c Difficile Diarrhea

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O 1997 by Am. Coll. of Gastroenterology Vol.92 ,No .5, 1997Printedn U.S.A.

guidelines

Guidelines for the Diagnosis and Management of Clostridiumdfficile-AssociatedDiarrhea and ColitisRobert Feketv.M.D.

Guidelines for clinical practice are intended to suggestapproaches o particular medical problems asby interpretation and collation of scientifi-research, derived from extensive review ofliterature. When data are not available thatwithstand objective scrutiny, a recommendationbe made based on a consensus of experts. Guide-are intended to apply to the clinical situation for allwithout regard to specialty. Guidelines areto be flexible, not necessarily indicating theapproach, and should be distinguishedstandards of care that are inflexible and rarelyGiven the wide range of choices in any healthproblem, the physician should select he course best

to the individual patient and the clinical situationThese guidelines are developed under theof the American College of GastroenterologyParameters Committee. These guide-are also approved by the governing boards ofCollege of Gastroenterology and Practice Pa-Committee. Expert opinion is solicited frome outset for the document. Guidelines are reviewed inby the committee, with participation from expe-clinicians and others in related fields. The finalare based on the data available at thethe production of the document and may bewith pertinent scientific developmentsat a laterfollowing guidelines are intended for adultspediatric patients.

INTRODUCTIONAntibiotic-associated iarhea and colitis are imporrantrequentcomplicationsof antibiotic ther-theseoccur most often in hospitalsand nursinghey also occur in the community. Antibiotic-asso-dianhea s even more common; it is causedbv Clos-

tridium dfficile in only l5-207o of cases, nd s of unknowncause n most of the remaining cases(1-3). The type ofantibiotic-associatediarrhea hat s not causedby C. dffi-cile is relativelymild, self-limited,unassociated ith intes-tinal lesions, s treatablewith nonspecificsupportivemea-sures and by discontinuationof antibiotics, and is alsoreferred o by a variety of termssuchas simple,benign,orenigmaticantibiotic-associatediarrhea. n contrast,C. difficile associated iarrhea s usually associatedwith colitiscausedby the combinedeffectsof toxins A andB producedby C. dfficile within the intestinal umen and is a seriousand potentially ife-threatening isease.C. dfficile, a spore-forming obligate anaerobicbacillus, s a componentof thenormal fecal flora of many infants,and about5% of healthyadults; t may be found in the stools of l07o or more ofhospitalizedadultswithout diarrheawho have receivedan-tibiotics or cancer chemotherapeuticagents. C. dfficilecausesa spectrumof diarrhealsyndromes hat vary widelyin severityand mergewith one another; hey are also com-monly referred to by a variety of names, including C.dfficile diarrhea,C. dfficile colitis, antibiotic-associated .dfficile colitis, andpseudomembranousolitis.Unlessspec-ified otherwise, he general erm "C. difiicile diarrhea"willbe usedherein o refer to theentirespectrumofthe diarrhealdiseasescaused by this organism. The diarrheal illnesscausedby C. dfficile may and often doesclosely resemblethe more frequent benign or simple antibiotic diarrhea.Patientswith antibiotic-associatediarrhea n which C. dfficile cannotbe incriminated, which is true about 80o/a f thetime, are assumedo have the simpleor benigndiarrheaofunknown cause.

C. dfficile diarrhea, colitis without pseudomembranes,and pseudomembranousolitis are toxin-mediatedmucosalinflammatoryprocesseshatare usuallycharacterizedy thepresence f grosslyor microscopicallyvisible pseudomem-branesconsistingof nodules or large plaquescontainingleukocytes, ibrin, mucus, and epithelial cells loosely ad-herent o the surfaceofthe underlying nflamedand necroticmucosa.Almost all casesof antibiotic-associatedolitis orpseudomembranousolitis are causedby both toxin A andectivetl Oct. 10, 1996: accepted an. 28, 1997


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740 FEKETYB producingstrainsof C. dffici le. Most patientswith C.dfficile diarrhea can be found to have gross and/or micro-scopic colitis with or without pseudomembranesf theyundergoa workup that includescolonoscopywith biopsies.When pseudomembranesre not evident n patientswith C.diflicile diarrhea who have undergone colonoscopy, thediarrhealprocessmay have resulted rom a purely secretorydiarrheawithout colonic inflammation. Because, or a va-riety of reasons,many if not most patientswith antibiotic-associated iarrheado not undergo endoscopyand biopsy,the general term "C. dfficile diarrhea" is used more andmore often when one of more laboratory tests or C. dfficileare positiveand the organism s considered o be the causeof the diarrhea,and it is not certainwhether or not colitisand/or pseudomembranes re present.C. dfficile diarrheawith colitis andpseudomembranesan ead o toxic dilationand/orperforationof the colon, dehydration,hypovolemia,shock,and death.Although pseudomembranousolitis waswell-recognized n the preantibioticera (and was thought obe causedby staphylococci),t is now uncommon to diag-nose t in a patientwho has not received antibiotics and inwhom C. dfficile cannotbe implicated.As many as 20Voofpatientswith C. dfficile diarrheado not develop symptomsuntil as long as 6-8 weeks after discontinuation f antibi-otic therapy. n addition,patientshave developedC. dfficilediarrhea after the use of cancer chemotherapeutic gents,manyof which have significant n vitro antibacterial ctivity(4-1).PATHOPHYSIOLOGY OF C. DIFFICILE DIARRHEA

C. difricile diarrhea s caused rimarily 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 isolatesproduceboth toxins, but depending on whether they are obtainedfrom infants, healthy adults, the environment, or personswith antibiotic-associated iarrhea,about 5 to 25Toof iso-latesof C. dfficile produceneither oxin A nor B, and do notcausecolitis or diarrhea (5, 6, 8). Toxin A is a 308-kDaenterotoxin apable f causing x tensivemucosal amagenexperimental nimals; t is cytotoxic for certaincell lines nculture, a chemoattractantor neutrophils,and an activatorof macrophages nd mast cells, causing them to producevarious nflammatory mediators 8). Toxin A causesactindisaggregation nd intracellular calcium release,and alsoappears o damageneurons (3-6). Toxin B is a 270-kDacytotoxin hat causes epolymerization f filamentousactin.Toxin B was first detected y virtue of its potent cytopathiceffects n cell culture monolayers,but because t was notcytotoxic for the colonic mucosaof various animal speciesit was originally consideredof little importance n causingcolitis in humans. Recent evidence ndicates oxin B dis-rupts the actin cytoskeleton,and is also a necrotizing en-terotoxin l0 times more Dotent han toxin A in causins

AJG - Vol. 92, No. 5, 1997damage o human colonic mucosa n cell cultures (9). Itseemsprobablethat both toxins are important in causingdiarrheal disease n humans. C. difricile rarely damages hecolon of patientsby direct invasion, although t can occa-sionally do so (10), and it should be emphasized hat thediarrhea the organism produces s caused by the effects oftoxins that are produced within the intestinal lumen andadhere o the mucosalsurface 3-6).

