Enteropathogenic Organisms: New Etiologic Agents and Concepts of Disease

Symposium on Infectious Diseases

Enteropathogenic Organisms New Etiologic Agents and Concepts of Disease

Herbert L. DuPont, M.D. *

Recent advances in our knowledge of the agents associated with intestinal infection have helped to establish that most acute diarrhea is caused by infectious microorganisms and therefore is susceptible to therapy, control, or prevention. Historically, physicians have treated all patients with acute diarrhea in a similar fashion since an etiologic diagnosis was seldom made. Now that the clinical importance of newer enteropathogens is being established and the pathogenic mechanisms of infection are being characterized it is possible to classify diarrheal illness into one of several categories based on clinical presentation. In this review, we will examine the agents which commonly cause acute diarrhea with a focus on characteristics of virulence and methods of detection, pathogenesis of infection, and clinical features. We will then briefly discuss the problem of traveler's diarrhea and finally present an approach to the work-up and management of patients with acute diarrhea.

ETIOLOGIC AGENTS IN ACUTE DIARRHEA Escherichia coli (Enterotoxigenic, Enteropathogenic, and Invasive E. Coli) During the 1940's and 1950's, outbreaks of acute diarrhea occurred in hospital nurseries and strains of E. coli identified by serotype were isolated from stool and occasionally the blood of affected infants. These studies lead to the conclusion that certain serotypes of E. coli were etiologic agents in infantile diarrhea. These strains identified by serotype have been called enteropathogenic E. coli, or EPEe. In 1970, *Professor and Director, Program in Infectious Diseases and Clinical Microbiology, The University of Texas Medical School at Houston, Houston, Texas Studies reported herein were supported by grant AI 12699 and contract N01 AI 72534 from the National Institutes of Health. I Bujnoch helped to prepare the manuscript.

Medical Clinics of North America - Vol. 62, No. 5, September 1978

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HERBERTL. DUPONT

Figure 1. Dilated rabbit intestine 18 hours after instillation of a filtrate containing heat-labile E. coli enterotoxin.

an outbreak of diarrhea was described among a British military population stationed in the Middle East, and was found to be caused by an 0148 strain of E. coli,42 later shown to produce an enterotoxin. This was the first time that adults were shown to be at significant risk for the development of enteric disease caused by strains of E. coli. The properties whereby strains of E. coli produce diarrhea in man are just now being characterized. As with other microbial pathogens, the ability of an organism to adhere to the intestinal epithelium may be the primary prerequisite for enteric infection. 17 For many strains of E. coli, the adhesive factor appears as a surface protein of fimbriate morphology which has been called colonization factor antigen (CFA). Colonization potential of various enteric bacteria can be determined by showing colony counts of bacteria in the upper gut in suckling rabbits after intragastric inoculation. 17 The colonization factor antigen can be screened from among bacterial isolates in view of the occurrence of a mannose-resistant hemagglutination of human erythrocytes 16 and can be confirmed morphologically by immune electron microscopy.17 Many pathogenic strains of E. coli produce either a heat-labile enterotoxin (LT) which is antigenically and physiologically related to cholera toxin or a non-antigenic heat-stable toxin (ST) of smaller molecular weight. Some strains may produce both. E. coli which produce a heat-labile enterotoxin lead to diarrhea by stimulating the sjl1all intestinal mucosa to secrete fluid and electrolytes, probably via adenyl cyclase/cyclic AMP mechanisms. 13 The mode of action of heat~stable toxin is unknown. Production of heat-labile enterotoxin has traditionally been assayed by showing dilatation of ligated loops of rabbit ileum secondary to the secretory effects of filtrates containing the toxin -(Fig. 1). Animal assays for heat-labile enterotoxin and tissue culture techniques 5 probably will be replaced by serologic procedures 14 now that the toxin has been purified. Heat-stable toxin is currently detected by the suckling mouse assay. 4 Cell-free filtrates (0.1 ml) are injected into the milk-filled stomachs of 1 to 4 day old mice and the animals are sacrificed 2 to 4 hours later. A ratio of intestinal weight to body weight of 0.09 or greater indicates activity of heat-stable toxin (see Fig. 2). Production of colonization factor antigen and heat-stable and heatlabile enterotoxin appears to be under plasmid control, so that any

