-0739S03.

00/0 0002-927 0/97/9205

THE ANTERICAN JouRNAL oF GlsttouttgxoLocy Copyright O 1997 by Am. Coll. of Gastroenterology

V o l . 9 2 ,N o . 5 , 1 9 9 7 Printed in U.S.A.

Practiceguidelines

Guidelines for the Diagnosis and Management of Clostridium

dfficile-Associated Diarrhea and Colitis

Robert Feketv.M.D.

Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When data are not available that will withstand objective scrutiny, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. Given the wide range of choices in any health care problem, the physician should selectthe course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. These guidelines are also approved by the governing boards of American College of Gastroenterology and Practice Parameters Committee. Expert opinion is solicited from the outset for the document. Guidelines are reviewed in depth by the committee, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time. The following guidelines are intended for adults and not for pediatric patients.

INTRODUCTION Antibiotic-associateddiarhea and colitis are imporrant and increasinglyfrequent complications of antibiotic therapy. While these occur most often in hospitalsand nursing homes,they also occur in the community. Antibiotic-associated dianhea is even more common; it is causedbv ClosRectivetl Oct. 10, 1996: acceptedJan. 28, 1997

tridium dfficile in only l5-207o of cases, and is of unknown cause in most of the remaining cases (1-3). The type of antibiotic-associated diarrhea that is not causedby C. dfficile is relatively mild, self-limited, unassociated with intestinal lesions, is treatablewith nonspecific supportivemeasures and by discontinuation of antibiotics, and is also referred to by a variety of terms such as simple, benign, or enigmatic antibiotic-associated diarrhea.In contrast,C. dif diarrhea is usually associated with colitis ficile associated causedby the combinedeffects of toxins A and B produced by C. dfficile within the intestinal lumen and is a serious and potentially life-threateningdisease. C. dfficile, a sporeforming obligate anaerobicbacillus, is a componentof the normal fecal flora of many infants,and about 5% of healthy adults; it may be found in the stools of l07o or more of hospitalizedadults without diarrheawho have receivedantibiotics or cancer chemotherapeuticagents. C. dfficile causesa spectrumof diarrheal syndromesthat vary widely in severity and merge with one another;they are also commonly referred to by a variety of names, including C. dfficile diarrhea,C. dfficile colitis, antibiotic-associated C. dfficile colitis, and pseudomembranous colitis. Unlessspecified otherwise,the generalterm "C. difiicile diarrhea" will be usedhereinto refer to the entire spectrumofthe diarrheal diseasescaused by this organism. The diarrheal illness causedby C. dfficile may and often does closely resemble the more frequent benign or simple antibiotic diarrhea. Patientswith antibiotic-associated diarrheain which C. df of the ficile cannotbe incriminated, which is true about 80o/a time, are assumedto have the simple or benign diarrheaof unknown cause. C. dfficile diarrhea, colitis without pseudomembranes, and pseudomembranous colitis are toxin-mediatedmucosal inflammatory processes that are usually characterized by the presence of grossly or microscopicallyvisible pseudomembranes consisting of nodules or large plaques containing leukocytes, fibrin, mucus, and epithelial cells loosely adherentto the surfaceofthe underlyinginflamed and necrotic mucosa.Almost all casesof antibiotic-associated colitis or pseudomembranous colitis are causedby both toxin A and

740

FEKETY

AJG - Vol. 92, No. 5, 1997 damage to human colonic mucosa in cell cultures (9). It seemsprobable that both toxins are important in causing diarrheal diseasein humans. C. difricile rarely damagesthe colon of patientsby direct invasion, although it can occasionally do so (10), and it should be emphasizedthat the diarrhea the organism produces is caused by the effects of toxins that are produced within the intestinal lumen and adhereto the mucosal surface(3-6). EPIDEMIOLOGY OF C. DIFFICILE DIARRHEA

B producing strainsof C. dfficile. Most patientswith C. dfficile diarrhea can be found to have gross and/or microif they scopic colitis with or without pseudomembranes undergoa workup that includes colonoscopywith biopsies. When pseudomembranes are not evident in patientswith C. diflicile diarrhea who have undergone colonoscopy, the diarrhealprocessmay have resultedfrom a purely secretory diarrhea without colonic inflammation. Because,for a variety of reasons,many if not most patients with antibioticdiarrhea do not undergo endoscopyand biopsy, associated "C. dfficile diarrhea" is used more and the general term more often when one of more laboratory tests for C. dfficile are positive and the organism is consideredto be the cause of the diarrhea,and it is not certain whether or not colitis and/or pseudomembranes are present. C. dfficile diarrhea with colitis and pseudomembranes can lead to toxic dilation and/or perforation of the colon, dehydration,hypovolemia, colitis was shock, and death.Although pseudomembranous well-recognizedin the preantibioticera (and was thought to be causedby staphylococci),it is now uncommon to diagnose it in a patient who has not received antibiotics and in whom C. dfficile cannot be implicated. As many as 20Voof patientswith C. dfficile diarrheado not develop symptoms until as long as 6-8 weeks after discontinuationof antibiotic therapy.In addition,patientshave developedC. dfficile diarrhea after the use of cancer chemotherapeutic agents, many of which have significant in vitro antibacterialactivity (4-1). PATHOPHYSIOLOGY OF C. DIFFICILE DIARRHEA

C. difricile diarrheais causedprimarily by the elaboration within the intestinal lumen of both toxin A and toxin B produced by C. dfficile during its multiplication. These toxins bind to the colonic mucosa and then exert their damaging effects upon it. Most toxigenic isolatesproduce both toxins, but depending on whether they are obtained from infants, healthy adults, the environment, or persons with antibiotic-associated diarrhea,about 5 to 25Toof isolatesof C. dfficile produceneithertoxin A nor B, and do not cause colitis or diarrhea (5, 6, 8). Toxin A is a 308-kDa mucosal in capable of causing extensive damage enterotoxin experimentalanimals;it is cytotoxic for certain cell lines in for neutrophils,and an activator culture, a chemoattractant of macrophagesand mast cells, causing them to produce various inflammatory mediators (8). Toxin A causesactin disaggregationand intracellular calcium release,and also appearsto damage neurons (3-6). Toxin B is a 270-kDa cytotoxin that causes depolymerizationof filamentousactin. Toxin B was first detectedby virtue of its potent cytopathic effects in cell culture monolayers,but becauseit was not cytotoxic for the colonic mucosaof various animal species it was originally consideredof little importancein causing colitis in humans. Recent evidence indicates toxin B disrupts the actin cytoskeleton,and is also a necrotizing enterotoxin l0 times more Dotentthan toxin A in causins

The frequencyand incidenceof C. dfficile diarrheavaries widely not only geographicallybut within different institutions in the same area, and dependson patternsof antimipatternsof the prevcrobial use, on antimicrobial resistance alent C. dfficile isolates,on epidemiologicfactors favoring transmissionof the organism, on patients' risk factors, on clinicians index of suspicion, and especially on the frequency with which endoscopy and/or various laboratory tests for the presenceof toxins A or B in stools are perdiarrhea(4-6, formed on patientswith antibiotic-associated 8, I 1). Ironically, as the frequency of postoperativewound infections has declined over the past few decades,in no small measure becauseof the skill of surgeonsand their perioperativeantibiotic proappropriateuse of short-course phylaxis in high-risk patients,the frequency of C. dfficile diarrhea has markedly increasedin hospitalsin the United States,especiallyin the elderly (12). Almost every popular antimicrobial has been implicated in the causation of C. dfficile diarrhea,but ampicillin and other penicillin derivatives,cephalosporins and clindamycin, are implicated most frequently (l-6). Less frequently incriminated are erythro. mycin, aminoglycosides, fluoroquinolones, sulfamethoxazole-trimethoprim,and perhaps surprisingly, both vancomycin and metronidazole, which are the drugs of choice for treatment of C. dfficile dianhea. Tetracyclines and chloramphenicol are now rarely implicated, but they were frequently implicated in what was diagnosed as staphylococcal enterocolitisin the early antibiotic era (1, 5, 13). C. dfficile diarrhea occurs both sporadically and in clusters or outbreaks in hospitals,nursing homes and chronic care facilities, but the frequencyof the diseaseis very much lower in the community. C. difficile canbe detectedin the stools of 5Voor more of healthy adults, and even more frequently in the stools of healthy infants (30-507a) and patientswithout diarrheain some hospitalsand nursing homes (up to 307o). Infants who carry the organism rarely develop C. dfficile colitis, and there is evidencesuggestingthe reasonfor this apparentprotectionis that the toxins do not bind well to the its binding sitesare immature (3, 5, colonic mucosabecause 6). C. dfficile is widely distributed in the soil, water, and environment of patients with C. dfficile diarrhea (14). In some hospitalsand nursing homes, as many as 20-30Vo or more of patients who have received antibiotics have been found to be asymptomatic carriers and shedders of the spreadof the organisminto the environment.Consequently,

AIG - May 1997

CLOSTRIDIUM DIFFICILE-ASSOCIATEDDIARRHEAANDCOLITIS
TABLE I P r a c t i c e G u i d e t i ne s fo r, - t ;;:; ::^: :o