EPIDEMIOLOGY OF C. DIFFICILE DIARRHEAThe frequencyand ncidenceof C. dfficile diarrhea aries

widely not only geographicallybut within different nstitu-tions in the same area, and dependson patternsof antimi-crobial use,on antimicrobial esistance atternsof the prev-alent C. dfficile isolates,on epidemiologic actors avoringtransmissionof 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 presenceof toxins A or B in stools are per-formed on patientswith antibiotic-associatediarrhea 4-6,8, I 1). Ironically, as the frequencyof postoperativewoundinfections has declined over the past few decades, n nosmall measurebecauseof the skill of surgeonsand theirappropriateuse of short-course erioperative ntibioticpro-phylaxis in high-risk patients, he frequency of C. dfficilediarrheahas markedly increased n hospitals n the UnitedStates,especially n the elderly (12). Almost every popularantimicrobial has been implicated in the causationof C.dfficile diarrhea,but ampicillin and other penicillin deriv-atives,cephalosporins nd clindamycin,are mplicatedmostfrequently(l-6). Less frequently ncriminated are erythro.mycin, aminoglycosides, luoroquinolones, sulfamethox-azole-trimethoprim,and perhapssurprisingly, both vanco-mycin and metronidazole,which are he drugs of choice ortreatment of C. dfficile dianhea. Tetracyclines and chlor-amphenicol are now rarely implicated, but they were fre-quently mplicated n what was diagnosed s staphylococca lenterocolitisn the early antibiotic era (1, 5, 13). C. dfficilediarrhea occurs both sporadically and in clusters or out-breaks n hospitals,nursing homes and chronic care facili-ties, but the frequencyof the diseases very much lower inthe community. C. difficile canbe detectedn the stoolsof5Voor more of healthy adults,and evenmore frequently nthe stoolsof healthy nfants (30-507a) andpatientswithoutdiarrhea n some hospitalsand nursing homes(up to 307o).Infants who carry the organismrarely develop C. dfficilecolitis, and there s evidencesuggesting he reason or thisapparent rotection s that the toxins do not bind well to thecolonic mucosabecausets binding sitesare mmature(3, 5,6). C. dfficile is widely distributed n the soil, water, andenvironment of patientswith C. dfficile diarrhea(14). Insome hospitalsand nursing homes, as many as 20-30Vo ormore of patientswho have received antibioti cs have beenfound to be asymptomatic carriers and sheddersof theorganism nto the environment.Consequently, preadof the


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- May 1997o others here who have been treatedwith anti-

and are hereforesusceptibleo colonizationby smallC. dfficile sporesmay be frequent. Transmis-

of the C. dfficile seemsmost often to be via the handspersonnel, nd alsoby contactwith contaminatednd fomites 11 , 13).

OF C. DIFFICILEDIARRHEA

e typical manifestationsof Clostridium dfficile diar-recramping abdominalpain, profusediarrheaconsist-

of mucoid, greenish, oul-smelling, watery stools, owever, and leukocytosis.These can start a few days

antibiotic therapy is begun or up to 8 weeks after itsMany patients with C. dfficile diarrhea

40'C and leukocytosisas high aser mm (3); in fact, eukemoid eactions n the range

per mm3 have been reporled. t is not rare foro have watery diarrhea similar to that seen n theantibiotic diarrhea of unknown cause (l-6). Al-colitis can occur throughout he colon, it is usually

severe n the distal colon and rectum. When patientslocalized o the cecum and right side of the

little or no diarrhea. nstead, fever,d ower abdominal pain and tenderness,

and decreasedntestinal motility mayonly clues o the disease. his presentations not rare

t is especially serious, in part because diagnosis andmay be delayed becauseof the lack of diarrhea,

seems o occur more frequently when antiperistaltichave been given postoperatively.Unlesscomputerized omography or other tests are

and suggest he diagnosis and the need for specificthese patientsmay progress apidly in

and require emergent abdominal laparotomy andolectomy becauseof toxic megacolonor colonic(15, 16). Other complications of C. dfficilenclude dehydration,hypovolemia,hypoalbumine-

anasarca, lectrolytedisturbance, hock,and a reactive4-6).of C. difficile diarrhea ncludes

or simple antibiotic-associated iarrhea, acute anddiarrheacausedby other entericpathogens, dverse

o variousmedicationsother han antibiotics, sch-is, idiopathic inflammatory bowel diseases, nd

OF C. DIFFICILE DIARRHEA ANDCOLITIS

iagnosidiagnosis are presented n Table 1. The

and most rapid way to establish he diagnosis of C.colitis is by endoscopywith biopsy of suspiciouss expensive ndusually eservedbr

CLOSTRIDIUM DIFFICILE-A SSOCIATEDDIARR HEAANDCOLITIS 141TABLE I

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

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

l. The diagnosisshould be suspectedn anyone with dianhea who hasreceivedantibioticswithin the previous2 months and/or whosediarrhea began 72 h or more after hospitalization.

2. When the diagnosisof C. dfficile diarrhea s suspected, single stoolspecimen should be sent to the laboratory for testing for the presenceof C. diff icile and/or its toxins.

3. If the resultsof those ests are negativebut diarrheapersists, ne ortwo additional stools can be sent or testinswith the sameordifferent tests.

4. Endoscopy s reserved or special situations, uch as when a rapiddiagnosis s neededand test resultsare delayed or the test s nothighly sensitive,or the patient has leus and a stool is not available,or when other colonic diseases re in the differential.

special situations,such as when the patient s seriously lland the resultsof rapid but not highly sensitivenoninvasivetests are negative or delayed and C. dfficile diarrhea isstrongly suspected, r when someotherdisease rocesshatcan be diagnosedby endoscopy s also being considered(2-6). Endoscopy s diagnosticwhen it demonstrates har-acteristic, raised, yellowish nodules or plaque-likepseudomembranes,ften with skip areasof normal mucosa.The nodulesare usually 2-10 mm in diameter,but in ad-vancedstages hey are increased n number, enlarged,andcoalesced o form plaquesor membranes hat cover largesegmentsof the inflamed mucosabut are easily strippedfrom it (hence the term pseudomembrane). odules andsmall pseudomembranes re easily dislodged during theprocessingof biopsies.Microscopic examinationof the le-sions shows epithelial necrosis,goblet cells distendedwithmucus, edema, and infiltration of the lamina propria withleukocytes,epithelial cells, fibrin, and mucin. The terms"summit lesions" or "volcano lesions" have been used todescr ibehese esions 1,3,4) . Gross esionsmay be socharacteristico experienced ndoscopistshat biopsy s notneeded,but it is best to obtain a biopsy if there is doubtabout the diagnosis.When the colonic mucosashows onlyerythema, friability, or edema without nodules orpseudomembranes,t is suggestive f the so-callednonspe-cific colitis or simple colitis that may be caused by C.dfficile as well as a variety of other conditions.Biopsy ofsuch esions,even when small, may confirm the presence finflammation(colitis)along with pseudomembraneshat arenot grossly apparent. In a study of 22 patients withpseudomembranous olitis, it was found that endoscopywith a rigid endoscope etected ewer casesof colitis thanwith a flexible sigmoidoscope (77 vs 9lVo), and thatcolonoscopydetectedadditionalcases 97aof the total) notreached sing lexiblesigmoidoscopy17).C. di.fficile-specific iagnoslic /csls