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Figure 2. Suckling mouse model for heat-stable E. coli enterotoxin. The mouse on the right has a dilated intestine and the one on the left shows a negative response.

gram-negative rod theoretically is capable of becoming virulent for man. However, there appears to be a relationship between the production of these virulent properties, and somatic and flagellar antigens 15 which suggests that certain "carrier" bacteria are better recipients of the plasmids for virulence. The importance of enterotoxigenic E. coli as a cause of human illness has been defined only for a few populations. E. coli producing heat-labile enterotoxin represents the most important single cause of diarrhea among United States travelers to Mexico and is isolated from diarrheal stools in approximately half the cases. These strains have been identified as causes of diarrhea in Bangladesh 44 and in Kenya45 as well. While a few studies have supported the role of heat-labile E. coli in pediatric cases of diarrhea, more recent studies conducted over a greater period of time in different geographic locations of North America show a rarity of organism isolation in diarrheal stools. 25 , 38 Evidence has been offered that there is an age-related acquistion of antibodies to heat-labile enterotoxin from birth to 3 years of age,43 suggesting that the strains may commonly produce an asymptomatic infection. The most characteristic clinical finding in heat-labile E. coli infection is watery diarrhea. Vomiting may occur early in the infection and

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mild to moderate abdominal cramping or pain usually is described. When fever occurs, it is usually low grade and not a prominent feature. While the average disease in adults in Mexico consists of the passage of 12 unformed stools over a period of 5 days, the spectrum of clinical symptoms ranges from 1 unformed stool and self-limiting illness to a cholera-like disease with massive fluid losses. Little is known about the clinical expression of illness caused by the heat-stable strains. In recent years there has been a great deal of discussion about the significance of serotype-identified E. coli (the EPEe strains). Some currently believe that serotyping is of little value in determining pathogenicity of E. coli isolates. 19 Others have adamantly maintained that these strains are important causes of human illness since they are associated with 10 to 20 per cent of cases of pediatric diarrhea and because serotypically identified common strains have been isolated from both stool and blood of infants during nursery outbreaks. 24 It is generally agreed that the classical serotypes of enteropathogenic E. coli do not usually produce heat-labile or heat-stable toxins as they are currently assayed. 20 However, these strains may be virulent for man by a mechanism(s) as yet unrecognized. One virulent property recently identified in certain strains of enteropathogenic E. coli is production of a toxin closely resembling that elaborated by Shigella dysenteriae 1, the Shiga bacillus. 35 The cytotoxin is assayed in HeLa cells and is neutralized by Shiga antitoxin. In a study of the clinical characteristics of acute diarrhea, patients with an enteropathogenic E. coli in stool appeared to have a distinct clinical syndrome. 26 These findings, together with the demonstration that enterotoxigenic E. coli from various parts of the world often are of the same serotype, including 06:H16, 08:H9, 015:Hll, 025:H42, 078:Hll and 078:H12,36 have led to a renewed interest in serotyping as a means of detecting enteropathogens. It is likely, however, that prevalent serotypes of enteropathogenic E. coli will have to be re-evaluated on a prospective yearly basis to allow the laboratory to keep up with shifts in serotype which undoubtedly must occur with E. coli as it does with other microbial agents. Studies examining pathogenic potential and virulence must continue before the true importance of serotype-identified strains of E. coli in human diarrhea will be known. Strains of E. coli have been identified that behave identically with shigella isolates wherein invasion of the intestinal mucosa occurs and typical bacillary dysentery is seen.7 The invasiveness as studied in shigella strains is a chromosomal property and not likely to be transmitted between bacterial strains. The similarity of these two groups of bacteria is further appreciated in view of the fact that most isolates of invasive E. coli agglutinate in the presence of shigella antiserum. Between October and December of 1971, there was a series of outbreaks in the United States caused by an invasive strain of E. coli that had contaminated imported French cheese. 31 Except for this epidemic, invasive E. coli have not been shown to be an important cause of diarrhea in the United States. To prove that an organism isolated from

