Acute Infectious Diarrhea
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《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
An otherwise healthy 23-year-old man presents after the acute onset of watery diarrhea that has persisted for two days. He reports associated nausea and cramping but no emesis and is febrile, with a temperature of 38.7°C (101.7°F). How should he be evaluated and treated?
The Clinical Problem
Despite reductions in mortality worldwide, diarrhea still accounts for more than 2 million deaths annually1 and is associated with impaired physical and cognitive development in resource-limited countries.2 In the United States, an estimated 211 million to 375 million episodes of acute diarrhea occur each year (1.4 episodes per person per year); such episodes are responsible for more than 900,000 hospitalizations and 6000 deaths annually.3,4
Acute diarrhea, defined as an increased frequency of defecation (three or more times per day or at least 200 g of stool per day) lasting less than 14 days, may be accompanied by nausea, vomiting, abdominal cramping, clinically significant systemic symptoms, or malnutrition. We focus here on acute infectious diarrhea in immunocompetent adults in industrialized countries.
Strategies and Evidence
Microbiology
The Foodborne Diseases Active Surveillance Network (FoodNet) of the Centers for Disease Control and Prevention (CDC) collects data on the incidence of diarrhea attributable to nine enteropathogens in 13 percent of the U.S. population (37.4 million people) living in nine states. Of these, the pathogens responsible for the most cases of diarrhea in 2002 were salmonella (16.1 cases per 100,000 population), campylobacter (13.4 cases per 100,000 population), shigella (10.3 cases per 100,000 population), Escherichia coli O157:H7 (1.7 cases per 100,000 population), and cryptosporidium (1.4 cases per 100,000 population); vibrio, yersinia, listeria, and cyclospora were reported in fewer than 1 person per 100,000.5 Other enteropathogens for which diagnostic testing is readily available include Clostridium difficile, giardia, rotavirus, and Entamoeba histolytica. Additional agents of infectious diarrhea for which clinical diagnostic testing is not routinely available include enterotoxigenic, enteropathogenic, enteroaggregative, and enteroinvasive strains of E. coli, toxin-producing Clostridium perfringens, Staphylococcus aureus, Bacillus cereus, and noroviruses.
Evaluation
Thorough clinical evaluation of a patient who presents with acute diarrhea is essential in order to guide a cost-effective, evidence-based approach to initial diagnostic testing and therapy. In six studies conducted between 1980 and 1997, the diagnostic yield of stool cultures ranged from 1.5 to 5.6 percent.6 The estimated cost of $952 to $1,200 per positive culture can be reduced through improved selection and testing of the specimens submitted. As is indicated in Figure 1, the initial clinical evaluation of the patient with acute diarrhea should focus on the assessment of the severity of the illness, the need for rehydration, and the identification of likely causes on the basis of the history and clinical findings.
Figure 1. Approach to the Evaluation and Management of Infectious Diarrhea.
To assess dehydration, note the general appearance and alertness of the patient, the pulse, the blood pressure, the presence or absence of postural hypotension, the mucous membranes and tears, sunken eyes, skin turgor, capillary refill, and jugular venous pressure. Rehydration is usually possible with oral rehydration solution: 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, 1.5 g of potassium chloride, and 20 g of glucose or glucose polymer (such as sucrose) in 1 liter of water provides a solution with 90 mM sodium, 20mM potassium, 80 mM chloride, 30 mM bicarbonate, and 111 mM glucose. Alternatively, one level teaspoon of table salt and eight level teaspoons of sugar per liter of water provide 86 mM sodium to which one cup of orange juice or two bananas can be added for potassium. Details on the clinical and epidemiologic features of diarrhea caused by common enteropathogens are provided in Table 1. Reporting requirements are available from the CDC (http://www.cdc.gov/epo/dphsi/phs/infdis.htm).
Because most diarrheal illnesses are self-limited or viral, and nearly half last less than one day,3 microbiologic investigation is usually unnecessary for patients who present within 24 hours after the onset of diarrhea, unless such patients are dehydrated or febrile or have blood or pus in their stool. The characteristics of the illness, the epidemiologic setting, and the public health implications help to determine whether and what types of fecal testing are appropriate. The major epidemiologic and clinical features associated with common enteropathogens are listed in Table 1.
Table 1. Epidemiologic Settings and Clinical Features of Infection with Selected Diarrheal Pathogens.
In the United States, most diarrheal illnesses occur during the winter months; these illnesses are commonly associated with noroviruses (in families and in outbreaks, including those in nursing homes)7 or rotaviruses (in young children). Since these illnesses are typically short-lived (lasting one to three days) and self-limited, supportive fluid therapy is usually sufficient. Systemic illness, fever, or bloody stools should prompt routine stool testing for salmonella, shigella, campylobacter, and (especially if there are bloody stools) Shiga toxin–producing E. coli. When diarrhea is persistent or recurring, or if the history (for instance, of fever or tenesmus) is equivocal, fecal testing by means of microscopy for polymorphonuclear leukocytes or by means of immunoassay for the neutrophil marker lactoferrin can quickly provide additional laboratory evidence to support a presumptive diagnosis of inflammatory diarrhea.
In equivocal cases, the negative predictive value of fecal lactoferrin testing may help to determine the need for routine bacteriologic culture for campylobacter, salmonella, and shigella.8 In developed countries, the sensitivity and specificity of fecal leukocytes for inflammatory diarrhea are 0.73 and 0.84, respectively, and the sensitivity and specificity of lactoferrin for inflammatory diarrhea are 0.92 and 0.79, respectively; in resource-poor countries, the ranges are broader.9
Other testing is necessary in special circumstances (Figure 1). In patients who present with an acute onset of bloody diarrhea (especially without fever) or the hemolytic–uremic syndrome, fecal testing for Shiga toxin should be performed, along with cultures for E. coli O157:H7. Bloody diarrhea in recent immigrants or travelers returning from regions where E. histolytica is endemic (such as tropical Africa, Asia, or Latin America) should also prompt fecal testing for that pathogen.10 A report by a patient of recent ingestion of shellfish should prompt special cultures for vibrio species. Persistent abdominal pain, fever, mesenteric adenitis, erythema nodosum, or other immunologic manifestations may suggest Yersinia enterocolitica or Y. pseudotuberculosis, culture for which is enhanced by cold enrichment.
The microbiologic evaluation of hospitalized patients or those with recent exposure to antibiotics in whom diarrhea develops should focus on the diagnosis of toxigenic C. difficile,11 the most common recognized cause of nosocomial diarrhea. Testing for other pathogens in patients who have been hospitalized for more than 72 hours is discouraged, except in an outbreak or in patients 65 years of age or older with preexisting medical conditions, patients with human immunodeficiency virus (HIV) infection, patients with neutropenia, and patients with suspected systemic spread of enteric infection.12
Exposure of a traveler or hiker to untreated water and illnesses that persist for more than seven days should prompt evaluations for protozoal pathogens, especially giardia and cryptosporidium. The testing of one or two specimens by means of enzyme immunoassay has a sensitivity of more than 95 percent and is considerably better than older methods based on microscopical examinations. Less common but readily treatable protozoal causes of persistent diarrhea in normal or immunocompromised persons include Cyclospora cayetanensis and Isospora belli (which can be identified by means of acid-fast staining of stool specimens). In patients with advanced HIV disease, especially those who have fewer than 50 CD4+ lymphocytes per cubic millimeter, stool studies for cryptosporidium, microsporidia, cyclospora, and isospora and blood cultures or biopsies for Mycobacterium avium complex and cytomegalovirus should be considered.13 Fecal evidence of inflammation in persistent diarrhea should arouse concern about inflammatory bowel disease,14 particularly if the presence of a treatable inflammatory pathogen such as shigella, salmonella, campylobacter, C. difficile, or E. histolytica has been ruled out.
