Therapy for acute infectious diarrhea in children Larry K. Pickering, MD From the Division of Infectious Diseases, Department of Pediatrics, University of Texas Medical School, Houston

This article reviews current recommendations of therapy with antidiarrheal compounds and antimicrobial agents for acute infectious diarrhea in children. In most infants and children with acute infectious diarrhea, treatment with antidiarrheal compounds is not indicated. Many of these compounds interfere with identification of enteropathogens in stool specimens, and the antimotility class has an overdose potential. Antimicrobial therapy is given to reduce symptoms and to prevent the spread of infection by decreasing fecal shedding of organisms. Although effective therapy is not a v a i l a b l e for patients with enteric viruses, Cryptosporidium, and Microsporldium, therapy is useful for children with amebiasis, antimicrobial-associated colitis, cholera, giardiasis, various forms of Escherichia coli diarrhea and Salmonella disease, isosporiasis, shigellosis, and strongyloidiasis. For several other conditions, antimicrobial therapy is of questionable benefit (infection with Campylobacterjejunior Yersinia enterocolitica, intestinal salmonellosis and enterohemorrhagic E. call infection). C o m p o u n d s such as the fluoroquinolones, which are effective in the treatment of a c u t e infectious diarrhea in adults, are not a p p r o v e d for use in children b e c a u s e of potential side effects. Many bacterial, viral, and parasitic organisms cause a c u t e infectious diarrhea; a p p r o p r i a t e antimicrobial therapy requires the accurate, rapid identification of the o f f e n d i n g e n t e r o p a t h o g e n . In children with an underlying illness such as a c q u i r e d i m m u n o d e f i c i e n c y syndrome, manifestations may be prolonged, severe, and recurrent despite appropriate therapy. (J PEDIATR1991; 118:$118-28)

Enteric infections are generally self-limited conditions, but nonspecific therapy can provide relief for some patients, and specific antimicrobial therapy may eradicate fecal shedding of the causative organism, abbreviate clinical symptoms, or prevent future complications. The number of enteropathogens capable of producing gastroenteritis is vast, and their response to therapy is varied. The major therapeutic considerations for patients with gastroenteritis include (1) fluid and electrolyte replacement, (2) dietary intake, (3) nonspecific therapy with antidiarrheal compounds, and (4) specific Supported in part by National Institutes of Health grants HD13021, AI-27551, and HR-96040. Reprint requests: Larry K. Pickering, MD, Division of Infectious Diseases, Department of Pediatrics, University of Texas Medical School, 6431 Fannin St., Room 1.739, Houston, TX 77030.

9/0/24903

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therapy with antimicrobial agents. This review will focus on the latter two categories. I

AAC AIDS TMP-SMX

Antimicrobial-associated colitis Acquired immunodeficiency syndrome Trimethoprim-sulfamethoxazole

[

BASIC PRINCIPLES Several basic principles underlie the treatment of patients with acute infectious gastroenteritis. 1. Many bacterial, viral, and parasitic enteropathogens are capable of causing gastroenteritis. These organisms have varying degrees of rcsponse to antimicrobial agents (Table I). 2. The majority of enteropathogens are acquired through the fecal-oral route by contaminated food or water, or are

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spread from person to person. Infected persons generally represent a threat to others because enteropathogens can be transmitted in various settings, such as day-care centers. 3. Infections in patients with defects in their host defense mechanisms, such as patients infected with the human immunodeficiency virus, are often severe, commonly disseminate, require prolonged therapy, and frequently relapse when therapy is stopped. 4. Development of resistance by bacterial enteropathogens has been reported from many areas of the world. 5. In vitro drug susceptibility does not always predict an in vivo clinical response. 6. Safety factors and side effects preclude the use in children of certain antimicrobial agents (e.g., the quinolones) that are administered to adults. POPULATIONS INFECTIONS

AT RISK FOR ENTERIC

Populations at risk for enteric infections include (1) persons more likely to acquire an enteropathogen because of the presence of various epidemiologic factors and (2) persons who are immune deficient. The first group includes children in day-care centers, persons who travel from industrialized regions to developing countries, and those who ingest contaminated food or water. 1-5The second group includes those in whom an abnormality in host defense mechanisms enhances their chances of acquiring gastrointestinal tract infections with uncommonly encountered organisms, such as Isospora or Microsporidium species, or of having a protracted course of disease caused by any enteropathogen.6, 7 The latter phenomenon is common in patients with acquired immunodeficiency syndrome, but it may also occur in those with T or B cell immunodeficiencies or with secondary or acquired immunodeficiencies.8 The clinical course of these patients is often characterized by severe, prolonged, or recurrent disease that requires long-term therapy. Signs and symptoms of disease are related to the degree of immune deficiency. ANTIDIARRHEAL

COMPOUNDS

Table I1 lists nonprescription and prescription compounds available for relief of symptoms of diarrhea9-31; most are not approved for children less than 2 or 3 years of age. These compounds may be classified by their mechanisms of action, which include alteration of intestinal motility, adsorption, alteration of intestinal microflora, and alteration of fluid and electrolyte secretion. Many persons with diarrhea will have medicated themselves or their children before they seek medical care. Although self-medication usually results in no harm, two problems may happen. First, adverse side effects may occur, such as worsening of diarrhea because of slowing of intes-

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T a b l e I. Potential benefit of antimicrobial therapy for

enteropathogens or diseases produced by enteropathogens Potential benefit

Therapy not available Established benefit

Enteropathogen or disease

Enteric viruses Cryptosporidiosis Microspora Amebiasls Antimicrobial associated colitis (C. difficile) Cholera Enterotoxigenic E. coli Giardiasis Invasive E. coli Isosporiasis Shigella