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Figure 3. Guinea pig eye model (Sereny test) for invasiveness. An invasive E. coli or a shigella strain produce purulent keratoconjunctivitis.

stool of patients with bacillary dysentery is invasive (either an E. coli or shigella isolate), the most reliable test'is the guinea pig eye model, the Sereny test. 46 Heavy suspensions of the freshly isolated strain are dropped into--the conjunctival sac of a guinea pig. Within 1 to 7 days, purulent keratoconjunctivitis develops (Fig. 3). Strains must be tested within one month of primary isolation since the property of invasiveness appears to be reduced or lost with age of the isolate. Shigella Species Shigella strains have been implicated as causes of diarrhea since the turn of the century. The approximately 40 serotypes of shigella are divided into four serogroups: A, S. dysenteriae, B, S. flexneri, C, S. boydii, and D, S. sonnei. During acute illness, the organism is present in sufficient numbers so as to be easily cultivated by routine microbiologic diagnostic techniques. Shigella produce clinical symptoms after invading the gut wall and causing inflammation and tissue destruction. Early in the infection there is a small bowel phase (which may be mediated by an enterotoxin released by the growing bacteria) associated with voluminous watery stools, high fever, and occasionally vomiting. Later in the illness, when the organisms no longer are found in the small intestine, they have reached the colon and invaded the mucosa, and patients characteristically experience fecal urgency, tenesmus, and bloody, mucoid stools (dysentery) of greater frequency and smaller volume. During this stage of illness, proctoscopy reveals an erythematous colonic mucosa with ecchymoses, friability, excess mucus secretion, and occasionally small ulcerations. If stool or mucus is examined microscopically, utilizing a methylene blue wet mount preparation,28 numerous polymorphonuclear leukocytes will generally be seen (Fig. 4). Shigella strains can be identified as causative agents in somewhere between 10 and 20 per cent of cases of acute diarrhea, its incidence being highest in the summer time. The illness tends to be more serious than other common forms of diarrhea and it is common for patients, particularly children, to be admitted to the hospital. Often, affected children are admitted to the hospital with hyperpyrexia with or without an aS'sociated seizure, and diarrhea occurs only later, after admission.

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Figure 4. Methylene blue wet mount preparation of stool showing numerous leukocytes. Such an exudative response indicates the presence of a diffuse colitis.

Salmonella Species Not all of the more than 1000 serotypes of salmonella appear in man. While any serotype may on occasion produce diarrhea, the majority of cases are caused by less than 20 serotypic variations. In contrast to shigella strains which are more easily recovered in diarrhea, stools from patients in whom infection by salmonella species is suspected should be enriched by overnight incubation in Selinite, tetrathionate, or gram-negative broth to assure multiplication to levels easily detectable by routine diagnostic microbiologic techniques. Salmonellae are invasive bacteria which are able to penetrate the epithelial cell directly, without destruction,48 and reach the lamina propria. The nature of intestinal inflammatory response appears to influence the type of illness which results. In typhoid fever, a mononuclear cell response appears to be produced and the leukocytes appear to transport the organisms to mesenteric lymph nodes and finally into the portal circulation. In the case of nontyphoidal salmonellosis, the bacteria elicit a polymorphonuclear leukocytic exudate, are phagocytized and locally confined, and the clinical expression is most commonly acute gastroenteritis with vomiting and diarrhea. Worldwide, salmonellosis appears to be approximately as important as shigellosis as a human illness. It is more likely to be spread by common sources (water or food) than shigellosis, which is characteristically spread from person to person. Stools often contain mucus, and gross blood is unusual. As in shigella infection, stools from patients with salmonellosis usually show an inflammatory exudate when examined microscopically. 28