There is as yet no simple, inexpensive, apid, sensitive,and specific test for diagnosing C. dfficile diarhea andcolitis. nor areall the available estssuitable or adootionbv


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742 FEKETYevery laboratory (18). However, each laboratory shouldconsider providing one of the rapid, inexpensive ests andalso, if practical, a specific test for the presenceof theorganismor its toxins. Many institutionsprovidean enzymeimmunoassay EIA) test or rapid detectionof toxin A or Band also a cell culture assay or toxin B, the cytotoxin.Tissue culture tests for toxin B. The

"Gold Standard"Iaboratory est for establishing he diagnosisof C. dfficilecolitis s still the demonstrationn cell culture monolayersofthe characteristiccytopathic effect of toxin B in filtrates ofdiarrheal stools. Specificity of the cytotoxicity is demon-stratedby showing that it is prevented neutralized)by useof antitoxin o C. dfficile or Clostridium sordellii toxin (theutility of the latter reflectsantigeniccross-reactivity) 1-6,18-21). There is no practical laboratorytest available ordetecting oxin A in stoolsby meansof its biological prop-erties.Cell culture tests to detect the specific cytopathiceffectsof toxin B arepositive n more than90%a f patientswith pseudomembranous olitis (1-6). False negative re-sults n this as well as he other estsused or detecting hesetoxins may be causedby a numberof factors:because f theinactivationof the heat and acid abile toxins during storageor transportation r by medications, ecause omecell linesused or this test are less sensitive han others o the cyto-pathic effect of the toxin (.2-6), and especiallybecauseoftestingstool specimens iluted in the laboratory.Therefore,it is important to recognize hat a negative est for toxin Bin cell culturesdoes not rule oil C. dfficile as thecauseofthe diarrhea. f toxin B is detected n high titer, it is highlylikely that C. dfficile is the causeof the diarrhea,but thereis little conelation n individual patientsbetween he heightof the toxin titer and the severity of the diarrhealdisease. tis not uncommon for patientswho have responded o ap-propriate herapy or C. dfficile diarrhea o continue o havestools that test positive for toxin B or the organism for ashort ime after discontinuation f otherwisesuccessfulher-apy. Experiencehas shown that most of thesepatientswillhave no furlher diarrhea and that it is not necessary operformculturesor tests or the toxin on stools rom patientswho no longerhavediarrhea 5, 6, 18,22).

Enzl,me immunoassay estsJbr toxin A and/or B. Thereare several ommercially availableEIA tests or detectionoftoxins A and/orB of C. diff ici le n stools l-3,5, 18-21).They are apidly performedand relatively nexpensivewhendone n batches, nd hey areprobably he most widely usedlaboratoryaids n the United Statesn diagnosingC. dfficilediarrhea. The EIA tests are more specific than they aresensitive.The sensitivity of the commercial EIA kits usedfor toxin A and B detectionhas varied widely when eval-uated n different laboratoriesusing the samekits but dif-fering criteria for a positiveendpoint.Whereassensitivitieshave ranged rom a low of about'707o o as high as 957o,specificity was generally very good. In most publishedreports,accuracyofthese testswasevaluated n the basisofprobable clinical diagnoses instead of upon diagnosesreachedusing both a cytotoxicity test for toxin B and en-

AJG - VoL 92. No. 5. 1997doscopy, arguably the two most accurateand dependablediagnosticaids.On average,EIA tests or toxin A and/or Bfailed to detectabout 07o (range5 to 33Vo) r moreof casesof C. dfficile diarrheadiagnosedclinically and by endos-copy with biopsyor by useof toxin B assaysn cell cultures.Newer and allegedlybetterEIA tests aswell as other noveltests) are becoming available, but proper clinical studiesdocumenting heir superiorit y have not yet been reported.Therefore, t shouldbe emphasized hat a negativeEIA testfor toxins A or B does not rule out the diagnosis of C.dfficile colitis. Sensitivity is rarely improved by sendingmore thanone stool on the sameday for EIA testing,so thispractice s probably not cost-effectiveand should be dis-couraged.However,when an EIA test,or other rapid test, sreportednegative, t 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 s critically ill or does not improve afterantibiotic therapy has been discontinuedand supportivetherapyhas beengiven. Alternatively,empiric therapywithmetronidazolemay be given to seriously ll patientswhenthe first test result s negativeand other diagnostic estsarenot availableor are in process.

Latex agglutination re.lt. Originally thought to detecttoxin A, this simple, rapid, and inexpensive mmunologictest actually detects he presenceof glutamatedehydroge-nase produced by C. dfficile, not toxin A (3, 4). Thisenzyme appears o play no role in the pathogenesis f C.dfficile diarrhea,but many clinicians and laboratory per-sonnel still incorrectlybelieve the latex agglutination estdetects oxin A. Nontoxigenicstrainsof C. difficile (whichdo not causediarrhea)are also positive with the latex test.In addition, the latex agglutination est is nonspecific,be-cause several other organismscommonly found in stoolscan producean antigen hat cross-reactswith the antibodydirected againstglutamatedehydrogenase roduced by C.dfficile. Overall, the latex agglutination test is about assensitiveasbut not as specificas he EIA tests or the toxins(19-21,23). Comments n the previoussectiondiscourag-ing thepracticeof sendingmore hanone diarrhealstoolperday for EIA testing apply equally well to the latex aggluti-nation test.

Both the EIA and latex agglutination tests are simple,rapid,and nexpensive f they areperformed n batchesandquantity, but neither one is as reliable and sensitive asdesired.Unfortunately,cliniciansare often unaware of thespecific test used or detectingC. difficile or its toxins intheir Iaboratoryand of their important differences n sensi-tivity and interpretation, n part because such results arecommonly reportedsimply as a positive or negative "C.dfficile test" without specifying he test used.A few labo-ratories have begun to use both the EIA and the latexagglutination ests, eserving he performanceof the latterfor specimens hat are negativeby the EIA. This strategyappears o improve sensitivityand to decrease pecificity,but many clinicians would conclude this errs in the right


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144 FEKETYTasls 2

Practice Guidelines .for Treatment of Cktstridium dfficile Diarrhea orColitis1. Antibiotics should be disc ontinued f possible.2. Nonspecificsupportive herapy should be given, and is often all that

is needed n treatment.Specific antibiotics should not be givenroutinely.

3. When the diagnosisof C. dfficile diarrhea s confirmed and specifictherapy s indicated,metronidazolegiven orally is preferred.

4. I f the diagnosisof C. dfficile diarrhea s highly likely and the patientis seriously ll, metronidazolemay be given empirically before hediagnosis s definitely established.

