Acute infectious diarrhea

GASTROINTESTINAL EMERGENCIES

0025-7125/93 $0.00

+

.20

ACUTE INFECTIOUS DIARRHEA LTC Christopher P. Cheney, MC, PhD, MD, FACP, and COL Roy K.H. Wong, MC, MD, FACP, FACG

Diarrheal illness is one of the most common outpatient infectious illnesses in the world. The majority of diarrheal illnesses are self-limited and respond to symptomatic therapy of oral fluid rehydration. However, many clinical questions arise when a patient presents to your clinic with diarrhea. Who can be safely treated with fluids verus who requires further evaluation? What evaluation is best suited for a given patient? Should antibiotics be given, and if so, what pathogen is being treated? The purpose of this article is to review the magnitude of diarrheal illness, general aspects of its epidemiology in high-risk populations, review various pathogenic mechanisms of diarrhea, review a selected approach to working up diarrheal illness with a discussion of who to treat and how best to treat them and a differential diagnosis regarding noninfectious etiologies. MAGNITUDE AND PREVALENCE OF INFECTIOUS DIARRHEA Prevalence Worldwide

Diarrheal illness is clearly the most common infectious disease in third world countries based on World Health Organization data from 1977 to 1978 obtained from Africa, Asia, and Latin America. m The prevalence of diarrhea has been estimated to be 3 to 5 billion cases per year and it is associated with 5 to 10 million deaths per year. This mortality From the Gastroenterology Service, WaIter Reed Army Medical Center, Washington, DC (CrC and RKHW); and the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (RKHW) MEDICAL CLINICS OF NORTH AMERICA VOLUME 77· NUMBER 5' SEPTEMBER 1993

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rate translates into approximately 27,000 deaths per day. The average number of days lost per episode of diarrhea is 3 to 5 days. Children younger than 5 years old have an average of three episodes of diarrheal illness per year with a mortality rate in the first year of life of 8 to 50 deaths per 1000 live births.65 Prevalence in United States

The United States is not isolated from this illness. The mortality in U.S. children in their first year of life is approximately 0.25 deaths per 1000 live births, based on Centers for Disease Control (CDC) estimates.72 The incidence of diarrhea in U.s. children younger than 5 years old is 2 to 2.5 episodes per child per year that decreases to 1.5 to 1.7 per year per adult. 27,65 There are no specific studies that give an accurate reflection of the magnitude of diarrheal disease in the United States. This is due to multiple reasons to include cost of diagnostic evaluation, availability of laboratories to identify all potential pathogens, easy empiric treatment plus variation in the etiologic agent in different socioeconomic groups, geographic locations, and the patient populations at risk. Patient groups at risk include children younger than 5 years old especially in day care centers, travelers and campers, patients with AIDS or immunocompromising conditions, patients in chronic care facilities with nosocomial infections and military personnel assigned overseas,66 The impact on the U.s. population has been estimated to vary between 25 to 99 million cases of diarrhea or vomiting per year with an estimated 10,000 deaths per year,56 Of these, 8.2 million patients seek medical advice with 250,000 patients requiring hospitalization. Fifty percent of the diarrheal cases lost at least 1 full day of activity. This translates into a projected cost of $23 billion dollars a year in the U.S. based on estimated medical costs and lost of productivity,56 HIGH-RISK GROUPS AND THE EPIDEMIOLOGY OF ASSOCIATED PATHOGENS

There are various clinical settings in which patients are at greater risk than the general population for developing diarrhea. This increased risk is usually associated with greater exposure to different modes of transmission than the general public (i.e" fecal-oral, poor sanitation, person to person via aerolization, homosexual activity). Table 1 gives a listing of the spectrum of etiologic agents in these high-risk populations. Of clinical note is that the frequency of the pathogens varies between the groups. Infants in Day Care Centers

The number of children in the United States enrolled in day care centers (DCCs) has been increasing yearly with current estimates of 10

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Table 1. EPIDEMIOLOGY OF ENTEROPATHOGENS ISOLATED FROM PATIENTS WITH DIARRHEA IN DIFFERENT CLINICAL SETTINGS (EXPRESSED IN PERCENTAGE OF ISOLATES) Homosexual Men Pathogen

Day Care Centers*

AIDS Diarrhea

Proctitist

Bacterial Enterotoxigenic E.

Travelers' Diarrhea Latin Americatt

Thailand

U.S. Military Persian Gulf War

28 to 76

6

29.7

o to 30 o to 16

41 4 18

0.5 26.2 1.6

coli

Enteroinvasive E.

coli Campylobacter sp. Shigella sp. Salmonella sp. C. difficile sp. C. trachomatis N. gonorrhea

Viral Rotavirus Herpes simplex

2.0 0.2 0.2

10.6 4.9

14.3 5.7

7.1 11.4 0.0

2.9 14.7 17.1

18.4

30

6.0

Protozoan G.lamblia E. histolytica Cryptosporidium Isospora belli

Number of Patients Reference

13

4.4 0.0 15.6 2.2

5.9 8.8 0 0

o to 36 o to 6 o to 6

635

49

35

1918

132

432

6

90

90

13

122

76

'Children aged 0 to 36 months. t68% of these patients had positive HIV serology. ttPercentages given are a range because of summation of multiple studies.

million or more.137 DCCs pose the risk of close contact between children that are not toilet trained and who are unaware of concepts of personal hygiene. The mode of transmission appears to be either through child to child or fomites (i.e., toys, bathrooms, shared diaper changing areas). Staff members and household contacts are also at risk. In 1974, outbreaks of Shigella sonnei in two urban centers were traced back to DCCs indicating a major role of DCCs in transmission of shigellosis. m Shigella is not the only enteropathogen spread outside of DCCs, a prospective study of 20 DCCs in Houston revealed not only Shigella but rota virus and G. lamblia being transmitted to family members at home.125 The attack rate in persons at risk of developing diarrhea at DCCs was highest with rotavirus at 71% followed by Shigella at 33% and G. lamblia at 17%.125 A 2-year prospective study on the epidemiology of diarrhea in DCCs revealed it occured both as outbreaks and sporadically. In only 20% of the cases was a pathogen identified. The offending pathogen varied between the infants and toddlers with rota virus most common in infants and Giardia more common in toddlers with Campylobacter being roughly equal in both groups.6 As expected the greatest risk for developing diarrhea was associated with lower scores on hygiene and child handling procedures. Recent viral studies have identified human enteric adenovirus as a significant pathogens in diarrhea outbreaks in DCCS. 168

.

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Chronic Care Facilities

As the population ages, more people will be confined to chronic care facilities and the pool of individuals at risk of nosocomial infections will increase. This population is at risk because of host-specific factors that include their general debilitated state, suppressed immune response, multiple concurrent chronic diseases, and fecal incontinence. The National Center for Health Statistics reviewed the mortality data in the United States from 1978 to 1987. 96 It found that in those patients who died with diarrhea listed as either an immediate cause or underlying cause of death, the majority (51%) of deaths were in persons older than 74 years old. The highest adjusted risk factor was being white, female, and residing in a chronic care facility. Currently, there is limited epidemiologic studies evaluating nosocomial diarrhea and the associated enteropathogens in chronic care facilities. Two studies ranked the incidence of diarrhea (at 33 cases per 100 patient years) fourth behind the incidence of urinary tract infections, lower respiratory tract infections, and skin/ soft tissue infections. 47 , 110 No detailed microbiologic profile of the enteropathogens was reported in either study. Sporadic reports have indicated C. difficile as a major endemic pathogen in chronic care facilities? Approximately one third of the residents had stools positive for C. difficile toxin or were culture positive. Of the toxin positive patients, 34% had diarrhea. New cases were nosocomially acquired even during attempts to eradicate the organisms with oral metronidizole? There have also been case reports of sporadic outbreaks of Aeromonas hydrophilia in elderly patients with one reported death17 as well as reported outbreaks of viral induced gastroenteritis secondary to calicivirus and rotavirus. 31 , 32 Homosexuals and AIDS Patients