Approaches to Therapy
Rehydration and Nutrition
Regardless of the causative agent, initial therapy should include rehydration. Unless the patient is comatose or severely dehydrated, oral rehydration with a glucose-based electrolyte solution is preferred. The standard formulation recommended by the World Health Organization (WHO) or a newer reduced-osmolarity formula for children can be lifesaving in resource-poor regions and is valuable in the industrialized world for infants, the elderly, immunocompromised patients, and anyone with profuse watery diarrhea (information is available on the Web at http://www.who.int/child-adolescent-health/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_01.22.htm). Most adults in developed countries who have acute diarrhea, including travelers, should be encouraged to drink fluids and take in salt in soups and salted crackers. Nutritional support with continued feeding improves outcomes in children. The use of a "BRAT" diet (bananas, rice, applesauce, and toast) with avoidance of milk products (since a transient lactase deficiency may occur) is commonly recommended, although supporting data are limited.15
Nonspecific Symptomatic Therapy
Nearly 400 over-the-counter products are promoted in the United States for their antidiarrheal properties, but few have been demonstrated to be effective in randomized, controlled trials. Only in the cases of loperamide, bismuth subsalicylate, and kaolin has sufficient evidence of efficacy and safety been collected to permit labeling as an antidiarrheal agent.16
Loperamide, the antimotility agent of choice for adults, inhibits intestinal peristalsis and has antisecretory properties, but unlike other opiates (such as codeine, diphenoxylate, and paregoric), it does not penetrate the nervous system and has no substantial potential for addiction.17 When it is used with antibiotics for traveler's diarrhea18 or bacillary dysentery,19 it may reduce the duration of diarrhea by as much as one day. Because antimotility agents have been implicated in prolonged fever in human volunteers with shigellosis,20 toxic megacolon in patients with C. difficile infection, and the hemolytic–uremic syndrome in children infected with Shiga toxin–producing E. coli,21 these agents should be avoided in patients with bloody diarrhea or suspected inflammatory diarrhea.
Although it has not been as effective as loperamide in direct comparisons,22 bismuth subsalicylate can alleviate stool output in children23 or the symptoms of diarrhea, nausea, and abdominal pain in patients with traveler's diarrhea.24 Bismuth subsalicylate significantly decreased the median duration of experimental norovirus illness from 27 hours to 20 hours.25 There are insufficient data from clinical trials to support the use of adsorbents such as kaolin–pectin, activated charcoal, and attapulgite. Given the limited scientific evidence, limited clinical benefit, and concern about the toxicity of antidiarrheal agents, pediatric guidelines discourage their use in children.26,27
Antimicrobial Therapy
Whereas appropriate antibiotics are effective in the treatment of shigellosis, traveler's diarrhea, C. difficile–associated diarrhea, and, if given early, campylobacteriosis, antibiotics may prolong the duration of shedding of salmonella28 or C. difficile29 and may increase the risk of life-threatening complications of Shiga toxin–producing E. coli infection.30 The clinical benefit should be weighed against the cost, the risk of adverse reactions, and the risk of harmful eradication of normal flora or the induction of Shiga-toxin production.31 Antibiotic therapies for specific pathogens are listed in Table 2.
Table 2. Antimicrobial Recommendations for Infections with Specific Pathogens.
Community-Acquired Pathogens
Randomized, controlled trials in patients with shigellosis have demonstrated that appropriate antimicrobial therapy shortens the average duration of diarrhea by 2.4 days or more, decreases the duration of fever and tenesmus, and reduces the excretion of infectious organisms.32,33 Antimicrobial therapy is of greatest benefit when it is started early, and it probably reduces person-to-person spread. Increased resistance now limits the effectiveness of trimethoprim–sulfamethoxazole, ampicillin, and nalidixic acid, which were once considered optimal therapies for shigellosis. Clinical trials have established the efficacy of newer fluoroquinolones for adults with shigellosis,33,34 and accumulating data suggest that ciprofloxacin is also safe and effective in children with shigellosis.35
In immunocompetent patients with campylobacteriosis, erythromycin reduces carriage of the organism but reduces diarrhea only when it is given within four days after the onset of symptoms.36,37 Immunocompromised patients (particularly those who have the acquired immunodeficiency syndrome and those who are pregnant, who have an increased risk of complications of campylobacter infection) and patients with severe, prolonged, or relapsing illness may benefit from antimicrobial therapy. Dramatic increases in the rate of fluoroquinolone resistance (contemporaneous with the widespread use of fluoroquinolones in poultry feeds) now limit the usefulness of these agents in campylobacter infections.38
In uncomplicated salmonella gastroenteritis, antibiotics are not recommended, since they typically do not alleviate the diarrhea39 and have been associated with prolonged carriage28 and even relapse.40 However, because bacteremia occurs in 2 to 4 percent of patients, persons who are at increased risk for dissemination or metastatic seeding should receive antibiotics. These patients include those 12 months of age or younger and those older than 50 years; those with lymphoproliferative disorders, cancer, hemoglobinopathies, or AIDS; transplant recipients; patients with vascular grafts, artificial joints, degenerative joint diseases, or valvular heart disease; and patients who are taking corticosteroids.
Clues to the diagnosis of Shiga toxin–producing E. coli infection include bloody diarrhea (especially if the patient is afebrile) and a history of eating rare hamburger meat or seed sprouts. Given the concern that antimicrobial agents such as trimethoprim–sulfamethoxazole and quinolones induce Shiga-toxin production31 and may increase the risk of the hemolytic–uremic syndrome,30 patients with suspected or documented infection with Shiga toxin–producing E. coli should receive supportive care. Risk factors for the development of the hemolytic–uremic syndrome with this infection remain controversial and are incompletely understood.41
Empirical Antibiotic Treatment for Community-Acquired Illness
Empirical antibiotic treatment in adults who present with severe, community-acquired diarrhea (Table 3) reduces the average duration of illness by one to two days.28,42,43 However, as noted above, the potential benefits must be weighed against the potential harm, such as prolonged fecal shedding of certain pathogens, the increased risk of relapse, and the increased risk of complications. In patients who have evidence of inflammatory diarrhea (fever, tenesmus, dysentery, or fecal leukocytes or lactoferrin) and in whom diarrhea is not thought to be attributable to Shiga toxin–producing E. coli or fluoroquinolone-resistant campylobacter, empirical treatment with an agent such as a fluoroquinolone antibiotic (or for children, trimethoprim–sulfamethoxazole), pending fecal testing, is reasonable.6,44 Given the increasing incidence of fluoroquinolone-resistant campylobacter,38,45 empirical therapy in immunocompromised or severely ill patients or travelers with inflammatory diarrhea (especially those who have traveled to southern Asia, where the rate of quinolone resistance exceeds 80 percent) might include erythromycin or azithromycin.