5. Vancomycin given orally is reserved or therapy of C. dfficile'associated iarrheauntil one or more of the following conditionsarepresent:(a ) The patient has failed to respond o metronidazole.(b ) The patient'sorganism s resistant o metronidazole.(c ) The patient s unable o toleratemetronidazole, r is a llergic to it ,

or is being treatedwith ethanolcontaining solutions.(d) The patient s either pregnantor a child under the age of l0 years

of age.(e) The patient s critically ill becauseof C. dfficile-associated

diarrheaor colitis.(i ) There is evidencesuggesting he diarrhea s causedbySl t nh| I ,C)CC US OU e t .

diarrhea,or in the early detectionof complicationsof C.dfficile diarrhea.However, because t is expensive,CT isreserved or specialsituations 30, 31). Radionuclidescansmay detectevidenceof colonic inflammation rapidly, butthe findings are nonspecific, expensive, ime-consuming.and not always readily available.

TREATMENT OF ANTIBIOTIC-ASSOCIATEDDIARRHEA/COLITIS

Nonspecific supportive the apyGuidelines or treatmentare presentedn Table 2. When

appropriatediagnostic measuresare in progress,but thediagnosisof C. dfficile diarrheahasnot yet beenestablishedand the patient is not seriously ll, nonspecific supportivetherapyshould be given and is often all that is needed orresolutionof diarrhea,evenwhen t is caused y C. dfficile.Nonspecific therapy may have the additional benefit ofreducing he ikelihood of a relapse,as compared o specificantibiotic therapy. Supportive therapy usually consistsofreplacementherapywith fluids and electrolytes.f possible,antibioticsgiven to treat an infection shouldeither be dis-continuedor switched to alternateappropriateantibiotics.The administration f antiperistaltic nd opiatedrugs shouldbe avoided,because hey may mask he patient'ssymptomsand alsocausepoolingof toxin-laden luids within the colon(2, 4). Some patientswith C. dfficile diarrheahave wors-ened after being given antiperistalticsor opiates,but thismay have been coincidental 32), since many patientswiththe diseasehave been given antiperistalticswithout anyadverseconsequences.

AJG Vol. 92. l,,lo.5, 1997Specific antimicrobial the apv

When appropriatediagnostic ests have been performedand the diagnosisof C. dfficile dianhea is likely or con-firmed, or the patient s a nonpregnant dult or a child overl0 yr of age who is worsening or has not responded osupportive herapy given for 2 or 3 days, specific antimi-crobial therapymay be initiated. Metronidazole,vancomy-cin, teicoplanin which is not available n the United States),and, essoften,bacitracinhavebeenused o treatC. dfficilediarrhea because hese antimicrobials nhibit growth andtoxin production by C. dfficile. Metronidazoleand vanco-mycin are by far used most often in the United States.Therapygiven by the oral route s alwayspreferred,becauseC. dfficile diarrhea s not caused y tissue nvasion,and hetoxinsproducedby the organismwithin the ntestinal umencausediarrheaonly after binding to specific eceptors n thecolonic mucosa. C. dfficile diarrheal syndromesusuallyrespond well to oral therapy with either metronidazoleorvancomycin if therapy s startedearly enough,but the re-sponse s sometimesessgood when metronidazoleor van-comycin are given to patientswho are critically ill with thediseasel-6) .

A controlled study comparing therapy of C. dffiicile di'arrhea with either metronidazole given orally in a dose of250 mg four times per day or vancomycin n a dose of 500mg four times per day for 10 days showedthat the onlystatisticallysignificant difference between them was thatvancomycinwas more costly (33).The durationof diarrheaand the frequency of side effects,posttreatment elapses,and carriage of the organism in convalescencewere notsignificantly different. All 52 patients given vancomycinwere cured, but 2 of 42 patients ailed to respond o met-ronidazole (a difference that was not statistically signifi-cant), and were cured when therapywas changed o vanco-mycin, a fact that has led some investigators o prefervancomycin when the patient s critically ill. Interestingly,34 (22.87o)of the 149 patients n this study responded osupportive herapy alone within a 48- to 72-h observationperiod while the diagnosiswas being established, nd didnot require therapy with either vancomycin or metronida-zole. Specificoral therapywith metronidazole r vancomy-cin is usuallygiven or only 7 to 10 days,unless he llnessis severeor the diarrhea s slow to resolve 1,2, 4,33).Patientswho require therapyfor more than l0 days oftenhave severecolitis, or a delay n diagnosisand treatmentofcolitis, or an underlyingconditionpredisposing o diarrhea,such as actose ntolerance,rritablebowel disease, iabeticenteropathy, r diarrheadue to an adverse eaction o med-icationsor diet.

Metronidazolegiven intravenousll, as been used o treatpseudomembranous olitis in patients who are unable totake t orally. The reported esultshave beengood,althoughtreatment ailureshaveoccurred.A possibleexplanation ortreatment failures when metronidazole is given intrave-nously s that the stool concentrations chievedare usually


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G - May 1997than thoserequired or inhibition of the organism n(34). Even though stool concentrationsare also lowmetronidazoles given orally (34,35), such herapy ssuccessful, nd this paradox s as yet unexplained.he oral route s preferredwhen it can be usedwealthof clinical experiencendicates t is highly

Oral metronidazole(Flagyl) is prefercedfor therapyof C.diarrhea. An expert committee of hospital infec-control practitionershas recently recommended hatis preferred for specific or empiric antimi-treatment of C. dfficile diarrhea,and their recom-has been widely adopted n the United StatesOne of themain reasons or their recommendationwaso curtail the use of vancomycinbecause f fearuse will encourage he spreadof vancomycin-resis-VRE), and ultimately the emergenceandf vancomycin-resistant taphylococci,whereasmet-will not. Other reasons ncluded were that met-s much lessexpensive han vancomycin, hat itwell-toleratedwhen given orally for short periods,andas effective as vancomycin or most patients 33).metronidazole as not beenapprovedby the FoodAdministration specifically for treatmentof C.diarrhea, it has been approved by the FDA for theof serious nfectionscausedby susceptible naer-bacteriasuch as C. dfficile.A few caveatsconcerning the preference for metronida-are n order,becauseuse of vancomycin for treatmentC. dfficile diarrhea s justified in specialcircumstances.

metronidazoles usually well-tolerated, t has anmetallic tasteand may also causenausea, om-diarrhea, abdominal pain, pruritus, erythematouseadache, onfusion,dizziness,and reversibleneu-and additional patientsmay becomeallergic to it.taking oral metronidazole should be cautioneddrinking alcoholic beveragesbecause his mightin disulfiram (Antabuse)-likereactions.Also, raref C. dfficile are resistant o metronidazolen vitro,here s little evidence hat resistances responsibler treatment ailures.At the University of Michigan Hos-6 (.3Vo) f 200 isolatesof C. dfficile obrained romand tested n vitro over the period from 1980 towere resistant o metronidazole t concentrationsang-g from 16 to 128 p,g/ml,whereasall were highly suscep-to vancomycin (37). Becausemetronidazole s a car-mutagenic n some animal species and in vitro,he placentalbarrier and is fetotoxic for pregnantshould be used during pregnancyonly if clearlySimilarly, because he safetyof metronidazole orhas not beenproven,many prefer not to use t forof children unlessnecessary.For treatmentof adultswith C. dfficile diarrhea,metro-s usually givenorally in a dosageof 250-500 mg

times per day or 500-750 mg three times per day fordays; for children, a dosageof 35-50 mgkg/24 h