141

organismto others there who have been treated with antibioticsand are thereforesusceptible to colonizationby small numbersof C. dfficile sporesmay be frequent. Transmission of the C. dfficile seemsmost often to be via the hands of hospitalpersonnel,and also by contactwith contaminated surfaces and fomites (11, 13). CLINICAL MANIFESTATIONS OF C. DIFFICILE DIARRHEA The typical manifestationsof Clostridium dfficile diarrheaare cramping abdominalpain, profusediarrheaconsisting of mucoid, greenish,foul-smelling, watery stools, low gradefever, and leukocytosis.These can start a few days after antibiotic therapy is begun or up to 8 weeks after its discontinuation.Many patients with C. dfficile diarrhea havefever that exceeds40'C and leukocytosis as high as per mm (3); in fact, leukemoid reactionsin the range 50,000 of 100,000per mm3 have been reporled. It is not rare for patients to have watery diarrhea similar to that seenin the benign antibiotic diarrhea of unknown cause (l-6). Althoughcolitis can occur throughout the colon, it is usually mostseverein the distal colon and rectum. When patients developcolitis localized to the cecum and right side of the colon,they may have little or no diarrhea. lnstead, fever, markedright-sided lower abdominal pain and tenderness, markedleukocytosis,and decreased intestinal motility may bethe only clues to the disease. This presentation is not rare but is especially serious, in part because diagnosis and treatment may be delayed becauseof the lack of diarrhea, and seems to occur more frequently when antiperistaltic agents or opiates have been given postoperatively.Unless endoscopy or computerizedtomography or other tests are done and suggestthe diagnosis and the need for specific antibiotic therapy, these patients may progress rapidly in severityand require emergent abdominal laparotomy and subtotalcolectomy becauseof toxic megacolon or colonic perforation (15, 16). Other complications of C. dfficile diarrhea include dehydration,hypovolemia,hypoalbuminemia, anasarca, electrolytedisturbance, shock, and a reactive (4-6). arthritis The differential diagnosisof C. difficile diarrheaincludes benign or simple antibiotic-associated diarrhea, acute and chronicdiarrheacausedby other enteric pathogens, adverse reactions to various medicationsother than antibiotics,ischemic colitis, idiopathic inflammatory bowel diseases,and intra-abdominal sepsis. DIAGNOSIS OF C. DIFFICILE DIARRHEA AND COLITIS Ertdoscoltic diagnosi s Guidelines for diagnosis are presentedin Table 1. The best and most rapid way to establish the diagnosis of C. diffic'ilecolitis is by endoscopywith biopsy of suspicious lesions, but endoscopy is expensive and usuallyreserved fbr

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 diagnosisshould be suspected in anyone with dianhea who has received antibiotics within the previous 2 months and/or whose diarrhea began 72 h or more after hospitalization. 2. When the diagnosisof C. dfficile diarrhea is suspected, a single stool specimen 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 negativebut diarrhea persists,one or two additional stools can be sent for testins with the same or different tests. 4. Endoscopy is reservedfor special situations,such as when a rapid diagnosisis neededand test results are delayed or the test is not highly 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 ill and the resultsof rapid but not highly sensitivenoninvasive tests are negative or delayed and C. dfficile diarrhea is processthat strongly suspected, or when some other disease can be diagnosedby endoscopy is also being considered (2-6). Endoscopyis diagnosticwhen it demonstrates characteristic, raised, yellowish nodules or plaque-like pseudomembranes, often with skip areasof normal mucosa. The nodules are usually 2-10 mm in diameter, but in advanced stagesthey are increasedin number, enlarged,and coalescedto form plaques or membranesthat cover large segmentsof the inflamed mucosa but are easily stripped from it (hence the term pseudomembrane). Nodules and small pseudomembranes are easily dislodged during the processingof biopsies.Microscopic examinationof the lesions shows epithelial necrosis,goblet cells distendedwith mucus, edema, and infiltration of the lamina propria with leukocytes, epithelial cells, fibrin, and mucin. The terms "summit "volcano lesions" or lesions" have been used to describe t h e s el e s i o n s( 1 , 3 , 4 ) . G r o s sl e s i o n sm a y b e s o characteristic to experienced endoscopists that biopsy is not needed,but it is best to obtain a biopsy if there is doubt about the diagnosis.When the colonic mucosa shows only erythema, friability, or edema without nodules or pseudomembranes, it is suggestiveof the so-callednonspecific colitis or simple colitis that may be caused by C. dfficile as well as a variety of other conditions. Biopsy of such lesions,even when small, may confirm the presence of inflammation (colitis) along with pseudomembranes that are not grossly apparent. In a study of 22 patients with pseudomembranous colitis, it was found that endoscopy with a rigid endoscopedetectedfewer casesof colitis than with a flexible sigmoidoscope (77 vs 9lVo), and that colonoscopydetectedadditional cases(97aof the total) not (17). reached using flexible sigmoidoscopy C. di.fficile-specific diagnoslic /csls There is as yet no simple, inexpensive,rapid, sensitive, and specific test for diagnosing C. dfficile diarhea and colitis. nor are all the availabletestssuitablefor adootionbv

742

FEKETY

AJG - VoL 92. No. 5. 1997 doscopy, arguably the two most accurate and dependable diagnosticaids. On average,EIA testsfor toxin A and/or B failed to detectabout l07o (range5 to 33Vo) or more of cases of C. dfficile diarrhea diagnosedclinically and by endoscopy with biopsy or by useof toxin B assays in cell cultures. Newer and allegedlybetterEIA tests(as well as other novel tests) are becoming available, but proper clinical studies documenting their superiority have not yet been reported. Therefore,it should be emphasized that a negativeEIA test for toxins A or B does not rule out the diagnosis of C. dfficile colitis. Sensitivity is rarely improved by sending more than one stool on the sameday for EIA testing,so this practice is probably not cost-effective and should be discouraged.However, when an EIA test,or other rapid test,is reported negative, it may be then be worthwhile to send another stool the next day for testing by EIA or by different tests, especially if the patient with antibiotic diarrhea of unknown cause is critically ill or does not improve after antibiotic therapy has been discontinued and supportive therapyhas been given. Alternatively, empiric therapy with metronidazolemay be given to seriously ill patients when the first test result is negativeand other diagnostictestsare not available or are in process. Latex agglutination re.lt. Originally thought to detect toxin A, this simple, rapid, and inexpensive immunologic test actually detectsthe presenceof glutamate dehydrogenase produced by C. dfficile, not toxin A (3, 4). This enzyme appearsto play no role in the pathogenesis of C. dfficile diarrhea, but many clinicians and laboratory personnel still incorrectly believe the latex agglutination test detectstoxin A. Nontoxigenic strainsof C. difficile (which do not causediarrhea)are also positive with the latex test. In addition, the latex agglutinationtest is nonspecific, because several other organisms commonly found in stools can produce an antigen that cross-reacts with the antibody directed against glutamate dehydrogenase produced by C. dfficile. Overall, the latex agglutination test is about as sensitiveas but not as specificas the EIA testsfor the toxins (19-21,23). Commentsin the previoussectiondiscouraging the practiceof sendingmore than one diarrheal stool per day for EIA testing apply equally well to the latex agglutination test. Both the EIA and latex agglutination tests are simple, rapid, and inexpensiveif they are performed in batchesand quantity, but neither one is as reliable and sensitive as desired.Unfortunately,clinicians are often unaware of the specific test used for detecting C. difficile or its toxins in their Iaboratoryand of their important differencesin sensitivity and interpretation,in part because such results are commonly reported simply as a positive or negative "C. dfficile test" without specifying the test used. A few laboratories have begun to use both the EIA and the latex agglutinationtests,reservingthe performance of the latter for specimensthat are negative by the EIA. This strategy appearsto improve sensitivity and to decreasespecificity, but many clinicians would conclude this errs in the right