Impaired immune function leads to the gastrointestinal tract being a major organ secondarily infected by a wide variety of enteropathogens in AIDS patients. Diarrhea is a complaint in 30% to 60% of AIDS patients surveyedY6, 154 Their diarrhea is usually chronic, watery, nonbloody, and frequently associated with progressive weight loss. The spectrum of etiologic agents is far broader than that seen in patients with normal Thelper cell function. The spectrum encompasses the usual enteropathogens plus the less common agents to include the protozoans Cryptosporid-

ium, Entamoeba histolytica,132 Isospora belli,35 Enterocytozoon bieneusi149 , 152 (micro sporidium), the bacteria Neisseria gonorrhea, and Chlamydia trachomatis,90 and the viruses to include cytomegalovirus, herpes simplex virus, and HIV.88, 108 Mycobacteria avium intracellulare is a frequent pathogen in

chronic culture negative AIDS patients. 63 A survey of 243 asymptomatic homosexual or bisexual man (28% HIV serology positive) revealed 12% harboring an enteric pathogen. 9o The most common agents being Chla-

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mydia trachomatis (2.9%), Campylobactor jejuni (2.6%), HSV (2.5%), and G. lamblia (2.1 %). An enteric pathogen was found in 55% of all symptomatic AIDS patients with the most common agent being HSV (18.4%) followed by Cryptosporidium at (15.6%), and C. trachomatis (11.4%) (Table 1). Given the risk of anal intercourse, this group of patients can often present with symptoms of proctitis rather than diarrhea. The most frequent pathogens found in patients with proctitis is HSV (30%) followed by N. gonorrhea (17.1%), c. trachomatis (14.7%) and Campylobactor sp (14.3%).90 A group of advanced AIDS patients with diarrhea who originally had stools negative for enteric pathogens and parasites were selected for further evaluations to include duodenal and colorectal biopsies obtained at endoscopy. The study revealed M. avium-intracellulare and microsporidia to be the most common occult agents. 63 Microsporidia were only detected in the doudenal epithelium by electron microscopy however other studies have since claimed to be able to detect the parasite under light microscopy.149 Unfortunately, although these more extensive evaluations detected a pathogen, there is no effective antimicrobial regimen to eradicate the organisms. Travelers' Diarrhea

There is estimated to be 300 million international travelers per year, 8 million of whom originate in the United States. 29 One third of these travelers are suspected to developed acute diarrhea with the onset usually in the first week of the trip or soon after returning home. The diarrhea begins abruptly with 4 to 6 loose stools per day, associated with abdominal cramps, nausea, bloating, and malaise in the majority of cases. Vomiting is seen in 15% of the cases, and fever, dysentery, or both in 10%.30 The diarrhea is usually self-limited with a median duration of 3 to 4 days, with 10% lasting more than 1 week, 2% lasting more than a month, and less than 1% lasting longer than 3 months. 3o The incidence of Travelers' diarrhea depends on several factors to include dietary indiscretions, destination of travel, and host risk factors. In patients who have recently traveled, a dietary history should focus on questions assessing for risks of consumption of fecally contaminated food and water. S,uch questions should include consumption of uncooked food, raw vegetables, raw meat, raw seafood, tap water, ice, dairy products, eating at restaurants, or use of street vendors. A detailed study in Swiss travelers identified high risk locations to include, developing Latin American countries, Africa, Middle East, and all of Asia.155 Intermediate risk countries included Southern Europe, and a few Caribbean islands. Low-risk countries included North America, Northern Europe, Australia, New Zealand, and a few Caribbean islands. Host factors that may play a role include younger adults «30 year old), patients with impaired gastric-acid barrier secondary to gastrectomy, chronic antacid or H2 blocker therapy, achlorhydria, immunosuppression, and a previous history of severe Travelers' diarrhea.

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The incidence of a specific etiologic agent isolated in Travelers' diarrheas varies with location of the surveyY, 159 Black!3 has summarized multiple surveillance studies in third world countriesY With respect to bacterial pathogens, enterotoxigenic Escherichia coli (ETEC) has been recognized as the most important cause of Travelers' diarrhea with an median incidence of 42% in Latin America, 36% in Africa, and 16% in Asia. Isolation of Shigella sp is less frequent varying from 0 to 15%. Campylobactor jejuni varied from a median incidence of 1% in Mexico up to 15 to 17% in Bangladesh and Thailand. The median incidence of Salmonella sp was 1.0% in Latin America, up to 4% in Asia while it wasn't isolated in any travelers from Africa. Other bacterial pathogens isolated included Vibrio parahemolyticus especially in Japanese tourists visiting southeast Asia and as expected, it was associated with consumption of raw seafood. Other pathogens reported included Aeromonas hydrophila, enteroadherent E. coli (EAEC), Plesiomonas shigelloides, E. histolytica, C. lamblia, and Cryptosporidium as will as rotavirus. Diarrhea in Military Operations

Diarrhea has had a profound impact on U.S. military operations throughout our history. Diarrhea has historically been the cause of a large degree of mortality and morbidity associated with combat operations. This reflects deployment to areas with different pathogens than found in the United States, the soldiers lack of mucosal immunity to these pathogens, acquistion of fecally contaminated local food and drinking water, and the decline in personal hygiene and sanitation. The mortality rate from dysentery was higher than battle wound casualties in the revolutionary war and represented more than 25% of all fatalities in the Civil War.123 By World War 11, diarrhea became associated more with morbidity than mortality. In 1942 in the Middle East, diarrhea had a prevalence of 497 cases of diarrhea per 1000 men.117 Little has change regarding the prevalence as seen during Operation Desert Storm where a survey of soldiers revealed an attack rate of 57% within the first 2 months in Saudi Arabia?6 Twenty percent of the soldiers with diarrhea were temporarily incapacitated and lost to their combat units. MECHANISMS OF PATHOGENESIS IN INFECTIOUS DIARRHEA

Enteropathogens have developed multiple mechanisms to induce diarrhea in humans. Some of these mechanisms have been thoroughly investigated whereas others only on a limited basis. Intensive discussions of these pathologic mechanisms are available for review elsewhere.!,20, 27,94 The following section briefly reviews some of the major mechanisms utilized by bacteria to induce diarrhea. These mechanisms include adherence of bacteria to intestinal epithelial cells with and without mucosal

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damage, mucosal invasion of epithelial cells, and production of enterotoxins and cytotoxins. It must be kept in mind that many pathogens employ more than one of these mechanisms to overcome host defenses. Figure 1 summarizes the various mechanisms described below. Adherence

In order for bacteria to colonize the bowel, it has to resist the clearing action of peristalsis, a major host-defense mechanism. Some pathogens circumvent this problem by attaching or adhering to the mucosal surface. The role of adherence is to promote colonization and possibly increase the efficacy of enterotoxins by decreasing the distance that enterotoxins have to travel to reach target intestinal epithelial cells. Two main mechanisms of adherence have been described. The first adherence mechanism is confered by bacterial surface protein structures called pili or fimbria expressed by certain pathogens especially ETEC. 94 Many types of fimbria have been described in both human and animal bacteria. ss,94 These structures are large polymeres composed of repeating small sub units (14 to 22 kilodaltons). Fimbria vary in diameter from 2 to 7 nm wide and in length from 0.5 to 2 f-Lm long and are visualized only with the aid of an electron microscope. They bind to specific ligands/ receptors on intestinal epithelial cells in a lectinlike fashion.116 The initial pilus to be described, Type I pili, confers mannose sensitive adherence. Type I pili are commonly found but are not usually involved in the pathogenesis of bacterial diarrhea. Fimbria called colonization factor antigens (CFA) are more commonly found on enteropathogens and to date, more than seven such fimbria have been described. ss, 94 Animals models using enterotoxin possessing strains of E. coli found that diarrhea occured more frequently in the animals who were infected with both enterotoxin positive and pili positive organisms. 80 A second and distinctly different mechanism of enteroadherence is seen in enteropathogenic E. coli (EPEC). Diarrhea in patients infected with EPEC strains have been shown to have the organism closely adherent to intestinal epithelial cells in vivo. 166 The epithelial cells have lost their normal microvillus membrane surface and the apical surface membrane can be seen under electron microscopy to be cupping the EPEC organism forming a pedistallike structure.20 This histologic pattern has also been referred to as attaching and effacing lesions. In vitro adherence assays in HEp 2 Cells have shown that a large plasmid (60 megadaltons) confers the adhesive property of EPEC and this gene has been called EPEC adherence factor (EAF).S' 107 The initial adherence is probably mediated through bundle forming pili. 38 The formation of the attaching and effacing lesion is controlled by another as of yet unidentified gene locus. The process appears to involve changes in intracellular calcium concentration together with alterations in the cytoskeleton architecture located under the microvillus membrane. 38 Although closely adherent to the epithelial cell surface, no extensive intracellular invasion has been de-