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS 145TaeI-e 3

Practice Guidelinesfor Management of Relapses1. Reconfirm the diagnosis.2. Discontinuemedications hat may be contributing o the diarrhea,andtreat the patient with nonspecific supportive therapy.3. If specific herapy s needed, reat he patientwith a standard ourse

of metronidazolegiven orally fo r 7 to l0 days, or with vancomycin,as n the TreatmentGuidelines Table 2) .4. When possible,avoid treating(minor) infectionswith antibiotics orthe next 2 months after treatment of a relapse.5. No treatmentavailable n the United Stateshas beenproven toprevent recurrences. f the patient has suffered from multiplerecurrences, onsiderusing one of the following antimicrobialregimenswith or without one of t he other therapeuticmeasures s anadjunct. These are not presented n an order of preference.(a ) Oral metronidazole or vancomycin,as in Table 3) .(b ) Specifictherapy with vancomycin or metronidazolegiven orallyfb r I to 2 months,either ntermittently(sucb as every other dayor week) or with gradual apering,with or without adiunctivetherapywith an oral anion-binding egimen such ascholestyramine r colestipolbegun near he end of antimicrobialtherapyand gradually tapered.(c ) Oral vancomycin plus rifampin.(d) Oral yogurt, Lactobacillus preparations, or Lactobacillus GG.(e ) Saccharomyces oulardii (500 mg orally twice daily), if available,may be given for I month, if the patient is not

immunocompromi.sed,eginning 4 days beforea lO-daycourseofspecific antibiotictherapyhas beencompleted.(f ) Human immune globulin by intravenous nfusion, or patientswithdocumenteddeficiencie".

divided into three doseshasbeenused. f metronidazolesused ntravenously or treatingpatientswho are critically il land/orunable o tolerateoral medications,t can be used na dosageof 500-750 mg three or four times per day. Asstatedearlier,metronidazolegiven intravenously or treat-ment of C. dfficile diarrhea s probably not as reliable aseither metronidazoleor vancomycingiven orally. Metroni-dazole should be used via the intravenous oute for treat-ment of C. dfficile diarrheaonly when it is not possible otreat via the oral route, and never for reasonsof conve-nience.When metronidazole s used ntravenously o treatC. dfficile diarrhea,consideration hould also be given tothe simultaneous se of vancomycinenterally,as discussedbelow.

Indicationsfor treatmentwith vancomycin.Vancomycinstill has a role in the management f C. dfficile diarrhea,although t is a much smallerone than was the casebeforethe recommendation that metronidazole is preferred fortherapy of C. dfficile diarrhea.Becausevancomycin ispoorly absorbedsystemicallywhen given orally, effectiveconcentrationsare easily achieved in stools and serioussystemicside effects are rare (2-6). Nevertheless. anco-mycin should not be used for treatment of C. dfficile diar-rheaunless he patient s unable o toleratemetronidazole, rbecause f the other ndicationsoutlined he PracticeGuide-l ines n Table3.It should be pointed out here that pseudomembranousenterocolitiswas a well-recognized linical comolicationof


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146 FEKETYsurgery n the preantibiotic and early antibiotic era, that itwas commonly attributed to toxin-producing, antibiotic-resistantS. aureus,and that it was treatablewith oral van-comycin. Some investigatorshave retrospectivelyques-tioned the role of staphylococci in the cause of thoseillnesses1), andsuggestedhey were actuallycausedby C.dfficile, whose mportance n this syndromewas not estab-lisheduntilabout1978 1, l3). Staphylococcalnterocolit isbecame very much less frequent in the 1960s after theintroductionand useof vancomycinandsemi-synthetic en-icillinase-resistantB-lactam antimicrobials fo r treatingstaphylococcalnfections.However, there s a considerablebody of evidencesuggesting hat staphylococcican indeedcausediarrheaand colitis after the use of antimicrobials.Before the antibiotic era, many patients diagnosed withstaphylococcal nterocolitishad extensive nflammatory e-sions n the colon at postmortemexamination,and often inthe leum, ejunum, an d stomachas well (13).These ind-ings are not characteristic f C. dfficile diarrhea,althoughileitis has occasionallybeen documentedn patientswith it ,especially f they have an ileostomy (38). After recognitionin the late 1970sof the important and unquestionably om-inant role of C. dfficile in the causationof antibiotic-associated seudomembranous olitis, little attention wasgiven to S. aureus as an etiologic agent of antibiotic-asso-ciateddiarrheaor colitis. However, here s no question hatdiarrheacan be causedby S. aureus.For example,diarrheais common n patientswith the toxic shocksyndrome ausedby inf-ectionwith enterotoxigenicstaphylococci,often thesite is one that is minor and hard to detect (39). Morealarming s that methicillin-resistantS. aureusenteritishasbeen reported within the past few years as an importantcauseof antibiotic-associatednteritis n Japan n patientswith negativestudies or C. dfficile and ts toxins (13, 40).Ifthese reportsareconfirmedoutsideofJapan, hen enteritiscausedby methicillin-resistantS. aureus and methicillin-sensitiveS. aureus,organisms hat are resistant o metroni-dazole,may emerge as an important complication of anti-biotic use elsewhere,ncluding in the United States.Suchcaseswould most likely be recognizedwhen patientswithantibiotic-associated iarrhea presumed to be caused C.dfficile failed to respond o treatmentwith metronidazole.Staphylococcimay alreadycausemore nosocomialdiarrheaor colitis in the United Statesand other countries han isappreciated, n part becauseselectiveculture media andother tests needed o implicate this organism are neitherwidely availablenor oftenused or patientswith nosocomialantibiotic diarrhea. Finally, in 1978, three patients inhospitals in the United States were reporled to havepseudomembranousolitis, which was well documentedntwo of them, andgood aboratorystudies ailed to detectC.difficile and ts toxins n their stools,but werepositive or S.aureus and a unique cytotoxin similar to one producedbytheir staphylococcin vitro (41).Therefore, t is possible hatthe preference br metronidazole n treatmentof C. difficilediarrheamay be associatedn the uture with a resurgence f

AJG - Vol. 92, No. 5, 1997diarrheaand enterocolitiscausedby staphylococci.Theseissuesare discussedn greaterdetail elsewhere 13).

When therapywith vancomycin or C. dfficile diarrheasjustified, it is usuallygiven orally in a dosageof either 125mg four timesper day for 7-10 days,or 500 mg four timesper day if the patient s critically ill or has mpending leus,colonic dilation, or perforation. These regimens seemedequally effective n reportedstudies 4,22). For infants andchildren, an oral dose of 5OOmg/1.73m (2) every 6 h hasbeen used.Vancomycinshould not be given intravenouslyas the sole therapy for C. dfficile diarrhea,since effectiveconcentrationswithin the colonic lumen are not reliablyachievedwhen it is given in this way. If patientscannot betreatedorally with vancomycin,or they haveparalytic leus,and he patient s to be treatedby the instillationof the drugby perfusionvia a tube or pigtail catheterdirectly into thececum or ileostomy,200 or 500 mg vancomycin n 500 ml(400 or 1000pgiml) given up to four times per day can beused, f tolerated.Another regimen hathasbeenused n thissettingconsists f giving vancomycin ntracolonically 2000mg followed by 100 mg every 4 h and 100 mg after eachstool) via a pigtail catheterpositioned during colonoscopy(42). Reconstituted olutions ontainingvancomycinmustbe diluted with at least 100 ml of diluent per 500 mgvancomycin.

