effective as vancomycin in treatment ofrelapses, and it is less expensive and generally well toler-ated. There is little or no evidence that patients sufferingfrom multiple recumences do so because they have under-lying abnomalities of their gastrointestinal tract or host

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS 141

resistance factors that accounts for their proclivity for de_velopment of recurrences, although a few children and oneadult have been reported who may have had a specificimmunoglobulin deficiency that predisposed them to re-lapses (48-50). Whereas vancomycin and metronidazolealmost always kill the vegetative forms of C. dfficile thatproduce the toxins causing diarrhea, they do not reliably killthe spore fbrms of the organism, the persistence of whichseems the root cause of the trouble. In fact, antimicrobialtreatment appears to encourage formation of spores (51),which are hardy and can persist in the intestines or envi_ronment of patients for long periods of time (14), duringwhich they may germinate, or the patient may becomereinfected, and diarhea may occur if the patient has notre-established intestinal resistance to the colonization,growth and toxin production by C. dfficile. The mecha_nisms, such as competition fbr nutrients (52), by whichcertain organisms of the normal flora are responsible for"colonization resistance" to C. dfficile are poorly under_stood. Paradoxically, derangements in colonization resis_tance are even seen after treatment with vancomycin andmetronidazole, since both are capable of inducing C. ctrfft_cile dianhea as well as of treating it. Unfortunately, the f'ecalflora and its colonization resistance may not return to nor_mal for many months after exposure of patients to antibi_otics. lt therefore seems prudent that an effort should bemade in managing patients experiencing relapses to avoiclthe use of antibiotics as much as possible so as to hasten thereturn of the protective normal fecal flora. Accordingly, it isrecommended that the unnecessary prophylaxis or treatmentof infections, especially minor ones, with antibiotics shouldbe avoided within the first 2 months after treatment of anepisode of C. dfficile diarrhea (47).

When patients experience a recumence of C. rtifricitediarrhea within a few months after a successfully treatedepisode, the diagnosis should again be confirmed (especiallyif the episode is atypical). Unless diarrhea is mild, thepatient should again be treated specifically, preferably withmetronidazole, even if it was used for treatment of the firstepisode (or vancomycin, according to the treatment Guide-lines in Table 3), usually for only 7-10 days in standarddoses if the patient responds promptly (47).

Some authorities believe that patients suffering fiom re-peated recurrences should be treated using a regimen con-sisting of the intermittent administration of metronidazole(or vancomycin) over a period of weeks or even months andfollowed by their gradual tapering, or by prophylaxis withlow doses of these antibiotics given daily or on alternatingdays or weeks, or by use of cholestyramine or other anionbinding medications along with specific antibiotics, espe-cially at the end of therapy (6, 53). Cholestyramine can bindvancomycin as well as the toxins of C. dfficile and as aresult may interfere with specific therapy; it may also causeobstipation as a side effect. Such regimens may appear rohave been successful in preventing further relapses, butnone have been validated in properly controlled studies, so

148 FEKETY

the favorable result may be only coincidental. Treatment

with the combination of vancomycin and rifampin given

orally was thought to be effective in termination of relapses

in a small uncontrolled study (54), but there is no evidence

that this antimicrobial combination has any synergistic or

other unique activity against C. dfficile or its spores, the

hope of which was the reason it was tried in the first place.

Various other unproven measures have tried to restore the

colonization resistance of the fecal flora of patients with

relapses. Many of them fall into a category referred to as

probiotics. These include the oral or rectal administration of

yogurt, lactobacilli (55), enemas containing feces from

healthy persons (56) or mixtures of various bacteria nor-

mally found in the intestinal tract (57). Use of the Lacto'

bacillus GG strain seems to be more effective and rational

than yogurt or other lactobacilli (55). Another promising

new approach involves treating patients who have relapsed

with the oral administration of a live yeast (Saccharomyces

boutardii) for about 4 wk, beginning 4 days before the end

of conventional antibiotic therapy for a recurrence. This

novel measure was evaluated in the United States in a well

designed multicenter placebo-controlled study and was re-

ported to be safe as well as effective. Its use in patients who

had experienced at least one relapse was associated with a

reduction of about 5O7o (p : 0.04) in the frequency of

further relapses (58) compared with those receiving placebo.