Absolute

Questionable or unknown

Strongyloidiasis Any bacterium that produces bacteremia (e.g., typhoid fever) Disseminated strongyloidiasis C. jejuni

Intestinal salmonellosis Enterohemorrhagic E. coli Y. enterocolitica

tinal motility by agents that alter this function, 1~ salicylate or bismuth absorption from bismuth-subsalicylate preparations, 1921 or prevention of absorption of medicines or nutrients in the gastrointestinal tract when they come in contact with these adsorbents. 22 A second problem is that these compounds may interfere with the identification of enteropath0gens by microscopy, enzyme-linked immunosorbent assay, or culture. Drugs that alter intestinal motility usually have a rapid onset of action by producing segmental contractions of the intestine. 27-29 This action serves to retard movement of intestinal contents responsible for diarrhea and to restrict the intestinal distension responsible for pain. These agents may also inhibit intestinal secretion. 9 Side effects include dizziness, dry mouth, drowsines s, tachycardia, constipation, and vomiting. These drugs should be avoided in Patients with high fever, toxemia, or bloody mucold stools because they may worsen the clinical course of shigellosis}~ and perhaps infections with other invasive bacteria as well. The condition of patients with antimicrobial-associated colitis has become worse when diphenoxylate With atropine (Lomotil) has been given; 23 therefore, the use of oPiates and other antiperistaltic agents should be avoided in such patients. Because an overdose potential exists, their use is not recommended in children. 11,12 The combination of trimethoprim-sulfamethoxazole plus loperamide was effective in the treatment of adults with travelers' diarrhea. 31 Adults

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Table II. Nonspecific diarrheal medications for patients with acute diarrhea Earliest recommended a g e (yr)

Class (reference)

Generic n a m e

Alteration of intestinal motility

Kaolin, pectin, atropine, scopolamine

Donnagel

Loperamide

Imodium

2

Diphenoxylate-atropine

Lomotil*

2

Kaolin-pectin

Kaopectate

3

Activated attapulgite

Diasorb Rheaban Lactinex

3 6 --

Pepto-Bismol

3

Sandostatin*

--

Adsorbents

Alteration of intestinal microflora Alteration of secretion

Lactobacilluscontaining compounds Bismuth-subsalicylate Octreotide

Trade name

Comments

Category III (insufficient data to prove effective); causes drowsiness, dry mouth, dizziness, tachycardia Side effects include drowsiness, dry mouth, dizziness, hypersensitivity, constipation, and emesis Side effects are drowsiness, dizziness, dry mouth, respiratory depression, coma Category III; adsorbs nutrients and drugs Adsorbs nutrients and drugs Adsorbs nutrients and drugs Contraindicated in patients with lactose intolerance; may cause gastric irritability and emesis Category III; contains salicylates and bismuth Used for relief of diarrhea caused by Cryptosporidium; not FDA approved for this indication

*Requires prescription.

treated with this combination had the shortest mean duration of diarrhea in comparison with patients taking placebo or TMP-SMX alone. Concerns about the safety of loperamide may preclude its use in infants. 28 Several antidiarrheal compounds are used internally as adsorbents.13, 14 Kaolin-pectin (Kaopectate) and activated attapulgite (Diasorb and Rheaban) adsorb bacterial toxins and water and improve the symptoms of diarrhea by producing more formed stools. Few controlled studies show the effectiveness of adsorbents in reducing the duration of diarrhea or the loss of fluid and electrolytes. Disadvantages include adsorption of nutrients, enzymes, and antibiotics in the intestine, 22 particularly if these agents are used for a prolonged time. Attapulgite is a clay that acts as an adsorbent and has been shown to be effective in animals. 24, 25 It relieves diarrhea by reducing the number of bowel movements and improving stool consistency. Lactobacillus preparations are given to recolonize the intestine with saccharolyric flora and to alter the intestinal pH to deter potential pathogens. However, no evidence exists that lactobacillus compounds are effective in the symptomatic treatment of diarrhea.15-~7 Bismuth subsalicylate has been shown to be effective in the treatment and prevention of acute diarrhea among adult students in Mexico. Laboratory studies have shown that bismuth subsalicylate inhibits intestinal secretion caused by E. coli organisms and cholera toxin. 18 Studies supporting the benefit of this compound in children with diarrhea are

limited. 3~Problems relate to the absorption of salicylate and bismuth.19-zl Octreotide acetate (Sandostatin) is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin, which inhibits secretion from a variety of endocrine and exocrine tissues, including inhibition of secretion of growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, insulin, glucagon, gastrin, secretin, pancreozymin, and pepsin. This agent is indicated for the symptomatic treatment of patients with metastatic carcinoid tumors; it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. It is also indicated for the treatment of the profuse, watery diarrhea associated with vasoactive intestinal peptide-secreting tumors. It has been used in patients with AIDS who have severe diarrhea because of infection with Cryptosporidium, 26 but it has not been approved by the U.S. Food and Drug Administration (FDA) for this purpose. ANTIMICROBIAL

THERAPY

Many children with acute infectious diarrhea will not benefit from therapy with an antimicrobial agent (Table I). Currently, no antimicrobial agents are effective for the treatment of patients with gastroenteritis caused by the viral enteropathogens that include rotavirus, enteric adenovirus, calicivirus, astrovirus, and Norwalk-like viruses or by Cryptosporidium or Microspora. Patients with infec-

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T a b l e Ill. Antimicrobial therapy for gastroenteritis caused by bacterial pathogens

Organism

Antimicrobial agent

C. difficile

Vancomycin Or metronidazole

C. jejuni

None or erythromycin

Y. enterocolitica V. parahaemolyticus V. cholerae

None None Tetracycline Or TMP-SMX

Enterotoxigenic E. coli Enteroinvasive E. coli Max. Maximum.