Alternative therapies.Bacitracin (43), teicoplanin(44),or nonabsorbable nion binding resins (45) such as cho-lestyramineor colestipolmay be given orally for treatmentof mild C. dfficile diarrhea 4), but theseagentsareneitheras reliable nor as rapidly effective as metronidazoleorvancomycin.Anion binding resinsbind toxin B of C. dffi-cile, but experience suggests heir capacity to do this islimited and probably nadequate n severecases.They mayalso bind vancomycinand herebydiminish ts efficacy, andcan cause severe constipation and intestinal obstructiononce diarrheahas resolved.Neither teicoplaninnor bacitra-cin for oral administration re eadilyavailable n the UnitedStates. t shouldbe cautioned hat teicoplaninhasa propen-sity similar to that of vancomycin for encouraging thespread of vancomycin-resistant nterococci,and that theclinical responseo bacitracin s slowerand esscertain hanit is with vancomycin, possibly becausesome isolatesareresistant o bacitracin(37).

MANAGEMENT OF RELAPSES OR RECURRENCESOF C. DIFFICILE DIARRHEA OR COLITIS

Guidelines or management f relapsesare presentednTable 3. Relapses recunences)of diarrhea or colitis arerecognizedwhen there s a return of symptoms,signs andpositive diagnostic ests a few weeks to months after dis-continuationof successful ntibiotic therapy for C. dfficilediarrhea.Because he patientshad previously responded,these occurrencesshould not be thought of as treatmentfailures.Relapses ccur n about 15-357oof patients,with amean fiequency of about 207o (4, 22, 23). Because C.


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G - May 1997diarrhea and colitis have markedly increased nn hospitals n the United Statessince lgg4 (11,so has the frequency of encounteringpatients withor relapsing C. dfficile diarrhea. Relapsing C.diarrhea s a serious,difficult, and still unsolvedroblem, especiallywhen patientshaveexpe_hreeor more episodes 47). However, it is impor_to remember s that it is rarely difficult to treat eachuccessfullyusing standard herapywith metro_(or vancomycin);what is still difficult to accom-is the preventionof further recurrences.Recurrencesmay be causedeither by persistence f thestrain of C. dfficile or by reinfection with the samea different strain. Some strains seem more likely thanto causerecurrences 47), whereasstrains hat arenever do so. Recurrences sually begin withe retum of diarrhea 2 wk to 2 months after successfulherapyof an episodeof C. dfficile diarrhea.are characterizedby the return of typical symp-and signsof C. dfficile diarrhea, positive assays or C.toxins in stools,and cultures hat yield vancomycinmetronidazole susceptible strains of C. dfficite. Theof recurrences oesnot seem o be influencedbye specific nature of the original inciting antibiotic, bymetronidazoleor vancomycin was usedfor treat-of the initial episode,or by the dosageor durationofwith vancomycin or metronidazole. n some re_recurrencesoccurred more often in patientswhosecultures remain positive after successfulantibioticor C. dfficile diarrhea,bur not in others 29,47).Incase,becausehere s no way to reliably eradicatehedfficile carrier state, there is no good reason to obtaincultures o determinewhethera patient s at high riskr a relapse.Relapses ppear o be ess ikely to occur f theepisodewas reatedonly with supportive herapy.Somepatients have experiencedmany recurrences;than 6 episodes s not unusual and more than 20 iso be the record,each after a courseof apparentlyreatment.Fortunately,patientscan be reassuredo nol have a tendency o becomeprogres-more severe 47), even thoughthey may causemoreconcernwith eachepisode.Many different treatmentshavebeenused n an attempt torecurrences, nd most expertshave their own fa-regimen. However, no specific treatment regimenavailable in the United States has beenin properly controlled, double blinded, randomizedto prevent multiple recurrencesor relapsesofC.diarrhea. Standardantibiotic therapy should betreat relapsesand is usually successful,even if itnot prevent further recurrences 47). Metronidazoleo be as effective as vancomycin in treatmentofnd it is lessexpensiveand generallywell toler-There is little or no evidence hat patients sufferingmultiple recumences o so because hey have under-abnomalities of their gastrointestinal ract or host

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA AND COLITIS 141resistanceactors that accounts or their proclivity for de_velopmentof recurrences, lthougha few childrenand oneadult have been reported who may have had a specificimmunoglobulin deficiency that predisposed hem to re-lapses (48-50). Whereas vancomycin and metronidazolealmost always kill the vegetative forms of C. dfficile thatproduce he toxinscausingdiarrhea, heydo not reliablykillthe spore brms of the organism, he persistence f whichseems he root causeof the trouble. In fact, antimicrobialtreatmentappears o encourage ormation of spores (51),which are hardy and can persist n the intestinesor envi_ronment of patients or long periods of time (14), duringwhich they may germinate, or the patient may becomereinfected,and diarhea may occur if the patient has notre-established ntestinal resistance to the colonization,growth and toxin production by C. dfficile. The mecha_nisms, such as competition fbr nutrients (52), by whichcertain organismsof the normal flora are responsible or"colonization resistance" o C. dfficile are poorly under_stood. Paradoxically,derangementsn colonization resis_tance are even seenafter treatmentwith vancomycin andmetronidazole, inceboth are capableof inducing C. ctrfft_cile dianheaas well asof treating it. Unfortunately, the f'ecalflora and its colonizationresistancemay not return to nor_mal for many months after exposureof patients o antibi_otics. lt thereforeseemsprudent that an effort should bemade in managingpatientsexperiencing elapses o avoiclthe useof antibioticsas much aspossibleso as o hasten hereturnof theprotectivenormal fecal flora. Accordingly, t isrecommendedhat he unnecessary rophylaxisor treatment

of infections,especiallyminor ones,with antibioticsshouldbe avoidedwithin the first 2 months after treatmentof anepisodeof C. dfficile diarrhea(47).When patients experiencea recumenceof C. rtifricitediarrheawithin a few months after a successfully reatedepisode,he diagnosis houldagainbe confirmed especiallyif the episode is atypical). Unless diarrhea is mild, thepatientshouldagainbe treatedspecifically,preferablywithmetronidazole, ven f it was used or treatmentof the firstepisode or vancomycin,according o the treatmentGuide-lines in Table 3), usually for only 7-10 days in standarddoses f the patientrespondspromptly (47).Some authoritiesbelieve hat patientssuffering fiom re-peated ecurrences houldbe treatedusing a regimen con-sisting of the intermittent administrationof metronidazole(or vancomycin)over a periodof weeksor evenmonthsandfollowed by their gradual apering,or by prophylaxiswithlow dosesof theseantibioticsgiven daily or on alternatingdays or weeks,or by useof cholestyramine r other anionbinding medicationsalong with specific antibiotics,espe-cially at theendof therapy 6, 53).Cholestyramine an bindvancomycin as well as the toxins of C. dfficile and as aresultmay interferewith specific herapy; t may also causeobstipationas a side effect. Such regimensmay appear o

have been successful n preventing further relapses,butnone havebeenvalidated n properly controlledstudies,so