every laboratory (18). However, each laboratory should consider providing one of the rapid, inexpensivetests and also, if practical, a specific test for the presence of the organismor its toxins. Many institutionsprovide an enzyme immunoassay(EIA) test for rapid detectionof toxin A or B and also a cell culture assayfor toxin B, the cytotoxin. Tissue culture tests for toxin B. The "Gold Standard" Iaboratory test for establishingthe diagnosisof C. dfficile colitis is still the demonstration in cell culture monolayersof the characteristic cytopathic effect of toxin B in filtrates of diarrheal stools. Specificity of the cytotoxicity is demonstratedby showing that it is prevented(neutralized)by use of antitoxin Io C. dfficile or Clostridium sordellii toxin (the utility of the latter reflects antigenic cross-reactivity)(1-6, 18-21). There is no practical laboratory test available for detectingtoxin A in stools by meansof its biological properties. Cell culture tests to detect the specific cytopathic effects of toxin B are positive in more than 90%a of patients with pseudomembranous colitis (1-6). False negative resultsin this as well as the other testsusedfor detectingthese toxins may be causedby a number of factors:because of the inactivationof the heat and acid labile toxins during storage or transportation or by medications,becausesome cell lines used for this test are less sensitivethan others to the cytopathic effect of the toxin (.2-6), and especially becauseof testing stool specimens diluted in the laboratory.Therefore, it is important to recognizethat a negative test for toxin B in cell cultures does not rule oil C. dfficile as the causeof the diarrhea.If toxin B is detectedin high titer, it is highly likely that C. dfficile is the causeof the diarrhea,but there is little conelation in individual patientsbetweenthe height of the toxin titer and the severity of the diarrhealdisease. It is not uncommon for patients who have respondedto appropriatetherapy for C. dfficile diarrheato continueto have stools that test positive for toxin B or the organism for a shorttime after discontinuationof otherwisesuccessful therapy. Experiencehas shown that most of these patientswill have no furlher diarrhea and that it is not necessaryto perform culturesor testsfor the toxin on stoolsfrom patients who no longer have diarrhea(5, 6, 18,22). Enzl,me immunoassay testsJbr toxin A and/or B. There are severalcommercially availableEIA testsfor detectionof toxins A and/orB of C. difficile in stools(l-3,5, 18-21). They are rapidly performedand relatively inexpensivewhen done in batches, and they are probably the most widely used laboratoryaids in the United Statesin diagnosingC. dfficile diarrhea. The EIA tests are more specific than they are sensitive.The sensitivity of the commercial EIA kits used for toxin A and B detection has varied widely when evaluated in different laboratoriesusing the same kits but differing criteria for a positive endpoint. Whereassensitivities have ranged from a low of about'707oto as high as 957o, specificity was generally very good. In most published reports,accuracyofthese testswas evaluatedon the basisof probable clinical diagnoses instead of upon diagnoses reachedusing both a cytotoxicity test for toxin B and en-

'rele^\oH '(97) e,rrtu8euan apcrlJip 'J Jo! slset sselun lnoqlr,\\ euoJpu^s leuruopqB elncB ue qlr^\ lueseJdoq,r\ srlloJ poprs-lq8u qlr.ry\ ueql JoJ setpnls reqlo ro sernllnc urBlqo 01 e^rl3oJJo-lsor sluerldur lueuodur fpelncrgud eq 'seuerqueuopnesd 'uruepe'uorleru 'e11au plno,ry\ sr ll puu 'eozolord ro 'relceqoyfdruec'e11a3rqs ro teql s8urpur; lou -oules se qons sueSoqledJrJelueluorlueluoc ,{q pesnuc -ruuuur JruolocJo ecuepr^aSuncelepur InJesneq ,{uru(13) flerer sr plrdsoq eql ol uorssrrupu pezrrelndruo3'se8uls reuu s,{eperou ro g Suru ,{qderSoruol JoIBI eq ,(etu le sno-re8uup -ur8eq pelurcossu-crlorqrlu eeq.uerp u.4Aoqs seq ,{eql puu 'eequerp alp{Jjp '3 ,(gua Surrnp suortrpuocreqto ecueu leql -edxg 'suaSoqpdotalua to{ polg satnllnc 1no 3urlnr ur ldecxe yn;esn ,(re,r. lou eJu stueuelsuJJuoJ lDuouuaAuoJ '(o69 ol luelstser tunueg 'do1e,r,ep uolor eql Jo uolleJoled ro uorlelrpcrxol se noqe) olozepruorleru ,{peerle eJB selulosr Ieuorsuccoesneceqpuu luetuluoJlJoJ qrns suorlEcrldruoc ueq,| lnJdleq eq uec feql tnq 'EeqrJErp elozepruorleu Sursn:og ecuere;ard3ur,uo-r8 eql Jo esneceq atp{llp , .Jo sesuc plnu ro ,{pee go srsou8erpur enle^ eJnlnJ eql ur fresseceu eJoru euoJeq feu lsel srql lnq oIIII eru ,(eq1 'uoloJ popuelsrpro snoleruepeuB ,^doqs .Jo 'selulosralp{llp 'sorpnlscrSolorper crlorqrtuu uro;red ,{eu 'stulg lnocs ro se1e1d J uo stsat,firlrqrldecsns 1ugsBqcns luur .{1eut1nor serroteroqel'fue ;r ',!\eC '(gZ 'VZ'9 'V-d tt4?Il -uopqv 'satnpaco.td puo sanbtuqcalSutSotut crlsouSorq 'luerlud JrlsrJelJeJeqJ slr Surlerlsuourep An Jepun Joloc esneJueqc ,(q ro flpcrureqcorq tusrue8ro eql 3ur,{;rluepr ,(1e,r,p u ur equerp atp{!!p '3 ro; fde,reql curdtue 11r,{1ere,res -dtunserdJoJ pue 's{ud-seg ro s.rufcrqoJeeuu ur uorleqnc SuruurSeq ,{gpsnfol luarrrJJnssr Beqxurp pelelJosse-crlorq 'euuesolc,(c Sururul -rluu qlr,r luerlud e ruorJ slools ur urueJolcsl 'lo se1,(co>1na1 -uI pue JeSeur esolJn{ puu 6urlrxoJec -uoc erpour elrlceles Sursnesoql ,{pulncrged 'rusruu8Jo eql aq,L'GZ '97) se1,(co>1ney;o e 'urxeJolc?l lcnpo-rd ;o ecuasard 3ur1e1osr roJ elqelre^e euoceq o^uq spoqleu eldurs 're^e oql roJ flprder pelsel eq uec sloots ',(1-re1rur5 ;o ecueserd -,uo11',(lrcrue8rxol puE '(g1) peurulqoeq plnoqs rccocolfqdels s1l Surlsel roJ elBlosr eql Jo uorleJrJ -lluopr pue uorlelosr popoeu roJ esrlredxe pue serlrlrcJ eql JoJ e^rlJelos erpeu Sursn sernllnJ Iools leql osle pue 6srl eAEqseIJolBJoqBI lou leql pue 'e,rrsuedxe f1e,,rr1e1er '5 ere -rlocorelue IIe sna"tnD se1,{co1ne1 ;o ,{Ilrqrssod eql stseSSns ,{eqt tuqt 'stlnser 8ur1re,r,ru eyrq,u, s,(ep E-7 1o f,vpp u sr eJeql SuoyusrelsnlJ ur rJJor e,rrtrsod-uurg Jo sroq IeceJ qtr.4A luql opnlcursernllnc Iools qlr,\\ suelqord reqlo 'eJusf1e,rr1e -runu a8rul Jo uorloeleposneceq'peue;erd sr urels s.rueJg 'elozepruolleu qlrl\ ,(duraqt -lor pue e,rrsuedxeur sr qcrq,^A E lnq 'pesn ,(luoturuocJsorueJu surulsestuerg Jo 's.ruBJC .{;rtsnftq8rru;1es1,,(qornllnc e,trlrsodB 'ueqilerp oreles seq 'en1qeue1,(qte6 ',{1a41,(re,t seruocequeqrrerpatlrtglp 'J scrlorqrluuqlr,4A peleerl luerled e Jr 'eJoJereql 'crueSrxolsr pue ruo palnt KlexlceJJepue ,{11crnbsr equerp crlorqrtue elelosreql ;l flprcedse 'asnel ,{1e1ry lsoru eqt sl tl teql esuc 'srrlorqrluu qlr,^d ;o ed,{1 u8rueq ;o eldrurs pelluJ-os eql eql osl sr 1 'eequerpcrlorqrlues.luerlude Jo esneceql sr ll {lluecer peleorl ueeq seq oq,\\ luerled u ur punoJ sr lr ueq^\ 1eql e,,'ordlou seop atlrr.JIlp J Jo uorlBlosreql lur{l onrl sl tl 'sesnur ,,{ueru ruor; llnsor feru leql SurpurJcgrcedsuou lnq suereqa 'snql '(02) crue8rxoluoueJe,^d eequurp polurcoss 'splerg,ftp-q8rq erour ro eerql ur e sr srso1,{co{nel IUJoC -crtorqrtue qlr^\ sluorled ruo4 selelos\ lo ob1l lnoqe ,{1uo se1,{co1na1 eJoruJo e,r.rg 8ur1celep lsel e,trlrsodV Jo slsrsuoc ,(pn1s reqlouu ur ',(lesre,tuoJ'Beqrrurp Sursnec;o elquducur 't4tadotd auop 'e,rrlrsuas lt InJesnaq uec lr pue eldurs sr 1 ,(lqeurnserd puu (6I) crue8rxoluou eJeA\ eeqrrurp lnoqlr.r\Jo rou cgrcedsreqlreu sr 1se1 e1,{colnelIuJeJeql q8noql ua^g 'suosred{qlpeq 'slueJur qllt\ pezrplrdsoq sluelled puu tuo4 'QZ'VZ'91) uequerpatp{llp J qtl^\ sluertud Jo prrql-ouo obgz lnoqu ',{pn1seuo uI peurelqo setlosratp{llp ') to paurels ur lueserd e:e lnoqe ur slools Ieeqxurp Jo sJeer.us 'rusrue8Jo eql;o eSeruuJleurlsolurlBlueprouroJ Jo esneJoq pceJ Jo sreqwnu lBurrouqv 's1sa1 se1,{co4ne1 Sutuaattg eoqxerp crlorqrluueldturs qlr.\\ sluerludur sllnseJ..errrlrsod spto tttsouSotp r)qJO -eslJ,, :o Sutpeelsru plerf ,{eur seJntlnJpols 'apc{lip '3 'uerplrqJ'sluegur ,(qtpeq.(ueu Jo srerueceq ,(eurstlnpepuu acug 'a1tc{rtp 'J {o a?nutoc ?ur1ca1ap tot satrulnc polg 'uo1{d rat.rDqo) -naH pue at!r#!p 'J sB qcns susrue8Jo surerlsluelsrseJ Jo -elozepruorleur;o peerds eql uelseq lqSnu 1r leql spuno;3 eql uo pe8urnocsrp eq ot sr e,rrlrsodeJe sllnseJeql Jr eloz 'eurlnor -epruorle{ucrlcu1,{qdord luerled eql 3ur^6 Jo pue e,ttleredoerd u se surxol sy rc apcgfiip 'J roJ pelsel eq ol eequurp lnoqlr,r\ sluertudruo4 slools Surpues;o ecrlcurd eqt ',{lluuld 'lsel uorleurtnlSSe xe1e1 eql ol rouedns ,(lqeqord er? g Jo V surxol 8ur1ce1ep roJ (VIg) s{esseountuurr eu.{z -ue eql 'peuro;:ed eq uec s1se1 prder elqelre^Bfluouruoc eql .+oeuo ,(1uo y1 'elereue8,(eqt suoder aql Jo ^lrprdur pue ',(lrcr;rceds ',{1,rr1rsues eql qloq eznurxuruol se os g urxol re. elouoru alnllnJ IIaJ e ro 'tusrue8ro Jo gdJ eql roJ 1se1 eql roJ arnllnc u se qcns 'tsal e qlrl\ Suop rueql luoroJJrp 'luerlud u roJ uorlcerrp 11r,{lsnorres '1.92'tl) elozepruorleuot tu?lsrs -aJ eJu rccocol,,(qde1s esnuceqsrlrlocoJelue Jo luarulueJlJoJ pasn oq plnoqs urcfurocue,r'e,trlrsodeJe eseql JI 'sJelsnlc ur rcJoc e,rrlrsod-ruergJo sJeqrunua8rul pue selfco>1ne1 roJ >lool ol reeus peurels s.ueJC B qlrA\ 3uo1upelsenber eq plnoqs re8e tles Iolruueru Jo re8 y.{qte1.{ueqd se qcns Brpeu elrlcales Sursn snarnD snccocol[.qdo1s' JoJ eJnllnc JoJseJnllnoyoolsSururelqo ol uorl Iools 'sueSoqtedcrJalue -lppe ul'uorluntrs srql uI 'esneJolqrssod aql se peraprsuoc eq plnoqs sursrue8ro eseql 'surxol slr ro/pue altcr.lfrp'3 to1 qlr.ldlueued e ur eputusr srlrloJpJlrJossu-Jrlo slsele,trle8eu 'GZ'tl 't) sursrue8ro -lqlue ,;o srsou8erp e uoql11 reqlo ro '3 ed,fi sua?urtttad wnrprrtsolJ'EIIeuotulBS'rccocolfqdels ,{q pesneceq ol po^erleq se,^A leql srlrlocoreluocgrcedsuou Jo snoueJqueuopnesd pedola,rep,tlleuorsecro elq surxol slr pue atlrtIfip '3 ro; e,tr1e3eu ere,^ slools esoq,r sluerled E'L SIII'IOJ CNV V!IHddVIC Jo euo pesn e^eq sroqlo WNrcIAJSOT) CSIVIJOSSV-SZJIIilA