TMP-SMX See Table V

tions by certain other bacterial and protozoal agents will benefit from therapy. BACTERIA Antimicrobial-associated colitis. Pseudomembranous colitis refers to the presence in the colon of a pseudomembrane, or multiple plaque-like lesions, induced by the administration of an antimicrobial agent. The specific cause is a toxin produced by Clostridium difficile. Although nearly all antimicrobial agents have been reported to produce this condition, ampicillin, clindamycin, lincomycin, the cephalosporins, erythromycin, and TMP-SMX have been the most frequently implicated. 32 In patients with AAC, the most important aspect of therapy is discontinuance of the antimicrobial agent. Patients with mild disease may respond to discontinuing tile precipitating antibiotic and to providing fluid and electrolyte therapy. If symptoms persist or worsen, or if the disease is severe, specific therapy with vancomycin, 33' 34 metronidazole,35 or bacitracin 3638 should b e administered (Table III). Oral vancomycin is the treatment of choice for patients with severe AAC. Its major disadvantages are expense and bitter taste. Oral preparations of metronidazole and bacitracin are less expensive alternatives for treating patients with mild-to-moderate disease, but they are not approved by the FDA for treatment of patients with this condition. Bacitracin, although a useful alternative to metronidazole and vancomycin, has a response rate that is slower and less certain than that of vancomycin, 37' 38 and bacitracin can produce potentially toxic effects if absorbed from an inflamed intestine. Patients who are unable to take vancomycin orally should be treated with both intravenously administered metronidazole and vancomycin and with vancomycin administered by nasogastric tube (or ostomy if present). All

Dose 5 mg/kg (max 125 rag) every 6 hr for 7 days 7 mg/kg orally (max 500 rag) every 8 hr for 7 days 10 mg/kg (max 250 rag) every 6 hr for 5-7 days None None 10 mg/kg (max 250 rag) every 6 hr for 3-5 days TMP 5 mg/kg (max 160 rag) plus SMX 25 mg/kg (max 800 mg) every 12 hr orally or IV for 3 days 3-Day course adequate Same dose as for shigellosis

strains of C. difficile are susceptible to vancomycin, whereas resistance to metronidazole and bacitracin has been reported. Teicoplanin, a glycopeptide antibiotic, has been used successfully to treat patients with AAC, 39 but additional studies are needed. Salmonella. Several clinical syndromes are produced by Salmonella: (1) the carrier state, (2) acute gastroenteritis, (3) bacteremia or enteric fever or both, and (4) dissemination with localized suppuration (e.g., abscesses or osteomyelitis). The type of syndrome produced by Salmonella dictates the selection and duration of antimicrobial therapy (Table IV). Antibiotics should not be used in the treatment of persons who are nontyphoid Salmonella carriers or in patients who have mild gastroenteritis unless the illness appears t Obe evolving into one of the systemic syndromes such as bacteremia or metastatic pyogenic infection. Antimicrobial therapy should also be considered in newborn infants and in patients with enterocolitis who have an underlying condition or disease that impairs host resistance, such as those with AIDS, a hemoglobinopathy including sickle cell anemia, lymphoma, or leukemia. Antimicrobial therapy may on occasion convert intestinal carriage to systemic disease with bacteremia, 4~ produce a bacteriologic and symptomatic relapse,41,42 or encourage the development or selection of resistant strains. Antibiotic treatment of patients with Salmonella infection generally is restricted to those with (1) typhoid fever (patients with clinical illness and carriers), (2) bacteremia from nontyphoidal strains, and (3) dissemination with localized suppuration. Recommended antibiotics are ampicillin, chloramphenicol (intravenously or orally administered), and TMP-SMX. 43,44 Chloramphenicol-resistant strains of Salmonella have emerged in all parts of the world; ampicillin is the current drug of choice when susceptibility

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Table IV. Antimicrobial therapy for Salmonella infections in children Clinical manifestation

Carrier state Acute gastroenteritis Bacteremia or enteric fever or both

Antimicrobial agent

Dose

None Probably none Ampicillin Or chloramphenicol Or TMP-SMX

Or ceftriaxone Or cefotaxime Dissemination with localized suppuration (osteomyelitis) Max. Maximum.

Same as above

testing has not been performed. In the United States, attention has focused on resistance of nontyphoidal Salmonella strains, which have their major reservoir in animals. Several outbreaks of multiresistant Salmonella infection have been traced to animal sources in the United States, necessitating susceptibility testing of all human isolates of

Salmonella. In the United States, antimicrobial resistance has been a minor problem; only 2% t O 3% ofS. typhi strains are resistant to ampicillin and chloramphenicol.45 However, because of travel and the potential for importation of a resistant strain, resistance should always be considered. From 1975 to 19841 62% of the cases of acute typhoid fever in the United States were acquired in other countries, with Mexico (39%) and India (14%) being the major sources. 45 California, Texas, and New York reported the greatest number of cases. In general, S. typhi has remained susceptible in comparison with the nontyphoidal Salmonella strains. Third-generation cephalosporins such as cefotaxime, ceftriaxone, and cefoperazone are effective against S. typhi and nontyphoidal Salmonella strains that are resistant to ampicillin, chloramphenicol, and TMP-SMX. 46-48 In a prospective, randomized study of 59 children with confirmed typhoid fever, 48 ceftriaxone administered once daily for 5 days was as effective and safe as a 3-week course of chloramphenicol. Second-generation cephalosporin antibiotics have been less effective than third-generation antibiotics and should not be used. Ciprofloxacin is active in vitro against Salmonella, including S. typhi, 49 and has been used clinically with success. 50 Many othe r antibiotics are active in vitro against Salmonella strains, including S. typhi, but the susceptibility correlates poorly with an in vivo response. 51 Cortico-

