0/91 0002-921 /921l - I 962$03.

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THli A\ltRlc,\\ Copyright Jot Hnlt- op GAsTROF:NrrrRolocY O 1997 by Am. Coll. of Castrocnterology

Vol 9 2 . N o . I l . 1 9 9 7

in Printed U.S.A.

Practicesuidelines Guidelines on Acute Infectious Diarrhea in Adults

Herbert L. DuPont, M.D., and The Practice Parameters Committee of the American College of Gastroenterology Arlington,Virginia Commiltee, Guidelines ACG rlt' College Gastroenterology, PracticePorarneters TlrcAmerit'un

Guidelines for clinical practice are intended to suggest preferable approachesto particular medical problems as established by the interpretation and collation of scientifically valid research, derived from an extensivereview of published literature. When data are not available that will withstand objective scrutiny, a recommendation may be made based on a consensusof 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 the American Gastroenterology Association and the American Society of Gastrointestinal Endoscopy. 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.

the uation, management, internationaltraveler, and the impatient. munocompromised IMPORTANCE OF DIARRHEA In the United States acute diarrhea is one of the most common diagnosesin generalpractice. Acute diarrheacan be defined as the passageof a greater number of stools of form from the normal lasting less than 14 days.It decreased with other signs or symptoms sugis generally associated vomiting, abgestingentericinvolvement including nausea, dominal pain and cramps, increasein intestinal gas-related complaints, fever, passageof bloody stools (dysentery), of tenesmus(constantsensation urge to move bowels), and fecal urgency.When diarrhealastsas long as l4 days,it can be considered persistent.Many restrict the term chronic dianhea to indicate illness lasting at least I month. In this review, diagnosis and treatment of acute and persistent diarrhea will be consideredbecauseboth tend to be shortterm illnesses,infectious agents characteristicallyproduce both, and the testsproceduresand treatmentsof both fbrms s of diarrhea howsimilarities. The annual rate of diarrheal illness in the United States and western Europe among adults averagesabout one episode per personper year (1,2). In one study, it was estimated that for a single year, 99 million casesof gastroenteritis or acutediarrheaoccurredamong adultsin the United States(1). In this study, half of the personswith gastroenteritis or diarrheahad restriction of their activities for more in than a full day, a physicianwas consulted 8.2 million of the cases,250,000 persons were hospitalized,1.9 million and more personssaw a physicianyet were not hospitalized, illness without seekingmedical than 90 million experienced attention.In a secondstudy,it was fbund that gastroenteritis ofhospitalizationsof and acutediarrheaaccountedtor 1.57o adults >20 yr of age in the United States (3). Sixty-two for percentof the admissions diarrheawere in adultsgreater than 20 yr of age.In this study and othersmost of the deaths associatedwith diarrheal illness in the United States occurredin the elderly (3-5).
t962

INTRODUCTION In developing the guidelinesfor evaluationand management of the patient with acute diarrhea,the fbllowing maimportanceof diterial is divided into eight subheadings: and extraintestinal arrhea,patient evaluation,noninf'ectious patients,laboratoryevalcauses. empiric therapyin selected
ReceivetlMar. 11, 1997: ucceptedJuh' 16, 1997

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GUIDELINES ON ACUTE INFECTIOUSDIARRHEA IN ADULTS Recommendation

1963

Although statisticallythe rate of diarrheain adults in the United States and other industrialized regions is approximately one episode per person per year, diarrhea actually does not occur in all persons annually. Food- and waterborne outbreaksinvolving a relatively small subsetof the generalpopulation and recunent bouts of illness in others make up the bulk of the casesof the illness. Diarrhea is a specialproblem among adults who are exposedto children and nontoilet-trainedinfants particularly in a day care setting, travelers to tropical and semitropical regions, homosexualmales,persons with underlyingimmunosuppression. and those living in an unhygienic environment and having exposureto contaminatedwater or fbods. PATIENT EVALUATION Most casesof diarrhea are managedby the affected patient or by a family member without need for medical attention. Recommendation l. Medical evaluation should occur for a subset of patients with more severe illness. Specific indications for medical evaluation include: profuse watery diarrhea with dehydration; dysentery, passage of many small volume stools containing blood and mucus; fever (temperature> 38.5'C, l0l.3"F); passage > 6 unformedstools/24 or a of h duration of illness > 48 h; diarrheawith severeabdominal pain in a patient above the age of 50 yr; diarrhea in the patient elderly (>70 yr of age) or the immunocompromised (AIDS, after transplantation,or receipt of cancer chemotherapy). Indications.formedical evaluation. Dehydration,defined as dry mucous membranes, decreased urination, and tachycardia,is the most common complication of a small bowel secretorydiarrhea and should be promptly evaluated and treated (6). Osmotic diarrhea seen in patients with small intestinalinjury due to an infectious agent who attempt to (magnesium,salts, ingestcarbohydrates other substances or fiber) may present with watery diarrhea and dehydration. Patients with dysentery will have more intense and prolonged illness without antimicrobial therapy (7). Fever is with an invasive pathogenthat usually a finding associated produces intestinal inflammation. These cases optimally will be studied for etiologic agents and many will benefit from antimicrobial therapy (8). Similarly more intensediarrhea(>6 unformed stools/24h) and that lasting more than 48 h should be evaluated for cause of illness or treated empirically (8, 9). Patients with severe abdominal pain particularly if above the age of 50 yr may have a compli(10).Diarrhea catingillnesssuchas ischemicbowel disease in the elderly is more likely to be severeand possibly fatal (4, l1), and patientswho are immunocompromised usually havecomplicated and difficult to managedianhea (12).

2. The clinical and epidemiologic history is central to patient medical evaluationand management. The history. From the standpoint of functional impairment from the illness, diarrheamay be categorizedas mild (no changein normal activities),moderate(fbrced changein activities),or severe(disability generally with confinement to bed). In Table 1 the clinical syndromesseen in enteric infections are detailed along with suspected causeand anatomic location of the diseaseprocess.Assessmentof the severity of illness, presenceof dehydration, character of stool pattern,presence fever, vomiting, or dysenteryoften of will help to focus the evaluation to determine the likely causeof the illness. When diarrhealasts as long as 2 wk, a different list of etiologic agents and conditions should be consideredwhen compared with the person with acute di> arrhea. When fever (oral temperature 38.5"C,or l0l.3"F) present,the patient has intestinalinflammation characteris istically due to invasive bacteria (Shigella, Salmonella, Campylobacter),one of the enteric viruses. or a cytotoxic organismresulting in mucosal histologicdamageand inflammation (C. dfficile or Entamoebahistolytica). Finally, in taking a history epidemiologic factors and associations should be considered(Table 2). In the homosexualmale with diarrhea,threedisease transmission or clinical scenarios may explain the entericdisease (13). First, becauseof the sexual practicesof many homosexual men, there is an increasedrate of fecal oral transmission of all agents showing this route of spread.This includes Shigella, Salmonella,Campt'ktbacter,and the intestinal protozoa. Second,in homosexualmales who have been the recipients of anal intercourse,direct rectal inoculation of a pathogen(seeTable 1) may lead to proctitis ( l3) associatedwith rectal pain and tenesmusand passageof small volume stoolsolten containingblood and mucus.The third setting of diarrhea in a homosexualmale is when the individual has developedAIDS (12) (see Management of the ImmunocompromisedPatient with Diarrhea section). Foodborne or waterborne outbreaksof diarrhea are becoming more common (14-16). The incubationperiod of resultant illness and the predominant symptoms ofien will help the clinician to determine the cause of the outbreak based on clinical grounds. When diarrhea and vomiting occurswithin 6 h of exposureto a food item, food poisoning secondaryto the ingestion of preformed toxin of StaphyloWhen coccusaureusor Bacillus cereusshouldbe suspected. the incubationperiod of an outbreakof diarrhealdiseaseis 8-14 h, Clostridiumperfringens enteric infection shouldbe When the incubationperiod is greaterthan l4 h suspected. and vomiting is the prominent feature of the diarrheal disWhen fever and or ease,viral agentsshould be suspected. dysentery is present in a majority of casesduring an outbreak, the invasive pathogensshould be consideredsuch as Shigella, Salmonella, or Catnpl,lobacter.Other pathogens can oroducethe sameclinical featuresof an invasive oatho-

1964

DUPONT
T,qst-nI romes Assoc i at ed w it h Di a r rhe u C I ini r:a I Sy-nd Syndrome Anatomic Location Stomach and small intestine Clinical Features v Nausea. omitingand ulterl diarrhea Voluminous stools,upper abdominal pain and cramps Many small volume stools,fecal urgency, tenesmus,and dysentery