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951

Miscellaneous Bacterial Pathogens Recent evidence suggests that campylobacters are important causes of diarrhea,47 possibly approximating the frequency of cases caused by shigella and salmonella. These microaerophilic vibrios have special media, temperature and oxygen requirements. The development of a selective culture medium has simplified the isolation of campylobacters from feces. Further studies are indicated to determine their overall importance as causative agents of diarrhea. Vibrio parahemolyticus is the most important cause of summertime diarrhea in Japan. This marine vibrio contaminates fish and shellfish and has produced rare foodborne epidemics in the United States. The illness is associated with fever and occasionally dysentery (bloody, mucoid stools) suggesting that the strain produces disease after intestinal invasion. Other agents occasionally identified as causing diarrhea are Bacillus cereus, Aeromonas species and Yersinia enterocolitica. Clostridium perfringens is an important cause of mild food poisoning occasionally implicated in huge outbreaks. The organism is a strict anaerobe but resembles toxigenic E. coli in that a secretory toxin is released during illness, leading to intestinal loss of fluids and electrolytes,6 probably also in relation to adenyl cyclase mechanisms. 4o Certain strains of Staphylococcus aureus produce a heat-stable toxin in food which is not properly refrigerated and produce a striking syndrome shortly after the food containing the exotoxin is eaten. Staphylococcal food poisoning is an intoxication, and not an infection and the bacteria may be destroyed be re-heating the food vehicle prior to ingestion. The clinical illness, which includes vomiting and retching out of proportion to diarrhea, along with the lack of a positive rabbit loop response, strongly suggests that the staphylococcal toxin is primarily a neurotoxin and not a secretory enterotoxin. Viral Agents Electronmicroscopic detection of rotaviruses and parvovirus-like agents has helped to establish these agents as major causes of acute diarrhea. Currently, rotaviruses are detected in stool by electron microscopic examination of fecal suspensions (Fig. 5). The virus is a 70 nm particle which resembles a reovirus. In children, the agent is present in high concentrations, and tedious ultracentrifugation techniques are not necessary.39 Serologic procedures are just now becOIning available for identification of virus or for characterization of humoral immune response to infection including counterimmune electrophoresis, com- . plement fixation, and an enzyme-linked immunosorbent assay (ELISA)51 using animal rotaviruses which are antigenically related to the human agent(s). Once these tests are readily adaptable for the routine diagnostic laboratory, we will quickly accumulate information on this agent. Rotavirus diarrhea is a common problem in infants and children under 3 years of age with a seasonal wintertime peak in temperate climates. In warmer environments, there is a less impressive relationship with seasonality. The agents probably explain 30 to 50 per cent

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Figure 5. Rotavirus (identified by electron microscopy) in stool from a child with diarrhea.

of pediatric diarrhea. Clinical symptoms include a sudden onset, high frequency of vomiting, low-grad~ fever, and watery diarrhea of brief duration. While illness is usually mild and self-limiting, fatalities may occur. 3 Secondary transmission of rotavirus illness to family members occurs,21 and infection may' be more common in adults than commonly appreciated. 2 Parvovirus-like agents are smaller (27 nm in size) and are apparently not important causes of endemic disease. ~ey produce large outbreaks of diarrhea in children and adults. Differing antigenic types of virus have been identified by cross-challenge experiments in volunteers. 50 As in rotavirus infection, the most prominent symptom is vomiting, which is followed in frequency by low-grade fever and watery diarrhea. The agent is difficult to identify in cases or diarrhea, and infection may be detected by finding the virus in stool by immune electronmicroscopy utilizing serum obtained from persons convalescing from infection 29 or by showing seroconversion to the agent by serologic methods. 23 Protozoal Agents

A clear relationship between infection by parasitic agents and occurrence of acute diarrhea exists only for Giardia Lamblia and Entamoeba histolytica. They should be considered as possible agents when diarrhea persists longer than one to two weeks. G. Lamblia is a more important agent than is commonly appreciated, and E. histolytica is often overestimated in importance, especially in chronic diarrhea.

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ENTEROPATHOGENIC ORGANISMS

Giardiasis is a small bowel infection associated with a highly variable clinical expression. Patients may present with acute, watery diarrhea, with or without fever, or they may give a history of chronic and recurrent diarrhea with malabsorption lasting months and even years. Approximately half of patients with giardiasis will have the causative agent identified in stool (either cysts or trophozoites of C. lamblia) , whereas in some cases it is necessary to examine small bowel fluid or d:u.odenal mucosal biopsy touch preparations for the trophozoites. Amebiasis is suggested by finding bloody stools. The optimal way to look for E. histolytica is to obtain rectal mucosal scrapings with a glass spatula or to select material from an ulceration visualized through a proctoscope and quickly examining a wet mount preparation microscopically for the motile trophozoites with ingested red blood cells. Because of the lack of an intense inflammatory reaction between colonic mucosal ulcerations, a much less impressive leukocytic exudate is usually found when stool or mucus from patients with amebiasis is examined microscopically. It has been emphasized since the early 1900's that the fecal leukocyte test could readily distinguish between bacillary and amebic dysentery.