None See text for exceptions 35 mg/kg (max 1 gm) every 4 hr IV for 2 wk 20 mg/kg (max 1 gm) every 6 hr IV or orally for 2 wk TMP 5 mg (max 160 mg) plus SMX 25 mg (max 800 mg) every 12 hr orally for 2 wk 100-150 mg/kg/day every 12 hr for 2 wk (max 4 gin/day) 200 mg/kg/day every 6 hr for 2 wk (max 12 gm/day) Administer for 4-6 wk

steroids, although they may increase the relapse rate, 52 can be beneficial in patients with typhoid fever for whom prompt relief of toxemia manifestations might be lifesaving.53 All the antibiotics listed in Table IV can be used for the treatment of Salmonella. although chloramphenicol should not be used if infection is localized at intravenous sites. Patients with defective host defense mechanisms, such as AIDS patients, should be treated with ampicillin or a third-generation cephalosporin.5456 Ciprofloxacin has been reported to be effective in the treatment of recurrent Salmonella sepsis. 57 The duration of therapy is influenced by the site of infection and by the host. Patients with bacteremia without a localized infection should be treated for 14 days, whereas those with localized infection, such as osteomyelitis or endocarditis, or patients with AIDS and bacteremia should receive 4 to 6 weeks of therapy to prevent relapse. In patients without gallbladder disease, ampicillin with probenecid or amoxicillin for 6 weeks is the treatment of choice for chronic enteric carriers. 58, 59 When gallbladder disease was present, the failure rate of ampicillin was about 75%. 60 Amoxicillin,59 norfloxacin,61 and ciprofloxacin62 have been reported to be successful in eradicating S. typhi in chronic carriers. Shlgella. T h e 32 serotypes of Shigella are divided into four serogroups: (1) S. dysenteriae, (2)S. flexneri, (3) S. boydii, and (4) S. sonnei. In the United States, 60% of reported cases are due to S. sonnei; S. flexneri serotypes account for the majority of the remaining cases. S. dysenteriae is an uncommon cause of diarrhea in the United States. Table V outlines suggested antimicrobial therapy for children who have presumed shigellosis or in whom Shigella has been isolated from stool. The treatment of choice for shigellosis is TMP-SMX because of the increasing fre-

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T a b l e V. Antimicrobial therapy for shigellosis Antimicrobial agent

Dose

Comment

Drug of choice, some strains are resistant

Nalidixic acid

TMP 5 mg/kg (max 160 mg) plus SMX 25 mg/kg (max 800 rag) every 12 hr orally or IV for 5 days 20 mg/kg orally or IV every 6 hr for 5 days (max 500 rag/6 hr) 55 mg/kg/day every 6 br for 5 days

Norfloxacin

400 mg twice daily for 3-5 days

Ciprofloxacin

500 mg twice daily for 3-5 days

TMP-SMX

Ampicillin

Only for ampicillin-susceptiblestrains Use for TMP-SMX and ampicillinresistant strains Resistant strains, approved for persons >17 yr of age Resistant strains, approved for persons > 17 yr of age

Max, Maximum.

T a b l e Vl. Antimicrobial therapy for giardiasis Antimicrobial agent

Quinacrine HCI (Atabrine) Metronidazole (Flagyl) Furazolidone (Furoxone)

Dose

6 mg/kg/day in 3 doses orally for 7 days (max 300 mg/ kg/day) 15 mg/kg/day in 3 doses orally for 7 days (max 750 mg/day) 6 mg/kg/day in 4 doses orally for 7 days (max 400 mg/day)

Common side effects

Comment

Dizziness, headache, vomiting, diarrhea Nausea, headache, dry mouth, metallic taste Nausea, vomiting

Considered investigational for this condition by FDA Available in liquid form

Max, Maximum.

quency of ampicillin resistance among Shigella isolates. 6369 The history of resistance among Shigella strains has shown the progressive acquisition of multiorganism resistance-first to sulfonamides shortly after they became commercially available, then to tetracycline, chloramphenicol, and streptomycin less than 10 years after they were introduced, and subsequently to ampicillin, kanamycin, and TMP-SMX. 7~ S. flexneri strains have remained relatively susceptible to ampicillin, whereas approximately half of the S. sonnei strains are resistant. 66 In children with ampicillinsusceptible strains, ampicillin is the treatment of choice and can be given orally or intravenously. Amoxicillin is not as effective as ampicillin and should not be used.71 Single-dose tetracycline therapy is effective in the treatment of Shigella infection in adults regardless of clinical expression of illness and may be useful in the treatment of disease from tetracycline-resistantstrains .67 Treatment with tetracycline must be limited to adults because of its side effects, including tooth discoloration, in children less than 8 years of age. Patients who are transient symptom-free carriers may be managed without antimicrobial therapy if they employ excellent standards of personal and public hygiene. Treatment of these patients, however, will reduce fecal shedding of the organism and may prevent the spread of infection.68, 69