Table 3. Considerations for Empirical Antimicrobial Therapy for Infectious Diarrhea.
Traveler's Diarrhea
Although most cases of traveler's diarrhea are self-limited, several clinical trials have demonstrated that fluoroquinolones or other agents — many of which are no longer used because of increased resistance — reduce the duration of diarrhea from three or four days to one or two days with as little as a single dose.46 Although such data support a recommendation that travelers carry appropriate antibiotics for the self-treatment of diarrhea, most experts do not recommend antimicrobial prophylaxis for travelers (even those who are immunocompromised, whose highest risk may be for infection with pathogens that are not covered by the standard antimicrobial agents used). Use of bismuth subsalicylate (one to two 262-mg tablets taken four times daily) decreases the incidence of traveler's diarrhea by 35 to 65 percent and appears to be safe when used for up to three weeks but may result in the blackening of the tongue and the stools.47,48
Nosocomial Diarrhea
The treatment of C. difficile–associated diarrhea has been discussed in detail previously.11 Many patients have improvement if therapy with broad-spectrum antibiotics can be discontinued. Oral metronidazole (which is less expensive) and oral vancomycin are effective in the treatment of C. difficile–associated diarrhea, with response rates of more than 90 percent and a mean time to improvement of three days, but relapses are common.11
Persistent Diarrhea
The protozoal pathogens that are most frequently associated with diarrhea that persists for more than 7 to 10 days, both in the United States and worldwide, are giardia and cryptosporidium. Giardia infections typically respond to metronidazole (the use of larger doses, if they are tolerated, may result in fewer treatment failures) or tinidazole. Cryptosporidium infection, in contrast, is notoriously difficult to treat, particularly in patients with AIDS and low CD4+ lymphocyte counts, in whom the most effective strategy is to facilitate immunologic reconstitution with optimal antiretroviral therapy.49 Nitazoxanide, which was recently approved by the Food and Drug Administration (FDA) for use in children, may reduce oocyst shedding and diminish diarrhea.50 Since these hardy oocysts are difficult to filter or to kill with chlorine, infections caused by them are best prevented by heating water or food to near-boiling temperatures. Finally, cyclospora infection, which can be detected by means of acid-fast staining of fecal specimens, is readily treated with trimethoprim–sulfamethoxazole.51,52
Areas of Uncertainty
The inability to determine the specific causative agent when a patient is first seen greatly complicates management. Technology that will permit rapid, pathogen-specific diagnostic testing could mitigate the inappropriate use of antibiotics, help to track sources and outbreaks, and identify resistant pathogens or fecal contamination of food or water. Whether certain antibiotics increase risk whereas others prevent the hemolytic–uremic syndrome in patients with Shiga toxin–producing E. coli infections remains controversial.30,41
Drugs such as calmodulin inhibitors, chloride-channel blockers, enkephalinase inhibitors, and agents that block prostaglandin-mediated pathways are under study as antisecretory agents; at present, their role remains uncertain. A poorly absorbed antibiotic, rifaximin, is effective in the treatment of traveler's diarrhea53 and may prove useful for other bacterial diarrheal illnesses but has not been approved by the FDA. Improved therapy must also address the repair of damaged or inflamed mucosa, since the associated reduction in absorptive function and resulting malnutrition may impair child development and potentially reduce the efficacy of therapies for associated diseases.
Guidelines
Several groups have published guidelines for the management of acute diarrhea in adults.6,44,54 The guidelines that the Infectious Diseases Society of America published in 2001, with which we still concur (available at http://www.idsociety.org), detail diagnostic strategies, treatment recommendations, and public health implications for adults, listing the quality and strength of evidence supporting each recommendation.6 Several pediatric guidelines emphasize fluid management and the fact that antidiarrheal compounds are not useful.26,27,55
Conclusions and Recommendations
In healthy patients with an acute onset of diarrhea, such as the patient described in the vignette, epidemiologic and clinical evaluation should be used to guide laboratory evaluation and management. For example, a recent history of eating raw oysters should prompt consideration and special culture for vibrio, and a recent history of antibiotic use should prompt testing for C. difficile toxin. Bloody diarrhea or a history of blood in the stool or of the ingestion of undercooked beef should prompt testing for Shiga toxin–producing E. coli; the presence of bloody diarrhea would also warrant testing for shigella, salmonella, and campylobacter. A history of immunocompromise, sickle cell disease, severe atherosclerosis, or intravascular prosthetic material should prompt the testing of blood and stool cultures for salmonella. Recent travel to a developing country would suggest infection with pathogens that typically cause traveler's diarrhea and would warrant empirical therapy with a single dose of a quinolone antibiotic (unless the travel was to southern Asia, which should arouse concern about infection with quinolone-resistant campylobacter). One might also consider empirical treatment for inflammatory diarrhea whose cause was suspected, on the basis of the exposure history, to be shigella or campylobacter infection (Table 2 and Table 3).
If none of the above pathogens were present, but symptoms worsened or persisted for more than five days (especially if there was fever), we would order a fecal examination for inflammation to direct further testing for invasive pathogens (including salmonella, shigella, campylobacter, C. difficile, or E. histolytica); if the examinations were negative for these pathogens, we would evaluate the patient for inflammatory bowel disease. Patients with illness lasting more than seven days should be tested for parasites (including giardia, cryptosporidium, cyclospora, and isospora). Finally, patients with recurrent or refractory giardiasis should be tested for possible immune compromise, such as immunoglobin A deficiency, and patients with refractory cryptosporidiosis, cyclosporiasis, or isosporiasis should be tested for HIV infection.
Drs. Thielman and Guerrant are named as coinventors on a patent held by the University of Virginia for the use of glutamine derivatives in oral rehydration therapy. Dr. Guerrant is named as a coinventor on a patent held by the University of Virginia for a fecal lactoferrin assay. Neither coinventor receives any patent royalties.
Source Information
From the Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, N.C. (N.M.T.); and the Department of Medicine, Division of Infectious Diseases and International Health and the Center for Global Health, University of Virginia School of Medicine, Charlottesville (R.L.G.).
Address reprint requests to Dr. Guerrant at the Center for Global Health, HSC #801379, University of Virginia School of Medicine, Charlottesville, VA 22908, or at rlg9a@virginia.edu.
References
Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003;81:197-204.
Guerrant RL, Kosek M, Lima AA, Lorntz B, Guyatt HL. Updating the DALYs for diarrhoeal disease. Trends Parasitol 2002;18:191-193.
Herikstad H, Yang S, Van Gilder TJ, et al. A population-based estimate of the burden of diarrhoeal illness in the United States: FoodNet, 1996-7. Epidemiol Infect 2002;129:9-17.
Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607-625.
Preliminary FoodNet data on the incidence of foodborne illnesses -- selected sites, United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:340-343.
Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331-351.
Norovirus activity -- United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:41-45.
Choi SW, Park CH, Silva TM, Zaenker EI, Guerrant RL. To culture or not to culture: fecal lactoferrin screening for inflammatory bacterial diarrhea. J Clin Microbiol 1996;34:928-932.