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scribed with EPEe and the actual mechanism of diarrhea remains unknown but may be secondary to production of a shiga like toxin. 98 Oral challenge studies have demonstrated EAF positive EPEe strains produce diarrhea in 9 of 10 subjects while EAF negative EPEe strains elicited diarrhea in 2 of 9 volunteers.94 Further evaluation of the adherence process in the HEp-2 cell assay system has revealed EAF positive adherence is associated with focal or localized adherence and causes infantile diarrhea. EAF negative adherence caused a diffuse adherence pattern to HEp-2 cells and these EPEe strains are not diarrheagenic E. coli. Finally a third pattern of EPEe adherence has been described called aggregative pattern. Plasmid probe analysis of these pathogens reveals no genetic homology to enteroinvasive, enterotoxigenic or enterohemorrhagic E. coli and may represent a new class of pathogens. 106 Invasion

Shigella is the classic enteroinvasive organism. This organism has been shown to adhere to and invade mucosal epithelial cells.53, 92, 157 Invasion is the result of Shigella's ability to induce it own phagocytosis in the nonphagocytic intestinal epithelial cells by utilizing the intestinal epithelial cells' cytoskeleton of microfilaments. 29 The entry site of Shigella appears to be the basolateral membrane and not through the microvillus apical surface as previously described in the literature.104 Once within

Phagocytosis

Ingestion & colonization

ENTEROINVAS10N

llJJ

r"'~;"",r·~7 W~~ Cholera IOxin

Toxin producrion

Toxin binding

Heat labile tOxin

Heat stable tOxin

ENTEROTOXIN OR CYTOTOXIN

Shiga tOxin

Pili/fimbria mediated adherence

ENTEROADI-IERENCE

Pedislal Formation EAF mediated adherence

Attaching & Effilcing lesions

Figure 1. Illustration continued on opposite page (See legend on opposite page)

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intestinal epithelial cells, they multiply intracellularly within phagosomes and spread to contiguous epithelial cells again utilizing the cytoskeletal apparatus to project themselves into adjacent cells in the colon. lO, 146 Invasion and multiplication elicits an intense inflammatory response followed by epithelial cell death.ls7 The mucosal inflammatory reaction is not clearly understood but probably involves local release of inflammatory mediators to include leukotrienes, interleukins, kinins, and other vasoactive agents. As mention previously, Shigella also produces a toxin called shiga toxin that is felt involved in cell destruction.113 The summation of these events is manifested clinically by fever, abdominal cramps, malaise, and the dysentery associated with shigellosis. Recent studies by molecular biologist have focus on the molecular genetics of this process.69 , 70, 146 As expected, multiple genes located on both chromosomal and plasmid DNA have been identified that control this complex orchestration of events. Other enteropathogens that utilize mucosal invasion include enteroinvasive E. coli (EIEC),94 Salmonella.79 Enterotoxin Production

Cholera toxin is the classic prototype enterotoxin. Patients infected with this organism demonstrate cholera toxin's powerful biologic activity in that they can produce voluminous quantities of watery stools over several hours leading to potentially life threatening dehydration. The

Intercellular Spread

Intracellular Multiplication

[JiJO

Q CJ Q

Dy~ntery

Mucosal inflammation Cdldeath Stimulates Adenyl cyclase

~ +cyclic At\1P ...

.......

Shigella Salmonella EIEC

Yersinia Campylobacrcr V. parahemolytica Inhibits absorption Enhances secretion

Stimulates Guanyl cyclase

PROTOTYPE

.......

Watery diarrhea

t cydic GMP '-

ETEC

V. cholerJ

Shigella Interfe rs with ribosomes

.......

Inhibits pro,ein synthesis

Cdl Death

EPEC

EHEC

V. parahemolytica PROTOTYPE

ETEC

EPEC

Figure 1. Schematic illustration of major mechanisms of pathogenesis used by various bacteria to directly elicit or enhance diarrhea.

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mechanism for this large volume purge lies in the action of cholera toxin on intestinal epithelial cells. Cholera toxin is a 84,000 dalton molecule composed of a mixture of subunits (one A subunit and 5 B subunits).1 The B subunit binds to monosialoganglioside GMI on the microvillus membrane surface of the small bowe1. 52,87 Subunit A is composed of 2 components, Al and A2. A2 plays a role in the internalization the toxin into the epithelial cells while subunit Al possesses enzymatic activity that ultimately leads to stimulation of adenyl cyclase activity. Adenyl cyclase stimulation is accomplished via ADP ribosylation of GTP-regulatory Gs protein of adenyl cyclase. I, 59,103 The result of adenyl cyclase activation is an increase in the intracellular concentration of cAMP which is involved in control of fluid and electrolyte transport across intestinal epithelial cell membranes. The net effect is inhibition of sodium and chloride absorption in villus tip cells with stimulation of chloride and HC03 secretion in mucosal crypt cells. 49 ,54 The overall effect leads to marked increase in the luminal small bowel fluid that is delivered to the colon. This fluid overwelms colonic absorptive capacity thereby causing watery diarrhea. It should be noted that heat labile (LT) toxin produced by ETEC possesses the same biologic activity and is almost identical with respect to its biochemical and immunological structure. 24,33 ETEC can produce another enterotoxin called heat-stable (ST) toxin, This is a much smaller molecule at approximately 2000 daltons. I ,20 As with cholera toxin, ST is composed of 2 subunits (STa and STb).20 STa binds to receptors on intestinal epithelial cells especially villus tip cells. 33,36 STa stimulates guanyl cyclase with a resultant rise in the intracellular concentration of cyclic GMP.50, 134, 169 The sequence of events after elevation of intracellular cGMP that leads to net fluid secretion are unclear. 58 However, data suggest that increase cGMP may activate a GMP dependent protein kinase which has been postulated to phosphorylate specific mircovillus membrane proteins promoting opening of chloride ion channels and active chloride secretion. 167 The effect of STa appears to be different along different segments of the gut, in that STa promotes a net secretion in the ileum and a decreased net absorption in the colon, resulting in overall intestinal fluid secretion. 100 Cytotoxins

Besides stimulation of fluid secretion, some organisms can synthesize and secrete a toxin that causes cytotoxicity in cultured cell lines (HeLa and Vero cells lines). The classic prototype cytotoxin is the shiga toxin produced by Shigella dysenteria. 113 , lIS Shiga toxin is not only cytotoxic in vitro but stimulates fluid secretion in rabbit ileal loop preparations and is neurotoxic in mice. 85 Shiga toxin is a relatively small protein molecule composed of A and B subunits.ll8 The A subunit (32 kilodaltons) causes inhibition of protein synthesis via disruption of 60S ribosomes and blocks elongation-factor dependent binding of tRNA to

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ribosomes. 18,42 The B sub unit (7 kilodaltons) binds to a membrane glycolipid globotriaosylceramide and may enhance translocation of cytotoxin into intestinal cells.86, 101 Multiple other organisms have been found to produce shiga toxin or shigalike toxins. The most notable are enterohemorrhagic E. coli (EHEC) of serogroup 0157 that causes hemorrhagic colitis and hemolytic uremia syndorne. ll4 EHEC was orginially described as producing verotoxin based on it ability to synthesize and secrete a protein toxic to Vero cells but it is now felt that verotoxin and shiga toxin are one and the same.82, 141 Other organisms secreting shiga toxin include enteropathogenic E. CO[z'23 and V. parahaemolyticus. 1l2 DIAGNOSTIC WORK UP