Ciprofloxacin and norfloxacin have been used successfully to treat adults with shigellosis. Norfloxacin given as a single dose to adults was as effective as 5 days of treatment with TMP-SMX. 72 Quinolones are effective in treating adults with resistant strains. Nalidixic acid can be used in children as an alternative drug 73 although resistance has been described. 7~ Campylobaeter. Several studies have evaluated the susceptibility of C. jejuni species to antimicrobial agents. 7476 C. jejuni is susceptible to a wide variety of antimicrobial agents including erythromycin, furazolidone, the quinolones, aminoglycosides, tetracycline, chloramphenicol, and clindamycin; by contrast, penicillin, ampicillin, and the cephalosporins are relatively inactive. Isolation of Campylobacter from stool does not indicate the need for antibiotics; the decision to institute therapy should be made on clinical grounds. In patients with Campylobacter enteritis, erythromycin represents the agent of choice if a decision is made to initiate therapy. In double-blind, placebo-controlled trials of treatment of patients with Campylobacter enteritis, erythromycin promptly eradicated Campylobacter from the feces but did not alter the natural course of enteritis when administered 4 days or longer after the onset of symptoms. Studies in which therapy was started early in the

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Table VII. Antimicrobial therapy for amebiasis Clinical manifestations

Asymptomatic cyst excretor

Antimicrobial agent

Iodoquinol (Yodoxin) or

Paromomycin (Humatin) or Diloxanide furoate (Furamide) * Mild to moderate intestinal disease

Severe intestinal disease

Liver abscess or other extraintestinal amebic disease

Metronidazole first

Followed by iodoquinol or paromomycin Metrnnidazole first Followed next by iodoquinol Or dehydroemetine

Dose

30 mg/kg/day in 3 doses for 20 days (max 2 gm/day) 25-30 mg/kg/day in 3 doses for 7 days 20 mg/kg/day in 3 doses for 10 days (max 1500 rag/day) 35-50 mg/kg/day in 3 doses for 10 days (max 2250 mg/day)

Do not exceed max dose, because of possibility of optic neuritis

Available from Centers for Disease Control Drug Service* Not recommended for pregnant women, especially in first trimester

Same as above Same as above Same as above 1 to 1.5 mg/kg/day (max 90 mg/day) IM in 2 doses for up to 5 days

Followed finally by iodoquinol Metronidazole first

Same as above

Followed next by iodoquinol Or dehydroemetine Followed finally by chloroquine

Same as above

Plus iodoquinol

Comment

See comment for

iodoquinol above; as effective as and less toxic than emetine, which may be substituted

Same as above

Same as above 10 mg base/kg/day (max 300 mg base/day) for 2-3 wk Same as above

Max, Maximum. *Telephone number: (404) 639-3670 or 639-2888. course of illness gave conflicting results with regard to clinical resolution, although C. jejuni was rapidly eliminated from stools. 77'78 Ciprofloxacin and tetracycline are alternative treatments in adults; clindamycin or amoxicillin plus clavulanic acid are alternative choices in children. The treatment of choice for patients with septicemia appears to be gentamicin, although chloramphenicol, tetracycline, and erythromycin have been effective. Other bacteria. Other bacteria that rarely produce diarrhea in children in the United States are E. coli, Yersinia enterocolitica, Vibrio cholerae, and V. parahaemolyticus. The Y. enterocolitica species appears to be a common cause of diarrhea among children in Europe and Canada, 79 although it has been recognized infrequently in the United States. 8~ It is usually susceptible in vitro to arninoglycoside antibiotics, chloramphenicol, tetracycline, T M P - S M X , third-generation cephalosporins, and quinolones.81,82

Strains are often resistant to penicillin, ampicillin, and first-generation cephalosporins. There are no data to support the use of antimicrobial agents in diarrhea caused by this organism. Patients with Y. enterocolitica-induced septicemia should be treated with either gentamicin or chloramphenicol. Good responses have been reported in patients treated with T M P - S M X and ciprofloxacin. Despite treatment, the mortality rate for this condition approaches 50%. The V. parahaemolyticus species is a halophilic marine organism that is recognized as a major cause of acute diarrhea in Japan and has been incriminated in food outbreaks involving raw or inadequately cooked shellfish in the United States. 83 The disease is self-limited, and antimicrobial therapy shortens neither the clinical course nor the duration of fecal excretion of the organism. Diarrhea caused by infection with V. cholerae is uncommon in the United States, although the organism may be

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T a b l e VIii. Antimicrobial therapy for enteric parasites in children

Organism

Antimicrobial agent

Cryptosporidium Isospora belli

None available TMP-SMX

Microsporidium Strongyloides

None available Thiabendazole

Dose

Side effects

TMP 5 mg/kg, SMX 25 mg/kg every 8 hr for 10 days, then every 12 hr/2 wk (max 160 mg TMP, 800 mg SMX/dose)

Considered an investigational drug for this condition by FDA

50 mg/kg/day in2 doses (max 3 gm/day) for 2 days

Dose may be toxic and require decrease; considered investigational drug for this condition by FDA

For Giardia lamblia, see TableVI; for Entamoeba histolytica, see Table VII. Max, Maximum.