Gill CJ, Lau J, Gorbach SL, Hamer DH. Diagnostic accuracy of stool assays for inflammatory bacterial gastroenteritis in developed and resource-poor countries. Clin Infect Dis 2003;37:365-375.
Haque R, Huston CD, Hughes M, Houpt E, Petri WA Jr. Amebiasis. N Engl J Med 2003;348:1565-1573.
Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346:334-339.
Bauer TM, Lalvani A, Fehrenbach J, et al. Derivation and validation of guidelines for stool cultures for enteropathogenic bacteria other than Clostridium difficile in hospitalized adults. JAMA 2001;285:313-319.
Thielman NM, Guerrant RL. An algorithmic approach to the workup and management of HIV-related diarrhea. J Clin Outcomes Management 1997;4:36-47.
Fine KD, Ogunji F, George J, Niehaus MD, Guerrant RL. Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenterol 1998;93:1300-1305.
King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep 2003;52:1-16.
Food and Drug Administration. Antidiarrheal drug products for over-the-counter human use: final monograph: final rule. Fed Regist 2003;68:18869-18882.
DuPont HL, Flores Sanchez J, Ericsson CD, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med 1990;88:15S-19S.
Petruccelli BP, Murphy GS, Sanchez JL, et al. Treatment of traveler's diarrhea with ciprofloxacin and loperamide. J Infect Dis 1992;165:557-560.
Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118:582-586.
DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. JAMA 1973;226:1525-1528.
Cimolai N, Basalyga S, Mah DG, Morrison BJ, Carter JE. A continuing assessment of risk factors for the development of Escherichia coli O157:H7-associated hemolytic uremic syndrome. Clin Neprhol 1994;42:85-9.
Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA 1986;255:757-760.
Fugueroa-Quintanilla D, Salazar-Lindo E, Sack RB, et al. A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N Engl J Med 1993;328:1653-1658.
DuPont HL, Sullivan P, Pickering LK, Haynes G, Ackerman PB. Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university. Gastroenterology 1977;73:715-718.
Steinhoff MC, Douglas RG Jr, Greenberg HB, Callahan DR. Bismuth subsalicylate therapy of viral gastroenteritis. Gastroenterology 1980;78:1495-1499.
Armon K, Stephenson T, MacFaul R, Eccleston P, Werneke U. An evidence and consensus based guideline for acute diarrhoea management. Arch Dis Child 2001;85:132-142.
Murphy MS. Guidelines for managing acute gastroenteritis based on a systematic review of published research. Arch Dis Child 1998;79:279-284.
Wistrom J, Jertborn M, Ekwall E, et al. Empiric treatment of acute diarrheal disease with norfloxacin: a randomized, placebo-controlled study. Ann Intern Med 1992;117:202-208.
Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole: a randomized, placebo-controlled trial. Ann Intern Med 1992;117:297-302.
Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930-1936.
Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, Acheson DW. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis 2000;181:664-670.
Tong MJ, Martin DG, Cunningham JJ, Gunning JJ. Clinical and bacteriological evaluation of antibiotic treatment in shigellosis. JAMA 1970;214:1841-1844.
Bennish ML, Salam MA, Haider R, Barza M. Therapy for shigellosis. II. Randomized, double-blind comparison of ciprofloxacin and ampicillin. J Infect Dis 1990;162:711-716.
Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis. V. Comparison of azithromycin and ciprofloxacin: a double-blind, randomized, controlled trial. Ann Intern Med 1997;126:697-703.
Zimbabwe, Bangladesh, South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatr Infect Dis J 2002;21:1136-1141.
Salazar-Lindo E, Sack RB, Chea-Woo E, et al. Early treatment with erythromycin of Campylobacter jejuni-associated dysentery in children. J Pediatr 1986;109:355-360.
Anders BJ, Lauer BA, Paisley JW, Reller LB. Double-blind placebo controlled trial of erythromycin for treatment of Campylobacter enteritis. Lancet 1982;1:131-132.
Smith KE, Besser JM, Hedberg CW, et al. Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. N Engl J Med 1999;340:1525-1532.
Sanchez C, Garcia-Restoy E, Garau J, et al. Ciprofloxacin and trimethoprim-sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double-blind trial. J Infect Dis 1993;168:1304-1307.
Neill MA, Opal SM, Heelan J, et al. Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: experience during an outbreak in health care workers. Ann Intern Med 1991;114:195-199.
Safdar N, Said A, Gangnon RE, Maki DG. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA 2002;288:996-1001.
Dryden MS, Gabb RJ, Wright SK. Empirical treatment of severe acute community-acquired gastroenteritis with ciprofloxacin. Clin Infect Dis 1996;22:1019-1025.
Goodman LJ, Trenholme GM, Kaplan RL, et al. Empiric antimicrobial therapy of domestically acquired acute diarrhea in urban adults. Arch Intern Med 1990;150:541-546.
DuPont HL. Guidelines on acute infectious diarrhea in adults. Am J Gastroenterol 1997;92:1962-1975.
Nachamkin I, Ung H, Li M. Increasing fluoroquinolone resistance in Campylobacter jejuni, Pennsylvania, USA, 1982-2001. Emerg Infect Dis 2002;8:1501-1503.
Cheng AC, Thielman NM. Update on traveler's diarrhea. Curr Infect Dis Rep 2002;4:70-77.
DuPont HL, Ericsson CD, Johnson PC, Bitsura JA, DuPont WW, de la Cabada FJ. Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate. JAMA 1987;257:1347-1350.
Steffen R, DuPont HL, Heusser R, et al. Prevention of traveler's diarrhea by the tablet form of bismuth subsalicylate. Antimicrob Agents Chemother 1986;29:625-627.
Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998;351:256-261.
Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2001;184:103-106.
Pape JW, Verdier RI, Boncy M, Boncy J, Johnson WD Jr. Cyclospora infection in adults infected with HIV: clinical manifestations, treatment, and prophylaxis. Ann Intern Med 1994;121:654-657.
Verdier RI, Fitzgerald DW, Johnson WD Jr, Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients: a randomized, controlled trial. Ann Intern Med 2000;132:885-888.
Steffen R, Sack DA, Riopel L, et al. Therapy of travelers' diarrhea with rifaximin on various continents. Am J Gastroenterol 2003;98:1073-1078.
Manatsathit S, Dupont HL, Farthing M, et al. Guideline for the management of acute diarrhea in adults. J Gastroenterol Hepatol 2002;17:Suppl:S54-S71.
Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. The management of acute gastroenteritis in young children. Pediatrics 1996;97:424-435.(Nathan M. Thielman, M.D.,)
An otherwise healthy 23-year-old man presents after the acute onset of watery diarrhea that has persisted for two days. He reports associated nausea and cramping but no emesis and is febrile, with a temperature of 38.7°C (101.7°F). How should he be evaluated and treated?
