In clinical practice, routine microbiologic identification of pathogens utilizes

selective media which favors the growth of suspected pathogens.

7 Stool cultures are

recommended for patients with one of the following: acute diarrhea that is severe or

associated with a temperature >38.5°C; dysentery—which is an inflammatory

diarrheal illness characterized by bloody or mucoid stools with abdominal cramps;

profuse cholera-like watery diarrhea; dehydration; elderly or immunocompromised

patients; nursing home patients; food handlers; and day-care workers.

3 Hospitalized

patients should be evaluated for C. difficile infection. Culture of specimens from

extraintestinal sites of infection (e.g., blood cultures) can be used to identify the

microbial etiology.

PCR-based diagnostic tests are widely available in industrialized countries,

offering improved sensitivity but focusing on genes versus virulence factors.

3

Drug Therapy

Drug therapy for infectious diarrhea includes medications to provide symptomatic

relief or to eradicate the causative pathogen.

LOPERAMIDE AND DIPHENOXYLATE/ATROPINE

Loperamide and diphenoxylate/atropine reduce the frequency of diarrheal stools by

slowing intestinal transit time; additionally, loperamide possesses antisecretory

properties.

8 Loperamide is preferred over diphenoxylate/atropine because of its

greater efficacy, better tolerance, and over-the-counter availability.

Diphenoxylate/atropine causes drowsiness, dizziness, dry mouth, and urinary

retention owing to the atropine component, and its use in the elderly is not

recommended (see Chapter 107 Geriatric Drug Use).

The use of antimotility drugs is not recommended in persons with fever, bloody

diarrhea,

3 or when invasive pathogens are suspected.

1 The primary concern is that

prolongation of clearance of pathogens from the intestinal tract could worsen the

severity of illness. However, in non-critically ill patients with bacillary dysentery,

loperamide was not harmful when administered with antimicrobials to which the

infecting pathogen was susceptible.

9

BISMUTH SUBSALICYLATE (BSS)

Bismuth subsalicylate’s antidiarrheal properties are because of its antisecretory,

adsorbent, and antimicrobial properties.

10 Problems with BSS include the

inconvenience of dosing 4 times per day, and adverse effects such as darkening of the

tongue and stools, and tinnitus secondary to salicylate absorption. Each

recommended antidiarrheal dose of BSS of 526 mg contains 263 mg of salicylate,

and this needs to be considered in patients already taking salicylate products.

CROFELEMER

Crofelemer is a recently U.S. Food and Drug Administration (FDA)–approved nonabsorbable agent indicated for the symptomatic treatment of noninfectious diarrhea in

HIV-infected persons on antiretroviral therapy.

11

Its antisecretory effect is because of

the unique inhibition of two distinct channels responsible for chloride and fluid

secretion into the GI tract. Crofelemer improves diarrheal symptoms in patients with

noninfectious diarrhea; larger trials are needed to further assess its efficacy and

safety in patients with infectious diarrhea. Common side effects of cofelemer include

flatulence (7%) and abdominal pain (5%).

11

PROBIOTICS

Interest in probiotics stems, in part, from their potential to decrease the use of

antibiotics. These live microbial mixtures of bacteria and yeasts are used to restore

the normal intestinal flora, thereby reducing intestinal colonization with pathogenic

organisms. Probiotics also produce pathogen-inhibiting substances, prevent pathogen

adhesion to the GI tract, inhibit the action of microbial toxins, and stimulate immune

defense mechanisms.

12 Further studies are needed to clarify the role of specific

probiotics for the treatment and prevention of acute infectious diarrhea.

12

,

13

ANTIMICROBIALS

In selected cases, antimicrobials are prescribed to decrease the duration and the

severity of diarrheal illnesses, to prevent the progression to invasive infection, and

prevent person-to-person transmission of pathogens. Antimicrobials are generally

recommended for the severely ill, for patients with conditions compromising normal

enteric defenses, for immunocompromised patients, and for the treatment of

extraintestinal infection.