endemic along the Gulf Coast. 84 Oral fluid-and-electrolyte therapy is the mainstay of treatment. Antimicrobial therapy for gastroenteritis from cholera will shorten the duration of diarrhea and reduce fluid losses. For most patients, tetracycline is the drug of choice (Table III).85-87 Other effective antimicrobial agents are ampicillin, chloramphenicol, TMP-SMX, furazolidone, and multiple- and singledose doxycycline.88' 89 V. cholerae has remained relatively susceptible to antibiotics, most likely because only a few types of plasmids are stable in these organisms. Nevertheless, resistance to tetracycline, streptomycin, chloramphenicol, sulfonamides, ampicillin, kanamycin, and TMP-SMX has been reported. 7~ Diarrhea from enterotoxigenic E. coli is usually self-limited, but studies have shown that antimicrobial agents such as TMP-SMX or ciprofloxacin are effective. 9~ Little is known about the treatment of enteroinvasive E. coli infection because it is usually not diagnosed. Antimicrobial therapy should be similar to that provided to patients with shigellosis, and susceptibility studies should be performed on the organism. Little is known about therapy for enterohemorrhagic E. coli infections. Protozoal agents. With the advent of the AIDS epidemic, there has been a renewed interest in the treatment of parasitic infections of the gastrointestinal tract. In patients with normal immune systems, infections with these organisms are generally of short duration and respond to therapy when available; however, the clinical course may be protracted in children with AIDS. Parasitic diseases of the gastrointestinal tract that fit the Centers for Disease Control surveillance definition for AIDS are those caused by Cryptosporidium and Isospora. 9I Tables VI, VII, and VIII show the recommended therapy for infection with enteric parasitic organisms.92 Several of these compounds have severe adverse effects that should be considered against the potential benefit of therapy.

Quinacrine hydrochloride, metronidazole, and furazolidone are effective in treating patients with infection caused by G. lamblia. 93 Metronidazole may be better tolerated than quinacrine, but it is more expensive and may be slightly less effective. In addition, metronidazole is carcinogenic in rodents and mutagenic in bacteria, and is considered an investigational drug for this condition by the FDA. Outside the United States, ornidazole and tinidazole are also used. Quinacrine hydrochloride may produce a yellow discoloration of the skin that is harmless and disappears after the drug is stopped. 94 Furazolidone is the only one of these three compounds available in a liquid form; like quinacrine, it is less expensive than metronidazole. It can be used in children95 if compliance is a problem with quinacrine and metronidazole, both of which have an objectionable taste. The dosage schedule for children and adults is given in Table VI. Iodoquinol is the recommended drug to eradicate both cysts and trophozoites in the lumen of the gastrointestinal tract (Table VII). Invasive amebiasis of the intestine, liver, or other organs necessitates the additional use of tissue amebicides such as metronidazole. Table VII shows the recommended drugs for treatment of children with various forms of amebiasis.92 Infection with Cryptosporidium is self-limited in immunocompetent individuals; however, patients with AIDS have large-volume, intractable diarrhea. Specific antimicrobial therapy for Cryptosporidium is not available. Spiramycin has been used 96 but is generally thought to be ineffective. Orally administered bovine transfer factor, hyperimmune colostrum, and cow milk immunoglobulin are all being evaluated. 97,98 Octreotide (Sandostatin), 300 to 500 ~g three times per day subcutaneously, may control the severe diarrhea that occurs in patients with AIDS, although it has no effect on the infection.26 Unlike Cryptosporidium, lsospora organisms respond to

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t r e a t m e n t with T M P - S M X (Table V I I I ) . However, recurrent s y m p t o m a t i c disease occurs in 50% of patients. 99 Recurrent disease m a y be prevented by prophylaxis with T M P - S M X or weekly doses of pyrimethamine-sulfadoxine (Fansidar). Both of these compounds are considered investigational for isosporiasis by the FDA. In sulfonamide-sensitive patients, such as those with A I D S , p y r i m e t h a m i n e has been effective in adults. 1~176 In i m m u n o c o m p r o m i s e d patients, therapy may need to be continued indefinitely. Patients who receive T M P - S M X or pyrimethamine-sulfadoxine should be monitored carefully for bone m a r r o w suppression, skin reactions, and allergic manifestations. Persons infected with S. stercoralis should be treated with thiabendazole. In i m m u n o c o m p r o m i s e d patients with Strongyloides hyperinfection, it m a y be necessary to continue therapy for 2 to 3 weeks; however, the mortality rate is high despite therapy. A thorough e x a m i n a t i o n should be performed before immunosuppressive t h e r a p y is given to a patient with a history of infection with S. stercoralis. T r e a t m e n t with albendazole or ivermectin has also been effective. N o effective therapy is available for patients infected with Microsporidium. 1~ I thank Irene Townsend, RN, for her assistance in preparing this manuscript. REFERENCES

1. Pickering LK, Evans DG, DuPont HL, Vollet J J, Evans DJ. Diarrhea due to Shigella, Rotavirus and Giardia in day-care centers: prospective study. J PEDIATR 1981;99:51-6. 2. Pickering LK, Bartlett AV, Woodward WE. Acute infectious diarrhea in day-care children: epidemiology and control. Rev Infect Dis 1986;8:539-47. 3. Kean BH. Travelers' diarrhea: an overview. Rev Infect Dis 1986;8:5111-6. 4. Levine WC, Stephenson WT, Craun GF. Waterborne disease outbreaks, 1986-1988. MMWR 1990;39:1-13. 5. Bean NH, Griffin PM, Goulding JS, Ivey CB. Foodborne disease outbreaks: 5-year summary, 1983-1987. M M W R 1990;39:15-23. 6. Doyle MG, Pickering LK. Gastrointestinal tract infections in children with AIDS. Semin Pediatr Infect Dis 1989;1:64-72. 7. Pickering LK, Cleary KR. Gastrointestinal and nutritional problems in children with AIDS. In: Pizzo PA, Wilfert CM, eds. Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Baltimore: Williams & Wilkins (in press). 8. Arbo A, Santos JI. Diarrheal disease in the immunocompromised host. Pediatr Infect Dis J 1987;6:894-906. 9. Higgins JA, Code CF, Orvis AL. The influence of motility on the rate of absorption of sodium and water from the small intestine of healthy persons. Gastroenterology 1956;31:708-16. 10. DuPont HL, Hornick RB. Adverse effect of Lomotil therapy in shigellosis. JAMA 1973;226:1525-8. 11. Ginsburg CM. Lomotil (diphenoxylate and atropine) intoxication. Am J Dis Child 1973;125:241-2. 12. Rumack BH, Temple AR. Lomotil poisoning. Pediatrics 1974;53:495-500.