AJG

Vol. 92. No. I l. 1997

SuspectedEtiology Viral agentsor preformed toxrn produced by S. auretts or B. cereus. any enteric pathogen Any enteric pathogen Shigella, Camp-vlobacter most common, also consider Salmonello,Shigatoxin producing E. coli (.e.g.0:157 H:1) i n r a s i v eE . c o l i . E . h i . s t u l v t i c u . Aeromonas spp, noncholera ViDrlos, dia t rachomati s, infl ammatory Chlo n,bowel diseasetin a recipient of anal intercourseconsiderNei t st rirt gonorrhoeae, herpessimplex. Ch lamyclictt ra(homat is, Treponenru pallidum

Gastroenteritis

Acute watery (often secretory) diarrhea Colitis and proctitis

Small intestine,colon may be involved Colitis:colonicinllammation documented eyond l5 cm. b

Persistent,>l.l days, diarrhea

Proctitis: inflammation confined to distal 15 cm of colon will dependupon Small intestine,colon may be Clinical f-eatures intestinal location of disease involved process

Parasiticinf'ection(Giardia. c C n pt ospo ri diunt, C v" kt spo ru, Microspnridium), bacterial infection, small bowel bacterial overgrowth syndrome,lactasedeficiency, Brainard syndrome,malabsorptionsyndrome

Trer-n2 EpidemiobgicFactorsIntportantin the Evaluationof the Patient -'ith AcuteDiarrhea

Epidemiologic Consideration Travel to a developing region, to mountainousareasor recreationalbodies of water of North America or to Russia Etiologic Agent to Consider Bacterial agentsare considered among those who travel to developing regions, Giarulia fbr travel to mountainousareasand recreationalwaters associated with wildlife and Cryptosporidium or Giardict for those visiting Russia ClostridiLtnt dfficile All enteric pathogensshowing l ' e c a lo r a l r o u t eo l ' t r a n s m i s s i o n ; those spreadby receptiveanal intercourseor a variety of agentsif AIDS is present(see Table 1 and text) Any agent spread by fecal oral route, commonly Shigella spp, G iardia, or C mptospnridium The incubation period and clinical featuresof the illness often will give clues as to etiology, the laboratory will be important to identification of enteric pathogen(see text)

NONINFECTIOUS AND EXTRAINTESTINAL CAUSES Noninfectious and extraintestinalprocesses may present as acute diarrhea.In all patientswith dianhea, particularly persistentor chronic diarrhea or when there is severeabdominal pain or underlying diseaseprocesses, noninfeca tious causeof the illnessshouldbe considered. Someof the important diagnoses considerinclude irritable bowel synto drome,inflammatory bowel disease, ischemicbowel disease (particularly in someoneolder than 50 yr of age with other evidenceof peripheral vascular disease),partial bowel obstruction,and pelvic abscess the areaof the rectosigmoid in colon. Perniciousanemia,pellagra,malaria, Whipple's disease, diabetes mellitus, small bowel scleroderma,small bowel diverticulosis,and various malabsorptionsyndromes may presentas acute or persistentdiarrhea resembling infectious diarrhea. EMPIRIC THERAPY OF SELECTED PATIENTS There are two types of patientswho might be considered for empiric antimicrobial therapy without additional evaluation. They include patients in whom bacterial diarhea is suggestedby clinical f'eaturesand/or by the presenceof occult blood or fecal leukocytesin stool samples. patients or in whom diarrhea has persisted for 2 wk or longer and Patientsnot treatedempirically should Giardia is suspected. be studiedto determinethe presenceof etiologic agentsby using laboratory tests and procedures(Table 3).

Recentantimicrobial therapy (past 2 months) Male homosexual

Day care center contact

Foodborne or waterborne outbreak

gen such as invasive Escherichiacoli, Aeromorzas spp, and noncholera Vibrios. EnterohemorrhagicE coli infection ofien is associatedwith the passageof bloody stools, but fever is generally absentor low grade.

AJG - November1997

GUIDELINES ON ACUTE INFECTIOUS DIARRHEA IN ADULTS

1965

Taer-E3 Selected Luboratory- Tests and Procedures Used in the Etioktgic Diagnosis oJ Putient.s vvith Diarrhea Test or Procedure Stool culture fbr enterohemorrhagic E. coli ( e . g .S h i g a t o x i n r o d u c i n gO 1 5 7 : H 7 ) p lndications Epidemic foodborne dysenteryespecially diarrhea or bloody hamburger-associated dianhea with few or no fecal leukocytesor diarrhea in a case(s)of hemolytic uremic syndrome Severe and profuse watery diarrhea in a choleraendemic area or seafood associateddiarrhea or diarrhea after consumption of inadequately cooked seafood,including sushi or ceviche Febrile dysentery or diarrhea and severe abdominal pain or pseudoappendicitis-like Likely Etiologic Agents 026:Hl l. etc.) Cytotoxigenic E. coli (.O157:H7,

Stool culture for Vibrios

V. cholerae and noncholeraVlbrlos

Stool culture tor Yersinio including cold enrichment C. dfficile toxin assay

Y. enterocolitica

symptoms In a patient with diarrhea who has received an antimicrobial in the past 2 months Waterborne or fbodborne illness with incubation Virus examination period >12 h in which vomiting is the (see likely etiologic agents) predominant symptom Duodenal intubation or l4-c-d-xylose breath In a patient with persistentdianhea not respondingto empiric therapy test Flexible sigmoidoscopywith biopsy of abnormalities Homosexual male with moderateto severe diarrhea,any patient with persistentdiarrhea and clinical colitis (see Table l) not respondingto antimicrobial therapy or without diagnosisafter laboratory evaluation Any patient with persistentdianhea without evidence of colitis (see Table l) and without responseto empiric therapy

C. diJJicile Rotavirus, enteric adenovirus(type 40, 41), Norwalk virus,* and other small round structured viruses G i a rd i a, C ryp tosp or i di um, rarely Strongy ktide s stercoralis, small bowel bacterialovergrowth syndrome See causesof colitis and proctitis (Table I above)

Flexible sigmoidoscopyand upper endoscopywith biopsy of abnormalities

Causesof colitis and proctitis (Table 1 above) as well as upper intestinal int'ectionby Giardiu, lospora, M icrospori di um, C rt'pxtsporidium, C.'-c c cytomegalovirus,HlY, M 1" obacteri um avi um intracellulare complex

* Norwalk virus detection is presently done only in a researchlaboratory

Recommendation 3. In patientswith fever (oral temperature> 38.5'C, or 101.3'F) plus either leukocyte-, lactoferrin-, or hemoccultpositive stools or in patients with acute dysentery or in patientswith moderateand severetravelers' diarrhea,antimicrobial therapy may be given empirically (Table 4). Empiric therapy for presumed bacterictl diathea. In patients with fever and either fecal leukocyte-,lactoferrin-,or hemoccult-positivestools, inf-ectionwith invasive bacterial pathogens such as Shigella,Salmonella,and Campylobacter (17, l8). A majority of patientswith shouldbe considered numerous fecal leukocytes will respond favorably to antimicrobial therapy (19-21). Finding hemoccult-positive stool in patients with acute diarrhea has the same clinical (18, 22). fecal leukocytes as significance finding numerous of with the presence numerassociated The samepathogens ous l'ecalleukocyteswill generallybe found in patientswith acute dysenteric disease(23, 24). Patients with travelers' diarrhea,particularly those with moderateto severeillness infected with bacterial pathogensand are characteristically their illness is shortenedby antimicrobial therapy (25*21). Recommendation 4. Patientswith diarrhea lasting 2 to 4 wk without systemic symptoms or dysentery may be studied for causeof

rdia therillness or may be treatedempirically with anti-Gra (Table 4). apy Empiric treatmentof presumedgiardiasis. While many clinicians would pref'erto evaluatethe patient with persistent diarrhea for cause of illness some elect to treat empirically for presumed giardiasis. This approach is in reasonable view of the importance of Giardia in this syndrome(28) and becauseat least half of studiedstools of patientswith giardiasiswill be negativefor the parasite (29, 30). Work-up of those failing to respond to empiric therapy for Giardict(usually stool enzymeimmunoassay) may then be indicated.The most frequently used empiric therapy of presumedgiardiasisis metronidazole(seeTable 4), which also may be eff'ectiveagainsta small bowel with persistent bacterialovergrowth syndromeassociated problem occasionally seen after an enteric diarrhea, a i n f e c t i o n( 3 1 ) .

LABORATORY EVALUATION may be used to evaluate Laboratory testsand procedures patients with illness calling for medical evaluation (see above)and fbr other patientsin whom a definablepathogen by is suggested the history (Tables I and 2).