The Clinical Problem
Despite reductions in mortality worldwide, diarrhea still accounts for more than 2 million deaths annually1 and is associated with impaired physical and cognitive development in resource-limited countries.2 In the United States, an estimated 211 million to 375 million episodes of acute diarrhea occur each year (1.4 episodes per person per year); such episodes are responsible for more than 900,000 hospitalizations and 6000 deaths annually.3,4
Acute diarrhea, defined as an increased frequency of defecation (three or more times per day or at least 200 g of stool per day) lasting less than 14 days, may be accompanied by nausea, vomiting, abdominal cramping, clinically significant systemic symptoms, or malnutrition. We focus here on acute infectious diarrhea in immunocompetent adults in industrialized countries.
Strategies and Evidence
Microbiology
The Foodborne Diseases Active Surveillance Network (FoodNet) of the Centers for Disease Control and Prevention (CDC) collects data on the incidence of diarrhea attributable to nine enteropathogens in 13 percent of the U.S. population (37.4 million people) living in nine states. Of these, the pathogens responsible for the most cases of diarrhea in 2002 were salmonella (16.1 cases per 100,000 population), campylobacter (13.4 cases per 100,000 population), shigella (10.3 cases per 100,000 population), Escherichia coli O157:H7 (1.7 cases per 100,000 population), and cryptosporidium (1.4 cases per 100,000 population); vibrio, yersinia, listeria, and cyclospora were reported in fewer than 1 person per 100,000.5 Other enteropathogens for which diagnostic testing is readily available include Clostridium difficile, giardia, rotavirus, and Entamoeba histolytica. Additional agents of infectious diarrhea for which clinical diagnostic testing is not routinely available include enterotoxigenic, enteropathogenic, enteroaggregative, and enteroinvasive strains of E. coli, toxin-producing Clostridium perfringens, Staphylococcus aureus, Bacillus cereus, and noroviruses.
Evaluation
Thorough clinical evaluation of a patient who presents with acute diarrhea is essential in order to guide a cost-effective, evidence-based approach to initial diagnostic testing and therapy. In six studies conducted between 1980 and 1997, the diagnostic yield of stool cultures ranged from 1.5 to 5.6 percent.6 The estimated cost of $952 to $1,200 per positive culture can be reduced through improved selection and testing of the specimens submitted. As is indicated in Figure 1, the initial clinical evaluation of the patient with acute diarrhea should focus on the assessment of the severity of the illness, the need for rehydration, and the identification of likely causes on the basis of the history and clinical findings.
Figure 1. Approach to the Evaluation and Management of Infectious Diarrhea.
To assess dehydration, note the general appearance and alertness of the patient, the pulse, the blood pressure, the presence or absence of postural hypotension, the mucous membranes and tears, sunken eyes, skin turgor, capillary refill, and jugular venous pressure. Rehydration is usually possible with oral rehydration solution: 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate, 1.5 g of potassium chloride, and 20 g of glucose or glucose polymer (such as sucrose) in 1 liter of water provides a solution with 90 mM sodium, 20mM potassium, 80 mM chloride, 30 mM bicarbonate, and 111 mM glucose. Alternatively, one level teaspoon of table salt and eight level teaspoons of sugar per liter of water provide 86 mM sodium to which one cup of orange juice or two bananas can be added for potassium. Details on the clinical and epidemiologic features of diarrhea caused by common enteropathogens are provided in Table 1. Reporting requirements are available from the CDC (http://www.cdc.gov/epo/dphsi/phs/infdis.htm).
Because most diarrheal illnesses are self-limited or viral, and nearly half last less than one day,3 microbiologic investigation is usually unnecessary for patients who present within 24 hours after the onset of diarrhea, unless such patients are dehydrated or febrile or have blood or pus in their stool. The characteristics of the illness, the epidemiologic setting, and the public health implications help to determine whether and what types of fecal testing are appropriate. The major epidemiologic and clinical features associated with common enteropathogens are listed in Table 1.
Table 1. Epidemiologic Settings and Clinical Features of Infection with Selected Diarrheal Pathogens.
In the United States, most diarrheal illnesses occur during the winter months; these illnesses are commonly associated with noroviruses (in families and in outbreaks, including those in nursing homes)7 or rotaviruses (in young children). Since these illnesses are typically short-lived (lasting one to three days) and self-limited, supportive fluid therapy is usually sufficient. Systemic illness, fever, or bloody stools should prompt routine stool testing for salmonella, shigella, campylobacter, and (especially if there are bloody stools) Shiga toxin–producing E. coli. When diarrhea is persistent or recurring, or if the history (for instance, of fever or tenesmus) is equivocal, fecal testing by means of microscopy for polymorphonuclear leukocytes or by means of immunoassay for the neutrophil marker lactoferrin can quickly provide additional laboratory evidence to support a presumptive diagnosis of inflammatory diarrhea.
In equivocal cases, the negative predictive value of fecal lactoferrin testing may help to determine the need for routine bacteriologic culture for campylobacter, salmonella, and shigella.8 In developed countries, the sensitivity and specificity of fecal leukocytes for inflammatory diarrhea are 0.73 and 0.84, respectively, and the sensitivity and specificity of lactoferrin for inflammatory diarrhea are 0.92 and 0.79, respectively; in resource-poor countries, the ranges are broader.9
Other testing is necessary in special circumstances (Figure 1). In patients who present with an acute onset of bloody diarrhea (especially without fever) or the hemolytic–uremic syndrome, fecal testing for Shiga toxin should be performed, along with cultures for E. coli O157:H7. Bloody diarrhea in recent immigrants or travelers returning from regions where E. histolytica is endemic (such as tropical Africa, Asia, or Latin America) should also prompt fecal testing for that pathogen.10 A report by a patient of recent ingestion of shellfish should prompt special cultures for vibrio species. Persistent abdominal pain, fever, mesenteric adenitis, erythema nodosum, or other immunologic manifestations may suggest Yersinia enterocolitica or Y. pseudotuberculosis, culture for which is enhanced by cold enrichment.
The microbiologic evaluation of hospitalized patients or those with recent exposure to antibiotics in whom diarrhea develops should focus on the diagnosis of toxigenic C. difficile,11 the most common recognized cause of nosocomial diarrhea. Testing for other pathogens in patients who have been hospitalized for more than 72 hours is discouraged, except in an outbreak or in patients 65 years of age or older with preexisting medical conditions, patients with human immunodeficiency virus (HIV) infection, patients with neutropenia, and patients with suspected systemic spread of enteric infection.12
Exposure of a traveler or hiker to untreated water and illnesses that persist for more than seven days should prompt evaluations for protozoal pathogens, especially giardia and cryptosporidium. The testing of one or two specimens by means of enzyme immunoassay has a sensitivity of more than 95 percent and is considerably better than older methods based on microscopical examinations. Less common but readily treatable protozoal causes of persistent diarrhea in normal or immunocompromised persons include Cyclospora cayetanensis and Isospora belli (which can be identified by means of acid-fast staining of stool specimens). In patients with advanced HIV disease, especially those who have fewer than 50 CD4+ lymphocytes per cubic millimeter, stool studies for cryptosporidium, microsporidia, cyclospora, and isospora and blood cultures or biopsies for Mycobacterium avium complex and cytomegalovirus should be considered.13 Fecal evidence of inflammation in persistent diarrhea should arouse concern about inflammatory bowel disease,14 particularly if the presence of a treatable inflammatory pathogen such as shigella, salmonella, campylobacter, C. difficile, or E. histolytica has been ruled out.