- )tV 166l ,\DW

144

FEKETY
Specific antimicrobial therapv

AJG

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

Tasls 2 Practice Guidelines .for Treatment of Cktstridium dfficile Diarrhea or Colitis 1. Antibiotics should be discontinuedif possible. 2. Nonspecific supportivetherapy should be given, and is often all that is neededin treatment.Specific antibiotics should not be given routinely. 3. When the diagnosisof C. dfficile diarrhea is confirmed and specific therapy is indicated,metronidazolegiven orally is preferred. 4. If the diagnosisof C. dfficile diarrhea is highly likely and the patient is seriouslyill, metronidazolemay be given empirically before the diagnosisis definitely established. 5. Vancomycin given orally is reservedfor therapy of C. dfficile' diarrheauntil one or more of the following conditions are associated present: (a) The patient has failed to respond to metronidazole. (b) The patient's organism is resistantto 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 becauseof C. dfficile-associated diarrheaor colitis. (i) There is evidence suggestingthe diarrhea is causedby
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, becauseit is expensive,CT is reservedfor special situations(30, 31). Radionuclide scans may detect evidence of colonic inflammation rapidly, but the findings are nonspecific, expensive, time-consuming. and not always readily available. TREATMENT OF ANTIBIOTIC-ASSOCIATED DIARRHEA/COLITIS Nonspecific supportive therapy Guidelinesfor treatmentare presentedin Table 2. When appropriate diagnostic measuresare in progress, but the diagnosisof C. dfficile diarrheahas not yet beenestablished and the patient is not seriously ill, nonspecific supportive therapy should be given and is often all that is neededfor resolutionof diarrhea,even when it is causedby C. dfficile. Nonspecific therapy may have the additional benefit of reducingthe likelihood of a relapse,as comparedto specific antibiotic therapy. Supportive therapy usually consists of If possible, replacement therapywith fluids and electrolytes. antibiotics given to treat an infection should either be discontinued or switched to alternateappropriate antibiotics. The administrationof antiperistalticand opiatedrugs should they may mask the patient's symptoms be avoided,because and also causepooling of toxin-ladenfluids within the colon (2, 4). Some patients with C. dfficile diarrhea have worsened after being given antiperistalticsor opiates, but this may have been coincidental (32), since many patientswith the disease have been given antiperistalticswithout any adverseconsequences.

When appropriatediagnostic tests have been performed and the diagnosis of C. dfficile dianhea is likely or confirmed, or the patient is a nonpregnantadult or a child over l0 yr of age who is worsening or has not respondedto supportive therapy given for 2 or 3 days, specific antimicrobial therapy may be initiated. Metronidazole,vancomycin, teicoplanin(which is not availablein the United States), and, less often, bacitracinhave been usedto treat C. dfficile diarrhea becausethese antimicrobials inhibit growth and toxin production by C. dfficile. Metronidazole and vancomycin are by far used most often in the United States. Therapy given by the oral route is always preferred,because C. dfficile diarrheais not causedby tissueinvasion,and the toxins producedby the organismwithin the intestinallumen causediarrheaonly after binding to specificreceptorson the colonic mucosa. C. dfficile diarrheal syndromes usually respond well to oral therapy with either metronidazoleor vancomycin if therapy is startedearly enough, but the responseis sometimesless good when metronidazoleor vancomycin are given to patientswho are critically ill with the (l-6). disease 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 500 mg four times per day for 10 days showed that the only statistically significant difference between them was that vancomycin was more costly (33). The duration of diarrhea and the frequency of side effects, posttreatmentrelapses, were not and carriage of the organism in convalescence significantly different. All 52 patients given vancomycin were cured, but 2 of 42 patients failed to respond to metronidazole (a difference that was not statistically significant), and were cured when therapy was changedto vancomycin, 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 respondedto supportive therapy alone within a 48- to 72-h observation period while the diagnosis was being established,and did not require therapy with either vancomycin or metronidazole. Specific oral therapywith metronidazoleor vancomycin is usuallygiven for only 7 to 10 days,unlessthe illness is severeor the diarrheais slow to resolve (1,2, 4,33). Patients who require therapy for more than l0 days often have severecolitis, or a delay in diagnosisand treatmentof colitis, or an underlying condition predisposingto diarrhea, diabetic such as lactoseintolerance,irritable bowel disease, enteropathy,or diarrheadue to an adversereaction to medications or diet. Metronidazolegiven intravenousll,has been used to treat pseudomembranous colitis in patients who are unable to take it orally. The reportedresultshave been good, although treatmentfailures have occurred.A possibleexplanationfor treatment failures when metronidazole is given intraveachievedare usually nously is that the stool concentrations