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TaeLL, 4 Indications for Empiric and Specific Antimicrobial Therapt in InJectious Diarrheu

AJG - Vol. 92, No. I I, 1997

Indication for Antimicrobial Therapv > F e v e r( o r a l t e m p e r a t u r e 3 8 . 5 ' C o r 1 0 1 . 3 ' F )t o g e t h e r with one ol the following: dysentery(grossly bloody or stools) or those with leukocyte-, lactof'errin-, h e m o c c u l t - p o s i t i vs t o o l s e Moderate to severetravelers' diarrhea Persistent diarrhea (possible Graruliainf'ection) Shigellosis

SuggestedAntimicrobial Therapy Quinolone:'kNF 4(X) mg, CF 500 m, OF 300 rng b.i.d. for 3-5 days (see text)

Intestinal salmonellosis

Campylobacteriosis E. Enteropathogenic coLi diarrhea (EPEC) EnterotoxigenicE colr diarrhea (ETEC) EnteroinvasiveE. colr diarrhea (EIEC) E. Enterohemorrhagtc coLi diarrhea (EHEC)

Quinolone:+ NF 400 mg. CF 500 mg, OF 300 rng b.i.d. for 1-5 days (see text) Metronidazole250 mg g.i.d. fcrr 7 days mg b.i.d. If acquired in the U.S. give TMP/SMX 160/tt(X) for 3 days, if acquired during internationaltravel treat as f'ebriledysentery(above)l check to be certain of susceptibilityto drug employed If healthy host with mild or moderatesymptoms, no with f'ever therapyi fbr severediseaseor that associated and systemictoxicity or other important underlying mg condition (see text) use TMP/SMX 160 mg/t3(X) or quinolone:'kNF 400 rng, CF 500 mg, OF mg bid lbr 5 to 7 days dependingon speedof response 500 mg h.i.d. for 5 days Erythrornycin stearate Treat as f'ebriledysentery Treat as moderateto severetravelers' diarrhea Treat as shigellosis Antin'ricrobialsare generally withheld except in particularly of severecasesin which usefulness thesedrugs is uncertaln (see text) Treat as febrile dysentery Treat as febrile dysentery For most cases,treat as febrile dysentery,for severecases give ceftriaxone 1 g q.d. lY fbr 5 days Metronidazole250 mg q.i.d. for 7 days or (if available) tinidazole 2 gr in a single dose or quinacine 100 mg t.i.11. fbr 7 days Metronidazole750 mg t.i.d. fbr 5 l0 days plus a drug to treat cysts to prevent relapses:diiodohydroxyquin 650 mg t.i.d. for 20 days, or paromomycin 500 mg r.l.d. fbr l0 days or diloxanide furoate 500 mg t.i.ri. fbr l0 d None, fbr severecases,considerparomomycin 500 mg fbr r.1.21. 7 days mg b.i.d. fbr 7 days TMP/SMX 160 rng/t100 TMP/SMX 160 rng/tt00 mg D.i.rl fbr 7 days

Aeromonas diarrhea Noncholera Vibrb dianhea Yersiniosis Giardiasis

Intestinal anrebiirsis

C n ptospo rid i urn diarrhea Isospora diarrhea Ctt:losporu diarrhea

i'Fluoroquinolones include nortloxacin (NF), ciprofloxacin (CF). and ofloxacin (OF).

Rec'ommendilion 5. The f-ecalleukocyte, lactof'errin,or hemoccult blood test is a useful screeningtest in patients with moderateto severe acute infectious diarrhea becausethey support the use of empiric therapyin the febrile patient (seeabove) and when negative may eliminate the need for stool culture in some casesof diarrhea. Laboraton screening. Fecal leukocytes, lactoferrin, or occult blood are fbund in diarrhea patients with difluse colonic inflammation(17, l8). The most commonly identiin fied pathogens patientswith a positive test result include: rs Ae Lla, Shigella, Salmone Cump,,-lobacter, romonas,Ye inia, noncholeraVibrios (17, l8), and Clostridium dfficile (32). Low numbersof fecal leukocvtesare found in patientswith intestinalamebiasis.

Recommendcttion 6. A stool culture shouldbe obtainedin a patientwith one of the following: severediarhea; a temperature> 38.5'C, of or 101.3'F,(orally);passage bloody stools;stoolscontain leukocytes,lactoferrin, or hemoccult blood; or, the patient with persistentdiarrhea has not been treated with antibacterial agentsempirically. Routine stool culture. The bacterial enteropathogens identified by normal stool culture are Shigella, Salmonella, CampyIobacter, Aer omonas, and Yer sinia. Severe(i ntense) diarrhea, moderate to high f'ever,dysentery,finding f'ecal leukocytes,lactoferrin, or hemoccult blood positive stools all are predictive of finding an identifiablebacterialenteropathogenswhen fecal samplesare submittedto the laboratory for culture. The bacterial pathogensmay cause more

AJG - November 1997

GUIDELINES ON ACUTE INFECTIOUSDIARRHEA IN ADULTS

1961

prolongeddiarrheawhen comparedwith pathogen-negative nonspecificdiarrhea (25, 33, 34). Studiesin the United Stateshave found that stool studies arefrequently inappropriatelyorderedresultingin excessive medicalcosts(35). In two studies,stool culturesas obtained routinely in selectedlocations were found to have a positivity rate of 2Voor less,making the cost of the test between $900 and $1200 per pathogendetected(35, 36). Stool cultures should not be ordered routinely but reservedfor the a a p p r o p r i a tp a t i e n t n d s e t t i n g . e Recommendation 7. Patientsnot treated with empiric antiparasitictherapy should be studied for parasitic causesof diarrhea if they have persistent diarrhea; diarrhea has followed travel to Russia, Nepal, or mountainous regions; they have been exposedto infants attendingday care centers;diarrheahas occurred in a homosexual male or a patient with AIDS; diarrheais part of a community waterborneoutbreak;or has bloody diarrhea with few or no fecal leukocytes. Laboratory evaluationfor parasites. Although less well studiedthan the value of routine stool culture, the common "O in and P's" (ova and parasites) patientswith obtainingof acutediarrheais not cost effective (37). As indicatedabove, patientswith giardiasisoften have persistentdiarrhea.The with Cryptosporidium (28) and diarrhealillness associated (38) may be protracted.Infection by Entamoebahistolytica Cryptosporidium, Giardia, or both, should be suspected wheneverdiarrheafollows trips to Russia (28,39); Cyclospora should be consideredin travelers to Nepal (40); and in Giardia should be suspected personswho have recently traveled to mountainousareasor to recreationalwaters of North America (41). Among infants in day care centers, Giardia (42) and Cryptosporidium(43) are common causes of diarrheaand may be spreadto adult contactsbecauseof the low inoculum required for human infection (44, 45). Homosexualmales may be infected with a variety of parasites including Giardia and Entttmoebahi.stolytica.In pathe represent diarrhea,parasites tientswith AIDS-associated major definablepathogens(46). The specific agentsto consider in this settingare mentionedbelow. Both Giardia (41) and Cryptosporidium(16) may causeextensivecommunity Numerousleukocytesare not usually waterbomeoutbreaks. found in the stools of patients with intestinal amebiasis becauseof the presence of uninflamed mucosa between ulcerations and because of the lytic effect of exotoxins producedby the organism (48). Therefore when a patient with diarrhea is passing bloody stools and there are few leukocytes,amebiasisshould be considered.Stools may be studiedby routine microscopic techniquesfor parasitic enor by teropathogens a well-trained parasitologist in the case of Giardia and Cryptosporidiwn, by a commercially availantibody tests(49) or by diagnostic able immunofluorescent (50), which may be more sensitive enzymeimmunoassays studies(5 I, 52). than microscopic