This report is the only well controlled and scientific study

concerning the prevention of relapses in humans that has

thus far been reporled. The mechanism of the presumed

protective effect of S. boulardii is not known, but it may be

because a protease it produces prevents the binding of the

toxins to the intestinal mucosa (59). Because S. boulardii is

available for treating relapses in Europe but not in the

United States, some physicians here have attempted to use

Saccharomyces cerevisiae (Brewer's yeast) in a similar

fashion. However, these two organisms are significantly

different from one another (60), and there are no reports

proving the efficacy of S. cerevislae, although there are a

few anecdotal reports claiming success with it.

Therapy with intravenous immune globulin, especially in

children with various immunoglobulin deficiencies, has ap-

peared effective in prevention of recurrences in anecdotal

reports (48-50). Other novel ways to actively or passively

immunize patients against C. dfficile and its toxins are the

subject of ongoing research related to this important and

increasingly frequent problem of recurrent C. dfficile diat-

rhea.

PREVENTION OF C. DIFFICILE DIARRHEA ANDCOLITIS

Guidelines for prevention are presented in Table 4' Pte-

vention of C. difficile diarrhea and colitis is based upon a

few simple practices and attitudes. Hospitalization and in-

tensive exposure to antibiotics are important risk factors for

acquisit ion of C. dffici le (4-6, 8, l l , l2). Avoidance of the

AJG - Vol. 92, No. 5, 1997

TasLs 4

Practice Guidelines .for Prevention of Clostridium dfficile Dirtrrhea

1. Limit the use of antimicrobial drugs.

2. Wash hands between contact with all patients.

3. Use enteric (stool) isolation precautions for patients with C. dfficile

diarrhea.4. Wear gloves when contacting patients with C. dfficile dianhea./colitis

or their environment.

5. Disinfect objects contaminated with C. dfficile with sodium

hypochlorite, alkaline glutaraldehyde, or ethylene oxide

6. Educate the medical, nursing, and other appropriate staff members

about the disease and its epidemiology.

unnecessary use of antimicrobial drugs is of obvious im-

portance, but is all too often easier said than done. Restraints

and limitations in the use of antimicrobials are of growing

importance because of alarming recent increases in the

emergence of new antibiotic-resistant pathogens in hospi-

tals, such as Enterococcus faecalis and E. faecium, Strep-

tococcus pneumoniae, Staphylococcus hemolyticus, Clos-

tridium dfficile, and numerous species of enteric Gram-

negative bacilli.Transmission of C. dfficile from one person to another

via the hands of personnel appears in hospitals to be more

important in spread of C. dfficile than does contact with

spores in the environment, but both probably occur. Careful

handwashing before and after contact with all patients, and

the use of gloves and stool (enteric) isolation precautions

when contacting patients wirh C difficile dianhea or who are

carriers of this organism are the most effective measures for

preventing its spread (4, 14, 61, 62). Single rooms with

private bathrooms should be provided when possible for

patients with C. dfficile diarrhea, at least until their diarrhea

has stopped. Patients with C. dfficile diarrhea and to a lesser

extent, those who are asymptomatic carriers of the organism

appear to contaminate their immediate environment with C.

dfficile spores, which then becomes a potential source of

reinfection for the patient as well as personnel and other

persons, particularly if they have recently received antibi-

otics (8, 14). Since many healthy persons and patients with-

out diarrhea who are in hospitals carry C. dfficile in their

intestines, there is little if any rationale for continuing En-

teric Isolation Precautions for patients who no longer have

diarrhea, or to test them for calriage of the organism after

diarrhea has stopped. Antibiotics do not reliably kill the

spores of C. dfficile even though they may kill the vegeta-

tive forms of the organism, and therefore treatment of car-

riers with metronidazole or vancomycin does not eradicate

the organism from their intestinal tracts (35), even though

these antibiotics may markedly decrease the numbers of

vegetative forms in stools (51). Suppression of excretion of

the organism by carriers with use of treatment with metro-

nidazole or vancomycin may have occasionally been useful

in terminating localized outbreaks in hospitals, but the ef-

fects of this approach have been far from striking. Alkaline

glutaraldehyde, sodium hypochlorite, and ethylene oxide are

A"

efofanfo.naitem(dircoparo(norelpr(the

horor€theabrpatwitunI

'l

tudrPartercUniGerM.I(MeF.AM . lNev(MaF.Ason,sitywellVA)SimfornH SMedo f \PeteHosl( J . Awiltdatic(FauF.A.rNam