As with any clinical decision, one needs to be sure that one will act on the information generated by any diagnostic workup and if a pathogen is identified, is there clinical data to prove efficacy for antimicrobial treatment. Much has been written regarding the cost effectiveness of stool cultures in a nonselective group of patients with diarrhea. Culture positivity rates for Salmonella and Shigella in unselected stools specimens from patients with diarrhea have been reported to be 1.5 to 2.4 per 100 specimens.67 This translates into a cost of $952 to $1,200 per positive stool culture which clearly ranks it as one of the most costly microbiologic tests per positive result. 67 Because of this prohibitive cost, attempts have been made to deSigns strategies that will maximize the diagnostic yield. One proven approach has been to develop algorithms that will select groups of patients based on historical clues and their symptoms that will increase the likelihood of finding a treatable diagnosis. One algorithm is displayed in Figure 2. This algorithm essentially ignores embarking on a diagnostic workup in those patients with limited duration of diarrheal illness who have no evidence of dysentery. Supportive care, oral rehydration and observation being the only recommendations. In contrast, an attempt should be made at obtaining a pathologic diagnosis in patients in whom you can elicit a history of recent ingestion of seafood, a recent travel or camping history, recent antibiotic use or homosexual activity or who complain of fevers, abdominal pain, tenesmus, or a prolonged duration of diarrhea. Step 1

The first questions to ask are does the patient have blood or mucus in their stools? If not, are there polymorphonuclear neutrophilleukocytes (PMNs) in the loose stools? A yes answer to either of these question indicates the potential presence of colonic pathogens such as Shigella, Salmonella, Campylobacter jejuni, enteroinvasive E. coli, C. difficile, or less likely Yersinia enterocolitica. At this point, it is recommended to submit a

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Step 1

Historical clues* Fever Dehydration Prolonged diarrhea Abdominal pain Tenesmus

No

Nonbloody stools Duration < 4 days Nontoxic appearance No fever

Observation Supportive care Oral hydration as needed

Yes

Yes

I Blood or mucus in stools r-No

± sigmoidoscopy

I Fecal PMNs No Step 2

I Fecal 0 and P

~ Sto~1 cUI~urest_-::-:--

Yes

DDX G.lamblia E. histo/ytica Cryptosporidium

DDX* Campylobacter Shigella Salmonella EIEC, EHEC Aeromonas C. difficile Pleisomonas

No Step 3

DDX Viruses Yersinia ETEC, EPEC Plesiomonas Aeromonas V. cholera V. parahemolyticus

Consider if indicated: Special cultures Sigmoidoscopy Upper endoscopy

Figure 2. An algorithm for diagnostic evaluation of acute infectious diarrhea. DDX = differential diagnosis. *Recent use of antibiotics, recent travel, homosexual activity, camping, seafood ingestion, and history of local outbreak of diarrhea. + In homosexual population with proctitis on sigmoidoscopy, include cultures for N. gonorrhea, Chlamydia trachamotis, HSV, and MAl. :j:Refer to Table 4 for noninfectious DDX.

liquid stool specimen for Salmonella, Shigella, or Campylobacter. You may need to notify the laboratory to include a culture for Campylobacter if they do not routinely culture for it. Using a strategy of culturing only stool specimens with PMNs, Guerrant's group found the rate of culture positivity rose to 76% (from 1.5 to 2.4%) and reduced the cost per positive culture to $30. 67 If the patient has hemorrhagic colitis and hemolytic uremic syndrome, one should consider EHEC as the pathogen. 13B This diagnosis can be made only via serotyping using commercially available antisera for the more frequent serotype 0157. There is no specific culture medium that differentiates EHEC from the other pathogenic types of E. coli (i.e., enteroinvasive E. coli, enteropathogenic E. coli, enterotoxigenic E. coli vs enteroadherent E. coli) but sorbital-MacConkey agar is a good screening media in combination with serotyping. 68 Presumptive diagnoses for any

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of these pathogens are based on either serotyping, bioassays or DNA hybridization assays which are usually only available at research centers.163 Mucosal invasion as seen in EIEC is determined in the Sereny test where organisms are injected into the conjunctiva of a guinea pig and development of keratoconjunctivitis is taken as a positive test. l5l Alternatively, DNA hybridization have been used to identify EIEC. 163 If a history of recent antibiotic use has been elicited, stools should be sent for C. difficile toxin. C. difficile produces two type of toxins; toxin A with properties of fluid secretion and toxin B with properties of cell cytotoxicity.163 Commercially available kits for detecting C. difficile toxin mainly measure cytotoxic activity in tissue culture systems22, 175 but ELISA kits91 are also available (Meridian Diagnostic, Inc, Oremos, MI). The tests are recommended to be performed on fresh loose stool specimens within 24 hours in order to optimize finding cytotoxin activity. A great deal of information can be obtained with an unprepared sigmoidoscopy to include determining the presence and severity of colitis and its anatomic extent (proctitis vs proctocolitis). One can obtain mucosal biopsies for pathologic tissue diagnosis, microbiologic cultures as well as obtaining samples of luminal content for culture or bioassays. Sigmoidoscopy may help make the diagnosis of pseudomembranous colitis in patients with a history of antibiotic use. The diagnosis of noninfectious diarrhea caused by either inflammatory bowel disease or ischemic colitis can be suggested on sigmoidoscopic examination. Furthermore, in the homosexual population it can immediately differentiate proctitis with more extensive proctocolitis. Proctitis is more likely to be associated with Neisseria gonorrhoeae, Chlamydia trachomatis (nonlymphogranuloma venereum types), Herpes simplex virus and Treponema pallidum. 90 In homosexuals with proctocolitis Entamobea histolytica, Shigella, and C. trachomatis (lymphogranuloma venereum types) are more common. 90 Step 2

If blood or mucus are not present in the stools and no PMNs are seen on fecal smears and the patient has appropriate risk factors (i.e., camping, consumption of nonpurified water, travel to endemic areas known for parasites or an immunosuppressed hosts) then ova and parasites would be the next test to pursue. The commonly screened parasites include Giardia, E. histolytica, and Cryptosporidium. One note of caution is the false negative rate for these pathogens. In cases of chronic diarrhea with the same risk factors but negative stools for ova and parasites, one could consider an upper endoscopy to obtain samples to help make a diagnosis. 57 Samples that can be obtained from upper endoscopy include mucosal biopsies of the duodenum for light and electron microscopy (looking for Giardia, Cryptosporidium, and Microsporidium), duodenal luminal aspirates for Giardia and Cryptosporidium plus quantitative colony counts to rule out small bowel overgrowth. Alternate means of obtaining

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duodenal fluid can be achieved using the string capsule (Entero-Test, HDG Corporation, Mountain View, CA). Step 3

If no parasites are found then the differential diagnosis is narrowed to include viruses (mainly rotavirus and Norwalk agent) which are selflimited processes, and a handful of bacterial pathogens (Yersinia, Vibriocholera, ETEC, and EPEC). If there is a clinical picture characteristic of Yersinia infection with high fevers, right lower quadrant tenderness, abdominal pain suggestive of mesenteric adenitis or appendicitis then special Yersinia cultures should be requested. Travel history to third world countries with the presence of voluminous diarrhea may suggest ETEC or Vibrio cholera. Cholera can be isolated from fecal samples by plating on thiosulfate, citrate, bile salts, sucrose medium (TCBS).163 This is a semi-selective medium (V. parahemolyticus also grows on TCBS) and diagnosis is confirmed with vibrio 0 group 1 antiserum. There is no selective medium for ETEC. ETEC produces two enterotoxins, LT or ST, which can be assayed for by multiple techniques, none of which are available outside research laboratories. 163 There are multiple biologic assays available to assess for the presence of LT and ST that include injection of culture broths into ligated rabbit ileal loops with the degree and timing of fluid accumulation monitored. Alternatively, tissue culture assays particularly the Chinese hamster ovary (CHO) cell assay64 and mouse Yl adrenal ceIP 42 assay can detect the presence of enterotoxin while the suckling mouse assay is used for ST toxin. 34 Finally, other pathogens to consider in chronic diarrhea that may be missed during routine screening describe above include the nonvibrio vibrionaceae, Aeromonas hydrophili£3 and Plesiomonas shigelloides?4, 81 Both these pathogens can elicit cramps and diarrhea while Plesiomonas also causes colitis with stool PMNs in more than 50% of the infected patients?4 TREATMENT OPTIONS