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148 FEKETYthe favorableresult may be only coincidental.Treatmentwith the combination of vancomycin and rifampin givenorally was thought to be effective in termination of relapsesin a small uncontrolledstudy (54), but there s no evidencethat this antimicrobial combinationhas any synergisticorother unique activity against C. dfficile or its spores, hehopeof which was the reason t was tried in the first place.Various other unprovenmeasureshave tried to restore hecolonizationresistanceof the fecal flora of patients withrelapses.Many of them fall into a category referred to asprobiotics.These nclude he oral or rectal administrationofyogurt, lactobacilli (55), enemas containing feces fromhealthy persons 56) or mixtures of various bacterianor-mally found in the intestinaltract (57). Use of the Lacto'bacillus GG strain seems o be more effective and rationalthan yogurt or other lactobacilli (55). Another promisingnew approach nvolvestreatingpatientswho have relapsedwith the oral administrationof a live yeast Saccharomycesboutardii) for about4 wk, beginning4 days before he endof conventional antibiotic therapy for a recurrence.Thisnovelmeasurewas evaluated n the United States n a welldesignedmulticenterplacebo-controlled tudy and was re-ported o be safeas well as effective. ts use n patientswhohad experienced t least one relapsewas associatedwith areductionof about 5O7o p : 0.04) in the frequency offurther elapses58) comparedwith those eceivingplacebo.This report s the only well controlled and scientific studyconcerning he prevention of relapses n humans that hasthus far been reporled. The mechanism of the presumedprotectiveeffect of S. boulardii is not known, but it may bebecause protease t producesprevents he binding of thetoxinsto the intestinalmucosa 59).BecauseS. boulardii isavailable for treating relapses n Europe but not in theUnited States, omephysicianshere have attempted o useSaccharomyces erevisiae (Brewer's yeast) in a similarfashion. However, these two organisms are significantlydifferent from one another (60), and there are no reportsproving the efficacy of S. cerevislae,although there are afew anecdotal eportsclaiming successwith it .

Therapywith intravenousmmune globulin, especially nchildrenwith various mmunoglobulindeficiencies, as ap-peared effective in prevention of recurrences n anecdotalreports 48-50). Other novel ways to actively or passivelyimmunizepatientsagainstC. dfficile and its toxins are thesubjectof ongoing research elated to this important andincreasingly requentproblem of recurrentC. dfficile diat-rhea.

PREVENTION OF C. DIFFICILE DIARRHEA ANDCOLITISGuidelines or prevention are presented n Table 4' Pte-

vention of C. difficile diarrheaand colitis is basedupon afew simple practicesand attitudes.Hospitalizationand in-tensiveexposure o antibioticsare mportantrisk factors oracquisit ion f C. dffici le (4-6, 8, l l, l2). Avoidance f the

AJG - Vol. 92, No. 5, 1997TasLs 4

Practice Guidelines.for Prevention of Clostridium dfficile Dirtrrhea1. Limit the use of antimicrobialdrugs.2. Wash hands betweencontactwith al l patients.3. Use enteric(stool) solationprecautionsor patientswith C. dfficile

diarrhea.4. Wear gloves when contactingpatientswith C. dfficile dianhea./colitis

or their environment.5. Disinfect objects contaminated with C. dfficile with sodiumhypochlorite,alkalineglutaraldehyde, r ethyleneoxide

6. Educate the medical, nursing, and other appropriate staff membersabout he disease nd its epidemiology.

unnecessary se of antimicrobialdrugs is of obvious im-portance, ut is all too ofteneasier aid handone.Restraintsand limitations in the use of antimicrobials are of growingimportance because of alarming recent increases in theemergenceof new antibiotic-resistant athogens n hospi-tals, such as Enterococcusaecalis and E. faecium, Strep-tococcuspneumoniae, Staphylococcushemolyticus,Clos-tridium dfficile, and numerous speciesof enteric Gram-negativebacilli.

Transmission of C. dfficile from one person to anothervia the hands of personnelappears n hospitals to be moreimportant in spread of C. dfficile than does contact withspores n the environment,but both probably occur. Carefulhandwashingbefore and after contact with all patients, andthe use of gloves and stool (enteric) solation precautionswhen contactingpatients wirh C difficile dianhea or who arecarriers of this organism are the most effective measures orpreventing its spread(4, 14, 61, 62). Single rooms withprivate bathrooms should be provided when possible forpatients with C. dfficile diarrhea,at leastuntil their diarrheahas stopped.Patientswith C.dfficile diarrheaand o a lesserextent, thosewho areasymptomaticcarriersof the organismappear o contaminate heir immediate environment with C.dfficile spores,which then becomesa potential sourceofreinfection for the patient as well as personnel and otherpersons,particularly if they have recently receivedantibi-otics (8, 14). Sincemany healthypersonsandpatientswith-out diarrhea who are in hospitals carry C. dfficile in theirintestines,here s little if any rationale or continuingEn-teric IsolationPrecautionsor patientswho no longer havediarrhea,or to test them for calriage of the organism afterdiarrhea has stopped.Antibiotics do not reliably kill thesporesof C. dfficile even hough hey may kill the vegeta-tive forms of the organism, and therefore treatment of car-riers with metronidazole r vancomycin doesnot eradicatethe organism rom their intestinal racts (35), even thoughthese antibiotics may markedly decreasethe numbers ofvegetative orms in stools 51). Suppression f excretionofthe organism by carriers with use of treatment with metro-nidazoleor vancomycinmay have occasionall ybeenusefulin terminating ocalized outbreaks n hospitals,but the ef-fects of this approachhave been far from striking. Alkalineglutaraldehyde,odiumhypochlorite,and ethyleneoxideare


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G- May 1997killing the sporesas well as he vegetative ormsC. dfficile (4 , ll, 14) that persiston fomites, nstruments

surfaces,but none of theseare satisfactorywhich is still best carried out with ordi-disinfectantsoapsor chlorhexidine,despite heir lim-power to kill C. dfficile spores (4, 63). Additionalhat havebeen used n facilities where C. dfficileoccurring at a high rate include identifying and(segregating)patientswho are carriers, restrictingwho are carriers to single rooms with private bath-andantibioticcontrol programs.Neither vancomycin

nor any other antimicrobial regimen areeffective n eradicating he C. dfficile carrierstate,because he sporesofthe organismare resistant oaction, unlike the vegetative forms.

It is important that everyone nvolved with patient care nursinghomes,and at homebe educated bout heand ts epidemiology,about ationalapproachesotreatment and care of patients with C. dfficile diarrhea,of handwashingbetweencontact withabout the use of gloves when caring for a patientdiarrhea, and about the avoidance of these of antimicrobials.