Recommendation 8. In patients with certain epidemiologic findings, fecal samplesshould be collected and sent to the laboratory for including enterohemorrhagicE. specific enteropathogens coli. Vibrio cholerae, noncholera Vibrios, and Yersinia. Selected patients may be studied for the presenceof C. dfficile toxin, or viruses or they may be studiedby endoscopy (seeTable 3). A Special bacterial enteropathogens. number of bactewill not be detectedby routine stool rial enteropathogens colitis culture. These pathogensinclude enterohemorrhagic producing E. coli 0157:H1 and other Shigatoxin producing E. coli (53), y. cholerae,other noncholeraVibrios (54), and Yersinia (55), although routine stool cultures will identify most of the strainsof Yersinia.Except for E. coli 0157:Hi , which is readily detectedby stool culture using specialized media, the other diarrheagenicE. coli are presently only detectedby researchlaboratories.Stool assaysfor C. dffi' cile toxin by tissue culture assayor enzyme immunoassay should be carried out in the patient who is currently receiving antimicrobialsor who has receivedantimicrobialsin the last 2 wk. In the case of food- or waterborneoutbreaks,in with vomiting as the major which the illness is associated clinical feature and the incubation period is > 12 h, viral agents should be considered (see Table 3). Homosexual diarrhea maleswith diarrheaand any patientswith persistent responding to empiric therapy may be evaluated by not endoscopy. MANAGEMENT Fluid and Electrolyte Treatment Recommendation 9. In all patientswith diarrhearequiring medical evaluation, fluid and electrolyte therapy and alteration of the diet should be part of the management. Fluid therapy and diet alteration. For most cases of acute diarrhea,the most important form of therapy consists of t'luid combined with electrolytes (56). Whereas such treatmentis life saving for young infants in the developing world, in the United Statesthe most important adult groups in which special attention should be given to fluid therapy For these perare the elderly and the immunosuppressed. sons solutions containing sodium in the range of 45 to 75 mEq/L are recommended(Pedialyte or Rehydrolyte soluotherwisehealthy person with tions). In the nondehydrated acute diarrhea, sport drinks, diluted fruit juices, and other flavored soft drinks augmentedwith saltine crackers and broths and soupscan meet the fluid and salt needsin nearly all cases.For dehydrating cholera-like diarrhea more aggressivefluid therapy will be required. Here the ideal formulation of oral fluids is Na 60-90 mBq[. K 20 mEq/L, Cl 80 mEq/L, citrate 30 mEq/L, and glucose20 g/L. A homemade version of this form of oral rehydration solution fbr glasses that more severediarrheais to preparetwo separate

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T a e r - c5 S\-nptomutic Treatmetlt oJ Acute Diarrhea

AJG

Vol. 92, No. I l, 1997

Phlil"l:91.s.lqT,
(lmodium) Loperan.ride

Indication/Perspective Acute diarrhea,f'ever is absentor low grade, dysenteryis not present/minirnal central opiate effects, the pref'erred symptomatic drug when used fbr most nonf'ebrile,nondysentericcases Acute diarrhea,t-everis absentor low grade, dysenteryis not presenVhas central opiate eff'ects,with overdose liability. atropine may cause side eflects without of lering antidianheal efl'ects Acute diarrhea,fever is absentor low grade, dysenteryis not present/occasionally useful in HlV-associated diarrhea when the saf'erloperamideis not Any fbrm of acute diarrhea/inmost casesis less efl'ective than loperan'rideand cannot be cornbined w i t h a n t i m i c r o b i a l ss h o u l d n o t b e u s e d i n H I V l positive patients with diarrhea AlDS-associateddiarrhea not respondingto other treatment/considered resort therapy for these last patients,once symptoms are controlled, the patient should be startedon other more convenient preparations

Dose and Administration 2 tablets (4 mg) initially then 2 mg after each unfbrmed stool not to exceed 8 mg/ day (OTC dose) or l6 mg/day (prescription dose) <2 days 2 tablets (.4 ng) q.i.d. fbr <2 days

Drphenoxylatewith a t r o p i n e( L o m o t i l )

Tincture of opium

0.5-l rnl p.o. cq4-6 h for <2 days

B i s m u t hs u b s a l i c y l a t e (Pepto-Bisrnol)

30 ml or two tablets each 30 minutes fbr eight doses,may repeat once again day two 100-500 pg subcutaneously t.i.d.

Octre0tide

are consumedalternately. The first contains8 ouncesof orange. apple.or other fruit juice (supplyingpotassium), % teaspoonof honey or corn syrup, and I pinch table salt; the glasscontains ounces second 8 clearwaterplus I /4 teaspoon of baking soda (56). During a bout of acute diarrhea,calories (energy) should be provided to facilitate enterocyterenewal (56). Diet fol(potatoes, lows clinical course. Boiled starches/cereals noodles/rice, wheat, oat) with some salt representideal foods yoduring episodesof watery diarrhea.Crackers,bananas, gurt, soup, and boiled vegetables can also be used.When stools are formed, diet may return to normal as tolerated. Many authorities would excludemilk productsearly in the illness but clinical lactose intoleranceis not commonly found in casesof acutediarrhea. NonspecificTherapy Rec'onunendcttion 10. When nonspecific therapy is desired, loperamide is the drug of choice for most casesof diarrhea. Svmptomatictreatment o.f acute diarrhea. In Table 5 a brief perspective the useof symptomaticallyacting drugs on is provided. The antimotilitydrugs(loperamide, diphenoxylate with atropine, and tincture of opium) are the most etfectivedrugs directedto treatingsymptoms.They work by f'low of liquid facilitatingintestinal slowingthe intraluminal (57). Loperamide generallythe recommended absorption is agent fbr most casesof diarrhea when symptomatic treatment is used becauseof saf'etyand expected efficacy in which stool numberis generallyreducedby approximately 807c(58. 59). Diphenoxylate may not be the ideal antimotility drug. althoughit is lessexpensive than the pref-erred loperamide.Diphenoxylatepossesses central opiate eff'ects

and may lead to death if a child takesa parent'smedication. Also, the atropine addedto the drug may lead to objectionable cholinergic side effects without adding antidiarrheal effects.The antimotility drugs should not be usedin patients with f'ebrile dysenteryin which diseasemay be prolonged (60). This disease prolongationby antimotility agentsis not commonly seen,and most clinicians do not need to worry about use of the drugs in nondysentericforms of diarrhea providingantimicrocaused invasivecolonic pathogens, by (61). In patients with enterohebial therapyis administered morrhagic E. coli (EHEC) infection, the hemolytic uremic syndrome(HUS) may be facilitatedby administering antimotility agents(62) or theseagentsmay worsen neurologic symptoms(63). Recommendation I l. Bismuth subsalicylateis the pref'erredagent when vomiting is the imponant clinical manif'estation enteric of infection. Bismuth subsalicylatetreatmentof gastroenteritis. Bismuth subsalicylateis effective in treating acute diarrhea, reducingthe numberof stoolspassed approximately507o by compared with a placebo (64). The antidiarrhealeff'ectof the drug is through its antisecretory salicylate(65, 66) The drug has antibacterial properties, which may explain its value in prevention of travelers' diarrhea when used as a prophylactic to agent(67, 68). Bismuth subsalicylate seems be the most eff'ectiveagent in improving the symptom of vomiting associated with enteric viral infection (69). Atta(Kaopectateor Diasorb), a clay-like material, abpulgite sorbswater and makesstoolsmore fbrmed. The preparation is less efl'ective than loperamide (70). Because it is not ubsorbed. is ouite safe. it

AJG

ltlovember1997

GUIDELINES ON ACUTE INFECTIOUS DIARRHEA IN ADULTS

1969

Recommendation 12.Loperamideis the recommended treatmentfor immupatientswith diarrheaof uncertainetiology. nocompromised Bismuthsubsalicylate shouldnot be usedin thesepatients. S\tmptomatictreatment oJ'diarrhea in the immunocompromisedpatient. A number of immunocompromisedpatientswith diarrheahave persistentdiarrheathat is difficult (12). In most of the cases treatable pathogen is to manage a not identified or if a potential agent is found the symptoms of diarrhea continue in the face of specific antimicrobial therapy.Table 5 lists the drugs available. As in the otherwisehealthypatient,thosewith underlyingimmunosuppression can best be managedwith symptomatic therapy (11). Bismuth subsalicylateshould not be given to immunocompromised patients with diarrhea to prevent the taking of excessive dosesand the occurrence bismuthencephalopof athy(72).In somepatients tinctureof opium has beenused with success treating patientsnot respondingto loperamin ide (unpublished observations). In otherwise refractory cases AIDS-induced diarrhea,octreotide,a syntheticcyof clic octapeptideanalog of somatostatin,may be effective. Whereasthe drug is best used in pathogen-negative diarrhea,it may be useful in somepatientswith microsporidiosis (73) and possibly other otherwise nontreatableconditions. The drug must be given subcutaneously,and it is quite expensive. shouldbe considered last resortto symptomIt a atlc management. Antimicrobial Therapy In Table 4 recommendations antimicrobial therapy in fbr infectiousdiarrhea are provided. Recomrnendation 13. Specificantimicrobialtherapyis given when a treatis ablepathogen identifiedin stool samples submitted the to laboratory. SpeciJicantimicrobial therapy. For specific therapy, the cause illnessis usuallydetermined laboratory of by demonstrationof a treatablepathogen(seeTable 4). Alternatively, a patient may be treated based on epidemiologic evidence and laboratory study of other casesduring a well-defined foodborneor waterborneoutbreak.A few specificinfections will be discussed. Most are listed in tables along with recommendations therapy without turther discussion. for Shigella-Recommendation 14: All patients with confirmed shigellosisare treated with an antimicrobial agent: trimethoprim/sulfamethoxazole acquired in the United if Statesand a fluoroquinolone if acquiredoutside or if resistant to trimethoprim. In Antimicrobialtherapyof shigellosis: shigellosis, antimicrobialtherapyis indicatedin all casesfbr two reasons. providingthe First,the illnessis shortened antimicrobials by is organisms susceptible the drug used(74). Second, to the required to cause inf'ectionis low (75) dose of ShigeLla explainingthe potentialfor int'ectingstrainsto be spread