After review of the patient's history, and preliminary laboratory findings the physician is left with the decision to treat the patient or not and if so what is the best treatment modality. The options include fluid resuscitation alone or in combination with antimotility agents and/ or specific antimicrobial agents. Each modality will be reviewed in detail regarding indications and contraindications. Fluid Resuscitation

The cornerstone of diarrheal therapy regardless of its etiology is the replacement of the extracellular fluid deficit. Assessment of the fluid

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deficit is a clinical decision, quickly made at the bedside, and relies on evaluation of mositness of mucus membranes, skin tugor, sunken eyes presence of tachycardia, orthostatic hypotension and fluctuation in mental status together with the overall appearance of toxicity in the patient. No one specific laboratory test will predict the degree of fluid deficit but the best quantitative parameter is acute weight loss. Once a clinical decision is made on the degree of fluid deficit, the next decision is how best to replace the volume. The two main options include oral rehydration versus intravenous replacement therapy. Because of the magnitude of diarrhea worldwide, the World Health Organization (WHO) developed an oral rehydration formula that is inexpensive, easy to administer, effective in all types of diarrhea and in all age groupS.174 The WHO formula and all other oral rehydration formulas are based on the principal that carbohydrate absorption (particularly glucose) in the small bowel facilitates sodium and water reabsorption of fluid from the intestinal lumen into the intravascular compartment. 12,71 Oral rehydration should begin early, keeping in mind the need to replace the fluid deficit already present plus replacing losses from both continuing diarrhea and normal basal metabolic losses. The only contraindications to oral replacement would be in patients with uncontrolled vomiting, presence of an ileus or in patients with severe fluid deficit with toxicity. In those patients with contraindications, intravenous hydration is the alternative option. Intravenous rehydration has the advantage of adding supplemental potassium and sodium bicarbonate to the fluid if the clinical situation dictates, Table 2 lists the electrolyte composition of normal and diarrheal stools in comparison to various commercial oral and intravenous rehydration formulas. It should be noted that diarrheal fluid is high in sodium, potassium, and bicarbonate. The commercially available products Table 2. COMPARISON OF ELECTROLYTE CONTENT OF DIARRHEAL STOOLS VERSUS ELECTROLYTE CONTENT OF ORAL AND INTRAVENOUS REHYDRATION FLUIDS Electrolyte Content (mEq/L) Carbohydrate ----------------------------------Content K+ CLHC03Citrate (g/L) NA" Stools Normal 61 Diarrheal 102,131

32 53-124

Oral rehydration fluids WHO formula 90 Pedialyte RS 75 Pedialyte 45 Gatorade 23

75 16-37

16 24-90

20 20 20 <1

80 65 35 17

4

154 109

Intravenous rehydration fluids Normal saline 154 Ringers' lactate 130 'Equivalent from lactate conversion.

32 18-48 30 30 30

28'

20 25 25 40

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vary in their composition and some authors are concerned with the potential for hypernatremia in solutions containing 90 mEq/L of sodium. 51 , 129, 148 However, cumulative experience has demonstrated the safety and efficacy of these solutions.95 The rate of replacement varies depending on the severity of fluid deficit and the age of the patient. As a general guide, infants and children can receive up to 50 to 100 mL/kg over 4 to 6 hours. Adults may need to drink up to 1000 mL/h to control their fluid depletion. l31

Use of Antimotility Agents

Opiates and their new synthetic derviatives have been used to delay intestinal motility thereby decreasing the degree of diarrhea. Their mechanism of action is felt to be mediated through an increase in segmental contraction of circular muscles in the bowel wall thereby decreasing forward proplusion with prolongation of intestinal transit time. Their usefulness has been debated and may be counter productive in that they may delay clearance of the pathogen and/ or its toxin causing prolonged duration of illness. Their use is of heightened concern with enteroinvasive pathogens where the potential of increasing the extent of invasion into the epithelial mucosa, as reflected by a prolonged fever in patients with shigellosis, has been shown. 40 The development of toxic megacolon is a feared complication when used in patients with dysentery. Antimotility agents available include loperamide (Imodium), diphenoxylate (Lomotil), codeine, and paregoric, the former two being more commonly used today. Studies evaluating their efficacy are difficult to interpret in that these agents are used to treat individuals with diarrhea for whom the infectious agent was not identified (Le., acute nonspecific diarrhea) or in patients representing several distinctly different infectious agents. Loperamide was first marketed in 1977 with potential lack of eNS side effects and decreased addictive potential. Studies comparing lop eramide to diphenoxylate suggest loperamide has greater efficacy.43 Its safety record and lack of abuse potential allowed for its use as a nonprescription drug in 1988, Loperamide at low doses (0.2 mg/kg per day) was found to be no better than placebo treatment in a group of 100 children. 12o However, higher doses of 0.8 mg/kg per day in 30 children decreased the duration of diarrhea by 3.5 days and lowered daily stool outpUt. 37 This study pointed out potential precautions in the use of this agent in infants, in that it caused an ileus in one patient and drowsiness in four other children. Loperamide has also been shown to be useful in adults with travelers' diarrhea in comparison to bismuth subsalicylate by lessening the duration of unformed stools and a better overall subjective feeling of wellness?8 A general guideline is to limit their use to 48 hours and if diarrheal symptoms continue, to discontinue its use. 30

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Absorbent Agents in Diarrhea

Cholestyramine is a nonabsorbable quanternary chloride exchange resin. Its main use has been primarily in helping to lower serum cholesterol by binding bile acids in the intestine thereby interfering with absorption of cholesterol. Extensive clinical use has revealed it to cause constipation with bloating as a frequent side effect. Based on this finding it has been tried in intractable diarrhea of multiple etiologies and found to be effective. 9,99, 158 One caution found during clinical studies was the development of prolonged hyperchloremic metabolic acidosis. 150 To avoid this complication, it is recommended not to institute its use until after adequate oral rehydration has begun?7 In pseudomembranous colitis caused by C. difficile, cholestyramine is felt to be active by binding luminal C. difficile toxin thereby enhancing mucosal recovery and clearance of toxin. 19, 75, 89 After initiation of therapy with cholestyramine resin, the mean time to cessation of diarrhea was 2.1 days. Therapy is recommended for 5 days after cessation of diarrhea to prevent recurrence.89 Role of Antisecretory Agents

The gut peptide somatostatin and its synthetic analogs (octreotide and vapreotide) are very powerful inhibitors of intestinal secretion. They appear to inhibit intestinal secretion stimulated by calcium, cAMP, and cGMP and enhance water and electrolyte reabsorption. These agents have been utilized in controlling chronic diarrhea in AIDS-related diarrhea of unknown etiology or diarrhea caused by cryptosporidosis where no single or multiple microbial regimen has shown any efficacy. Octreotide has been shown to cause complete or partial response in 29 to 76% of AIDS diarrhea patients.2 1,46 In a similar study of 34 AIDS patients with chronic diarrhea, vapreotide showed a significantly better response in patients without cryptosporidosis than in those with the pathogen. 6o Role of Antibiotics

After the appropriate workup has begun, it may take several days to obtain the laboratory result of fecalleukocytes, stool cultures and an endoscopic evaluation of the distal colon. Therefore, one needs to begin a decision analysis as to the most likely enteric pathogen based on your current history and clinical assessment and decide if one should institute any antimicrobial therapy. The need for antimicrobial agents in infectious diarrhea depends on several factors to include (1) potential pathogen and (2) the patient's clinical course superimposed on his/hers underlying medical problem(s). The course of the infectious illness as assessed by the degree and duration of diarrhea, the degree of dehydration and patient toxicity will