AJG - May 1997

effective in killing the spores as well as the vegetative formsof C. dfficile (4, ll, 14) that persist on fomites, instrumentsand contaminated surfaces, but none of these are satisfactoryfor handwashing, which is still best carried out with ordi-nary disinfectant soaps or chlorhexidine, despite their lim-ited power to kill C. dfficile spores (4, 63). Additionalmeasures that have been used in facilities where C. dfficilediarrhea is occurring at a high rate include identifying andcohorting (segregating) patients who are carriers, restrictingpatients who are carriers to single rooms with private bath-rooms, and antibiotic control programs. Neither vancomycinnor metronidazole nor any other antimicrobial regimen arereliably effective in eradicating the C. dfficile carrier state,probably because the spores ofthe organism are resistant totheir action, unlike the vegetative forms.

It is important that everyone involved with patient care inhospitals, nursing homes, and at home be educated about theorganism and its epidemiology, about rational approaches tothe treatment and care of patients with C. dfficile diarrhea,about the importance of handwashing between contact withpatients, about the use of gloves when caring for a patientwith C. dfficile diarrhea, and about the avoidance of theunnecessary use of antimicrobials.

ACKNOWLEDGMENTS

The author acknowledges with sincere thanks and grati-tude the expert advice, help, and counsel of the PracticeParameters Committee of the American College Gastroen-terology: J. Patrick Waring, M.D., F.A.C.G. Chair (EmoryUniversity, Atlanta, GA), Alan Barkun, M.D. (MontrealGeneral Hospital, Montreal, PQ, Canada), W. Scott Brooks,M.D. (Atlanta, GA), Kenneth R. DeVault, M.D., F.A.C.G.(Mayo Clinic, Jacksonville, FL), John Hughes, M.D.,F.A.C.G. (Kelsey Seybold Clinic, Houston, TX), DouglasM. Simon, M.D., F.A.C.G. (Albert Einstein Medical School,New Rochelle, NY), Thomas Viggiano, M.D., F.A.C.G.(Mayo Clinic, Rochester MN), James Achord, M.D.,F.A.C.G. (University of Mississippi Medical Center, Jack-son, MS), Eugene M. Bozymski, M.D., F.A.C.G. (Univer-sity of North Carolina, Chapel Hill, NC), Stephen H. Cald-well, M.D. (University of Virginia HSC, Charlottesville,VA), Michael J. Goldberg, M.D. F.A.C.G. (Chicago, IL),Simon K. Lo, M.D., F.A.C.G. (Harbor-University of Cali-fornia Los Angeles Medical Center, Torrance, CA), RobertH Squires, Jr., M.D. (University of Texas SouthwesternMedical Center, Dallas, TX), Paul Yeston, M.D. (Universityof Virginia Health Sciences Center, Charlottesville, VA),Peter A. Banks, M.D., F.A.C.G. (Brigham and Women'sHospital, Boston, MA), Patrick G. Brady, M.D., F.A.C.G.(J. A. Haley Veterans Administration Hospital, Tampa, FL),Will iam D. Carey, M.D., F.A.C.G. (Cleveland Clinic Foun-dation, Cleveland, OH), Norman D. Grace, M.D., F.A.C.G.(Faulkner Hospital, Boston, MA), George W. Meyer, M.D.,F.A.C.G. (Georgia Baptist Medical Center, Atlanta, GA),Namish Vakil, M.D., F.A.C.G. (Sinai Samaritan Medical

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS'749

Center, Milwaukee, WI), Gregory Zuccaro, Jr., M.D(Cleveland Clinic. Cleveland. OH).

Reprint requests and correspondence: Robert Fekety, M.D., Division ofInfectious Diseases, Department of Intemal Medicine, 3116 TaubmanHealth Center, University of Michigan Hospitals and Medical School, AnnArbor. MI 48109-0378.

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