The Rundown: Management of Acute and Chronic Diarrhea

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The Rundown: Management of Acute and Chronic Diarrhea
AND
AN ONGOING CE PROGRAM
OF THE UNIVERSITY OF CONNECTICUT
SCHOOL OF PHARMACY
AND DRUG TOPICS
2
CPE
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EARN CE CREDIT
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EDUCATIONAL OBJECTIVES
GOAL: The goal of this activity is to review the various risk
factors, etiologies, and treatments of diarrhea as well
as the pharmacist’s role in its management.
After participating in this activity,
pharmacists will be able to:
> Discuss the different causes of and risk
factors for diarrhea including IBS-D, infectious
diarrhea (including CDAD), and non-infectious
diarrhea
> Describe the available non-prescription
and prescription agents for the treatment
of diarrhea, including the mechanism of
action, indications, side effects, onset of
effect, duration of therapy, and clinical usage
considerations for each agent
> Outline the pharmacist’s role in providing
recommendations to treat diarrhea and
referral to a physician for inadequate response
to OTC therapies
After participating in this activity,
pharmacy technicians will be able to:
> Recall the basic definition of diarrhea
> Recall the risk factors for diarrhea
> List available OTC and prescription drug
therapies for diarrhea
> Recognize when to refer patients to the
pharmacist for recommendations on diarrhea
management
The University of Connecticut
School of Pharmacy is accredited
by the Accreditation Council for
Pharmacy Education as a provider of
continuing pharmacy education.
Pharmacists and pharmacy technicians are
eligible to participate in the knowledge-based activity,
and will receive up to 0.2 CEUs (2 contact hours) for
completing the activity, passing the quiz with a grade
of 70% or better, and completing an online evaluation.
Statements of credit are available via the CPE Monitor
online system and your participation will be recorded
with CPE Monitor within 72 hours of submission.
The Rundown:
Management of
Acute and Chronic
Diarrhea
Alexa A. Carlson, PharmD, BCPS
ASSISTANT CLINICAL PROFESSOR, DEPARTMENT OF PHARMACY AND HEALTH SYSTEMS SCIENCES, NORTHEASTERN UNIVERSITY,
SCHOOL OF PHARMACY, BOSTON, MA
Tayla N. Rose, PharmD
ASSISTANT CLINICAL PROFESSOR, DEPARTMENT OF PHARMACY AND HEALTH SYSTEMS SCIENCES, NORTHEASTERN UNIVERSITY,
SCHOOL OF PHARMACY, BOSTON, MA
Alycia Gelinas
STUDENT PHARMACIST, CLASS OF 2016, NORTHEASTERN UNIVERSITY, SCHOOL OF PHARMACY, BOSTON, MA
Abstract
Diarrhea is a common complaint seen in patients worldwide and can be caused by either
infectious or noninfectious sources, including bacteria, viruses, protozoa, food intolerances,
and irritable bowel syndrome. Management strategies for the adult patient with diarrhea
depend on the underlying cause but may include hydration, over-the-counter products, and
prescription medications. Pharmacists and pharmacy technicians must be familiar with the
characteristics of the various types of diarrhea and with the appropriate treatment options,
and they should recognize when it is appropriate to refer patients for medical evaluation.
ACPE# 0009-9999-16-029-H01-P
Grant funding: None
Faculty: Alexa A. Carlson, PharmD, BCPS, Tayla N. Rose, PharmD, Alycia Gelinas
Activity Fee: There is no fee for this activity.
Dr. Carlson is an assistant clinical professor in the Department of Pharmacy and Health Systems Sciences at
the Northeastern University, School of Pharmacy, Boston, MA. Dr. Rose is an assistant clinical professor in the
Department of Pharmacy and Health Systems Sciences at the Northeastern University, School of Pharmacy,
Boston, MA. Ms. Gelinas is a student pharmacist in the class of 2016 at the Northeastern University, School of
Pharmacy, Boston, MA.
Faculty Disclosure: Dr. Carlson, Dr. Rose, and Ms. Gelinas have no actual or potential conflicts of interest associated with this article.