AJG - May 1997

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS

TaeI-e 3 Practice Guidelines for Management of Relapses

145

lower than those required for inhibition of the organism in vitro (34). Even though stool concentrationsare also low when metronidazoleis given orally (34,35), such therapyis usually successful,and this paradox is as yet unexplained. Nonetheless, the oral route is preferredwhen it can be used because a wealth of clinical experienceindicatesit is highly efficacious. Oral metronidazole (Flagyl) is prefercedfor therapy of C. dfficile diarrhea. An expert committee of hospital infection control practitioners has recently recommendedthat metronidazole is preferred for specific or empiric antimicrobial treatment of C. dfficile diarrhea, and their recommendation has been widely adopted in the United States (36). One of the main reasonsfor their recommendation was their desireto curtail the use of vancomycinbecause of fear that its use will encouragethe spreadof vancomycin-resistant enterococci(VRE), and ultimately the emergenceand spread of vancomycin-resistant staphylococci, whereasmetronidazolewill not. Other reasonsincluded were that metronidazoleis much less expensivethan vancomycin, that it is well-tolerated when given orally for short periods, and that it is as effective as vancomycin for most patients(33). Although metronidazolehas not been approvedby the Food and Drug Administration specifically for treatment of C. dfficile diarrhea, it has been approved by the FDA for the treatmentof seriousinfections causedby susceptible anaerobic bacteria such as C. dfficile. A few caveats concerning the preference for metronidazole are in order, becauseuse of vancomycin for treatment of C. dfficile diarrheais justified in special circumstances. Although metronidazoleis usually well-tolerated,it has an unpleasant metallic taste and may also causenausea,vomiting, diarrhea, abdominal pain, pruritus, erythematous rashes,headache, confusion, dizziness,and reversibleneutropenia,and additional patientsmay become allergic to it. Patients taking oral metronidazole should be cautioned against drinking alcoholic beveragesbecause this might result in disulfiram (Antabuse)-like reactions. Also, rare isofatesof C. dfficile are resistantto metronidazolein vitro, althoughthereis little evidencethat resistance is responsible for treatmentfailures. At the University of Michigan Hospitals, 6 (.3Vo) of 200 isolatesof C. dfficile obrainedfrom patients and tested in vitro over the period from 1980 to 1990were resistantto metronidazole at concentrations ranging from 16 to 128 p,g/ml, whereasall were highly susceptible to vancomycin (37). Becausemetronidazoleis a carcinogen, mutagenic in some animal species and in vitro, crossesthe placental barrier and is fetotoxic for pregnant mice, it should be used during pregnancy only if clearly needed.Similarly, becausethe safety of metronidazolefor children has not been proven, many prefer not to use it for treatmentof children unlessnecessary. For treatmentof adults with C. dfficile diarrhea,metronidazoleis usually given orally in a dosageof 250-500 mg four times per day or 500-750 mg three times per day for 7-10 days; for children, a dosage of 35-50 mgkg/24 h

1. Reconfirm the diagnosis. 2. Discontinue medicationsthat 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 standardcourse of metronidazolegiven 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 for the next 2 months after treatment of a relapse. 5. No treatmentavailable in the United Stateshas been proven to prevent recurrences. If the patient has suffered from multiple recurrences, consider using one of the following antimicrobial regimens with or without one of the other therapeuticmeasures as an adjunct. These are not presented in an order of preference. (a) Oral metronidazole(or vancomycin, as in Table 3). (b) Specific therapy with vancomycin or metronidazolegiven orally fbr I to 2 months, either intermittently (sucb as every other day or week) or with gradual tapering, with or without adiunctive therapy with an oral anion-binding regimen such as cholestyramineor colestipol begun near the end of antimicrobial therapy 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 not immunocompromi.sed, beginning 4 days before a lO-day course of specific antibiotic therapy has been completed. (f) Human immune globulin by intravenousinfusion, for patientswith documenteddeficiencie".

divided into three doseshas been used. If metronidazoleis usedintravenouslyfor treatingpatientswho are critically ill and/or unable to tolerateoral medications,it can be usedin a dosageof 500-750 mg three or four times per day. As statedearlier, metronidazolegiven intravenouslyfor treatment of C. dfficile diarrhea is probably not as reliable as either metronidazoleor vancomycin given orally. Metronidazole should be used via the intravenousroute for treatment of C. dfficile diarrheaonly when it is not possibleto treat via the oral route, and never for reasonsof convenience. When metronidazoleis used intravenouslyto treat C. dfficile diarrhea,considerationshould also be given to the simultaneous use of vancomycin enterally,as discussed below. Indicationsfor treatmentwith vancomycin. Vancomycin still has a role in the managementof C. dfficile diarrhea, although it is a much smaller one than was the casebefore the recommendation that metronidazole is preferred for therapy of C. dfficile diarrhea. Because vancomycin is poorly absorbedsystemically when given orally, effective concentrationsare easily achieved in stools and serious systemic side effects are rare (2-6). Nevertheless.vancomycin should not be used for treatment of C. dfficile diarrheaunlessthe patientis unableto toleratemetronidazole, or because of the other indicationsoutlined the PracticeGuidelines in Table 3. It should be pointed out here that pseudomembranous enterocolitiswas a well-recognizedclinical comolicationof

146

FEKETY

AJG - Vol. 92, No. 5, 1997 diarrhea and enterocolitiscausedby staphylococci.These in greaterdetail elsewhere(13). issuesare discussed When therapywith vancomycinfor C. dfficile diarrheais justified, it is usually given orally in a dosageof either 125 mg four times per day for 7-10 days, or 500 mg four times per day if the patient is critically ill or has impending ileus, colonic dilation, or perforation. These regimens seemed equally effective in reportedstudies(4,22). For infants and children, an oral dose of 5OOmg/1.73m (2) every 6 h has been used. Vancomycin should not be given intravenously as the sole therapy for C. dfficile diarrhea, since effective concentrationswithin the colonic lumen are not reliably achievedwhen it is given in this way. If patientscannot be treatedorally with vancomycin,or they have paralytic ileus, and the patient is to be treatedby the instillation of the drug by perfusion via a tube or pigtail catheterdirectly into the cecum or ileostomy, 200 or 500 mg vancomycin in 500 ml (400 or 1000 pgiml) given up to four times per day can be used,if tolerated.Another regimenthat has beenusedin this settingconsistsof giving vancomycinintracolonically(2000 mg followed by 100 mg every 4 h and 100 mg after each stool) via a pigtail catheterpositioned during colonoscopy (42). Reconstituted solutionscontainingvancomycinmust be diluted with at least 100 ml of diluent per 500 mg vancomycin. Alternative therapies. Bacitracin (43), teicoplanin (44), or nonabsorbableanion binding resins (45) such as cholestyramineor colestipol may be given orally for treatment of mild C. dfficile diarrhea(4), but theseagentsare neither as reliable nor as rapidly effective as metronidazole or vancomycin. Anion binding resins bind toxin B of C. dfficile, but experience suggeststheir capacity to do this is in severecases.They may limited and probably inadequate also bind vancomycinand therebydiminish its efficacy, and can cause severe constipation and intestinal obstruction once diarrheahas resolved.Neither teicoplaninnor bacitracin for oral administrationare readily availablein the United States.It should be cautionedthat teicoplaninhas a propensity similar to that of vancomycin for encouraging the enterococci, and that the spread of vancomycin-resistant to bacitracinis slower and lesscertainthan clinical response it is with vancomycin, possibly becausesome isolatesare resistantto bacitracin (37). MANAGEMENT OF RELAPSES OR RECURRENCES OF C. DIFFICILE DIARRHEA OR COLITIS Guidelines for managementof relapsesare presentedin Table 3. Relapses(recunences)of diarrhea or colitis are recognizedwhen there is a return of symptoms, signs and positive diagnostic tests a few weeks to months after disantibiotic therapy for C. dfficile continuationof successful diarrhea. Becausethe patients had previously responded, these occurrencesshould not be thought of as treatment occur in about 15-357oof patients,with a failures.Relapses mean fiequency of about 207o (4, 22, 23). Because C.

surgeryin the preantibiotic and early antibiotic era, that it was commonly attributed to toxin-producing, antibioticresistantS. aureus, and that it was treatablewith oral vancomycin. Some investigators have retrospectively questioned the role of staphylococci in the cause of those (1), and suggested they were actually causedby C. illnesses dfficile, whose importancein this syndromewas not estabenterocolitis lisheduntil about 1978(1, l3). Staphylococcal became very much less frequent in the 1960s after the penintroductionand use of vancomycin and semi-synthetic icillinase-resistantB-lactam antimicrobials for treating infections. However, there is a considerable staphylococcal body of evidencesuggestingthat staphylococcican indeed causediarrhea and colitis after the use of antimicrobials. Before the antibiotic era, many patients diagnosed with enterocolitishad extensiveinflammatory lestaphylococcal sionsin the colon at postmortemexamination,and often in the ileum,jejunum, and stomachas well (13). Thesefindings are not characteristicof C. dfficile diarrhea,although ileitis has occasionallybeen documentedin patientswith it, especiallyif they have an ileostomy (38). After recognition in the late 1970sof the important and unquestionablydominant role of C. dfficile in the causation of antibioticcolitis, little attention was associatedpseudomembranous given to S. aureus as an etiologic agent of antibiotic-associateddiarrheaor colitis. However, there is no questionthat diarrheacan be causedby S. aureus.For example,diarrhea is common in patientswith the toxic shock syndromecaused by inf-ectionwith enterotoxigenicstaphylococci,often the site is one that is minor and hard to detect (39). More alarming is that methicillin-resistantS. aureus enteritis has been reported within the past few years as an important enteritis in Japan in patients causeof antibiotic-associated with negativestudiesfor C. dfficile and its toxins (13, 40). Ifthese reportsare confirmed outsideofJapan, then enteritis caused by methicillin-resistantS. aureus and methicillinsensitiveS. aureus, organismsthat are resistantto metronidazole, may emerge as an important complication of antibiotic use elsewhere,including in the United States.Such caseswould most likely be recognizedwhen patients with diarrhea presumed to be caused C. antibiotic-associated respond to treatmentwith metronidazole. failed to dfficile causemore nosocomialdiarrhea may already Staphylococci and other countries than is in the United States or colitis culture media and part because selective in appreciated, organism are neither implicate this needed to other tests patients with nosocomial used for nor often widely available antibiotic diarrhea. Finally, in 1978, three patients in hospitals in the United States were reporled to have pseudomembranous colitis, which was well documentedin good laboratory studiesfailed to detect C. two of them, and its in difficile and toxins their stools,but were positive for S. aureus and a unique cytotoxin similar to one produced by ln vitro (41). Therefore,it is possiblethat their staphylococci in treatmentof C. difficile preference fbr metronidazole the of with a resurgence in the future diarrheamay be associated