from person-to-person. Therefbre, there is a public health reasonfbr treatmentof inf'ectedpatients.The treatmentsof choice fbr culture proven shigellosis are TMP/SMX or a fluoroquinolonegiven fbr 3 to -5days. It the Shigella inf'ection is acquired in the U.S., TMP/SMX is the pref'erred initial treatmentof choice (16). If the inf'ectionis acquired during travel, TMP resistanceoccurs commonly (77). For these casesa quinolone is indicated. patientswith Salmonella-RecommendationI 5: Selected intestinalsalmonellosis be treatedwith a quinolone should for possible systemic infection including those with fever and systemic toxicity, those with dysenteryor with underlying immunosuppression. Antimicrobial therapyof intestinalsalmonellosis: Nontyphoid salmonellosisis an important form of diarrheal disease occurringin up to 2 million persons the UnitedStates in each year (78). The decision to treat patientswith intestinal salmonellosis with antimicrobialagentsshoulddependupon the age, underlying health of the host, and severity of clinical illness. In healthy personswith mild symptoms treatmentshould not be given because therapy may encourage the prolif'erationof the int'ecting organism, leading to prolongation of excretion of the strain (79). However, intestinalsalmonellosis associated is with bacteremia bein tween 2 and 14Va cases(80) and systemiccomplications of of the bacteremiamay occur. Certain underlying conditions increasethe fiequency of bacteremia.Bacteremia is common in infants under 3 monthsof age (8 I ) and in the elderly (>65 yr of age) (ll). Other risk factors for bacteremia include HIV infectionand AIDS (82); uremia (83); malignancy,includinghematologic, lymphatic,and solid tumors (84); after renal transplantation(85); and congenital and acquired immunodeficienciesincluding corticosteroid use (86). There are other conditionsthat may predispose patients to localized extraintestinalinfection when Salmonella gasThis includespatientswith an aortic troenteritis develops. aneurysm,prosthetic heart valve, vascular graft, or orthopedic prosthesis. Antimicrobialsare indicatedfbr casesof intestinalsalmonellosis complicatedby any one of these conditions as well as fbr otherwise healthy persons with f'ebrileillness,systemictoxicity or dysenteric disease. For all practical purposes, all patients with intestinal salmonellosisillness severeenough to lead to hospitalization should be given antimicrobial therapy (Table 4). Camltylobacter-Recommendationl6: Patientswith culture-proven Campylobacter inf'ection are treated with an antimicrobialagentto shortenillness,althoughdevelopment of antimicrobial resistance becoming a problem. is Treatment of Campylobacter diarrhea'. Cunpylobac'ter resemblesSalmonella in many ways. First they both show an animal, often poultry, reservoir fbr human inf-ection. Second,antimicrobialresistance occurs commonly during (87).Erythromycin therapyor over time in a population will shorten the duration of Camp,vbbacter dianhea (88). lf susceptibleto the drugs, the fluoroquinolones(89) are effective against campylobacteriosis. Unfbrtunately,quin-

t970

DUPONT
TABLE 6 Prevention of Travelers' Diarrhea

AJG - Vol. 92, No. 11, 1997 olone resistanceis increasing worldwide among Campr-to lobacter isolates(87, 90, 9l). It is necessary confirm in vllro susceptibilityof infecting strainsof Campylobacter.In addition to erythromycin, azithromycin may be used in quinolone-resistant CampyIobact er infections ( 87). Diarrheagenic coli: There are four major diarrheagenic E. E. coli: enteropathogenicE coli (EPEC), enterotoxigenic E. coli (ETEC), enteroinvasiveE. coli (EIEC), and enterohemonhagic E. coli (EHEC). EPEC diarrhea is primarily a problem of infant populations.The related HEp-2 cell adherentE coli arepathogens ofboth children and adults(33, 92). The diarrhea causedby HEp-2 cell adherentE. coli tends to be persistent (33, 93). These strains have been shown to be causesof prolonged diarrhea in patients with E. AIDS in Zambia (94). EPEC and HEp-2 cell adherent coli are highly resistantto most antimicrobialsexceptthe newer quinolones(95). It is not known whetherantimicrobialswill shortenthe illness. ETEC diarrheawill respondto antimicrobialtherapy(21, 25,96). This form is the major causeof travelers' diarrhea. TMP/SMX or the quinolones remain standardtherapy for infection dependingupon susceptibility.

All Travelers Diet and BeveragePrecautions Consumeonly safe items while in high risk area, including airplane leaving area: l) Steaming hot fbods and beverages(e.g. cooked foods, coffee, tea) 2) Acidic foods (e.g. citrus) 3) Dry foods (e.g. bread) 4) Foods with high sugar content (e.g. syrups,jellies) 5) Carbonateddrinks (e.g. bottled soft drinks and beer); bottled, water may not be safe uncarbonated SelectedTravelers Those who wish prophylaxis BSS* 2 tablets with meals and at bedtime (8 tablets/day) (62Vc effective in eliminating diarrhea) Those who might be encouragedto take prophylaxis include those with underlying illness: AIDS, prior gastric surgery and those taking proton pump inhibitors (omeprazole),or those who cannot afford an 8 hour illness (e.g. politician, honeymoon couple, or weekend scuba diver) Antimicrobial agent (same drug used normally for therapy (Table 4) in single daily dose during time at risk (907c effective in eliminating dianhea) Use of prophylactic antimicrobialsis controversial * BSS, bismuth subsalicylate.

Al-I Take ORT and

a r r a r r r r a r r : o a
\ v v v

t l o v l r v r \ e /

I
\/nmif inr-r is M:i61'

I
Diarrhea is Maior

Manifestation I l-l-nes s Yes

J

of

N o -

Mani festation of Ill-ness

i
l i ar;l rl-a

Bi-smuth
Qrrh<a

Mild Il-fness

Moderate to Severe I.l-l-ness

I

(see Table for dose)

I
Is

Fever and,/or f)rrsenferrr Prcsent?

No other
'l- rar l- mon I

No

Yes I

C o n si d e r
T,nno r:m i rla
Orr i nnl aJ-a
Y s + r r v + v r f v

or

bismut.h
i crrl

nna*

Quinolone*
tr \
/ q a a T : h l a 1 \

qrrl'rqal

/eoa'f:hl a n l r r q T.nnorrm i da /^^^ fr-Ll ^

(see Tabl-e 5)

Alone
tr\

Frc;. 1. Self-treatment gastroenteritis of and diarrheain the internationaltraveler.*From the interior of Mexico during the summertime,TMP/SMX may be used instead of a quinolone.

AJG - November1997

GUIDELINES

ON ACUTE

INFECTIOUS

DIARRHEA

IN ADULTS

t91 |

All Patients Furnish Two Ereshly Passed Stools For Routine Bacterj-ology, P:rasi tol ocv :nd C .li ffi ci Le Toxin and A Bl-ood Cui ture is On-[ElnEO for Bacteria And Mycobacteria I Tro:talrl e Pathncqn ldentified I Yes I
P:fhnaon Tro:toci /(aa
LW

{
No
1^ nO y, , -^ ^ u
Vr

^r

9U!r.