3

Ongoing surveillance of antimicrobial resistance is important to guide treatment

recommendations. Extensively used in the past and resulting in widespread resistance

to common enteropathogens, trimethoprim–sulfamethoxazole (TMP–SMX), the

aminopenicillins, nalidixic acid, and tetracyclines are unsuitable empiric choices for

the treatment of many enteropathogens. Depending on the circumstances surrounding

the diarrheal illness, including where the pathogen was acquired (e.g., domestic vs.

travel-related), age, and allergy history of the patient, commonly recommended

antimicrobials include selected third-generation cephalosporins (e.g., ceftriaxone or

cefotaxime), azithromycin, rifaximin, fluoroquinolones, and others.

3

The fluoroquinolones, although still recommended because of their efficacy against

susceptible organisms

3 and their availability as oral formulations, must be used

cautiously as common enteropathogens, e.g., Shigella, Salmonella, and

Campylobacter species, are frequently fluoroquinolone-resistant.

14 Another

consideration with using fluoroquinolones is that they are not FDA-approved for use

in children because lesions on cartilage tissue have been reported in juvenile

animals. Nevertheless, because of the emergence of multidrug-resistant

enteropathogens in some geographic areas, clinical trials using fluoroquinolones in

children have been performed,

15 and the available data suggest that a short course of

these agents is safe. Finally, antimicrobial use should be limited to instances where

their benefits outweigh their risks for adverse effects and resistance.

Prevention

Good personal hygiene along with proper food handling, cooking, and storage are

essential to prevent the spread of enteropathogens. When visiting areas with

inadequate facilities for the disposal of sewage, travelers should follow the rule,

“boil it, cook it, peel it, or forget it.” Effective vaccines are available to prevent

typhoid fever, rotavirus, and cholera (not available in the United States); studies of

vaccines to prevent Campylobacter, enterotoxigenic E. coli, and Shigella infections

are ongoing.

1

EVALUATION AND TREATMENT OF PATIENTS

WITH INFECTIOUS DIARRHEA

CASE 69-1

QUESTION 1: B.K. is a 78-year-old man presenting to his physician with a diarrheal illness for 1 day. His

illness began with vomiting and was followed by abdominal pain, nausea, and watery, but non-bloody, diarrhea.

Despite not feeling well, he is able to drink fruit juices. B.K.’s history of present illness is significant for eating

raw oysters at a localseafood restaurant 2 days ago, and he has

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since learned that other patrons are experiencing a similar illness. B.K. has no significant medical history. He

denies recent hospitalization, contact with small children, recent travel, or recent use of antimicrobials. On

physical examination B.K. is alert and oriented, is not “toxic” appearing, afebrile, and has stable vital signs. The

remainder of his examination is significant for decreased skin turgor and dry mucous membranes. What is your

general approach to the management of B.K.’s diarrheal illness?

Because infectious diarrhea is typically a self-limiting illness, patients may never

seek medical attention, and in many cases, replacement of fluids and electrolytes is

all that is required. In general, medical evaluation is warranted for patients with

profuse watery diarrhea with dehydration, bloody stools, temperature greater than

101.3°F, or illness of more than 48 hours duration. Other persons requiring medical

evaluation include patients older than 50 years of age with severe abdominal pain

and immunocompromised patients (e.g., those with acquired immunodeficiency

syndrome, organ transplant recipients, or patients being treated with cancer

chemotherapies). Noninfectious causes for the illness such as medications,

inflammatory bowel disease, consumption of poorly absorbable carbohydrates (e.g.,

sugarless candies or chewing gum), or malabsorption syndromes should be

considered.

6

CASE 69-1, QUESTION 2: What rehydration plan would you recommend for B.K.?

B.K.’s physical examination is significant for decreased skin turgor and dry

mucous membranes, findings consistent with mild-to-moderate volume depletion.

16

Given that B.K. is not “toxic” appearing, with stable vital signs, and is tolerating oral

liquids, oral beverages containing glucose (e.g., lemonades, sweet sodas, or fruit

juices) or soups rich in electrolytes are appropriate.

17

In developing countries,

significant reductions in dehydration-related mortality is attributed to oral

replacement therapy solutions containing optimal concentrations of sodium,

potassium, chloride, bicarbonate, and glucose; the glucose content of these solutions

is responsible for accelerating the absorption of sodium.