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help guide one towards considering use of antimicrobial agents. Specifically, a patient who appears toxic or profoundly dehydrated without evidence of a self limited process will direct one more towards empiric treatment. Enteric pathogens that clearly need to be treated and have clinical studies to document efficacy include the bacterial pathogens Shigella, Cholera, Travelers' diarrhea and the protozoans Entamobea histolytca, Giardia, and Isospora belli. Table 3 lists the specific antimicrobial agents for each pathogen, their dosing schedules, plus an alternative agent in case of drug allergy with references to clinical trials demonstrating their efficacy. One should remember the efficacy of these agents depends on the geographic location and drug resistance profile of the various pathogens in those areas. It is generally agreed that the above pathogens should be treated in all patients; however, there is another group of enteric pathogens which can also be treated but the clinical indication for antimicrobial use is narrower. This group of pathogens include enteropathogenic E. coli, enterohemorrhagic E. coli, non typhoidal Salmonella, Campylobacter jejuni, and Yersinia enterocolitica. In epidemic outbreaks of infantile diarrhea caused by EPEe, there is limited data regarding usefulness of antimicrobial therapy.93 Most studies have small numbers and limited control. Mecillinam and TMP-SMZ in placebo controlled studies have been shown to be effective. 162 Other agents with some effectiveness include oral neomycin and oral gentamicin.26, 93, 109 EHEC is a pathogen that causes hemorrhagic colitis,138 There are no Table 3. ANTIMICROBIAL THERAPY FOR ACUTE INFECTIOUS DIARRHEA Pathogen

Bacterial Shigellosis Vibrio cholera Travelers' diarrhea C. difficile

Protozoan Entamoeba histolytica Giardia lamblia Isospora belli

Antimicrobial Agent

Dosage

Frequency (per day)

TMP-SMZ Ciprofloxacin Norfloxacin Tetracycline Doxycycline Ciprofloxacin ± loperamide TMP-SMZ ± loperamide Metronidazole Vancomycin (PO) Bacitracin

160 mg/800 mg 500 mg 800 mg 500 mg 300 mg 500 mg 4 mg 160 mg/800 mg 4mg 250 mg 125 to 250 mg 20,000 units

2 2 1 4 1 2

5 5 0 3

2

5

Metronidazole followed by lodoquinol Quinacrine Metronidazole TMP-SMX

750 mg

3

10

650 mg 100 mg 250mg 160 mg/800 mg

3 3 3 2

20 7 7 7 to 14

4 4 4

Days

5

Reference

8,62 144 133,156 170 39,41 44, 122 160

10 84, 161 5 to 10 176 7 140, 165 140 165 35

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available placebo-controlled therapeutic studies on this strain of pathogens but ampicillin and TMP-SMZ are felt to be effective.93, 162 Similarly, there are no therapeutic placebo-controlled clinical trials for enteroinvasive E. coli but the prevailing judgement is to treat these strains in the same fashion as shigellosis (Table 3) because of the similar virulence properties, pathogenicity, and clinical presentations.93 ,162 Treatment of nontyphoidal salmonellosis has only been recommended for infants less then 12 weeks of age. 135, 164 The reason for targeting this age group is the increased likelihood of developing a systemic infection secondary to Salmonella bacteremia (i.e., septic arthritis or meningitis).135, 164 Although multiple antibiotic trials have elevated clinical efficacy, none of these trials modified the clinical parameters of duration and severity of diarrhea nor the duration of fever.4,83 Gorbach has suggested widening the treatment parameters in selected patients whose underlying illnesses increase their risk of developing secondary complications (i.e., patients with lymphoproliferative disorders, malignancies, hemoglobinopathies, AIDS, bone or organ transplants, valvular heart disease, vascular grafts, artificial joints; patients who are immunosuppressed or taking steroids; and the extremely elderly).61 Bacteremia itself requires antimicrobiol therapy regardless of the presence of any other concurrent illness. The drug of choice today in adults is ciprofloxacin 500 mg twice a day for 7 days.97, 127 Alternative regimens include either ampicillin or chloramphenicaP26 Campylobacter jejuni has been increasingly recognized as a common pathogen throughout the world. 16, 153 Initial studies failed to shown clinical benefit but shortened the duration of fecal excretion of C. jejuni. 2 , 128, 173 Two studies using erythromycin (250 mg four times a day) for 7 days demonstrated clinical efficacy.11, 145 These studies were carried out in patients with dysenteric-like illness and earlier in the course of the infection. Ciprofloxacin with and without loperamide has been shown to clear C. jejuni diarrhea but clinical relapse and ciprofloxacin resistance have been reported. m, 127 Yersinia enterocolitica has a spectrum of illness from diarrhea and dysentery in infants to mesenteric lymphadenitis in adolescents to extraintestinal manifestations of arthritis, erythema nodosum in adults. The organism is sensitive to multiple antibiotics in vitro; however, there is no substantial evidence that antibiotics alter the course of gastrointestinal infections of this pathogen. 14, 119, 121 V. parahemolyticus and the two nonvibrio vibrionaceae Plesiomonas shigelloides and Aeromonas hydrophilia are acquired either though uncooked shellfish for the first two and untreated well water or brackish water for Aeromonas. There are no clear clinical placebo controlled studies documenting clinical efficacy of antimicrobial therapy. However, in vitro sensitivities and case controlled studies have shown success with tetracycline for V. paraphernolyticus,15 TMP-SMZ, norfloxacin, or tetracycline appears effective in Pleisomonas74 , 81 and TMP-SMZ is effective in Aero-

monas?3

Enteric pathogens that should not be treated include suspected viral agents (i.e., rotavirus or Norwalk agent) where no effective antiviral

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agents exist. Crpytosporidosis in AIDS patient has been a distinctly difficult pathogen to erradicate. No one study clearly demonstrates a good clinical response. Spiramycin,45, 130, 143 paromomycin,3 eflornithine139 have been tried without much success. Bovine hyperimmune colostrum against cryptosporidium has shown preliminary results indicating some efficacy in humans with AIDS111 as well as monoclonal antibody studies in an animal model. 48 DIFFERENTIAL DIAGNOSIS OF ACUTE DIARRHEA

Not every patient presenting with diarrhea has an infectious etiology and one must be cognizant of alternative diagnoses in each patient. Table 4 breaks down the differential diagnosis of acute diarrhea into two large subgroups, watery versus bloody diarrhea. The diagnosis of noninfectious, watery diarrhea relies heavily on ingestion of exogenous agents either in the form of medications, toxins or dietetic products. Hence a careful medication, diet and occupational history would be helpful in identifing an offending agent. Table 4 gives an extensive list of medications that are designed either to loosen stools or agents whose side effect profile includes diarrhea. Many of these agents are commonly used in clinical practice to control common diseases like hypertension (diuretics), asthma (theophylline), and cardiac dysrhythmias (quinidine). Obese patients or patients with anorexic nervosa consuming large quantities of nonabsorbable carbohydrates such as sorbitol may experience osmotic diarrhea. An occupational history may identify industrial or farm exposure to insecticides (organophosphates) Table 4. DIFFERENTIAL DIAGNOSIS OF ACUTE DIARRHEA Acute watery diarrhea Medications Laxatives-Iactulose, polyethylene glycol purge, caster oil, milk of magnesia, magnesium citrate, phenolphthalein, senna, bisacodyl Cardiac-quinidine Gout-<:olchicine Diuretic-furosemide, thiazides Miscellaneous-theophylline, misoprostal, gold, mesalamine, anticholinesterase inhibitors, antacids Toxins-Arsenic, organophosphates, insecticides, mushroom (Amanita phalloides) Dietetic products-Sorbitol, mannitol, xylitol, diet colas, caffeine, methylxanthines Endocrine-Thyrotoxicosis Acute bloody diarrhea Inflammatory bowel disease-ulcerative colitis, Crohn's disease Intestinal ischemia Arterial embolism or thrombosis Venous thrombosis Nonocclusive mesenteric ischemia Bowel strangulation (predominantly venous) Drug induced injury-Gold and methyldopa