Disclosure of Discussions of Off-Label and Investigational Uses of Drugs: This activity may contain discussion of
unlabeled/unapproved use of drugs in the United States and will be noted if it occurs. The content and views
presented in this educational program are those of the faculty and do not necessarily represent those of Drug
Topics or University of Connecticut School of Pharmacy. Please refer to the official information for each product
for discussion of approved indications, contraindications, and warnings. Please refer to the official prescribing
information for each product for discussion of approved indications, contraindications, and warnings.
INITIAL RELEASE DATE: JUNE 10, 2016
EXPIRATION DATE: JUNE 10, 2018
To obtain CPE credit, visit www.drugtopics.com/cpe
and click on the “Take a Quiz” link. This will direct you
to the UConn/Drug Topics website, where you will click
on the Online CE Center. Use your NABP E-Profile ID and
the session code: 16DT29-YFJ22 for pharmacists or the session code: 16DT29-XFT88 for
pharmacy technicians to access the online quiz
and evaluation. First-time users must pre-register in
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DRUGTOPICS.COM | JUNE 2016 | DrugTopics
55
IMAGE: GETTY IMAGES / GPOINTSTUDIO
ACPE# 0009-9999-16-029-H01-T
CONTINUING EDUCATION
M A NAG E M E N T OF AC U T E A N D CH RON IC DI A R R H E A
Introduction
Diarrhea affects nearly all patients at
some point in their lives. Although diarrhea is commonly categorized as merely a
bothersome symptom in the United States
(US), the consequences of diarrhea can be
fatal if not properly managed. Each year,
an estimated 2 billion cases of diarrheal
disease and 2.5 million deaths due to
diarrhea-related illness occur worldwide.1,2
Diarrhea, in its most basic definition, is
a variation from normal bowel movements
with stools of increased frequency and/or
decreased consistency. Normal bowel habits vary among individuals, with frequency
ranging from three times per week to three
times per day, and these variations must
be considered when clinicians are evaluating patients and recommending treatments
for symptom management. To help guide
treatment recommendations, diarrhea can
be classified by suspected or proven etiology (infectious or noninfectious), duration,
and pathophysiologic mechanism. Diarrhea
is defined as acute, persistent, or chronic
based on the duration of symptoms, and
the pathophysiologic mechanism may fall
into one or more of the following clinical
groups: secretory, osmotic, exudative, or
motor (Table 1).2-4
Treatment recommendations vary
greatly depending on the etiology, duration, and pathophysiologic mechanism of
diarrhea; therefore, an attempt should be
made to classify a diarrheal episode upon
presentation. Pharmacists and pharmacy
technicians play an integral role in the management of diarrhea through self-treatment
recommendations or referrals for medical
evaluation. Thus, it is critical for pharmacists and technicians to be familiar with
the various classifications of diarrhea and
the prescription and over-the-counter (OTC)
products available for treatment and symptom management. This review will focus on
treatment and management of diarrhea in
immunocompetent adults.
Noninfectious diarrhea
Diarrhea is classified as noninfectious
when symptoms worsen or become chronic in the absence of an identifiable infectious organism (virus, bacterium, protozo56
DrugTopics | JUNE 2016 | DRUGTOPICS.COM
TABLE 1
Classification of Diarrhea
FREQUENCY CLASSIFICATION
Acute
≤14 days in duration
Persistent
>14 days in duration
Chronic
>30 days in duration
MECHANISTIC CLASSIFICATION
Secretory
Occurs when a substance either decreases absorption or increases secretion of
large quantities of water and electrolytes in the gastrointestinal tract
 Leads to large stool volume (>1 L/d)
 Fasting does not alter stool volume
 May be caused by bacterial toxins, laxatives, or excess bile salts
Osmotic
Occurs when a poorly absorbed substance retains intestinal fluids and leads to a
flux of water and electrolytes into the lumen as the gut adjusts to the osmolality
of the plasma
 Unlike other mechanisms, fasting causes diarrhea to stop
 May be caused by lactose intolerance or ingestion of magnesium-containing
antacids or poorly soluble carbohydrates (lactulose)
Exudative
Occurs when an inflammatory process in the GI tract causes discharge of
mucous, serum proteins, and blood into the gut, and discharged substances are
excreted in the stool
 Absorption, secretory, or motility functions are altered to accommodate
large stool volume
Motor
Occurs when altered intestinal motility leads to reduction in contact time of
chyme (semifluid combination of gastric fluids and partially digested food) in
the small intestine; premature emptying of the colon; and bacterial overgrowth.