^,,r rol_one

Table

7) 1
Srumntoms Di s:nncar

Admi ni s te red* J
Srrmnf nms Remain

l No Eurther Treatment

Symptomatic (See Text Treatment and Table 5) l

Symptoms Recur .t

or

are

uncontrofled

(Passage of Many Sma-Ll Volume Stools Evj-dence of Colitis is Present With Fecal Urgency With at Least One of the Following: Tenesmus,
nUc6-f
v -

6 r Lt /
I

E-aa: I

T,errkocrrf cq

nr

HemocCu]L-POSiCiVe

StOOI-S

I Yes

I No I

Ffexible Sigmoi-doscopy with Biopsy of Leslons Wlth Attention Lo CMV, Mycobacteria, Adenovirus, Fungi, and Herpes Simplex

with biopsy Gastroduodenoscopy Biopsy, Smears and Cultures For Fungi and CMV, Mycobacteria, Parasites Plus Flexible (See Detaifs in Sigmoidoscopy Adjacent Box)

Special

patients patientwith acuteor persistent Imrnunocolnpromised includethose diarrhea. Frc;.2. Approach the work-upof the immunocompromised to 'r'Quinolones include norfloxacin, ciprofloxacin, ofloxactn. or patients receiving cancer chemotherapy. with AIDS. afierorgantransplantation, those and

Rec'ommendation 17. Antimicrobialtherapyis currentlynot recommended tbr patientswith diarrhea due to E. coli 015'7:51and other Shigatoxinproducing E. coli. Antimicrobial treatment oJ' enterohemorrhagic E. coli diarrhea. The antimicrobial therapy of EHEC infection is controversial.Administration of antimicrobialsearly in inf'ectionmay enhancethe releaseof toxin from killed intracolonic organisms leading to greater absorption and increased propensity to develop the hemolytic uremic analyses have furthersyndrome(HUS) (97). Retrospective prior antimicrobial moreoft-ered suggestive infbrmation that therapy may in fact be a predisposingtactor in the develstudy.prior opmentof HUS (98, 99). In a singleprospective to receipt TMP/SMX late in the illnessdid not predispose of of the development HUS (100), making the whole issueof theraovuncertain.

THE INTERNATIONAL

TRAVELER

Diarrhea occurs during travel with rates varying according to levels of microbial contaminationin the host country and the region of origin. For personsfrom the United States, diarrhea occurs in 2 to 4o/oof travelers during travel to another low-risk region [United States, Canada, western with Europe,Japan(if raw fish, which may be contaminated noncholera Vibrios, is not consumed),South Africa, Australia, and New Zealandl. For travel fiom the United States to high-risk areas(most parts of Latin America, Africa, and For southernAsia. the rate of diarrheaoccurrenceis 40olo. travel to intermediaterisk regions (northernMediterranean the Middle East, China, and Russia)the rate of countries, is will be for diarrhea l0 to l5c/o.Theremainingdiscussion travelers fiom the United Statesduring travel to high-risk First, more regions. This illness has two unique f'eatures. pathogens. In than 80o/c the illnessis caused bacterial of by

1972

DUPONT

AJG - VoL 92, No. I I, 1997 (67). For patientswith certain is subsalicylate recommended serious underlying illnesses (e.9., AIDS, inflammatory bowel disease,hypochlorhydria induced by prior gastric surgery, or treatmentwith a proton inhibitor such as omeprazole, diabetesmellitus on insulin, and systemic malignancy) prophylactic antimicrobials may be used during travel to high-risk areas.Intermittent use of H, antagonists for gastroesophageal diseasedoes not appearto predispose to travelers' diarrhea and is not an indication for use of prophylaxis. In the settingsin which antimicrobial prophylaxis is considered,the uncommon risk of developing an adversereaction to therapy including a superinfectionmay be outweighedby beneficialeffect of the drug in preventing diarrhea.For a subsetof persons,a trip is so important that a short (6-10 h) illness would not be tolerated.For these personsan antimicrobial would be more advisablein view of its greaterprotectiveefficacy (Table 6). For all travelers exercisingcare about what one eats or drinks is the comerstoneof preventionof illness(101). Moist foods servedat room temperature generallyunsafeincluding many bufare fet items and lealy green vegetables.In Table 6 the safe foods are identified. While TMP/SMX is currently the most cost effective treatmentfor diarrhea among U.S. personsvisiting the interior of Mexico as studiedin Guadalajara(102) during the (our warmer months),for other regionsand dry rainy season wintertime in the interior of Mexico, TMP-resistantbacteria can be expected(103, 104). The quinolonesare the recommended treatment in these settings (27). In Figure l, a suggestedmanagementstrategy for travelers' diarrhea is provided. When dianhea persistsafter quinolone therapy, the illness should be treated as persistentdiarrhea in nontravelers(see Tables I and 3). THE IMMUNOCOMPROMISED PATIENT The patient with HIV infection and reducedCD 4 count (<200/mm3) and other personswith alteredimmunity (e.g., patientsafter organ transplantation when cancerchemoor therapy is being given) are at special risk of developing opportunistic enteric infection. The causesof diarrhea in patients with AIDS have been evaluatedand found to be varied. The most common definableagentsare the parasitic organisms including C. parvum, L belli, Cyclospora,Microsporidia, the bacterial enteropathogens enteritidis, S. Campylobacter,Shigella spp, and Ml,cobacterium-aviumintracellulare, and the viral pathogens cytomegalovirus, herpessimplex, adenovirus,and HIV itself. Recommendation 19. Immunocompromisedpatients with diarrhea should receivea limited evaluationfollowed by full evaluationonly for patients failing to respond to specific or symptomatic treatment.

Tasr-B 7 AntimicrobialTherapyin Infectious Diarrhea in Indications Specific for I mmunoomp c romiseda Patients
Indication for Antimicrobial Therapy Shigellosis

SuggestedAntimicrobial Therapy

Intestinal salmonellosis

Cryptosporidium diarrhea

Isospora diarrhea

Cyclospora dianhea Microsporidiosis

Cytomegalovirus diarrhea Mycobacterium avrum intracellulare complex

If acquired in the U.S. give TMP/SMX 160/800 ng b.i.d. for 7-10 days, if acquired during international travel treat as febrile dysentery (above) Check to be certain of susceptibilityto drug employed TMP/SMX 160 mg/800 mg b.i.d. or quinolone:i NF 400 mg, CF 500 mg, OF 300-400 mg b.i.d. for 14 days, repeat stool cultures 1 week after treatment Paromomycin 500 mg p.a. 4.i.d. with food for 14-28 days, then 500 mg b.l.d indefinitely, with treatment failures, may try azithromycin 2.4 g p.o. day 1, then 1.2 glday for 27 days, then 600 mg/day for maintenancetreatmentgiven indefinitely 320 mg TMP/I600 mg p.o. SMX b.i.d. fbr 2*4 wk then 160-320 mg TMP/800-1600 mg SMX q.d.(p.o.) TMP/SMX 160 mg/800 mg p.o. q.i.d. for l0 days then 160 mg/800 mg once three times a week indefinitely Albendazole 400 mg p.o. b.i.d. >4 wk or metronidazole500 mg p.o. t.i.d. or atovaquone150 mg p.o. r.i.d. continued indefinitely Ganciclovir 5 mg/kg i.v. q 12 h or q 8 h for 14-21 days and foscarnet60 mg/kg i.v. q 8 h or 90 mg/kg i.v. q 12 h for 14-21 days Clarithromycin 500 mg b.i.d. ethambutol l5 mg/kg/day plus one of the lbllowing CF 500-750 mg b.i.d. clofazimine 100 mg/ day, rifampin 6O0 mg q.cl.,or rifabutin 300 mg/day p.o. indefinitely

* Patientswith AIDS, after organ transplantation, and those receiving cancerchemotherapy. t Fluoroquinolonesinclude norfloxacin (NG), ciprofloxacin (CF), or ofloxacin (OF).

contrast, less than one-third of diarrhea occurring in the United Statesis causedby bacterial enteropathogens. Second, the traveler typically becomes ill while away from home and customarymedical help. Recommendation 18. Only a small proportion of travelers venturing into high-risk areasshould use chemoprophylaxis. All travelers should bring along with them loperamideand an antimicrobial agentand instructedon the self-therapyof diarrheathat may occur. Prophylaxis and self-therapy for travelers' diaruhea. Chemoprophylaxisis not generally recommendedfor most otherwise healthy personsduring travel to high-risk areas unlessthe traveler has an important predisposingillness or if the purpose of the trip is particularly important (27). If preventivemedicationis requested the traveler,bismuth by

AJG - November1997

GUIDELINES ON ACUTE INFECTIOUS DIARRHEA IN ADULTS

t913

Mmtagement of the immunocomltromisedpatient with acute diarrltea. The initial evaluation of the immunocompromised host with diarrhea is given in Figure 2. A more detailedevaluation not indicatedin view of the low yield is for treatableetiologic agentswhen an expensivework-up is undertaken. in infectionsoutsidethe gut in thesepatients, As when a treatableenteropathogen identified, curative treatis ment characteristically requiresprolonged treatment,and in many of the casessuppressive therapy is required fbr lifetime. When curative therapy is being attempted, stools should be obtained I wk after stopping medicationto verify the eradicationof the organism. If the organism is present, in vitro susceptibility should be perfbrmed if f'easible, and the drug begun again for a longer period of time, possibly for lif'etime. In Table 7 specific managementof inf-ectious diarrheain immunocompromised patientsis outlined. ACKNOWLEDGMENT Preparedfor The American College of Gastroenterology, ACG Practice ParametersGuidelines Committee. 4900 B South31st Street,Arlingron. Virginia 22206-1656
Reprint requestsand correspondence: Dr. H.L. DuPont, 6720 Bertner A v e n u e .M C I 1 6 4 , H o u s t o n .T X 7 7 0 3 0 .