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or toxic metals (arsenic). The avocation of mushroom picking may increase the chance of ingestion of toxin from Amanita phalloides. The differential diagnosis for bloody diarrhea is narrower. The major consideration is to rule out inflammatory bowel disease either as the initial presentation of the illness or a recurrent flare that should be suspected given a patient's past medical history. In elderly patients with severe peripheral vascular disease, coronary artery disease, or atrial fibrillation, mesenteric ischemia is always possible. Vascular emboli or thrombosis formation can compromise the mesenteric vascular supply causing abdominal pain and bloody stools. A history of intestinal angina is suggestive of this origin. Also any volvulus (i.e., sigmoid) can cause ischemia to the colon and with subsequent bloody stools. Finally, gold and methyldopa have been implicated in causing bloody diarrhea. The mechanism is not clear, the incidence is very low but the endoscopic and histologic pattern is identical to ulcerative colitis. SUMMARY

Diarrhea continues to be a major cause of mortality and morbidity in third world countries as well as a major symptomatic complaint in the primary care setting in the United States. The etiologic pathogen depends on an exposure history to include recent travel to foreign countries, consuming fecally contaminated water or food, prior use of antibiotics, or homosexual behavior. A careful history from patients directed at attempting to identify particular risk factors may help in making a diagnosis. Not all patients require a diagnostic workup. A large number of patients may only require oral rehydration, careful observation over time with or without use of antimotility agents. In toxic appearing patients or patients with fever, however, bloody stools, abdominal pain or tenesmus, a selective diagnostic workup is indicated. Antimicrobial treatments are not always required, some pathogens clearly call for treatment while some have less clear indications and other pathogens are not responsive to antimicrobial agents at all. Finally, one needs to remember that the differential diagnosis of acute diarrhea includes many noninfectious origins. References 1. Acheson DW: Enterotoxins in acute infective diarrhea. J Infect 24:225, 1992 2. Anders BJ, Lauer BA, Paisley JW, et a1: Double-blind placebo controlled trial of erythromycin for treatment of Campylobacter enteritis. Lancet 1:131, 1982 3. Armitage K, Flanigan T, Carey J, et al: Treatment of cryptosporidiosis with paromomycin. A report of five cases. Arch Intern Med 152:2497, 1992 4. Aserkoff B, Bennet JV: Effect of antibiotic therapy in acute salmonellosis on the fecal excretion of Salmonellae. N Engl J Med 281:636, 1969 5. Baldini MM, Kaper JB, Levine MM, et al: Plasmid-mediated adhesion in enteropathogenic Escherichia coli. J Pediatr Gastroenterol Nutr 2:534, 1983

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6. Bartlett AV, Moore M, Gary GW, et al: Diarrheal illness among infants and toddlers in day care centers. l. Epidemiology and pathogens. J Pediatr 107:495, 1985 7. Bender SB, Bennett R, Laughon BE, et al: Is Clostridium difficile endemic in chronic-care facilities? Lancet 11:11, 1986 8. Bennish ML, Salam MA, Haider R, et al: Therapy for shigellosis. H. Randomized double-blind comparison of ciprofloxacin and ampicillin. J Infect Dis 162:711, 1990 9. Berant M, Wagner Y, Cohen N: Cholestyramine in the management of infantile diarrhea. J Pediatr 88:153,1977 10. Bernardini ML, Mounier I, d'Hauteville H, et al: Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra- and intercellular spread through interaction with F-actin. Proc Natl Acad Sci USA 86:38-67, 1989 11. Bichile LS, Saraswati K, Popat UR, et al: Acute Campylobacter jejuni enteritis in 385 hospitalized patients. J Assoc Physicians India 40:164, 1992 12. Binder HJ: Sodium transport across isolated human jejunum. Gastroenterology 67:231, 1974 13. Black RE: Epidemiology of Travelers' diarrhea and relative importance of various pathogens. Rev Infect Dis 12:573, 1990 14. Black RE, Jackson RJ, Tsai T, et al: Epidemic Yersinia enterocolitica infection due to contaminated chocolate milk. N Engl J Med 298:76, 1978 15. Blake PA: Vibrios on the half shell: What the walrus and the carpenter didn't know. Ann Intern Med 99:558, 1983 16. Blaser MJ, Wells JG, Feldman RA, et al: Campylobacter enteritis in the United States. A multicenter study. Ann Intern Med 98:360,1983 17. Bloom HG, Bottone EJ: Aeromonas hydrophila diarrhea in a long-term care setting. J Am Geriatr Soc 38:804,1990 18. Brown JE, Griffin DE, Rothman SW, et al: Purification and biological characterization of Shiga toxin from Shigella dysenteriae 1. Infect Immun 36:996,1982 19. Burbige El, Milligan FD: Pseudomembranous colitis. Association with antibiotics and therapy with cholestyramine. JAMA 231:1157,1975 20. Cantey JR: Infectious diarrhea. Pathogenesis and Risk Factors. Am J Med 78(suppl 6B):65,1985 21. Cello JP, Grendell JH, Basuk P, et al: Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trail. Ann Intern Med 115:705, 1991 22. Chang TW, Lauermann M, Bartlett JG: Cytotoxicity assay in antibiotic-associated colitis. J Infect Dis 140:765, 1979 23. Cleary TG, Mathewson JJ, Faris E, et al: Shiga-like cytotoxin production by enteropathogenic Escherichia coli serogroups. Infect Immun 47:335,1985 24. Clements JD, Finkelstein RA: Isolation and characterization of homogenous heat-labile enterotoxins with high specific activity from Escherichia coli cultures. Infect Immun 24:760, 1979 25. Clerc P, Sansonetti PJ: Entry of Shigella flexneri into HeLa Cells: Evidence for directed phagocytosis involving actin polymerization and myosin accumulation. Infect Immun 55:2681, 1987 26. Coetzee M, Leary PM: Gentamicin in Escherichia coli gastroenteritis. Arch Dis Child 46:646,1971 27. Cohen MB: Etiology and mechanisms of acute infectious diarrhea in infants in the United States. J Pediatr 118:S34, 1991 28. Cohen MB, Mann EA, Lau C, et al: A gradient in expression of the Escherichia coli heat-stable enterotoxin receptor exists along the villus-to-crypt axis or rat small intestine. Biochem Biophys Res Commun 186:483, 1992 29. Consensus Conference: Travelers' diarrhea. JAMA 253:2700, 1985 30. Consensus development conference statement. Rev Infect Dis 8:5227, 1986 31. Cubitt WD, Holzel H: An outbreak of rota virus infection in a long-stay ward of a geriatric hospital. J Clin Pathol 33:306, 1980 32. Cubitt WD, Pead PI, Saeed AA: A new serotype of calicivirus associated with an outbreak of gastroenteritis in a residential home for the elderly. J Clin Pathol 34:924, 1981 33. Dallas WS, Falkow S: Amino acid sequence homology between cholera toxin and Escherichia coli heat-labile toxin. Nature 288:499, 1980