ACKNOWLEDGMENTSThe author acknowledgeswith sincere hanks and grati-

the expert advice, help, and counsel of the PracticeCommitteeof the American College Gastroen-J. Patrick Waring, M.D., F.A.C.G. Chair (EmoryGA), Alan Barkun, M.D. (MontrealHospital,Montreal,PQ, Canada),W. Scott Brooks,(Atlanta,GA), KennethR. DeVault,M.D., F.A.C.G.Clinic, Jacksonville, FL), John Hughes, M.D.,(Kelsey Seybold Clinic, Houston, TX), DouglasM.D., F.A.C.G.(Albert EinsteinMedical School,NY), Thomas Viggiano, M.D., F.A.C.G.

Clinic, Rochester MN), James Achord, M.D.,(University of Mississippi Medical Center,Jack-MS), EugeneM. Bozymski,M.D., F.A.C.G.(Univer-Carolina,Chapel Hill, NC), StephenH. Cald-(University of Virginia HSC, Charlottesville,

Michael J. Goldberg,M.D. F.A.C.G. (Chicago, L) ,K. Lo, M.D., F.A.C.G. (Harbor-University of Cali-Los Angeles Medical Center,Torrance,CA), RobertSquires, Jr., M.D. (University of Texas SouthwesternCenter,Dallas,TX), Paul Yeston,M.D. (UniversityVirginia Health SciencesCenter, Charlottesville,VA),A. Banks,M.D., F.A.C.G. (Brigham and Women'sBoston,MA), PatrickG. Brady, M.D., F.A.C.G..A. Haley VeteransAdministrationHospital,Tampa,FL),D. Carey,M.D., F.A.C.G. ClevelandClinic Foun-

OH), Norman D. Grace,M.D., F.A.C.G.Hospital, Boston,MA), GeorgeW. Meyer, M.D.,(Georgia Baptist Medical Center, Atlanta, GA),M.D., F.A.C.G. (Sinai SamaritanMedical

CLOSTRIDIUM DIFFICILE-ASSOCIATED IARRHEA AND COLITIS'749Center, Milwaukee, WI), Gregory Zuccaro, Jr., M.D(ClevelandClinic. Cleveland.OH).

Reprint requestsand correspondence:Robert Fekety, M.D., Division ofInfectious Diseases,Department of Intemal Medicine, 3116 TaubmanHealthCenter,University of Michigan Hospitalsand Medical School,AnnArbor. MI 48109-0378.REFERENCES

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12. Wilcox M. Cleaning up Clostridium dfficile infection. Lancet 1996;348:767-8.13 . Fekety R. Staphylococcalenterocolit isand dianhea. In: Crossley K,Archer G, eds. Staphylococcal nfections.New York: Churchill Liv-ingstone, 1997.14. Kim K-H, Fekety R, Barts DH, et al. Isolation of Clostridium dfficilefrom the environment and contacts of patients with antibiotic-inducedcolit is. J Infect Dis 1981:143:42-5O.15. Medich DS, Lee KK, Simmons RL, et al. Laparotomy for fulminantpseudomembranousolit is. Arch Surg 1992;127847 52.16. Triadifopoulos G, Hallstone AE. Acute abdomen as presentation fpseudomembranousolit is. Gastroenterology 99 ; 00:685-9 .17. Tedesco FJ. Antibiotic-associatedpseudomembranous olit is withnegative proctosigmoidoscopic xamination.Gastroenterology 979;'71:295-'7.18 . Gerding DM, BrazierJS. Optimal methods or identifying Clostridium

dfficile infections.Clin Infect Dis 1993;16(suppl ):5439-42.19. Martirosian G, Meisel-Mikolajczyk F, Stanczak , et al. Toxigenicityof Clostridium difficile strains isolated in the surgical ward. ActaMicrobiol Pol | 995 44:4'1,53.20 . StaneckJL , WeckbachLS , Allen SD, et al. Multicenter evaluationoffour methods for Cbstridium dfficile detectton: ImmunoCard C. dll:fcile, cytotoxin assay, culture, and latex agglutination. J Clin Micro-biol 1996;34:2718-21.21. Barbut F, Kajzer C, PlanasN, et al. Comparison of three enzymeimmunoassays, cytotoxicity assay,and toxigenic culture or diagno-sis of Clostridiumdfficile-associated iarrhea. Clin Microbiol 1993;31:963-i.22 . Fekety R, Silva J, Kauffman C, et al. Treatmentof antibiotic-associ-atedCktstridium dfficile colitis with oral vancomycin: Comparison oftwo dosage egimens.Am J Med 1989;86:15-9.23. Lyerly DM, Barroso LA, Wilkins TD. Identif icationof the latex-testreactive protein of C. dfficile as glutamate dehydrogenase.J ClinMicrobiol 1988:292639 42.24 . George WL, Sutter VL, Citron D, et al. Selective and differential


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25. Fekety R. Antibiotic-associated iarrheaand colit is. Curr Opin Inf'ectD is 1995:U :391.26. Angl im A, FarrB. Nosocomial ast ro intest inalnf 'ect ions.n: Mayhal lCC, ed.Hospita lepidemiology nd nf 'ect ion ont ro l .Bal t imore:Wil-l iams& Wilk ins. 1966,pp 196-225.27. Marx CE , Morr is A, Wilson ML, et a l . Fecal leukocytes n stoolspecimens ubnritted or ClostridiLon i.ff icile oxin assay.Diagn Mi-c r ob io l n t ec tD is 1993:16 :313-5 .28. GuerrantRL, Araiys V, SoaresE, et al. Measurementof f'ecal acto-f'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'ectious udinf lammatory nter i t is . rch InternMed l 994l l5z l :2660- .1.

30 . BolandGW. Lee MJ, Cats A, et al. Pseudomembranousolit is: Diag-nost ic ensi t iv i ty fthe abdorninal la in adiograph. l in Radiol 199.1;19:413 475.31. Boland CW, Lee MJ. Cats AM. et a l . Ant ib iot ic- induced ianhea:Specificity of abdonrinalCT lbr the diagnosisof Clostrirt iumdilliciledisease. adio logy 99zl ; l9 l : 103 6.32. Novak E. Lee JE, SeckmanCE, et al. Untavorableeffect of atropine-diphenoxylate (Lolnotil) therapy in lincomycin-caused dianhea.J AM A 1976 : 235 : 1 ,151 .33. TeasleyDG, GerdingDN, Olso n MN, et al. Prospect iv eandomizedtrial of metronidazole yerrus vancomycin for the treatment of C.tlift ici|e associa,tediarrhea and colit is. Lancet I983;2:I043-6.3.1. Bolton RP. Culshaw MA. Fecal metronidazole oncentrations uringoral and intravenous herapy fbr antibiotic associated olit is due toClostrit lium tlilJicile. Gut l9fl6: lU3: 169-72.35. Johnson , HomannSR, BettenKM, e t al. Treatment f as ymptomaticClo.tlridiumdilf icile c,rniers lecal excretors)with vancomycinor oralmet rcnidazole. nn InternMed 1992: l11:291305.36. Hospital Inf'ection Control Advisory Committee. Recommendationslbr preventing he spreadof vancomycin-resistant nterococci.Am J313 8 .

39..10.

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+ - ) .41

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