Approaches to Therapy
Rehydration and Nutrition
Regardless of the causative agent, initial therapy should include rehydration. Unless the patient is comatose or severely dehydrated, oral rehydration with a glucose-based electrolyte solution is preferred. The standard formulation recommended by the World Health Organization (WHO) or a newer reduced-osmolarity formula for children can be lifesaving in resource-poor regions and is valuable in the industrialized world for infants, the elderly, immunocompromised patients, and anyone with profuse watery diarrhea (information is available on the Web at http://www.who.int/child-adolescent-health/New_Publications/CHILD_HEALTH/WHO_FCH_CAH_01.22.htm). Most adults in developed countries who have acute diarrhea, including travelers, should be encouraged to drink fluids and take in salt in soups and salted crackers. Nutritional support with continued feeding improves outcomes in children. The use of a "BRAT" diet (bananas, rice, applesauce, and toast) with avoidance of milk products (since a transient lactase deficiency may occur) is commonly recommended, although supporting data are limited.15
Nonspecific Symptomatic Therapy
Nearly 400 over-the-counter products are promoted in the United States for their antidiarrheal properties, but few have been demonstrated to be effective in randomized, controlled trials. Only in the cases of loperamide, bismuth subsalicylate, and kaolin has sufficient evidence of efficacy and safety been collected to permit labeling as an antidiarrheal agent.16
Loperamide, the antimotility agent of choice for adults, inhibits intestinal peristalsis and has antisecretory properties, but unlike other opiates (such as codeine, diphenoxylate, and paregoric), it does not penetrate the nervous system and has no substantial potential for addiction.17 When it is used with antibiotics for traveler's diarrhea18 or bacillary dysentery,19 it may reduce the duration of diarrhea by as much as one day. Because antimotility agents have been implicated in prolonged fever in human volunteers with shigellosis,20 toxic megacolon in patients with C. difficile infection, and the hemolytic–uremic syndrome in children infected with Shiga toxin–producing E. coli,21 these agents should be avoided in patients with bloody diarrhea or suspected inflammatory diarrhea.
Although it has not been as effective as loperamide in direct comparisons,22 bismuth subsalicylate can alleviate stool output in children23 or the symptoms of diarrhea, nausea, and abdominal pain in patients with traveler's diarrhea.24 Bismuth subsalicylate significantly decreased the median duration of experimental norovirus illness from 27 hours to 20 hours.25 There are insufficient data from clinical trials to support the use of adsorbents such as kaolin–pectin, activated charcoal, and attapulgite. Given the limited scientific evidence, limited clinical benefit, and concern about the toxicity of antidiarrheal agents, pediatric guidelines discourage their use in children.26,27
Antimicrobial Therapy
Whereas appropriate antibiotics are effective in the treatment of shigellosis, traveler's diarrhea, C. difficile–associated diarrhea, and, if given early, campylobacteriosis, antibiotics may prolong the duration of shedding of salmonella28 or C. difficile29 and may increase the risk of life-threatening complications of Shiga toxin–producing E. coli infection.30 The clinical benefit should be weighed against the cost, the risk of adverse reactions, and the risk of harmful eradication of normal flora or the induction of Shiga-toxin production.31 Antibiotic therapies for specific pathogens are listed in Table 2.
Table 2. Antimicrobial Recommendations for Infections with Specific Pathogens.
Community-Acquired Pathogens
Randomized, controlled trials in patients with shigellosis have demonstrated that appropriate antimicrobial therapy shortens the average duration of diarrhea by 2.4 days or more, decreases the duration of fever and tenesmus, and reduces the excretion of infectious organisms.32,33 Antimicrobial therapy is of greatest benefit when it is started early, and it probably reduces person-to-person spread. Increased resistance now limits the effectiveness of trimethoprim–sulfamethoxazole, ampicillin, and nalidixic acid, which were once considered optimal therapies for shigellosis. Clinical trials have established the efficacy of newer fluoroquinolones for adults with shigellosis,33,34 and accumulating data suggest that ciprofloxacin is also safe and effective in children with shigellosis.35
In immunocompetent patients with campylobacteriosis, erythromycin reduces carriage of the organism but reduces diarrhea only when it is given within four days after the onset of symptoms.36,37 Immunocompromised patients (particularly those who have the acquired immunodeficiency syndrome and those who are pregnant, who have an increased risk of complications of campylobacter infection) and patients with severe, prolonged, or relapsing illness may benefit from antimicrobial therapy. Dramatic increases in the rate of fluoroquinolone resistance (contemporaneous with the widespread use of fluoroquinolones in poultry feeds) now limit the usefulness of these agents in campylobacter infections.38
In uncomplicated salmonella gastroenteritis, antibiotics are not recommended, since they typically do not alleviate the diarrhea39 and have been associated with prolonged carriage28 and even relapse.40 However, because bacteremia occurs in 2 to 4 percent of patients, persons who are at increased risk for dissemination or metastatic seeding should receive antibiotics. These patients include those 12 months of age or younger and those older than 50 years; those with lymphoproliferative disorders, cancer, hemoglobinopathies, or AIDS; transplant recipients; patients with vascular grafts, artificial joints, degenerative joint diseases, or valvular heart disease; and patients who are taking corticosteroids.
Clues to the diagnosis of Shiga toxin–producing E. coli infection include bloody diarrhea (especially if the patient is afebrile) and a history of eating rare hamburger meat or seed sprouts. Given the concern that antimicrobial agents such as trimethoprim–sulfamethoxazole and quinolones induce Shiga-toxin production31 and may increase the risk of the hemolytic–uremic syndrome,30 patients with suspected or documented infection with Shiga toxin–producing E. coli should receive supportive care. Risk factors for the development of the hemolytic–uremic syndrome with this infection remain controversial and are incompletely understood.41
Empirical Antibiotic Treatment for Community-Acquired Illness
Empirical antibiotic treatment in adults who present with severe, community-acquired diarrhea (Table 3) reduces the average duration of illness by one to two days.28,42,43 However, as noted above, the potential benefits must be weighed against the potential harm, such as prolonged fecal shedding of certain pathogens, the increased risk of relapse, and the increased risk of complications. In patients who have evidence of inflammatory diarrhea (fever, tenesmus, dysentery, or fecal leukocytes or lactoferrin) and in whom diarrhea is not thought to be attributable to Shiga toxin–producing E. coli or fluoroquinolone-resistant campylobacter, empirical treatment with an agent such as a fluoroquinolone antibiotic (or for children, trimethoprim–sulfamethoxazole), pending fecal testing, is reasonable.6,44 Given the increasing incidence of fluoroquinolone-resistant campylobacter,38,45 empirical therapy in immunocompromised or severely ill patients or travelers with inflammatory diarrhea (especially those who have traveled to southern Asia, where the rate of quinolone resistance exceeds 80 percent) might include erythromycin or azithromycin.
Table 3. Considerations for Empirical Antimicrobial Therapy for Infectious Diarrhea.