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34. Dean AG, Ching Y, Williams RG, et al: Test for Escherichia coli enterotoxin using infant mice application in a study of diarrhea in children in Honolulu. J Infect Dis 125:407, 1972 35. DeHovitz JA, Page JW, Boney M, et al: Clinical manifestations and therapy of Isospora belli infection in patients with the acquired immunodeficiency syndrome. N Engl J Med 315:87, 1986 36. de Sauvage FJ, Camerato TR, Goeddel DV: Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin. J Bioi Chem 266:17912,1991 37. Diarrhoeal Diseases Study Group: Loperamide in acute diarrhoea in childhood: Results of a double blind, placebo controlled multicentre clinical trial. Br Med J 289:1263, 1984 38. Donnenberg MS, Kaper JB: Enteropathogenic Escherichia coli. Infect Immun 60:39-53, 1992 39. Dupont HL, Corrado ML, Sabbaj J: Use of norfloxacin in the treatment of acute diarrheal disease. Am J Med 82(suppI6B):79, 1987 40. Dupont HL, Hornick RB: Adverse effect of lomotil therapy in shigellosis. JAMA 226:1525, 1973 41. Dupont HL, Reves RR, Galindo E, et al: Treatment of travelers' diarrhea with trimethoprim/suJfamethoxazole and with trimethoprim alone. N Engl J Med 307:841,1982 42. Endo Y, Tsurugi K, Yutsudo T, et al: Site of action of a Vero toxin (VT2) from Escherichia coli 0157:H7 and of Shiga toxin on eukaryotic ribosomes. Eur J Biochem 171:45, 1988 43. Ericsson CD, Johnson PC: Safety and efficacy of loperamide. Am J Med 88(suppl 6A):SlO,1990 44. Ericsson CD, Johnson PC, Dupont HL, et al: Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea. A placebo-controlled, randomized trial. Ann Intern Med 106:216, 1987 45. Fafard J, Lalonde R: Long-standing symptomatic cryptosporidiosis in a normal man: Clinical response to spiramycin. J Clin GastroenteroI12:190, 1990 46. Fanning M, Monte M, Sutherland LR, et al: Pilot study of sandostatin (octreotide) therapy of refractory HIV-associated diarrhea. Dig Dis Sci 36:476,1991 47. Farber BF, Brennen C, Puntereri AJ, et al: A prospective study of nosocomial infections in a chronic care facility. J Am Geriatr Soc 32:499, 1984 48. Fayer R, Guidry A, Blagburn BL: Immunotherapeutic efficacy of bovine colostral immunoglobulins form a hyperimmunized cow against cryptosporidiosis in neonatal mice. Infect Immun 58:2962, 1990 49. Field M: Model of action of enterotoxins from Vibrio cholerae and Escherichia coli. Rev Infect Dis 1:918, 1979 50. Field M, Graf LH, Laird WJ, et al: Heat stable enterotoxin of Escherichia coli. In vitro effects on guanylate cyclase activity, cyclic GMP concentration and ion transport. Proc Natl Acad Sci USA 75:2800, 1978 51. Finberg L, Harper P A, Harrison HE, et al: Oral rehydration for diarrhea. J Pediatr 101:497, 1982 52. Fishman PH, Moss J, Osborne CJ: Interaction of choleragen with the oligosaccharide of ganglioside GM1: Evidence for multiple oligosaccharide binding sites. Biochemistry 17:711,1978 53. Formal SB, Dammin GJ, LaBrec EH, et al: Experimental Shigella infections: characteristics of a fatal infection produced in guinea pigs. J Bacteriol 75:604, 1958 54. Forsyth GW, Hamilton DL, Goertz KE, et al: Cholera toxin effects on fluid secretion, adenylate cyclase, and cyclic AMP in porcine small intestine. Infect Immun 21:373, 1978 55. Gaastra W, DeGraaf FK: Host-specific fimbrial adhesins of noninvasive enterotoxigenic Escherichia coli strains. Microbiol Rev 46:129, 1982 56. Garthright WE, Archer OL, Kvenberg JE: Estimates of incidence and costs of intestinal infectious diseases in the United States. Public Health Reports 103:107, 1988 57. Giannella RA: Chronic diarrhea in travelers: Diagnostic and therapeutic considerations. Rev Infect Dis 8:S223, 1986 58. Giannella RA, Drake KW: Effect of purified Escherichia coli heat-stable enterotoxin on intestinal cyclic nucleotide metabolism and fluid secretion. Infect Immun 24:19,1979

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59. Gill OM, Meren R: ADP-ribosylation of membrane proteins catalyzed by cholera toxin: Basis of the activation of adenylate cyclase. Proc Natl Acad Sci 75:3050, 1978 60. Girard PM, Goldschmidt E, Vittecoq 0, et al: Vapreotide, a somatostatin analogue, in cryptosporidiosis and other AIDS-related diarrhoeal diseases. AIDS 6:715, 1992 61. Gorbach SL: Bacterial diarrhoea and its treatment. Lancet II:1378, 1987 62. Gotuzzo E, Oberhelman RA, Maguina C, et al: Comparison of single-dose treatment with norfloxacin and standard 5-day treatment with trimethoprim-sulfamethoxazole for acute shigellosis in adults. Antimicrob Agents Chemother 33:1101,1989 63. Greenson JK, Belitsos PC, Yardley JH, et al: AIDS enteropathy: Occult enteric infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med 114:366, 1991 64. Guerrant RL, Brunton LL, Schnaitman TC, et al: Cyclic adensosine monophosphate and alteration of the Chinese hamster ovary cell morphology: A rapid sensitive in vitro assay for enterotoxins of Vibrio cholerae and Escherichia coli. Infect Immun 10:320, 1974 65. Guerrant RL, Hughes JM, Lima NL, et al: Diarrhea in developed and developing countries: Magnitude, special settings and etiologies. Rev Infect Dis 12:541, 1990 66. Guerrant RL, Lohr JA, Williams EK: Acute infectious diarrhea. I. Epidemiology, etiology and pathogenesis. Pediatr Infect Dis 5:353,1986 67. Guerrant RL, Shields OS, Thorson SM, et al: Evaluation of diagnosis of acute infectious diarrhea. Am J Med 78(suppI6B):91, 1985 68. Haldane DJ, Damm MA, Anderson JD: Improved biochemical screening procedure for small clinical laboratories for Vero (Shiga-like)-toxin producing strains of Escherichia coli 0157:H7. J Clin MicrobioI24:652, 1986 69. Hale TL: Genetic basis of virulence in Shigella species. Microbiol Rev 55:206, 1991 70. Hale TL, Oaks EV, Formal SB: Identification and antigenic characterization of virulence-associated, plasmid-coded proteins of Shigella spp. and enteroinvasive Escherichia coli. Infect Immun 50:620,1985 71. Hirschhorn N, Kinzie JL, Sachar DB, et al: Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. N Engl J Med 279:176, 1968 72. Ho MS, Glass RI, Pinsky PF, et al: Diarrheal deaths in American children. Are they preventable? JAMA 260:3281,1988 73. Holmberg SO, Schell WL, Fanning GR, et al: Aeromonas intestinal infections in the United States. Ann Intern Med 105:683, 1986 74. Holmberg SO, Wachsmuth IK, Hickman-Brenner FW, et al: Plesiomonas enteric infections in the United States. Ann Intern Med 105:690, 1986 75. Humphrey CD, Condon CW, Cantey JR, et al: Partial purification of a toxin found in hamsters with antibiotic associated colitis (ACC): Reversible binding of the toxin by cholestyramine. Gastroenterology 74:1046,1978 76. Hyams KC, Bourgeois AL, Merrell BR, et al: Diarrheal disease during operation desert shield. N Engl J Med 325:1423,1991 77. Isolauri E, Vesikari T: Oral rehydration, rapid feeding, and cholestyramine treatment of acute diarrhea. J Pediatr Gastroenterol Nutr 4:366,1985 78. Johnson PC, Ericsson CD, DuPont HL, et al: Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA 255:757, 1986 79. Jones GW, Rabert OK, Svinarich OM, et al: Association of adhesive, invasive, and virulent phenotypes of Salmonella typhimurium with autonomous 60 megadalton plasmids. Infect Immun 38:476,1982 80. Jones GW, Rutter JM: Role of K88 antigen in the pathogenesis of neonatal diarrhea caused by Escherichia coli in piglets. Infect Immun 6:918, 1972 81. Kain KC, Kelly MT: Clinical features, epidemiology, and treatment of Plesiomonas shigelloides diarrhea. J Clin Microbiol 27:998, 1989 82. Karmali MA: Infection by verocytotoxin-producing Escherichia coli. Clin Microbiol Rev 2:15,1989 83. Kazemi M, Gumpert TG, Marks MI: A controlled trial comparing sulfamethoxazoletrimethoprim, ampicillin, and no therapy in the treatment of Salmonella gastroenteritis in children. J Pediatr 83:646, 1973 84. Keighley MR, Burdon DW, Arabi Y, et al: Randomised controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhoea. Br Med J II:1667, 1978

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