AJG - May 1997

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS

141

dfficile diarrhea and colitis have markedly increased in frequencyin hospitalsin the United Statessince lgg4 (11, 46), so has the frequency of encountering patients with recurrent or relapsing C. dfficile diarrhea. Relapsing C. dfficile diarrhea is a serious, difficult, and still unsolved management problem, especially when patientshave expe_ rienced three or more episodes(47). However, it is impor_ tant to remember is that it is rarely difficult to treat each recurrencesuccessfullyusing standardtherapy with metro_ nidazole (or vancomycin); what is still difficult to accomplish is the prevention of further recurrences. Recurrences may be causedeither by persistence of the original strain of C. dfficile or by reinfection with the same or a different strain. Some strains seem more likely than others to cause recurrences(47), whereas strains that are nontoxigenic never do so. Recurrencesusually begin with the retum of diarrhea 2 wk to 2 months after successful antimicrobial therapy of an episodeof C. dfficile diarrhea. Recurrencesare characterizedby the return of typical symptoms and signs of C. dfficile diarrhea, positive assaysfor C. dfficile toxins in stools,and culturesthat yield vancomycin and metronidazole susceptible strains of C. dfficite. The liequency of recurrences does not seemto be influencedby the specific nature of the original inciting antibiotic, by whether metronidazoleor vancomycin was used for treatment of the initial episode,or by the dosageor duration of treatmentwith vancomycin or metronidazole.In some re_ ports, recurrencesoccurred more often in patients whose stool cultures remain positive after successful antibiotic therapyfor C. dfficile diarrhea,bur not in others(29,47).In either case,because there is no way to reliably eradicatethe C. dfficile carrier state, there is no good reason to obtain stool culturesto determinewhether a patient is at high risk for a relapse.Relapses appearto be less likely to occur if the first episodewas treatedonly with supportivetherapy.Some unfortunate patients have experiencedmany recurrences; more than 6 episodesis not unusual and more than 20 is alleged to be the record, each after a course of apparently successful treatment.Fortunately,patientscan be reassured that recurrences do nol have a tendencyto becomeprogressively more severe(47), even though they may causemore and more concern with each episode. Many different treatmentshave been used in an attempt to prevent recurrences,and most experts have their own favorite regimen. However, no specific treatment regimen commercially available in the United States has been proven in properly controlled, double blinded, randomized studies to prevent multiple recurrencesor relapses ofC. difficile diarrhea. Standard antibiotic therapy should be used to treat relapsesand is usually successful,even if it does not prevent further recurrences(47). Metronidazole seems to be as effective as vancomycin in treatment of relapses,and it is less expensiveand generally well tolerated. There is little or no evidence that patients suffering from multiple recumences do so becausethey have underlying abnomalities of their gastrointestinaltract or host

resistancefactors that accountsfor their proclivity for de_ velopment of recurrences, although a few children and one adult have been reported who may have had a specific immunoglobulin deficiency that predisposedthem to relapses (48-50). Whereas vancomycin and metronidazole almost always kill the vegetative forms of C. dfficile that producethe toxins causingdiarrhea,they do not reliably kill the spore fbrms of the organism, the persistence of which seemsthe root cause of the trouble. In fact, antimicrobial treatment appearsto encourageformation of spores (51), which are hardy and can persist in the intestinesor envi_ ronment of patients for long periods of time (14), during which they may germinate, or the patient may become reinfected, and diarhea may occur if the patient has not re-established intestinal resistance to the colonization, growth and toxin production by C. dfficile. The mecha_ nisms, such as competition fbr nutrients (52), by which certain organisms of the normal flora are responsiblefor "colonization resistance"to C. dfficile are poorly under_ stood. Paradoxically, derangements in colonization resis_ tance are even seen after treatment with vancomycin and metronidazole,since both are capableof inducing C. ctrfft_ cile dianhea as well as of treating it. Unfortunately, the f'ecal flora and its colonization resistance may not return to nor_ mal for many months after exposureof patients to antibi_ otics. lt therefore seems prudent that an effort should be made in managing patients experiencingrelapsesto avoicl the use of antibioticsas much as possibleso as to hastenthe return of the protectivenormal fecal flora. Accordingly, it is recommended that the unnecessary prophylaxisor treatment of infections,especiallyminor ones,with antibioticsshould be avoided within the first 2 months after treatmentof an episode of C. dfficile diarrhea (47). When patients experience a recumenceof C. rtifricite diarrhea within a few months after a successfullytreated episode, the diagnosisshouldagainbe confirmed (especially if the episode is atypical). Unless diarrhea is mild, the patient should again be treatedspecifically,preferably with metronidazole, even if it was used for treatmentof the first episode(or vancomycin,accordingto the treatmentGuidelines in Table 3), usually for only 7-10 days in standard dosesif the patient respondspromptly (47). Some authoritiesbelieve that patientssuffering fiom repeated recurrences should be treated using a regimen consisting of the intermittent administrationof metronidazole (or vancomycin)over a period of weeksor even months and followed by their gradual tapering, or by prophylaxis with low dosesof theseantibiotics given daily or on alternating days or weeks, or by use of cholestyramineor other anion binding medicationsalong with specific antibiotics, especially at the end of therapy(6, 53). Cholestyramine can bind vancomycin as well as the toxins of C. dfficile and as a result may interferewith specific therapy;it may also cause obstipation as a side effect. Such regimens may appearro have been successful in preventing further relapses,but none have been validatedin properly controlled studies,so

148

FEKETY

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 precautionsfor patients with C. dfficile diarrhea. 4. Wear gloves when contacting patientswith C. dfficile dianhea./colitis or their environment. 5. Disinfect objects contaminated with C. dfficile with sodium or ethylene oxide hypochlorite, alkaline glutaraldehyde, 6. Educate the medical, nursing, and other appropriate staff members about the diseaseand its epidemiology.

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 reasonit was tried in the first place. Various other unproven measureshave tried to restore the colonization resistanceof the fecal flora of patients with relapses.Many of them fall into a category referred to as probiotics.Theseinclude the oral or rectal administrationof yogurt, lactobacilli (55), enemas containing feces from healthy persons (56) or mixtures of various bacteria normally 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 approachinvolves treating patientswho have relapsed with the oral administrationof a live yeast (Saccharomyces boutardii) for about 4 wk, beginning 4 days before the end of conventional antibiotic therapy for a recurrence.This novel measurewas evaluatedin the United Statesin a well designedmulticenter placebo-controlledstudy and was reportedto be safeas well as effective. Its use in patientswho with a had experiencedat least one relapsewas associated : of (p frequency in the 0.04) reduction of about 5O7o placebo. receiving (58) with those compared furtherrelapses This report is the only well controlled and scientific study concerningthe prevention of relapsesin humans that has thus far been reporled. The mechanism of the presumed protectiveeffect of S. boulardii is not known, but it may be a proteaseit producespreventsthe binding of the because toxins to the intestinalmucosa(59). BecauseS. boulardii is available for treating relapses in Europe but not in the United States,some physicianshere have attemptedto use Saccharomycescerevisiae (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 anecdotalreports claiming successwith it. Therapy with intravenousimmune globulin, especiallyin children with various immunoglobulin deficiencies,has appeared effective in prevention of recurrences in anecdotal reports (48-50). Other novel ways to actively or passively immunize patientsagainstC. dfficile and its toxins are the subject of ongoing researchrelated to this important and increasinglyfrequent problem of recurrent C. dfficile diatrhea. PREVENTION OF C. DIFFICILE COLITIS DIARRHEA AND