Diarrhea may also be caused by increased contact time, which leads to
overgrowth of fecal bacteria and rapid dumping of chyme into the colon that is
unable to absorb water
 May occur with bypass surgery, intestinal resection, or administration of
metoclopramide
Source: Refs 2,4
an). Infectious etiologies may be ruled out
with a negative stool culture and testing
for ova and parasites.5 Noninfectious diarrhea can occur acutely due to medication
and food intolerance or chronically due to
primary gastrointestinal (GI) disease, such
as inflammatory bowel disease.
Hydration and diet management
The main component of treatment for
acute noninfectious diarrhea is hydration
therapy to maintain water and electrolyte
balances despite the loss of important
salts in the stool. The World Health Organization (WHO) defines oral rehydration
therapy (ORT) as the administration of ap-
propriate solutions by mouth to prevent
or correct dehydration related to diarrhea.
ORT solutions recommended by the WHO
contain the following per 1 L of solution:
2.6 g sodium chloride, 2.9 g trisodium citrate, 1.5 g potassium chloride, and 13.5 g
glucose.6 ORT has been found to be a
cost-effective means of managing acute
diarrhea and reducing hospitalizations.2
ORT solutions such as Pedialyte are not
interchangeable with sports drinks and
more closely resemble the WHO ORT recommendations for replenishment during
diarrheal illness. However, in otherwise
healthy patients who present without
dehydration, adequate fluid intake may
CONTINUING EDUCATION
T H E RU N DOW N
be achieved with consumption of broths,
soups, diluted fruit juices, soft drinks, and
salted crackers.7
Specific dietary recommendations outside of ORT are not well supported in the
clinical literature. In fact, abstaining from
food consumption during the occurrence of
diarrheal symptoms appears to have little
positive effect on outcomes.8 ORT with
early refeeding is the preferred treatment
for dehydration to reduce the duration of
illness and improve nutritional outcomes.9
Adequate nutrition is also necessary to enable renewal of cells in the intestinal lining
called enterocytes.10
complete relief of acute nonspecific diarrhea and gas-related symptoms compared
with either agent administered alone.13
Bismuth subsalicylate (Pepto-Bismol) is
an alternative option for the symptomatic
treatment of diarrhea in adults.5 Bismuth
subsalicylate has demonstrated antisecretory, anti-inflammatory, and antibacterial
effects.4 Bismuth subsalicylate is administered in doses of 525 mg (two 262 mg tablets) every 30 to 60 minutes or 1,050 mg
(four 262 mg tablets) every 60 minutes as
needed for up to two days, with a maximum
dose of approximately 4,200 mg/24 h.
An initial response can be seen within
PAUSE AND PONDER
Which questions would you ask a patient to
differentiate among the potential etiologies of
diarrhea?
Symptomatic treatment
Loperamide (Imodium) is an OTC antidiarrheal that can be used for symptom
management in adult patients with acute
noninfectious diarrhea in the absence of
bloody stools or fever.5 Loperamide is an
antimotility agent that works by inhibiting
muscle contractions of the circular and
longitudinal intestinal muscles via opioid
receptors to slow peristalsis and prolong
transit time. This agent has been found
to reduce fecal volume, increase stool viscosity, and diminish fluid and electrolyte
loss; loperamide has also demonstrated
antisecretory activity.4 Loperamide is administered as a 4-mg dose, followed by 2
mg after each unformed stool, with a maximum total dose of 16 mg/d. Patients may
experience drowsiness or dizziness with
loperamide; however, it is generally well
tolerated. An initial response occurs in
one to three hours, and a full response occurs in 48 to 72 hours.11 Patients should
be advised to discontinue loperamide immediately if they experience worsening
of symptoms or abdominal distension.12
Patients should also be advised that loperamide/simethicone combinations have
been associated with faster and more
four hours of administration.14 Patients
should be advised that the medication
may cause temporary, harmless darkening
of the tongue and stool, which should be
distinguished from bloody or black stools.