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13. McClung H J, Beck RD, Powers P. The effect of kaolin-pectin adsorbent on stool losses of sodium, potassium, and fat during a lactose-intolerance diarrhea in rats. J PEDIATR 1980; 96:769-71. 14. Portnoy BL, DuPont HL, Pruitt D, Abdo JA, Rodriguez JT. Antidiarrheal agents in the treatment of acute diarrhea in children. JAMA 1976;236:844-6. 15. Clements ML, Levine MM, Black RE, et al. Lactobacillus prophylaxis for diarrhea due to enterotoxigenic Escherichia coil Antimicrob Agents Chemother 1981 ;20:104-8. 16. Levine MM, Hornick RB. Lactulose therapy in Shigella carrier state and dysentery. Antimicrob Agents Chemother 1975;8:581-4. 17. Pearce JL, Hamilton JR. Controlled trial of orally administered lactobacilli in acute infantile diarrhea. J PEDIATR 1974;84:261-2. 18. Ericsson CD, Evans DG, DuPont HL, Evans D J, Pickering LK. Bismuth subsalicylate inhibits activity of crude toxins of Escherichia coli and Vibrio cholerae. J Infect Dis 1977; 136:693-6. 19. Feldman S, Chen SL, Picketing LK, Cleary TG, Ericsson CD, Hulse M. Salieylate absorption from a bismuth subsalicylate antidiarrheal preparation (Pepto-Bismol). Clin Pharmacol Ther 1981;29:788-92. 20. Pickering LK, Feldman S, Ericsson CD, Cleary TG. Absorption of salicylate and bismuth from a bismuth subsalicylate containing compound (Pepto-Bismol). J PEDIATR 1981; 99:654-6. 21. Mendelowitz PC, Hoffman RS, Weber S. Bismuth absorption and myoclonic encephalopathy during bismuth subsalicylate therapy. Ann Intern Med 1990;112:140-1. 22. Parpia SH, Nix DE, Hejmanowski LG, Goldstein HR, Wilton JH, Schentag JJ. Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrob Agents Chemother 1989;33:99-102. 23. Novak E, Lee JG, Seckman CE, Phillips JP, DiSanto AR. Unfavorable effect of atropine-diphenoxylate (Lomotil) therapy in lincomycin-caused diarrhea. JAMA 1976;235:1451-4. 24. Rateau JG, Morgant G, Droy-Priot MT, Parier JL. A histological, enzymatic and water-electrolyte study of the action of smectite, a mucoprotective clay, on experimental infectious diarrhoea in the rabbit. Curr Med Res Opinion 1982;8:23341. 25. Fioramonti J, Droy-Lefaix MT, Bueno L. Changes in gastrointestinal motility induced by cholera toxin and experimental osmotic diarrhoea in dogs: effects of treatment with an argillaceous compound. Digestion 1987;36:230-7. 26. Cook D J, Kelton JG, Stanisz AM, Collins SM. Somatostatin treatment for cryptosporidial diarrhea in a patient with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1988;108:708-9. 27. Evans NAP, Hendrickse RG, Macfarlane SBJ and others in the Diarrhoea! Diseases Study Group (UK). Loperamide in acute diarrhoea in childhood: results of a double-blind, placebo-controlled multicentre clinical trial. Br Med J 1984;289: 1263-7. 28. Motala C, Hill ID, Mann MD, Bowie MD. Effect of loperamide on stool output and duration of acute infectious diarrhea in infants. J PED1ATR 1990;117:467-71. 29. Bergstrom T, Alestig K, Thoren K, Trollfors B. Symptomatic treatment of acute infectious diarrhoea: loperamide versus placebo in a double-blind trial. J Infect 1986;12:35-8.

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30. Soriano-Brucher HE, Avendano P, O'Ryan M, Soriano HA. Use of bismuth subsalicylate in acute diarrhea in children. Rev Infect Dis 1990;12(suppl):S51-6. 31. Ericsson CD, DuPont HL, Mathewson J J, West MS, Johnson PC, Bitsura JAM. Treatment of travelers' diarrhea with sulfamethoxazole and trimethoprim and loperamide. JAMA 1990;263:257-61. 32. Bartlett JG. Antimicrobial agents implicated in Clostridium diffieile toxin-associated diarrhea or colitis. Johns Hopkins Med J 1981;149:6-9. 33. Batts DH, Martin D, Holmes R, Silva J, Fekety FR. Treatment of antibiotic-associated Clostridium diffieile diarrhea with oral vancomycin. J PEDIATR 1980;97:151-3. 34. Fekety R, Silva J, Kauffman C, Buggy B, Decry HG. Treatment of Clostridium difficile antibiotic-associated colitis with oral vancomycin: comparison of two dosage regimens. Am J Med 1989;86:15-9. 35. Cherry RD, Portnoy D, Jabbari M, Daly DS, Kinnear DG, Goresky CA. Metronidazole: an alternate therapy for antlbiotic-associated colitis. Gastroenterology 1982;82:849-51. 36. Tedesco FJ. Bacitracin therapy in antibiotic-associated pseudomembranous colitis. Dig Dis Sci 1980;25:783-93. 37. Young GP, Ward PB, Bayley N, et al. Antibiotic-associated colitis due to Clostridium d~fficile: double-blind comparison of vancomycin with bacitracin. Gastroenterology 1985; 89:1038-45. 38. Dudley MN, McLaughlin JC, Carrington G, Frick J, Nightingale CH, Quintiliani R. Oral bacitracin vs. vancomycin therapy for Clostridium diffieile-induced diarrhea: a randomized double-blind trial. Arch Intern Med 1986;146: 1101-4.