Guidelines for prevention are presentedin Table 4' Ptevention of C. difficile diarrhea and colitis is based upon a few simple practicesand attitudes.Hospitalization and intensiveexposureto antibiotics are important risk factors for of C. dfficile (4-6, 8, ll,l2). Avoidanceof the acquisition

use of antimicrobial drugs is of obvious imunnecessary portance,but is all too often easiersaid than done.Restraints and limitations in the use of antimicrobials are of growing importance because of alarming recent increases in the pathogensin hospiemergenceof new antibiotic-resistant tals, such as Enterococcus faecalis and E. faecium, Streptococcus pneumoniae, Staphylococcushemolyticus, Clostridium dfficile, and numerous species of enteric Gramnegative bacilli. Transmission of C. dfficile from one person to another via the hands of personnel appearsin hospitals to be more important in spread of C. dfficile than does contact with sporesin 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 measuresfor 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 Patientswith C. dfficile diarrheaand to a lesser has stopped. extent, those who are asymptomatic carriers of the organism appear to contaminate their immediate environment with C. dfficile spores,which then becomesa potential source of reinfection for the patient as well as personnel and other persons,particularly if they have recently received antibiotics (8, 14). Since many healthypersonsand patientswithout diarrhea who are in hospitals carry C. dfficile in their intestines,there is little if any rationale for continuing Enfor patientswho no longer have teric Isolation Precautions diarrhea, or to test them for calriage of the organism after diarrhea has stopped. Antibiotics do not reliably kill the sporesof C. dfficile even though they may kill the vegetative forms of the organism, and therefore treatment of carriers with metronidazoleor vancomycin does not eradicate the organism from their intestinal tracts (35), even though these antibiotics may markedly decrease the numbers of of excretionof vegetativeforms in stools(51). Suppression the organism by carriers with use of treatment with metronidazoleor vancomycinmay have occasionallybeen useful in terminating localized outbreaksin hospitals,but the effects of this approachhave been far from striking. Alkaline sodiumhypochlorite,and ethyleneoxide are glutaraldehyde,

AJG - May 1997

CLOSTRIDIUMDIFFICILE-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 of Infectious Diseases, Department of Intemal Medicine, 3116 Taubman Health Center,University of Michigan Hospitalsand Medical School,Ann Arbor. MI 48109-0378.

effectivein killing the sporesas well as the vegetativeforms of C. dfficile (4, ll, 14) that persiston fomites, instruments and contaminated surfaces,but none of these are satisfactory for handwashing,which is still best carried out with ordinary disinfectant soapsor chlorhexidine, despite their limited power to kill C. dfficile spores (4, 63). Additional measures that have been used in facilities where C. dfficile diarrheais occurring at a high rate include identifying and cohorting (segregating)patients who are carriers, restricting patients who are carriers to single rooms with private bathrooms,and antibiotic control programs.Neither vancomycin nor metronidazole nor any other antimicrobial regimen are reliably effective in eradicating the C. dfficile carrier state, probably because the sporesofthe organismare resistantto their action, unlike the vegetative forms. It is important that everyone involved with patient care in hospitals, nursinghomes,and at home be educatedaboutthe organismand its epidemiology,about rational approaches to the treatment and care of patients with C. dfficile diarrhea, about the importance of handwashing between contact with patients,about the use of gloves when caring for a patient with C. dfficile diarrhea, and about the avoidance of the unnecessary use of antimicrobials. ACKNOWLEDGMENTS The author acknowledgeswith sincere thanks and gratitude the expert advice, help, and counsel of the Practice Parameters Committee of the American College Gastroenterology: J. Patrick Waring, M.D., F.A.C.G. Chair (Emory University, Atlanta, GA), Alan Barkun, M.D. (Montreal GeneralHospital, Montreal, PQ, Canada),W. Scott Brooks, M.D. (Atlanta,GA), KennethR. DeVault, M.D., F.A.C.G. (Mayo Clinic, Jacksonville, FL), John Hughes, M.D., F.A.C.G. (Kelsey Seybold Clinic, Houston, TX), Douglas M. Simon, M.D., F.A.C.G. (Albert EinsteinMedical 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, Jackson, MS), EugeneM. Bozymski, M.D., F.A.C.G. (University of North Carolina, Chapel Hill, NC), StephenH. Caldwell, 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 California Los Angeles Medical Center,Torrance,CA), Robert H Squires, Jr., M.D. (University of Texas Southwestern Medical Center,Dallas, TX), Paul Yeston,M.D. (University of Virginia Health SciencesCenter, Charlottesville, VA), Peter A. Banks, M.D., F.A.C.G. (Brigham and Women's Hospital,Boston,MA), Patrick G. Brady, M.D., F.A.C.G. (J. A. Haley VeteransAdministration Hospital, Tampa,FL), William D. Carey,M.D., F.A.C.G.(Cleveland Clinic Foundation, Cleveland,OH), Norman D. Grace,M.D., F.A.C.G. (FaulknerHospital, Boston,MA), GeorgeW. Meyer, M.D., F.A.C.G. (Georgia Baptist Medical Center, Atlanta, GA), Namish Vakil, M.D., F.A.C.G. (Sinai SamaritanMedical

REFERENCES
I . Bartlett JG. Treatment of C/ostridium dfficile colitis. Gastroenterology 1 9 8 5 ; 8 9I: 1 9 2 - 5 . 2. Fekety R, Shah A. Diagnosis and treatment of C. dfficile colitis. IAMA 1993''269:71-5. 3. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile coliris. N Engf J Med 1994;33O:257-62. 4. Fekety R. Antibiotic-associatedcolitis. In: Mandell G, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases,4th ed. New York: Churchill Livingstone, 1996, pp 978-806. 5. Mitty RD, LaMont T. Clostridium dfficile dianhea: Pathogenesis, epidemiology, and treatment. Gastroenterologist 1994;2:61-9. 6. Bartlett lG. Clostridium dfficile: History of its role as an enreric pathogen and the current state of knowledge about the organism. Clin Inf'ect Dis 1994;18(suppl 4):5265-72. 7. Cudmore M, Silva J, Fekety R, et al. Clostidium dfficile colitis associatedwith cancer chemotherapy.Arch Intem Med 1982;142:

333-5.
8. Johnson S, Gerding D. Clostridium difficile. In: Mayhall CG, ed. Hospital epidemiology and infection control. Baltimore: Williams & Wilkins, 1996, pp 399-408. 9. Riegler M, Sedivy R, Pothoulakis C, et al. Clostridium dfficile toxin B is more potent than toxin A in damaging human colonic mucosa ln vitro. J Clin Invest 1995:95:2004-l l. 10. Qualman S, Petric M, Karmali M, et al. Clostridium difficile invasion and toxin circulation in fatal pediatric pseudomembranous colitis. Am J Clin Pathol1990;94:410-6. ll. McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium dfficile. N Engl J Med 1989;320:204-10. 12. Wilcox M. Cleaning up Clostridium dfficile infection. Lancet 1996; 348:767-8. 13. Fekety R. Staphylococcalenterocolitisand dianhea. In: Crossley K, Archer G, eds. Staphylococcalinfections. New York: Churchill Livingstone, 1997. 14. Kim K-H, Fekety R, Barts DH, et al. Isolation of Clostridium dfficile from the environment and contacts of patients with antibiotic-induced colitis. J Infect Dis 1981:143:42-5O. 15. Medich DS, Lee KK, Simmons RL, et al. Laparotomy for fulminant pseudomembranous colitis. Arch Surg 1992;127 :847-52. 16. Triadifopoulos G, Hallstone AE. Acute abdomen as presentationof pseudomembranous colitis. Gastroenterology199I ; I 00:685-9 l. 17. Tedesco FJ. Antibiotic-associatedpseudomembranous colitis with negative proctosigmoidoscopic examination. Gastroenterology1979; '71:295-'7. 18. Gerding DM, Brazier JS. Optimal methodsfor identifying Clostridium dfficile infections.Clin Infect Dis 1993;16(suppl 1):5439-42. 19. Martirosian G, Meisel-Mikolajczyk F, StanczakJ, et al. Toxigenicity of Clostridium difficile strains isolated in the surgical ward. Acta Microbiol Pol | 995 :44:4'1,53. 20. StaneckJL, Weckbach LS, Allen SD, et al. Multicenter evaluationof four methods for Cbstridium dfficile detectton: ImmunoCard C. dll: fcile, cytotoxin assay, culture, and latex agglutination. J Clin Microbiol 1996;34:2718-21. 21. Barbut F, Kajzer C, Planas N, et al. Comparison of three enzyme immunoassays, a cytotoxicity assay,and toxigenic culture for diagnosis of Clostridium dfficile-associateddiarrhea.J Clin Microbiol 1993; 31:963-i. 22. Fekety R, Silva J, Kauffman C, et al. Treatment of antibiotic-associated Cktstridium dfficile colitis with oral vancomycin: Comparison of two dosageregimens. Am J Med 1989;86:15-9. 23. Lyerly DM, Barroso LA, Wilkins TD. Identification of the latex-test reactive protein of C. dfficile as glutamate dehydrogenase. J Clin Microbiol 1988:29 :2639- 42. 24. George WL, Sutter VL, Citron D, et al. Selective and differential