5

Intravenous replacement therapy is warranted for severe dehydration—

characterized by lethargy, very sunken and dry eyes, a very dry tongue and mouth, a

pulse that is fast, weak or non-palpable, poor urine output, and low blood pressure—

or for persons with intestinal ileus or who are unable to drink on their own.

16

CLINICAL PRESENTATION

CASE 69-1, QUESTION 3: How does B.K.’s clinical presentation as a noninflammatory versus

inflammatory diarrheal illness help to guide further treatment?

The clinical presentation (e.g., the specific symptoms, the severity and duration of

symptoms), along with the history of present illness (e.g., risk factors for infection),

allows for classification of diarrheal syndromes as noninflammatory versus

inflammatory illnesses. Such a classification allows the physician to consider a more

focused list of potential enteropathogen(s), and based on the list of suspected

organisms, a diagnostic and therapeutic plan can be developed.

7

B.K.’s history of present illness and clinical presentation are consistent with a

noninflammatory diarrheal illness. Voluminous, watery, non-bloody diarrhea is

characteristic of pathogens targeting the small bowel, which is responsible for

absorption of most fluids entering the GI tract.

7 The clinical manifestations of

noninflammatory, watery diarrheal illnesses are a consequence of bacterial

enterotoxins that promote the secretion of water and electrolytes into the intestinal

lumen; or of viruses infecting and damaging the absorptive villus tips, resulting in

voluminous watery diarrhea.

7 Like B.K., patients with noninflammatory diarrheal

illnesses are not severely ill, are afebrile and without significant abdominal pain

2

,

7

;

most patients require only supportive therapies. Noninflammatory diarrheas are

typically caused by viruses (e.g., rotaviruses and noroviruses), bacteria (e.g.,

Staphylococcus aureus, Bacillus cereus, and Clostridium perfringens), or parasites

(e.g., Cryptosporidium parvum and Giardia lamblia).

1

In contrast, inflammatory diarrheas are generally a more severe illness

characterized by diarrhea with or without dysentery, abdominal pain, and fever.

2

Pathogens targeting the distal small bowel and colon disrupt the epithelial barrier,

causing the bloody or mucoid stools.

2

In addition to supportive therapies, selected

persons with inflammatory diarrheal illnesses may benefit from antimicrobial therapy

directed at the causative pathogen. The clinical manifestations of inflammatory

diarrheal illnesses are a consequence of the production of cytotoxins (e.g., as

produced by C. difficile, Shiga toxin–producing E. coli, and enteroaggregative E.

coli), or of the pathogen’s ability to invade the intestinal mucosa (e.g.,

Campylobacter jejuni, Shigella species, and Salmonella species).

18

VIRAL GASTROENTERITIS

Clinical Presentation and Treatment

CASE 69-1, QUESTION 4: B.K.’s stool is negative for WBCs and RBCs. With B.K.’s history of dining at

the same restaurant as other patrons having a similar illness, the physician calls the Board of Health to find out

if similar illnesses are being reported throughout the city. The physician is informed that an outbreak of

norovirus (previously called Norwalk-like virus) gastroenteritis was confirmed at the restaurant where B.K. had

dined. Why is B.K.’s history of present illness and clinical presentation consistent with the presumptive

diagnosis of a viral gastroenteritis, specifically the norovirus? What supportive therapies are recommended?

Noroviruses are responsible for major outbreaks of foodborne viral illnesses in

both adults and children, usually in association with restaurants, schools, and daycare centers. The virus is spread by eating inadequately cooked clams and oysters

harvested from contaminated waters and other contaminated foods (e.g. salads,

sandwiches), by person-to-person contact, or by exposure to contaminated

recreational waters. Like B.K., within 12 to 48 hours after exposure to the virus,

patients complain of nausea, vomiting, diarrhea, and abdominal cramps. B.K. will

likely experience a mild intestinal illness lasting 1 to 3 days. Supportive therapies to

correct fluid and electrolyte losses and to replace ongoing losses are the mainstay of

treatment for viral gastroenteritis. Preventing future outbreaks will require the

restaurant to ensure proper food-handling practices.