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l. Carthwright W, Archer D, Kvenberg J. Estimatesof incidence and cost of intestinal inf'ectiousdiseasesin the United States. public H e a l t hR e p 1 9 8 8 1 0 3 1 0 7 - 1 5 . ; : 2. Feldman R, Banatvala N. The fiequency of culturing stools fiom a d u l t s w i t h d i a r r h o e ai n G r e a t B r i t a i n . E p i d e m i o l I n f ' e c t 1 9 9 4 : ll 3 : 41 4. 3 . G a n g a r o s a , G l a s sR . L e w J , e t a l . H o s p i t a l i z a t i o nis v o l v i n g g a s R n troenteritis in the United States 1985: The special burden of the d i s e a s e m o n g t h e e l d e r l y .A r n J E p i d e m i o l 1 9 9 2 ; 1 3 5 : 2 8 1 - 9 0 . a 4. Lew J. Glass R, GangarosaR, et al. Diarrheal deaths in the United States 1979 through l9tl7: A special problern fbr the elderly. JAMA 1 9 9 1 : 2 6 5 : 3 2 84 . 0 5. Class R. Lew J, GangarosaR, et al. Estimates of morbidity and niortality rates fbr diarrheal diseases American children. J pediatr in l99lrl l8:S27-33. 6. FaruqueA. MahalanabisD, Islam A, et al. Common diarrheapathogens and the risk ofdehydration in young children with acute watery diarrhea:A case-control study. Arn J Trop Med Hyg 1993149:93100. 7 . O l d f i e l d E . B o u r g e o i sA , O m a r A - K , e t a l . E m p i r i c a l r r e a t m e n t f o Shigella dysentery with trimethoprirn: Five-day course vs. single d o s e .A r n J T r o p M e d H y g 1 9 8 7 ; 3 7 : 6 1 6 - 2 3 . ll. DuPont H. Review article. Inf'ectiousdiarrhoea.Alirnent Pharmacol Ther 1994:ti:3-13. 9. EricssonC. PattersonT. DuPont H. Clinical presentation a guide as t o t h e r a p yf b r t r a v e l e r s 'd i a n h e a .A m J M e d S c i 1 9 t 3 7 ; 2 9 . 1 : 9 1 - 6 . 1 0 . P a r i s hK , C h a p r n a n , W i l l i a m s L . I s c h e m i cc o l i t i s :A n e v e r - c h a n g W i n g s p e c t r u mA m S u r g l 9 9 l t 5 7 : 1 1 8 . . I 1. Thuluvath P. McKendrick M. Salmonellu and complicationsrelated t o a g e - S h e f T r e l d x p e r i e n c eQ J M e d l 9 8 U ; 6 7 : , 1 9 7 - 5 0 3 . e . I 2. DuPont H, Marshall G. HlV-associateddiarrhoeaand wasting.Lancet 1995:3-16:3-526. 1 3 . Q u i n n T . S t a m n rW . G o o d e l l S . e t a l . T h e p o l y r n i c r o b i ao r i g i n o f l i n t e s t i n a li n t e c t i o n si n h o m o s e x u a l e n . N E n g l J M e d 1 9 8 3 ; 3 0 9 : m -576 82. l.{. DuPont H. How saf'eis the fbod we eat? JAMA 1992:268:3240. 1 5 . H e d b e r gC , M a c D o n a l dK , O s t e r h o l m . C h a n g i n ge p i d e m i o l o g y f M o l b o d - b o r n e i s e a s eA M i n n e s o t ap e r s p e c t i v eC l i n I n f ' e c t i s 1 9 9 , 1 ; d : . D l8:671 U2.

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acquired immunodeficiency syndrome (AIDS): A medical decision a n a l y s i s A n n I n t e r n M e d 1 9 9 0 ; l1 2 : 9 4 2 - 8 . . 72. Mendelowitz P, Hoffman R, Weber S. Bisrnuth absorptionand myoclonic encephalopathyduring bismuth subsalicylatetherapy. Ann I n t e r nM e d 1 9 9 0 : l 2 : 1 4 0 - 1 . 73. Simon D, Weiss L, Tanowitz H, et al. Light microscopicdiagnosisof to human microsporidiosisand variable response octreotide.Gastroe n t e r o l o g yl 9 9 l ; 1 0 0 : 2 7 1 3 . 74. Haltalin K, Nelson J, Hinton L, et al. Comparisonof orally absorbable antibiotics in shigellosis:A double blind study and nonabsorbable with ampicillin and neomycin. J Pediatr 1968:12:708-20. 75. DuPont H, Levine M, Hornick R, et al. Inoculum size in shigellosis and irnplications fbr expected mode of transmission.J Infect Dis I 9 8 9 ;I 5 9 :I I 2 6 - 8 . 76. Nelson J, Kusmiesz H, JacksonL, et al. Trimethoprim-sulfamethoxazole therapy for shigellosis.JAMA 1976;235:1239-43. ot 77. Tauxe R, Puhr N, Wells J, et al. Antimicrobial resistance ShigeLla J isolatesin the USA: The importanceof intemationaltravelers. Infect l7 D i s 1 9 9 0 1 1 6 2 : 1 1 l0 . III. Magni78. Chalker R, Blaser M. A review of human salmonellosis: tude of Salmonel1ainfection in the United States.Rev Infect Dis l 1 9 8 8 ; 1 0 :I 1 - 2 4 . 79. Neill M, Opal S, Heelan J, et al. Failure of ciprofloxacin to eradicate convalescentf'ecal excretion after acutg Salmonellosis:Experience workers. Ann Intern Med 1991;I l4: during an outbreakin healthcare 195-9. 80. Cherubin C, Neu H, Imperato P, et al. Septicemiawith nontyphoid SalmonellaMedicine l9'74:53:365 I 6. 81. Nelson S, Granoff D. Salmonella gastroenteritisin the first three m o n t h so f l i f e . C l i n P e d i a t r1 9 8 2 : 2 1 : ' 7 0 9 - 1 2 . 82. GruenewaldR, Blurn S, Chan J. Relationshipbetweenhuman immunodeficiency virus inf'ectionand salmonellosisin 20- to 59-year old 6 o residents f New York City. Clin InfectDis 1994118:358 3. 83. Lockyer W, Feinfeld D, Cherubin C, et al. An outbreakof SaLmonella enteritis and septicemia in a populaton of uremic patients. Arch Intern Med 19801140:943-5. in 84. Han T, Sokal J, Neter E. SalmoneLlosis disseminatedmalignant diseases. Engl J Med 196l;276:1045-52. N 85. Samra Y, Shaked Y, Maier M. Nontyphoid salmonellosisin renal transplantrecipients.Rev Infect Dis 1988;8:431-40. 86. Mandal B, Brennand J. Bactaeremiain salmonellosis:A 15 year unit. Br Med J study fiom a regional infectiousdiseases retrospective 1988:297:1242 . 3 87. Kuschner R, Trofa A, Thomas R, et al. Use of azithromycin for the treatment of campylobacter enteritis in travelers to Thailand, an area is where ciprofloxacin resistance prevalent.Clin Int'ectDis 1995;21: 536 41. 88. Pai C, Gillis FE, Marks M. Erythrornycin in treatment of canrpt,' l o b a c t e re n t e r i t i si n c h i l d r e n .A m J D i s C h i l d 1 9 8 3 : 1 3 7 : 2 8 68 . 89. Petruccelli B, Murphy G, SanchezJ, et al. Treatment of travelers' diarrhea with ciprofloxacin and loperamide.J Inf'ect Dis 1992;165: 557-60. 90. Rautelin H, RenkonenO, KosunenT. Emergenceoffluoroquinolone jejuni and Campvkfiacter coli in subresistancein Campl;lobacter jects from Finland. Antimicrob Agents Chemother l99l;35:2065-9. 9 I . SegretiJ, Gootz T, Goodman L, et al. High-level quinoloneresistance jejuni. J lnfect Dis 1992;165: in clinical isolatesof Campylobacter 661-10. 92. MathewsonJ, JohnsonP, DuPont H, et al. A newly recognizedcause of travelers' diarrhea: Enteroadherent Escherichia call. J Infect Dis 1985:l5l:471-5. 93. Cravioto A, Tello A, Navarro A, et al. Associationof Escherichiacoli Lancet patternswith type and durationof diarrhoea. HEp-2 adherence 1991l.331:262-4. 9.1. Mathewson I, JiangZ, Zumla A, et al. HEp-2 cell adherentEsclierichia coil in patientswith human immunodetlciencyvirus-associated d i a r r h e a I I n t ' e c tD i s 1 9 9 5 1 1 7 1 : 1 6 3 6 - 9 . . and adherence 95. Yamamoto T, EcheverriaP, Yokota T. Drug resistance to human intestines of enteroaggregative Escherichia coli. J lntecl Dis 1992:.165'.141-9. 96. DuPont H, Ericsson C, Mathewson J et al. Oral aztreonama poorly to yet therapyfor bacterialdiarrheain US travelers absorbed eff'ective 1 M e x i c o . J A M A 1 9 9 2 : 2 6:7 9 3 2 - 5 . 97. WalterspielJ. Ashkenazi S, Morrow A, et al. Effect ol subinhibitory