Traveler's Diarrhea
Although most cases of traveler's diarrhea are self-limited, several clinical trials have demonstrated that fluoroquinolones or other agents — many of which are no longer used because of increased resistance — reduce the duration of diarrhea from three or four days to one or two days with as little as a single dose.46 Although such data support a recommendation that travelers carry appropriate antibiotics for the self-treatment of diarrhea, most experts do not recommend antimicrobial prophylaxis for travelers (even those who are immunocompromised, whose highest risk may be for infection with pathogens that are not covered by the standard antimicrobial agents used). Use of bismuth subsalicylate (one to two 262-mg tablets taken four times daily) decreases the incidence of traveler's diarrhea by 35 to 65 percent and appears to be safe when used for up to three weeks but may result in the blackening of the tongue and the stools.47,48
Nosocomial Diarrhea
The treatment of C. difficile–associated diarrhea has been discussed in detail previously.11 Many patients have improvement if therapy with broad-spectrum antibiotics can be discontinued. Oral metronidazole (which is less expensive) and oral vancomycin are effective in the treatment of C. difficile–associated diarrhea, with response rates of more than 90 percent and a mean time to improvement of three days, but relapses are common.11
Persistent Diarrhea
The protozoal pathogens that are most frequently associated with diarrhea that persists for more than 7 to 10 days, both in the United States and worldwide, are giardia and cryptosporidium. Giardia infections typically respond to metronidazole (the use of larger doses, if they are tolerated, may result in fewer treatment failures) or tinidazole. Cryptosporidium infection, in contrast, is notoriously difficult to treat, particularly in patients with AIDS and low CD4+ lymphocyte counts, in whom the most effective strategy is to facilitate immunologic reconstitution with optimal antiretroviral therapy.49 Nitazoxanide, which was recently approved by the Food and Drug Administration (FDA) for use in children, may reduce oocyst shedding and diminish diarrhea.50 Since these hardy oocysts are difficult to filter or to kill with chlorine, infections caused by them are best prevented by heating water or food to near-boiling temperatures. Finally, cyclospora infection, which can be detected by means of acid-fast staining of fecal specimens, is readily treated with trimethoprim–sulfamethoxazole.51,52
Areas of Uncertainty
The inability to determine the specific causative agent when a patient is first seen greatly complicates management. Technology that will permit rapid, pathogen-specific diagnostic testing could mitigate the inappropriate use of antibiotics, help to track sources and outbreaks, and identify resistant pathogens or fecal contamination of food or water. Whether certain antibiotics increase risk whereas others prevent the hemolytic–uremic syndrome in patients with Shiga toxin–producing E. coli infections remains controversial.30,41
Drugs such as calmodulin inhibitors, chloride-channel blockers, enkephalinase inhibitors, and agents that block prostaglandin-mediated pathways are under study as antisecretory agents; at present, their role remains uncertain. A poorly absorbed antibiotic, rifaximin, is effective in the treatment of traveler's diarrhea53 and may prove useful for other bacterial diarrheal illnesses but has not been approved by the FDA. Improved therapy must also address the repair of damaged or inflamed mucosa, since the associated reduction in absorptive function and resulting malnutrition may impair child development and potentially reduce the efficacy of therapies for associated diseases.
Guidelines
Several groups have published guidelines for the management of acute diarrhea in adults.6,44,54 The guidelines that the Infectious Diseases Society of America published in 2001, with which we still concur (available at http://www.idsociety.org), detail diagnostic strategies, treatment recommendations, and public health implications for adults, listing the quality and strength of evidence supporting each recommendation.6 Several pediatric guidelines emphasize fluid management and the fact that antidiarrheal compounds are not useful.26,27,55
Conclusions and Recommendations
In healthy patients with an acute onset of diarrhea, such as the patient described in the vignette, epidemiologic and clinical evaluation should be used to guide laboratory evaluation and management. For example, a recent history of eating raw oysters should prompt consideration and special culture for vibrio, and a recent history of antibiotic use should prompt testing for C. difficile toxin. Bloody diarrhea or a history of blood in the stool or of the ingestion of undercooked beef should prompt testing for Shiga toxin–producing E. coli; the presence of bloody diarrhea would also warrant testing for shigella, salmonella, and campylobacter. A history of immunocompromise, sickle cell disease, severe atherosclerosis, or intravascular prosthetic material should prompt the testing of blood and stool cultures for salmonella. Recent travel to a developing country would suggest infection with pathogens that typically cause traveler's diarrhea and would warrant empirical therapy with a single dose of a quinolone antibiotic (unless the travel was to southern Asia, which should arouse concern about infection with quinolone-resistant campylobacter). One might also consider empirical treatment for inflammatory diarrhea whose cause was suspected, on the basis of the exposure history, to be shigella or campylobacter infection (Table 2 and Table 3).
If none of the above pathogens were present, but symptoms worsened or persisted for more than five days (especially if there was fever), we would order a fecal examination for inflammation to direct further testing for invasive pathogens (including salmonella, shigella, campylobacter, C. difficile, or E. histolytica); if the examinations were negative for these pathogens, we would evaluate the patient for inflammatory bowel disease. Patients with illness lasting more than seven days should be tested for parasites (including giardia, cryptosporidium, cyclospora, and isospora). Finally, patients with recurrent or refractory giardiasis should be tested for possible immune compromise, such as immunoglobin A deficiency, and patients with refractory cryptosporidiosis, cyclosporiasis, or isosporiasis should be tested for HIV infection.
Drs. Thielman and Guerrant are named as coinventors on a patent held by the University of Virginia for the use of glutamine derivatives in oral rehydration therapy. Dr. Guerrant is named as a coinventor on a patent held by the University of Virginia for a fecal lactoferrin assay. Neither coinventor receives any patent royalties.
Source Information
From the Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, N.C. (N.M.T.); and the Department of Medicine, Division of Infectious Diseases and International Health and the Center for Global Health, University of Virginia School of Medicine, Charlottesville (R.L.G.).
Address reprint requests to Dr. Guerrant at the Center for Global Health, HSC #801379, University of Virginia School of Medicine, Charlottesville, VA 22908, or at rlg9a@virginia.edu.
References
Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bull World Health Organ 2003;81:197-204.
Guerrant RL, Kosek M, Lima AA, Lorntz B, Guyatt HL. Updating the DALYs for diarrhoeal disease. Trends Parasitol 2002;18:191-193.
Herikstad H, Yang S, Van Gilder TJ, et al. A population-based estimate of the burden of diarrhoeal illness in the United States: FoodNet, 1996-7. Epidemiol Infect 2002;129:9-17.
Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607-625.
Preliminary FoodNet data on the incidence of foodborne illnesses -- selected sites, United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:340-343.
Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 2001;32:331-351.
Norovirus activity -- United States, 2002. MMWR Morb Mortal Wkly Rep 2003;52:41-45.
Choi SW, Park CH, Silva TM, Zaenker EI, Guerrant RL. To culture or not to culture: fecal lactoferrin screening for inflammatory bacterial diarrhea. J Clin Microbiol 1996;34:928-932.
Gill CJ, Lau J, Gorbach SL, Hamer DH. Diagnostic accuracy of stool assays for inflammatory bacterial gastroenteritis in developed and resource-poor countries. Clin Infect Dis 2003;37:365-375.
Haque R, Huston CD, Hughes M, Houpt E, Petri WA Jr. Amebiasis. N Engl J Med 2003;348:1565-1573.
Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346:334-339.
Bauer TM, Lalvani A, Fehrenbach J, et al. Derivation and validation of guidelines for stool cultures for enteropathogenic bacteria other than Clostridium difficile in hospitalized adults. JAMA 2001;285:313-319.
Thielman NM, Guerrant RL. An algorithmic approach to the workup and management of HIV-related diarrhea. J Clin Outcomes Management 1997;4:36-47.
Fine KD, Ogunji F, George J, Niehaus MD, Guerrant RL. Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenterol 1998;93:1300-1305.
King CK, Glass R, Bresee JS, Duggan C. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep 2003;52:1-16.
Food and Drug Administration. Antidiarrheal drug products for over-the-counter human use: final monograph: final rule. Fed Regist 2003;68:18869-18882.
DuPont HL, Flores Sanchez J, Ericsson CD, et al. Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea. Am J Med 1990;88:15S-19S.
Petruccelli BP, Murphy GS, Sanchez JL, et al. Treatment of traveler's diarrhea with ciprofloxacin and loperamide. J Infect Dis 1992;165:557-560.
Murphy GS, Bodhidatta L, Echeverria P, et al. Ciprofloxacin and loperamide in the treatment of bacillary dysentery. Ann Intern Med 1993;118:582-586.
DuPont HL, Hornick RB. Adverse effect of lomotil therapy in shigellosis. JAMA 1973;226:1525-1528.
Cimolai N, Basalyga S, Mah DG, Morrison BJ, Carter JE. A continuing assessment of risk factors for the development of Escherichia coli O157:H7-associated hemolytic uremic syndrome. Clin Neprhol 1994;42:85-9.
Johnson PC, Ericsson CD, DuPont HL, Morgan DR, Bitsura JA, Wood LV. Comparison of loperamide with bismuth subsalicylate for the treatment of acute travelers' diarrhea. JAMA 1986;255:757-760.
Fugueroa-Quintanilla D, Salazar-Lindo E, Sack RB, et al. A controlled trial of bismuth subsalicylate in infants with acute watery diarrheal disease. N Engl J Med 1993;328:1653-1658.
DuPont HL, Sullivan P, Pickering LK, Haynes G, Ackerman PB. Symptomatic treatment of diarrhea with bismuth subsalicylate among students attending a Mexican university. Gastroenterology 1977;73:715-718.
Steinhoff MC, Douglas RG Jr, Greenberg HB, Callahan DR. Bismuth subsalicylate therapy of viral gastroenteritis. Gastroenterology 1980;78:1495-1499.
Armon K, Stephenson T, MacFaul R, Eccleston P, Werneke U. An evidence and consensus based guideline for acute diarrhoea management. Arch Dis Child 2001;85:132-142.
Murphy MS. Guidelines for managing acute gastroenteritis based on a systematic review of published research. Arch Dis Child 1998;79:279-284.
Wistrom J, Jertborn M, Ekwall E, et al. Empiric treatment of acute diarrheal disease with norfloxacin: a randomized, placebo-controlled study. Ann Intern Med 1992;117:202-208.
Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole: a randomized, placebo-controlled trial. Ann Intern Med 1992;117:297-302.
Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930-1936.
Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, Acheson DW. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis 2000;181:664-670.
Tong MJ, Martin DG, Cunningham JJ, Gunning JJ. Clinical and bacteriological evaluation of antibiotic treatment in shigellosis. JAMA 1970;214:1841-1844.
Bennish ML, Salam MA, Haider R, Barza M. Therapy for shigellosis. II. Randomized, double-blind comparison of ciprofloxacin and ampicillin. J Infect Dis 1990;162:711-716.
Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis. V. Comparison of azithromycin and ciprofloxacin: a double-blind, randomized, controlled trial. Ann Intern Med 1997;126:697-703.
Zimbabwe, Bangladesh, South Africa (Zimbasa) Dysentery Study Group. Multicenter, randomized, double blind clinical trial of short course versus standard course oral ciprofloxacin for Shigella dysenteriae type 1 dysentery in children. Pediatr Infect Dis J 2002;21:1136-1141.
Salazar-Lindo E, Sack RB, Chea-Woo E, et al. Early treatment with erythromycin of Campylobacter jejuni-associated dysentery in children. J Pediatr 1986;109:355-360.
Anders BJ, Lauer BA, Paisley JW, Reller LB. Double-blind placebo controlled trial of erythromycin for treatment of Campylobacter enteritis. Lancet 1982;1:131-132.
Smith KE, Besser JM, Hedberg CW, et al. Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. N Engl J Med 1999;340:1525-1532.
Sanchez C, Garcia-Restoy E, Garau J, et al. Ciprofloxacin and trimethoprim-sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double-blind trial. J Infect Dis 1993;168:1304-1307.
Neill MA, Opal SM, Heelan J, et al. Failure of ciprofloxacin to eradicate convalescent fecal excretion after acute salmonellosis: experience during an outbreak in health care workers. Ann Intern Med 1991;114:195-199.
Safdar N, Said A, Gangnon RE, Maki DG. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. JAMA 2002;288:996-1001.
Dryden MS, Gabb RJ, Wright SK. Empirical treatment of severe acute community-acquired gastroenteritis with ciprofloxacin. Clin Infect Dis 1996;22:1019-1025.
Goodman LJ, Trenholme GM, Kaplan RL, et al. Empiric antimicrobial therapy of domestically acquired acute diarrhea in urban adults. Arch Intern Med 1990;150:541-546.
DuPont HL. Guidelines on acute infectious diarrhea in adults. Am J Gastroenterol 1997;92:1962-1975.
Nachamkin I, Ung H, Li M. Increasing fluoroquinolone resistance in Campylobacter jejuni, Pennsylvania, USA, 1982-2001. Emerg Infect Dis 2002;8:1501-1503.
Cheng AC, Thielman NM. Update on traveler's diarrhea. Curr Infect Dis Rep 2002;4:70-77.
DuPont HL, Ericsson CD, Johnson PC, Bitsura JA, DuPont WW, de la Cabada FJ. Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate. JAMA 1987;257:1347-1350.
Steffen R, DuPont HL, Heusser R, et al. Prevention of traveler's diarrhea by the tablet form of bismuth subsalicylate. Antimicrob Agents Chemother 1986;29:625-627.
Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998;351:256-261.
Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2001;184:103-106.
Pape JW, Verdier RI, Boncy M, Boncy J, Johnson WD Jr. Cyclospora infection in adults infected with HIV: clinical manifestations, treatment, and prophylaxis. Ann Intern Med 1994;121:654-657.
Verdier RI, Fitzgerald DW, Johnson WD Jr, Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients: a randomized, controlled trial. Ann Intern Med 2000;132:885-888.
Steffen R, Sack DA, Riopel L, et al. Therapy of travelers' diarrhea with rifaximin on various continents. Am J Gastroenterol 2003;98:1073-1078.
Manatsathit S, Dupont HL, Farthing M, et al. Guideline for the management of acute diarrhea in adults. J Gastroenterol Hepatol 2002;17:Suppl:S54-S71.
Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis. The management of acute gastroenteritis in young children. Pediatrics 1996;97:424-435.(Nathan M. Thielman, M.D.,)