19

Other common causes of viral gastroenteritis are rotaviruses and astroviruses

which are responsible for 30% to 60% of all cases of severe, watery diarrhea in

children. After an incubation period of 1 to 3 days, patients experience fever,

vomiting, and non-bloody, watery diarrhea; otherwise healthy persons are typically

ill for 5 to 7 days.

In the United States, two oral rotavirus vaccines are available for the prevention of

rotavirus gastroenteritis in infants and children, a pentavalent (three-dose series) and

a monovalent

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(two-dose series). Vaccine effectiveness in high and upper middle income

countries ranges from 79% to 100%, with the benefit of vaccination outweighing

vaccine risks, e.g., intussusception (when a part of the intestine folds into another

adjacent part of the intestine, referred to as “telescoping,” which can lead to

intestinal obstruction).

20 As rotaviruses are spread by the fecal–oral route, proper

hand washing and disposal of contaminated items are essential to limit the spread of

infection.

VIBRIO SPECIES

Vibrio species are curved gram-negative rods whose natural habitats are the

environmental waters throughout the world. V. cholerae 01 and 0139 are noninvasive

enteropathogens responsible for epidemic cholera in humans. The ongoing seventh

cholera pandemic began in 1961, subsequently spreading through Asia to Africa,

Europe, and Latin America.

5 Prevention of cholera relies on the provision of safe

drinking water and adequate sanitation. Cholera vaccines are not routinely

incorporated into cholera control efforts, in part related to financial and logistical

reasons.

5 Non-cholera Vibrio species (e.g., Vibrio parahaemolyticus) do not possess

the virulence factors required to cause epidemic cholera but do cause gastroenteritis,

wound infections, and in susceptible hosts, fulminant sepsis.

21

Vibrio Cholerae

RISK FACTORS AND CLINICAL PRESENTATION

CASE 69-2

QUESTION 1: M.M. is a 50-year-old man hospitalized for severe watery diarrhea, vomiting, muscle cramping

with weakness, and confusion, notably unable to recognize his family members. His history of present illness is

significant for returning 1 day ago from Haiti where he visited with relatives, several of whom were recovering

from diarrheal illnesses caused by V. cholerae. Approximately 24 hours before admission, he noted the onset of

watery diarrhea and immediately began drinking the oral rehydrating solution remaining from his trip to Haiti.

However, over the past several hours he has been unable to drink on his own, and his family noticed “white

flecks” in his stools. M.M. lives in Florida, and his past medical history is significant for peptic ulcer disease for

which he takes a proton-pump inhibitor.

In the emergency department, M.M.’s vitalsigns are as follows: afebrile, blood pressure is 70/40 mm Hg, and

heart rate is 130 beats/minute. Physical examination reveals a severely ill-appearing man with altered mental

status, sunken eyes, poor skin turgor, and dry mucous membranes. The physician’s assessment is severe

dehydration because of massive diarrhea, most likely caused by V. cholerae . What are his risk factors for

cholera and why is his clinical presentation consistent with this diagnosis?

Risk Factors

M.M. has two risk factors to explain his presumed diagnosis of cholera. First, he has

just returned from Haiti, a county suffering from epidemic cholera following a major

earthquake in 2010 that severely damaged public health facilities.

5

In developed

countries, cholera has been virtually eliminated because of modern sewage and water

treatment systems. However, sporadic cases, like M.M., occur in travelers returning

from areas where cholera is epidemic or endemic, or from the consumption of

contaminated and undercooked seafood (e.g., improperly preserved fish, raw oysters,

and shellfish) from waters off the Gulf Coast States or imported from endemic

areas.

22 Second, M.M.’s daily use of a proton-pump inhibitor reduces his stomach’s

acidity, thus allowing the acid-susceptible V. cholerae to pass from the stomach into

the small intestine.

5

Clinical Presentation

Cholera epidemics are caused by toxin-producing strains of V. cholerae 01 or 0139.

5

The characteristic voluminous, watery, and colorless stools with “white flecks” of

mucus (referred to as rice-water stools because of their similarity to the appearance

of water after washing rice) are caused by the cholera toxin which promotes the

intestinal secretion of fluids and electrolytes.

5

The severity of cholera and likelihood of infection is influenced by host factors

and the setting in which it occurs.