.16. Kotler D. FranciscoA, Clayton F, et al. Small intestinal injury and p a r a s i t i c i s e a s e sn A I D S . A n n I n t e m M e d 1 9 9 0 ; 1 1 3 : 4 4 4 - 9 . i d 17. Lopez C, Dykes A, Juranek D, et al. Waterborne giardiasis: A and a high rate of asymptomatic cornrnunity-wideoutbreakof disease . inf'ection.Am J Epidemiol l980ll 12:495-501 C 4 8 . R a v d i n R . A m e b i a s i s . l i n I n f e c t D i s 1 9 9 5 ; 2 0l:z t 5 3 6 6 . 49. Garcia L. Shum A, Bruckner D. Evaluation ol new monoclonal antibody combination reagent fbr direct lluorescencedetection of Giardia. Cysts and Cryprcsporidium oocytes in human fecal specirnens.J Clin Microbiol 1992l.30:3255-1. 50. Dagan R, Fraser D, El-On J, et al. Evaluation of an enzyme-immunoassayfbr the detectionof Cryptosporidian spp in stool specimens fion.rintants and young children in field studies.Am J Trop Med Hyg 1 9 9 5 : 5 2 : 1 3 ,8 . 1 o C 5 1 . R o s o t T J . S a n d e r s , S o n n a dS , e t a l . S t o o l d i a g n o s i s f g i a r d i a s i s using a cornmercially available enzyme immunoassayto detect Clzurlia-specificantigen65 (GSA 65). J Clin Microbiol 1989:21:199'72002. comparisonof direct 52. Alles A. Waldron M, SierraL, et al. Prospective and conventionalstainingmethodsfbr detection immunofluorescence o'i Giardia and Cnptosporidium spp in human fecal specimens.J Clin M i c r o b i o l 1 9 9 5 : 3 31 6 3 2 - 4 . : 53. Su C. Brandt L. EscherichiacoLi Ol5'7:H7 inf'ectionin hurnans.Ann -1 Intern Med 1995:123:698 14. 54. Morris J Jr. Black R. Cholera and other vibriosesin the United States. N Engl J Med 1985;312:343-50. -55. Lee L. Taylor J, Carter G, et al. Yersinia enterocolitica 0:3: An emerging cause of pediatric gastroenteritisin the United States. J I n f e c tD i s l 9 9 l : 1 6 3 : 6 6 0 3 . 56. The management of acute dianhea in children. oral rehydration, maintenance. and nutritional therapy.MMWR 1992;.{l(Octoberl6):

r-20.

57. Schiller L. Sannta Ana C. Morawski S, et al. Mechanism of the 1475 antidiarrhealeffect of loperamide.Gastroenterology1984;86: 80. 58. JohnsonP. Ericsson C, DuPont H, et al. Comparison of loperamide with bisrnuth subsalicylate the treatmentof acute travelers' diarfbr 5'7 rhea. JAMA 1986'.225:1 -60. 59. DuPont H, SanchezJ, Ericsson C, et al. Comparative efficacy of in loperamidehydrochloride and bismuth subsalicylate the manage6 m e n t o f a c u t ed i a r r h e a A m J M e d 1 9 9 0 ; 8 8 ( s u p p l . { ) : l 5 S - 1 9 5 . . 60. DuPont H, Hornick R. Adverse effect of Lomotil therapy in shigell o s i s .J A M A 1 9 1 : 2 2 6 : 1 2 5 - 8 . 3 5 61. Murphy G, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamidein the treatmentof bacillary dysentery.Ann Intern Med 1993:l8:582-6. 62. Cin'rolaiN, Carter J, Morrison B, et al. Risk factors for the progrest:oli 0157:H7 enteritis to hemolytic-uremic synsicrnof Esr'lrerir:hia drorne.J Pediatr 1990:l 16:582-92. 63. Cirnolai N, Morrison B, Carter J. Risk factors fbr the central nervous hemolytic-uremic of systemrnanif'estations gastroenteritis-associated syndrome.Pediatrics 1992:90:616-21. 6.1. DuPont H, Sullivan P, Pickering L, et al. Symptomatic treatmentof attendinga Mexamong students diarrheawith bismuth subsalicylate 15 ican university. Gastroenterology191'1t13:7 8. inhibits 65. EricssonC. Evans D. DuPont H, et al. Bismuth subsalicylate activity of crude toxins of Escherichia coli and Vibrio cholerae. J Int'ect Dis 19'7'7:136:693-6. 66. Powell D. Tapper E. Morris S. Aspirin-stimulatedintestinal electrolyte transport in rabbit ileum in vitro. Gastroenterology1979;76: t429-31. 67. DuPont H, Ericsson C, Johnson P, et al. Prevention of travelers' JAMA dianhea by the tablet fbrmulation of bismuth subsalicylate. -50. l98l :251:1341 68. Graham D, EstesM, Gentry L. Double-blind comparisonof bismuth subsalicylate and placebo in the preventionand treatmentof enteroE c y t o x i g e n r c s c h e r i c h i a o l r . G a s t r o e n t e r o l o g1 9 8 3 ; 8 5l:0 l l - 2 2 . M. 69. SteinhofT Douglas R Jr, GreenbergH, et al. Bismuth subsalicylate 1495-9. Gastroenterology1980178: therapy of viral gastroenteritis. 70. DuPont H, Ericsson C, DuPont M, et al. A randomized open-label comparison of nonprescription loperarnide and attapulgite in the symptomatic treatmentof acute diarrhea.Am J Med 1990;t3tt(suppl 6A ):20S-23S. 71. JohansonJ. SonnenbergA. Efllcient managementof diarrhea in the

AJG - November 1997

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concentrationsof antibiotics on extracellularShiga-like toxin 1. Inf'ection 1992120:25-9. 98. Pavia A, Nichols C, Green D, et al. Hemolytic-uremic syndrome during an outbreak of Escherichia coli Ol57:H1 inf'ectionsin institutions for mentally retarded persons: Clinical and epidemiologic o b s e r v a r i o n s . P e d i a t r1 9 9 0 1 1 1 6 : 5 4 4 1 . J 5 99 Ostroff S, Kobayashi J, Lewis J. Infections with Escherichia coli 0157:'H'7in Washington State: The first year of statewide disease s u r v e i l l a n c e .A M A 1 9 8 9 1 2 6 2 : 3 5 5 - 9 . J 100 Prouix F, Turgeon J, Delage G, et al. Randomizedcontrolled trial of antibiotic therapy for Escherichia coli 015'/:Hl enteritis. J Pediatr 1992:121:299-303 .

101. Kozicki M, Steffen R, Schiir J. it cook it peel it or fbrget it;" d o e st h i s r u l e p r e v e n tt r a v e l e r s ' d i a r r h o e aI? t J E p i d e m i o l l 9 t i 5 l l 4 : n '72. 169 102. Bandres J, Mathewson J, Ericsson C, et al. Trimethoprim/sulfamethoxazole remains active against enterotoxigenic E,scherichiat.oLi and Shigella spp in Guadalajara, Mexico. Am J Med Sci 1992;303:28991. 103. Munay B. Resistanceof Shigella, Salmonella and orher selected enteric pathogens to antimicrobial agents. Rev Infect Dis 1986; 8 ( s u p p 2 ) : S 1 7 28 1 . l 104. EricssonC, DuPont H. Travelers' diarrhea:Approachesro prevention and therapy. lin lnfect Dis 1993;16:616-26. C