39. deLalla F, Privitera G, Rinaldi E, Ortisi G, Santoro D, Rizzardini G. Treatment of Clostridium diffieile-associated disease with teicoplanin. Antimicrob Agents Chemother 1989; 33:1125-7. 40. Rosenthal SL. Exacerbation of Salmonella enteritis due to ampicillin. N Engl J Med 1969;280:147-8. 4I. Aserkoff B, Bennett JV. Effect of antibiotic therapy in acute salmonellosis on the fecal excretion of salmonellae. N Engl J Med 1969;281:636-40. 42. Nelson JD, Kusmiesz H, Jackson LH, Woodman E. Treatment of Salmonella gastroenteritis with ampicillln, amoxicillin, or placebo. Pediatrics 1980;65:1125-30. 43. Pillay N, Adams EB, Coombes DN. Comparative trial of amoxicillin and chloramphenicol in treatment of typhoid fever in adults. Lancet 1975;2:333-4. 44. Robertson RP, Wahab MFA, Raasch FO. Evaluation of chloramphenicol and ampicillin in Salmonella enteric fever. N Engl J Med 1968;278:171-6. 45. Ryan CA, Hargrett-Bean NT, Blake PA. Salmonella typhi infections in the United States, 1975-1984: increasing role of foreign travel. J Infect Dis 1989;11:1-8. 46. Bryan JP, Rocha H, Scheld WM. Problems in salmonellosis: rationale for clinical trials with newer beta-lactam agents and quinolones. Rev Infect Dis 1986;8:189-207. 47. Soe GB, Overturf GD. Treatment of typhoid fever and other systemic salmonelloses with cefotaximine, ceftriaxone, cefoperazone, and other newer cephalosporins. Rev Infect Dis 1987;9:719-36; 48. Moosa A, Rubidge CJ. Once-daily ceftriaxone vs. chloramphenicol for treatment of typhoid fever in children. Pediatr Infect Dis J 1989;8:696-9.

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71. Nelson JA, Haltalin KC. Amoxicillin less effective than ampicillin against Shigella in vitro and in vivo: relationship of efficacy to activity in serum. J Infect Dis 1974;129 (suppl):S222-7. 72. Gotuzzo E, Oberhelman RA, Maguina C, et at. Comparison of single-dose treatment with norfloxacin and standard 5-day treatment with trimethoprim/sulfamethoxazole for acute shigellosis in adults. Antimicrob Agents Chemother 1989; 33:1101-4. 73. Salam MA, Bennish ML. Therapy for shigellosis. I. Randomized, double-blind trial of nalidixic acid in childhood shigellosis. J PED~ATR 1988;113:901-7. 74. Chow AW, Pattern V, Bednorz D. Susceptibility of Campylobacter fetus to twenty-two antimicrobial agents. Antimicrob Agents Chemother 1978;13:416-8. 75. Karmali MA, DeGrandis S, Fleming PC. Antimicrobial susceptibility of Campylobacterjejuni with special reference to resistance patterns of Canadian isolates. Antimicrob Agents Chemother 1981;19:593-7. 76. Taylor DE, Courvalin P. Mechanisms of antibiotic resistance in Campylobacter species. Antimicrob Agents Chemother 1988;32:1107-12. 77. Salazar-Lindo E, Sack B, Chea-Woo E, et al. Early treatment with erythromycin of Campylobaeter jejuni-associated dysentery in children. J PEDIATR 1986;109:355-60. 78. Williams D, Schorling J, Barrett L J, et al. Early treatment of Campylobacter jejuni enteritis. Antimicrob Agents Chemother 1989;33:248-50. 79. Marks MI, Pai CH, Lafleur L, Lackman L, Hammerberg O. Yersinia enteroeolitiea gastroenteritis: a prospective study of clinical bacteriologic and epidemiologic features. J PED~ATR 1980;96:26-31. 80. Kohl S. Yersinia enterocolitica infection. Pediatr Clin North Am 1979;26:433-43. 81. Bottone EJ. Yersinia enterocolitica: a panoramic view of a charismatic microorganism. CRC Crit Rev Microbiol 1977;5: 211-5. 82. Hoogkamp-Korstanje JAA. Antibiotics in Yersinia enteroeolitiea infections. J Antimicrob Chemother 1987;20:123-31. 83. Barker WH Jr. Vibrio parahaemolytieus outbreaks in the United States. Lancet 1974;1:551-4. 84. Blake PA, Allegra DT, Snyder JD, et al. Cholera-a possible endemic focus in the United States. N Engl J Med 1980; 302i305-9. 85. Kobari K, Uylangco C, Vasco J, Takahira Y, Shimizu N. Observations on cholera treated orally and intravenously with antibiotics, with particular reference to the number of vibrios excreted in the stool. Bull WORLD Health Organ 1967; 37:751-62. 86. Lindenbaum J, Greenough WB III, Islam MR. Antibiotic therapy of cholera. Bull WORLD Health Organ 1967;36:87183.

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Therapy for acute infectious diarrhea in children.

This article reviews current recommendations of therapy with antidiarrheal compounds and antimicrobial agents for acute infectious diarrhea in childre...
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