DIARRHEA IN UNITED STATES TRAVELERS TO LATIN AMERICA The frequency and symptomatology of traveler's diarrhea have been known for some time. 30 Soon after arriving in a foreign country (the syndrome occurs in countries other than Mexico), a person experiences diarrhea with a variable degree of fever, abdominal pain and

Ves

Mild Illness'

~

....

(Table 2)

Ne~a~

);ative

No

High Fever, Profuse Diarrhea or Dehydration'

Symptomatic

Treatment

Stool leukocyte

Ves

Exam

Positive

(Figure 4)

Perform Stool Culture for Shigella, Salmonella

Positive for .... Salmonella ~

Treat as Salmonellosis, Withhold Antibiotics (Table 3)

NegatiY

Or

Treat for Amebiasis (Table 3)

Positive

Positive for

Stool Exam for E. histolytica

Shigella

Negat~ Stools Have Gross Blood'

Ves

--"" ~

Stool leukocyte

Exam

~7 Positive (Figure 4)

Treat for Shigellosis (Table 3)

• All patients should receive fluid and electrolyte therapy

Figure 6.

An algorithm for management of patients with acute diarrhea.

954

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cramps, and vomiting. Natural immunity is present in persons who live in endemic areas. IO The single most important cause of diarrhea is probably heat-labile toxin-producing E. coli,22 which appears to be responsible for approximately half the cases. The remaining cases are caused by the other common enteric pathogens including shigella and salmonella strains, G. lamblia, E. histolytica, and rotavirus. 2 , 10,32 Evidence suggests that food is the major vehicle through which infection occurs. 49 The major way to avoid the problem is to eat in restaurants which have a legitimate reputation for safety (Le., where past experience indicates a low frequency of associated diarrhea), to eat cooked food which is brought to the table steaming (the food that is spicy-hot is not inherently safe!), to eat peeled fruits and to drink bottled carbonated beverages. Leafy green vegetables should be avoided. 32 Diagnosis and treatment of this condition is similar to other forms of diarrhea (Fig. 6, Tables 2 and 3). APPROACH TO THE PATIENT WITH ACUTE DIARRHEA When Diarrhea Occurs with Associated Cases Initially, the physician should attempt to determine if other cases of diarrhea have occurred simultaneously among the patient's family members or social contacts. If they have, he should estimate the incubation period, determine the presence or absence of fever, and establish whether or not vomiting is out of proportion to diarrhea (Table 1). A short incubation period suggests intoxication by staphylococcal toxin, especially if vomiting is the prominent feature of the illness and the patient does not have fever. A longer incubation period and lack of fever in affected individuals suggests an enterotoxin-mediated infection; if it occurs in the United States and involves many persons, C. perfringens is the likely cause, whereas in Latin America, enterotoxigenic E. coli should be considered. When fever is an important feature of illness, invasive pathogens should be considered such as shigella and salmonella. Less commonly, febrile diarrhea is caused by invasive E. coli or by V. parahemolyticus (in the United States, in warm months where seafood is incriminated). When Diarrhea Occurs as a Single Case Most cases of diarrhea occur without obvious association with other cases. Figure 6 offers a conceptual approach to the evaluation of acute sporadically occurring diarrhea. The algorithm divides patients into three groups depending upon severity of underlying disease and presence of gross blood in stool. From a costlbenefit standpoint, laboratory studies of stools for etiologic agents cannot be justified in all patients with acute diarrhea. In those with more serious illness, the fecal leukocyte test (Fig. 4) is invaluable in helping to select a course of action. The finding of numerous white cells in stools is usually associated with the invasive colonic pathogens, shigella and salmonella;

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Table 1.