This medication is generally well tolerated
when administered at appropriate doses;
however, the active ingredient salicylate is
associated with a risk of salicylism (nausea, vomiting, and tinnitus) at high doses.
Before clinicians recommend bismuth
subsalicylate, they should ask patients
whether they are taking any medications
for anticoagulation, diabetes, gout, or arthritis because of the risk of drug interactions
with medications used for these medical
conditions. Patients who are taking other
salicylates, are allergic to aspirin, or who
have an ulcer, bleeding problem, or bloody
and/or black stools should be advised
against the use of bismuth subsalicylate.15
During treatment, patients who experience
worsening of symptoms, tinnitus, or hearing
loss should immediately discontinue use of
the product.15
Additional considerations
Lactose intolerance occurs when lactose
is not properly absorbed, travels to the
intestine, and is used as an energy source
for bacteria residing in the intestinal tract.
In addition to producing gas, undigested
lactose creates an osmotic pull in the GI
tract that leads to water retention in the
bowel and subsequent diarrhea.16 Patients
who experience gas and diarrhea after
consumption of lactose-containing products such as milk, ice cream, or cheese
may self-administer lactase tablets (eg,
Lactaid) before ingesting the aforementioned dairy products. However, as with
all food intolerances, avoidance of the
causative food products is highly recommended.
Noninfectious
diarrhea can occur
acutely due to
medication and
food intolerance or
chronically due to
primary GI disease,
such as inflammatory
bowel disease.”
Many people have food intolerances
to vegetables (eg, onions, peppers), fruits,
and various spices and experience diarrhea
after eating these foods. When consumed
in excess, high-salt beverages, high-fiber
foods, and foods containing sugars that
cannot be completely absorbed by the body
(eg, sorbitol and fructose) can also cause
diarrhea.17,18 In the case of food intolerances, patients should be advised to not
rely on OTC antidiarrheal medications and
to instead avoid the offending food product
to prevent future occurrences of diarrhea.
Diarrhea is also a side effect of many
medications such as magnesium-containing antacids, chemotherapeutic agents,
antihypertensives, nonsteroidal anti-inflammatory drugs, metformin, protease inhibitors, and proton pump inhibitors.4 When a
medication is suspected as the causative
agent, the patient should be evaluated to
DRUGTOPICS.COM | JUNE 2016 | DrugTopics
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M A NAG E M E N T OF AC U T E A N D CH RON IC DI A R R H E A
TABLE 2
DRUG
New Agents for the Treatment of IBS-D
MECHANISM
OF ACTION
DOSING
COMMON ADVERSE DRUG-DRUG
REACTIONS
INTERACTIONS
AMERICAN COLLEGE OF
GASTROENTEROLOGY
RECOMMENDATIONS
COST (AWP)
Eluxadoline Mu-opioid
100 mg twice
receptor agonist daily with food
 Abdominal pain
 Constipation
 Nausea
 Cyclosporine increases Approved after guideline
exposure to eluxadoline monograph issued
 Eluxadoline may
increase exposure to
rosuvastatin
 Strong CYP inhibitors
may increase exposure
to eluxadoline
$1152.00 (30-day
supply)
Rifaximin
 Increased ALT
 Nausea
 Cyclosporine increases Weak recommendation for
use to decrease bloating
exposure to rifaximin
and other symptoms in
IBS-D
$1539.31 (14-day
supply)
Rifamycin
antibacterial
550 mg
three times
daily for 14
days; maybe
repeated for
2 additional
courses
Abbreviations: AWP, average wholesale price; ALT, alanine aminotransferase.
determine the risk versus benefit for the
medication’s therapeutic effects and the
side effect of diarrhea. In patients taking
magnesium-containing antacids, antacids
with calcium carbonate may be recommended as an alternative.17 Any unapproved herbals or supplements such as St.