5 Severe disease is more common in previously

unexposed persons like M.M. who are immunologically naïve (e.g. epidemic

cholera), while less severe disease occurs in areas where cholera is endemic.

5

Following ingestion of contaminated foods, a watery diarrheal illness begins within

12 hours to 5 days and may progress to life-threatening dehydration.

5

TREATMENT

CASE 69-2, QUESTION 2: What are the signs and symptoms suggesting M.M. is severely dehydrated, and

how should his dehydration be treated?

M.M. is one of the 2% to 5% of persons with V. cholerae infection who

experience severe dehydration (≥10% dehydration), losing up to 1 L/hour of fluid,

and whose condition may, within hours, progress to hypovolemic shock and death.

5

M.M. shows signs of severe dehydration as manifested by his altered mental status,

sunken eyes, poor skin turgor, dry mucous membranes, low blood pressure, and

increased heart rate.

5 Acidosis may occur as a result of massive bicarbonate losses

through diarrheal stools, and it may be exacerbated by lactic acidosis from shock and

hypovolemic renal failure.

5 M.M. should receive vigorous IV hydration with

Ringer’s lactate solution to replace the large quantities of sodium, potassium, and

bicarbonate lost through his watery stools; his muscle weakness could be attributed

to depletion of electrolytes, specifically potassium and calcium.

5 Monitoring of

blood pressure and normalization of heart rate are critical interventions.

Once M.M. is able to drink fluids, oral hydration can be started, even with ongoing

IV hydration. Oral replacement solutions containing less than 75 mEq/L of sodium

are inappropriate because of the large amounts of sodium lost through cholera

stools.

5 Oral rehydration solutions can be made by mixing together one-half teaspoon

salt, six teaspoons sugar and 1 liter of safe water.

5

CASE 69-2, QUESTION 3: Would M.M. benefit from the administration of antimicrobials, and what

antimicrobial treatment options are available?

Antimicrobials are recommended for patients with moderate-to-severe

dehydration from cholera infection.

5 Effective antimicrobial therapy decreases the

volume of diarrheal losses, shortens the duration of illness by up to 50% and reduces

the period of shedding infectious organisms from >5 days

23

to 1–2 days.

5

Antimicrobials should be administered after the initial fluid deficit has been

corrected and if applicable, after vomiting has resolved.

5

Antimicrobials

If susceptible, the following single- and multiple-dose regimens are effective

treatments for V. cholerae ; single-dose regimens are preferred because of their ease

of administration, and compared to multiple doses of erythromycin, they are better

tolerated.

24

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p. 1452

Adults: doxycycline 300 mg orally × 1 dose, or azithromycin 1 g orally × 1 dose, or

ciprofloxacin 500 mg orally twice a day for 3 days,

5 or tetracycline 500 mg orally

every 6 hours for 3 days, or erythromycin 250 mg orally 4 times daily for 3 days.

5

TMP–SMX resistance precludes its empiric use for the treatment of cholera.

5

Children: ciprofloxacin 15 mg/kg/dose orally twice a day × 3 days, or azithromycin

20 mg/kg orally × 1 dose, or erythromycin 12.5 mg/kg/dose orally every 6 hours

for 3 days. Pediatric doses should not exceed maximum adult doses.

5

For M.M., a single 300 mg oral dose of doxycycline is a good empiric choice as

the strain of V. cholerae circulating in Haiti is currently susceptible to tetracycline

(indicative of susceptibility to doxycycline).

23 Empiric ciprofloxacin is not

recommended because the circulating strain in Haiti has reduced susceptibility to

ciprofloxacin which is associated with lack of clinical and microbiologic

improvement.

25 Additionally, until M.M. has recovered from this cholera infection,

he should refrain from taking his proton-pump inhibitor which, by reducing his

stomach’s acidity, allows the acid-susceptible V. cholerae to pass from the stomach

into the small intestine.

Vibrio Parahaemolyticus

CLINICAL PRESENTATION

CASE 69-3

QUESTION 1: C.T. is a 45-year-old man presenting to his physician with 1 day of non-bloody, watery

diarrhea. Two days before his illness, he ate a meal of raw oysters at a restaurant specializing in fresh local

seafood. C.T. lives along the coast of Florida and has no significant medical history. His physical examination

reveals no evidence of dehydration. Why is C.T.’s history of present illness and clinical presentation consistent

with non-cholera Vibrio gastroenteritis?