Frequent Agents in Common Source (Water or Food) Outbreaks of Diarrhea VOMITING OUT OF

INCUBATION

FEVER IN ONE

PROPORTION TO

PROBABLE

ESTABLISHMENT

PERIOD

OR MORE

DIARRHEA

ETIOLOGY

OF DIAGNOSES

Staphylococcus aureus toxin

4 hrs

No

Yes

>6-8 hrs

Yes

Yes or No

Shigella, invasS tool culture sive E. coli, Salmonella, V. parahemolyticus

>6-8 hrs

No

Yes or No

Clostridium perfringens, Enterotoxigenic E. coli

<

Clinically diagnosed

Diagnostic lab unable to routinely detect

these bacteria are the only ones routinely detected by stool culture. Prevalent fecal leukocytes indicate colitis and the finding is not pathognomonic of disease from a specific etiologic agent. In a patient with bloody stools, when numerous white cells are found in stool the probable diagnosis is bacillary dysentery (shigellosis) and the patient can be treated empirically (Table 3). Bloody stools without a fecal exudate are more consistent with amebiasis, and stools should be examined for E. histolytica. In any persons in whom diarrhea lasts longer than 1 to 2 weeks, the work-up should include stool culture and direct examination of fresh stool for C. Lamblia and E. histolytica. In selected cases, small bowel intubation should be carried out to look for the causative agent of giardiasis. Treatment of Diarrhea The major form of treatment for all patients with diarrhea is fluid and electrolyte replacement. Most of the serious complications of diarrhea relate to the development of dehydration which can be prevented in most cases by orally administered fluids. A glucose or sucrose solution taken orally will facilitate the absorption of sodium and water. 18 For most cases of mild to moderate diarrhea in healthy persons in the United States, Gatorade, carbonated soft drinks, and commercial solutions for children (such as Pedialyte) are satisfactory. In malnourished and dehydrated children with severe diarrhea, solutions with higher sodium content should be employed. 33 Table 2 lists common agents available for symptomatic treatment of diarrhea. As with other illnesses, patients often demand that some form of therapy be administered to alleviate symptoms. In many cases, particularly in mild diarrhea, the abnormal stools may reflect a host defense mechanism, and potent pharmacologic drugs should not be administered for prolonged periods of time. Drugs which influence gut motility (diphenQxylate, loperamide, paregoric) decrease diarrhea

Secretory Active Drugs (bismuth sub salicylate)

Adsorbents (kaopectate, aluminum hydroxide compound)

Motility Active Agents (diphenoxylate, loperamide, paregoric)

AGENT

TYPE OF

Yes

Increased Resistance To Flow

Yes

Possibly

Decreased Intestinal Volume

DECREASE IN DIARRHEA

Yes

TO DECREASED

STOOL FORM

Yes

Yes

DISTENTION

AND CRAMPS DUE

INCREASE IN

DECREASE PAIN

COMMENT

Promising drugs for future, delayed onset of action (4 hours)

Safe

Rapid onset, occasionally will worsen shigellosis or salmonellosis

Table 2. Proposed Scheme of Action of Important Antidiarrheal Compounds

>-l

Z

o

tj Cl "C

r

>-l

t>j ~

:

::r: t>j

U1 O'l

!.C

Metronidazole: 35-50 mg/kg/day in 3 doses (PO) for 10 days plus Diiodohydroxyquin: 40 mg/kg/day in equal doses tid (PO) for 21 days.

Amebiasis

*Alternatives are oxolinic acid and nalidixic acid. """For known sensitive strains-use chloramphenicol (see text for dosage). tMetronidazole is suitable alternative (see text for dosage).

Quinacrine: 5-7 mg/kg/day in 3 doses (PO) for 7 days.

None

Metronidazole: 750 mg tid (PO) for 10 days plus Diiodohydroxyquin: 650 mg tid (PO) for 21 days.

Quinacrine: 100 mg tid (PO) for 7 days.

None

Ampicillin: 1 gr q 4 hr (IV) for 1 week, then half dose for an additional week.