John’s wort should be stopped if they are
suspected of being the causative agent.
Irritable bowel syndrome-diarrhea
Irritable bowel syndrome (IBS) is a relapsing and remitting disorder of the bowel associated with abnormal defecation and abdominal discomfort/pain affecting 11.8%
of the US population.19,20 It is thought to
be more common in younger individuals
and in women.20,21 To receive a diagnosis of IBS, patients must be symptomatic
for at least six months. Diagnostic symptoms include abdominal discomfort/pain
that has occurred on at least three days
per month for the past three months and
that meets at least two of the following
stipulations: is accompanied by changes
in consistency of stool, is accompanied
by increased/decreased defecation, or is
alleviated upon defecation.22 Once diagnosed, cases may be further classified
into diarrhea-predominant IBS (IBS-D),
constipation-predominant IBS (IBS-C), or
mixed IBS (IBS-M).19,21 It is estimated that
58
DrugTopics | JUNE 2016 | DRUGTOPICS.COM
Source: Refs 22,26-28
40% of patients with IBS may be characterized as IBS-D.19
Loperamide has demonstrated efficacy
in decreasing fecal urgency and frequency
of stools as well as increasing the number
of formed stools in patients with IBS-D.23
However, it does not provide relief from
other symptoms such as pain and bloating. Current American College of Gastroenterology treatment guidelines do not recommend the use of loperamide for IBS-D
because of lack of strong evidence.22
Tricyclic antidepressants may be useful
in relieving symptoms of IBS-D because of
their ability to slow transit through the GI
tract.23 Guidelines include a weak recommendation for the use of tricyclic antidepressants but recognize that limited evidence is available and that patients may
find the anticholinergic adverse effects
intolerable.22
Eluxadoline is a mu-opioid receptor
agonist and delta-opioid antagonist that
reduces the symptoms of IBS-D by slowing
motility and relieving pain in the GI tract.24
Eluxadoline became available in December
2015 and is classified as a Schedule IV
controlled substance by the Drug Enforcement Administration.25 Decreases in abdominal pain, stool frequency, and urgency have been associated with eluxadoline
therapy in conjunction with improved con-
sistency of stools.23 Furthermore, eluxadoline has shown benefit in patients whose
symptoms are not adequately relieved with
loperamide.23,24 Common adverse effects
associated with this agent include nausea
and constipation (Table 2).22,23,26-28
Rifaximin is a rifamycin antibiotic similar to rifampin that is not significantly absorbed into systemic circulation.24 Its efficacy in IBS-D is attributed to alterations
in GI flora.23 Rifaximin has been shown to
decrease many symptoms of IBS-D, including abdominal discomfort/pain, unformed
stools, and bloating.23,24 Patients whose
condition relapsed after an initial course
of rifaximin achieved statistically significant
benefits with up to two additional courses.24 Rifaximin is generally well tolerated;
the most common adverse effects include
GI and upper respiratory symptoms.23,24
Current guidelines include a weak recommendation for the use of rifaximin for the
relief of bloating and other symptoms of
IBS-D.22
Serotonergic antagonists are believed
to provide benefit in IBS-D through modulation of secretion and motility in the GI
tract.23 Alosetron, which was removed
from the US market in 2001 because of
a risk of ischemic colitis, has been available since 2002 with access currently
restricted by a Risk Evaluation and Mitiga-
CONTINUING EDUCATION
T H E RU N DOW N
tion Strategy program.23 Benefits of this
agent include decreased symptoms of
IBS, decreased number of stools, and decreased loose stools.23 Interestingly, these
benefits originally appeared to occur only
in women, and so this agent is approved
only for use in women with severe IBS-D.23
However, more recent evidence suggests
that alosetron is in fact efficacious in men
and that the original studies simply did
not have enough male patients to show
the effect.29 Current guidelines include
a weak recommendation for the use of
alosetron in women with IBS-D; its use
should be considered only when all other
options have failed to provide adequate
control.22,24 Ramosetron, a serotonergic
antagonist currently available in Asia but
not in the US, may be a promising option
for the treatment of IBS-D in the future.29
This agent has been associated with improvements in quality of life, formation of
stool, and discomfort/pain in patients with
IBS-D. Initial evidence indicates that ramosetron may be equally effective in men
and women and may be associated with
a lower risk of constipation and ischemic
colitis. However, larger studies are needed
to elucidate the true potential and risks of
ramosetron for IBS-D.