A key piece of information from C.T.’s history of present illness consistent with

the presumptive diagnosis of non-cholera Vibrio gastroenteritis is consumption of

raw oysters harvested from the coastal areas of Florida, where V. parahaemolyticus

species have been identified. Diarrhea, abdominal cramps, nausea, vomiting, and

fever begin after a median incubation period of 17 hours (range, 4–90 hours); bloody

diarrhea occurs in 9% to 29% of cases.

TREATMENT

CASE 69-3, QUESTION 2: Should a course of antibiotics be prescribed for C.T.?

In otherwise healthy adults like C.T., V. parahaemolyticus gastroenteritis is usually

a mild, self-limiting illness lasting for a median of 2 to 6 days.

21 There are no data to

support the benefit of antibiotics in this setting, although patients with diarrhea lasting

longer than 5 days may benefit from treatment with tetracycline or a fluoroquinolone;

minocycline 100 mg orally every 12 hours and cefotaxime 2 g IV every 8 hours have

also been recommended.

21

Individuals with liver disease or alcoholism are at risk for severe Vibrio

infections including septicemia

21

; such individuals should avoid eating raw or

undercooked shellfish, and avoid exposure of open wounds to seawater especially

during the warmer months when water temperatures favor the growth of Vibrio

species.

STAPHYLOCOCCUS AUREUS, BACILLUS

CEREUS, AND CLOSTRIDIUM PERFRINGENS

S. aureus, B. cereus, and C. perfringens are important causes of toxin-mediated

foodborne illnesses. Gastrointestinal symptoms typically begin within 24 hours after

the ingestion of contaminated foods, which is in contrast to the longer incubation

periods for illnesses caused by Salmonella, Shigella, and Campylobacter species. B.

cereus causes two different intestinal syndromes: the short-incubation disease

characterized by vomiting and a long-incubation disease characterized by a diarrheal

illness.

1

Clinical Presentation and Treatment

CASE 69-4

QUESTION 1: S.A. is an otherwise healthy 23-year-old college student, who presents to the Student Health

Center with an acute gastrointestinal illness after eating at the school cafeteria. S.A. recalled eating the salad

and the cream-filled pastries, and stated that within 3 hours she felt nauseous and began vomiting. Why is

S.A.’s history of present illness and clinical presentation consistent with food poisoning caused by S. aureus or

B. cereus (short-incubation)?

Foodborne illnesses are often grouped by their usual incubation period: less than 6

hours, 8 to 16 hours, and greater than 16 hours.

26 The rapid onset (within 6 hours) of

S.A.’s intestinal symptoms after eating suggests the illness is caused by preformed

toxins, such as those produced by S. aureus or B. cereus (short-incubation disease,

emetic syndrome). Diarrhea and abdominal cramps may also occur. Although

cooking kills the toxin-producing bacteria, it does not destroy toxin that has already

been produced. Foods implicated in staphylococcal food poisoning include salads,

cream-filled pastries, and meats, whereas foods implicated in B. cereus food

poisoning include fried rice, dried foods, and dairy products.

26

CASE 69-5

QUESTION 1: C.P. is also an otherwise healthy 23-year-old college student presenting to the same Student

Health Center as S.A. (Case 69-4) with an acute gastrointestinal illness. C.P. recalled having lunch at the

cafeteria, selecting a fish and poultry meal. Approximately 10 hours after eating she experienced diarrhea and

abdominal cramps. Why is C.P.’s history of present illness and clinical presentation consistent with food

poisoning caused by C. perfringens or B. cereus (long-incubation disease)? Should empiric antibiotics be

prescribed to either of these students?

In contrast to S.A., the longer incubation period before the onset of symptoms is

consistent with illness caused by C. perfringens or B. cereus (long-incubation

disease, diarrheal syndrome). These bacteria are associated with an incubation

period of 8 to 16 hours and symptoms of diarrhea and abdominal cramps; vomiting is

not a prominent symptom in these illnesses.

26