TMP 160 mg/SOO mg each plus SMX: 2 tablets each 12 hrs (PO) for 5 days.

Trimethroprim (TMP) plus sulfamethoxazole (SMX), TMP 10 mg/kg/day plus SMX 50 mg/kg/day in 2 equal doses each 12 hr (PO) for 5 days. Ampicillin: 100-200 mg/kg/day in 4 doses (IV) for 2 weeks.

Tetracycline: 2.5 gr in a single dose (PO) or Ampicillin: 500 mg qid (PO) for 5 days.

Ampicillin: 50 mg/kg/day in 4 doses (PO, IM or IV) for 5 days.

For Adults

ANJ'IMICROBIAL AGENT, DOSE, ROUTE, DURATION

For Children

Giardiasist

Gastroenteritis or asymptomatic carriage

Salmonellosis Typhoid fever** or gastroenteritis with possible bacteremia

Known resistant strains*

Bacillary Dysentery (Shigellosis) Unknown sensitivity or known sensitive strains

DIAGNOSIS

Table 3. Antimicrobial Therapy of Enteric Infections

co

'l

(,ll

'"

~ '"I!:

~

o

Z (l

8t
:I:

'"d

,.,>

~

t
trI

,.,Z

958

HERBERT

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DUPONT

and abdominal pain probably by increasing segmental contractions of the intestine increasing resistance to the transit of intestinal contents and decreasing the bowel distention usually responsible for cramping and pain. They should be avoided in patients with high fever or toxemia and in those with bloody, mucoid stools since they may worsen clinical shigellosis or salmonellosis. 8 The drugs which adsorb bacterial toxins and water such as Kaopectate and aluminum hydroxide compounds improve the symptoms of diarrhea by producing more formed stools. The most exciting new group of drugs constitutes the ones which block secretion of water and electrolytes from the small intestinal mucosa. Here, the pathophysiology of diarrhea is being more directly approached. Our group has shown that a commercial preparation of bismuth subsalicylate, Pepto-Bismol, is effective in the treatment of acute diarrhea among students in Mexico with illness from a variety of enteropathogens l l and has offered evidence that its primary mode of action is through inhibition of intestinal secretion. 12 Table 3 lists currently recommended antimicrobial agents used in the treatment of enteric infection by identifiable pathogens. Shigellosis probably should be treated in all cases as it is a highly communicable infection and man is the only natural host. In adults, a single 2.5 gm dose of tetracycline is given orally.37 Ampicillin is used in children to avoid dental staining caused by the tetracyclines. In shigellosis caused by antibiotic-resistant strains, trimethoprim-sulfamethoxazole, oxolinic acid, and nalidixic acid are effective 9 , 27, 34 but have not yet been approved for this use. Typhoid fever represents- the one enteric infection in which antimicrobial agents must be administered. Since chloramphenicol-resistant strains of Salmonella have emerged in all parts of the world, ampicillin is probably the current drug of choice when organism susceptibility testing has not been performed. Salmonella gastroenteritis should not be treated with antimicrobial agents, because of their tendency to prolong fecal shedding of the strain1 and perhaps encourage the development of a more aggressive infectioV Patients who are severely ill with salmonellosis (for example, those requiring hospitalization due to high fever and toxemia) should receive antibiotics, assuming that they have a bacteremic form of illness. In giardiasis, metronidazole may be better tolerated than quinacrine (Atabrine) but it is far more expensive and no more effective. The dose of quinacrine for giardiasis is given in Table 3; metronidazole can be given a dose of 250 mg four times a day for 7 to 10 days. Amebiasis may be treated with metronidazole alone (in higher doses than for a giardia infection) but diiodohydroxyquin probably should also be administered to prevent treatment failures. Diiodohydroxyquin may be given after the course of metronidazole has been completed.

REFERENCES 1. Aserkoff, B., and Bennett, J. v.: Effect of antibiotic therapy in acute salmonellosis on the fecal excretion of Salmonellae. New Eng. J. Med., 281 :636-640, 1969. 2. Bolivar, R., Conklin, R. H., Vollet, J. J., et al.: Rotavirus in travelers' diarrhea: Study of an adult student population in Mexico. J. Infect. Dis.

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