150

FEKETY

AJG - Vol. 92, No. 5, 1997

45. de Lalla F, Nicolin R, Rinaldi E, et al. Prospective study of oral teicoplaninuer.rrsoral vancomycinfbr therapyof pseudomembranous colitis and Clo.stridium dilfit:ile- associated diarrhea. Antirnicrob Agents Cherncrther 1992;36:2192 6. 46. Kreutzer EW, Milligan FD. Treatment of antibiotic-associated pseudomembranou cs o l i t i s w i t h c h o l e s t y r a n r i nre e s i n .J o h n sH o p k i n s Med J 1978:143:67-72. 47. Jobe B, Grasely A, Deveney K, et al. Clostritlium rljficlle colitis: An increasing h o s p i t a l - a c q u i r ei d l l n e s s .A m J S u r g 1 9 9 5 ; 1 6 9 : 4 8 0 3. 48. Fekety R, McFarland LV, Surawicz CM, et al. RecurrentClo.stridiunt tliJficile disease. Clin Infect Dis (in press). 49. Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravegammaglobulin of chronicrelapsing nousiyadministered colitis induced by Clostriditutt dffir'ile toxin. J Pediatr l99l;l ltl:633 7. -50. Hassett J, Meyers S, McFarland L, et al. RecurrentCbstridium dfficile inf'ection in a patient with selective IgGl deficiency treated with intravenousimmune globulin awJSat'charont boulttrtlii Clin Inf'es^t v-t'es D i s I 9 9 - 5 1 2 0 ( s u p2 p)l: 5 2 6 6 - 8 . 5 1 . O n d e r d o n kA B , C i s n o e r o sR L . B a r t l e t t J G . C l o s t r i d i u md i f f l c i l e i n gnotobiotic mice. Infect Lnmun l9lJ0l28:27'7-82. 52. Wilson K, Perini F. Role of competitionfbr nutrientsin suppression of Clostridium diflicile by the colonic microllora. Inf'ect Imrnun 1988; 56:2610-4. 53. TedescoFJ. Treatrnentof recurrentantibiotic-associated pseudomembranouscolitis. Am J Gastroenterol1982,77:220-1 . 54. Buggy BP, Fekety R, Silva J. Therapy of relapsingCbstridium diffi' r:i/r-associated diarrhea with the combination of vancornycinand rif a m p i n . J C l i n C a s t r o e n t e r o1 l 987;9:155-9. 55. Gorbach SL. Successfultreatment of relapsing CLostridiumdi.fficile c o fi t i s w i t h L u d o b t r t i l l u s G C . L a n c e t 1 9 8 1 l . 2 : 1 5 1 9 . 56. Schwan A, Sjolins, TrottestamU, et al. RelapsingClostridiutntlffitile enterocolitiscur-edby rectal infusion of norrnal feces. Scand J Inf'ect Dis l9ti.t:16:2ll-5. 57. Tvede M, Rask-Madsen J. Bacteriotherapy fbr chronic relapsingClostridium di.flicile diarrhoea i n s i x p a t i e n t sL . a n c e t 1 8 9 8 ; l : 11 5 6 - 6 0 . 58. McFarland LV, Surawicz CM, GreenbergRN, et al. A randomized pfacebo-controlled trial of Satcltaronty-tes bou|ardii in combination with standard antibioticsfor Clo.stridium d/lit l/c disease. JAMA 19941 271:1913-8. 59. Pothoulakis C, Kelly CP, Joshi MA, et al. Suctlnromytes houlardii inhibits C/ostridium difficile binding and enterotoxicity in rat ileum. G a s t r o e n t e r o l o g1 y9 9 3 1 1 0 4 I: 108-l 5. (er60. McFarland LV. Saccharomyces boulardii is not Sarr'/raromyL(s eyisrae.Clin Inf'ectDis 1996:22:200 l. 6 l . W a r n y M , D e n i eC , D e l m e eM , e t a l . C a m m a g l o b u l i na d m i n i s t r a t i o n in relapsing C l ostri tl i run tl iffit' i l e itducetl pseudomembranous col iti s with a def'ective a n t i b o d yr e s p o n s e to toxin A. Acta Clin Belg 1995t 50:36-9. 62. Johnson S, Gerding DN, Olson MM, et al. Prospective,controlled study 0o1' vinyl glove use to interrupt Cktstridium r/ffir:l/e nosocomial transnrission A .m J M e d 1 9 9 0 : 8 8 : 1 3 7 - 4 0 . 63. Bettin K. Clabots C, Mathie P, et al. Efl'ectiveness of liquid soap vs. chforhexidinegluconatefbr the removal of Clo.stridiumdilficile from bare hands and gloved hands. Infict Control Hosp Epidemiol 1994; 15:691 102.

rnedium for isolation of Clostridium difficile. J Clin Microbiol 1979; 9:211 9. 25. Fekety R. Antibiotic-associated diarrhea and colitis. Curr Opin Inf'ect D i s 1 9 9 5 : U : 3 97 1. 2 6 . A n g l i m A , F a r r B . N o s o c o m i ag l f'ections l astrointestina in In . : Mayhall C C , e d . H o s p i t a le p i d e m i o l o g y and inf'ection c o n t r o l .B a l t i m o r e :W i l l i a m s & W i l k i n s . 1 9 6 6 ,p p 1 9 6 - 2 2 5 . 2 7 . M a r x C E , M o r r i s A , W i l s o n M L , e t a l . F e c a l l e u k o c y t e si n s t o o l specimenssubnrittedfor ClostridiLondi.fficile toxin assay.Diagn Mic r o b i o lI n t e c tD i s 1 9 9 3 : 1 6 : 3 1 3 - 5 . 28. Guerrant RL, Araiys V, SoaresE, et al. Measurementof f'ecallactof'ernn as a marker of f'ecal leukocytes. J Clin Microbiol 1992:30: 1238 42. 29. Miller JR, Barrett LJ, KotlofT K, et al. A rapid test fbr inf'ectiousaud inflammatory enteritisA . rch InternMed l994ll5zl:2660-.1. 30. Boland GW. Lee MJ, Cats A, et al. Pseudomembranous colitis: Diagn o s t i cs e n s i t i v i t y o f t h e a b d o r n i n ap l l a i n r a d i o g r a p hC . lin Radiol 199.1; 19:413 475. 31. Boland CW, Lee MJ. Cats AM. et al. Antibiotic-induced dianhea: Specificity of abdonrinalCT lbr the diagnosisof Clostrirtiumdillicile d i s e a s eR . adiologyl99zl;l9l: 103 6. 32. Novak E. Lee JE, SeckmanCE, et al. Untavorable effect of atropinediphenoxylate (Lolnotil) therapy in lincomycin-caused dianhea. JAMA 1976:235:1,151. 3 3 . T e a s l e yD G , G e r d i n g D N , O l s o n M N , e t a l . P r o s p e c t i v e randomized trial of metronidazole yerrus vancomycin for the treatment of C. tliftici|e associa,ted diarrhea and colitis. Lancet I983;2:I043-6. 3.1. Bolton RP. Culshaw MA. Fecal metronidazoleconcentrations during oral and intravenous therapy fbr antibiotic associatedcolitis due to Clostritlium tlilJicile. Gut l9fl6: lU3: I 169-72. 35. Johnson S , H o m a n nS R , B e t t e nK M , e t a l . T r e a t m e n o t f asymptomatic Clo.tlridiumdilficile c,rniers (lecal excretors)with vancomycin or oral m e t r c n i d a z o l eA . n n I n t e r n M e d 1 9 9 2 : l1 1 : 2 9 1 3 0 5 . 36. Hospital Inf'ection Control Advisory Committee. Recommendations lbr preventing the spreadof vancomycin-resistant enterococci.Am J -94. Infect Control 1995:23:81 31. Fekety R. Unpublisheddata. 3 8 .Tsutaoka B. Hansen J, Johnson D, et al. Antibiotic-associated pseudomembranous enteritis due to Clostridiun ttilficile. Clin Inf'ect D i s l 9 9 z l l:8 : 9 8 2 4 . 3 9 . L a r k i n S . W i l l i a m s D . O s t e r h o l mM , e t a l . T o x i c s h o c k s y n d r o m e : Clinical, laboratory,and pathologicalfindings in nine fatal cases.Ann I n t e r nM e d 1 9 t 3 2 : 9 6 : 8 5 8 - 6 . 1 . .10.L a r k i n S . W i l l i a m s D , O s t e r h o l mM , e t a l . T o x i c s h o c k s y n d r o m e : Clinical, laboratory,and pathologic findings in nine latal cases.Ann I n t e r nM e d 9 6 : 1 9 9 2 : t 1 5 8 97. 1 t . Takesue Y, Yokoyama T, Kodanra T, et al. Toxin involvenrent in m e t h i c i l l i n - r e s i s l ; nS l t u p h ' - l o t L ' ( ( r J( 1 r , - ( l s e n t e r i t i s i n g a s t r o e n t e r ofogical surgery. Gastroenterollpn 199l'.26:716-9. / a Batts D, Silva J, FeketyR. Staphylococca e l n t e r o c o l i t i sI.n : C u r r e n t chemotherapyand infectious diseases.Proceedingsof the I lth ICC and the l9th ICAAC, Washington, D.C. American Society of Microb i o l o g y l 9 l l 0 : 9 9 . 15 . + - ) . Pasic M, Jost R, Carell T, et al. Intracolonic vancomycin fbr pseudomembranou cs o l i t i s .N E n g l J M e d 1 9 9 3 ; 3 2 9 : 5 8 ( 3l e t t e r ) . 41 D u d l e y M N , M c l a u g h l i n J C , C a r r i n g t o nJ , e t a l . O r a l b a c i t r a e i n vs vanconrycintherapy tbr Clostridium dilJicile-inc\tcecl diarrhea.A randornized d o u b l e b l i n d t r i a l . A r c h l n t e r n M e d 1 9 8 6 : 1 4 6 :l 0 l . 1 .