In the United States
alone, there are more
than 200 million cases
of infectious diarrheal
illness annually;
worldwide, infectious
diarrhea is the second
most common cause of
morbidity and mortality.”
Infectious diarrhea
Infectious diarrhea is defined by the Infectious Disease Society of America (IDSA)
guideline as diarrhea due to infectious
etiology, which is commonly associated
with symptoms of nausea, abdominal
PAUSE AND PONDER
What counseling points would you provide to a patient
who will be traveling to a developing country regarding
the prevention of traveler’s diarrhea?
cramps, and vomiting. It is a common disease worldwide, with incidence varying by
age group and country for each causative
agent. In the US alone, there are more
than 200 million cases of infectious diarrheal illness annually; worldwide, infectious
diarrhea is the second most common
cause of morbidity and mortality.3 Those
at risk for infectious diarrhea include immunocompromised patients, those at the
extremes of age, travelers, military personnel with overseas assignments, patients
in chronic care facilities, and those with
altered GI physiology (including patients
taking proton pump inhibitors and antibiotics).30,31 Causative agents for this infection include viral, bacterial, and protozoal
sources, which may be passed through
contaminated food and drinks or by fecaloral contamination via sexual intercourse,
community pools, poor water sanitation,
gardening, and other sources.30
Infectious diarrhea can be subclassified as either watery or bloody diarrhea.
Watery diarrhea tends to be less severe
than bloody diarrhea, or dysentery, with norovirus commonly causing watery diarrhea.
Dysentery is associated with more severe
complications and is commonly caused by
Shigella species and Salmonella bacteria.
Some species such as Escherichia coli
may cause either watery or bloody presentations; for instance, enterotoxigenic E coli
(ETEC) is associated with watery diarrhea,
whereas enterohemorrhagic E coli is associated with bloody diarrhea.30
The cause of the diarrhea can often be
determined based on symptoms, incubation period, and the frequency and volume
of stool. For example, both viral gastroenteritis and foodborne illness are commonly
associated with nausea and diarrhea, but
foodborne illness has a shorter incubation
period than viral gastroenteritis. A patient
history should be obtained to assess for
risk factors.3 Stool cultures often have a
low yield for positive results; therefore, cultures should be performed only for patients
with severe diarrhea, diarrhea associated
with fever, or persistent diarrhea; for patients with dehydration or dysentery; for
patients who are immunocompromised,
elderly, and/or hospitalized; and when outbreak is a concern.31
Prevention of these infections is focused on patient education, proper hand
hygiene, and safe food preparation.3 Common management of infectious diarrhea
includes supportive therapy with fluids and
electrolytes to prevent and treat dehydration.3 Loperamide should be avoided in
patients with bloody diarrhea and in those
presenting with fever because of a risk of
complications.31 Infections for which specific prevention or treatment modalities
have been identified will be discussed in
the following sections.
Viral diarrhea
Viral sources are the leading cause of diarrhea worldwide.30 Viral gastroenteritis affects
the stomach and small intestine and commonly presents with diarrhea and nausea.31
Rotavirus is the primary source of
gastroenteritis in infants and children
and historically has caused 20 to 60
deaths, 55,000 to 70,000 hospitalizations, 200,000 emergency room visits,
and 400,000 physician office visits per
year.32,33 Cases of rotavirus tend to occur
from the late fall to early spring. This virus
is transmitted via the fecal-oral route and
through food and water contamination.
The infection lasts for approximately three
to seven days and is commonly associated with fever, nausea, vomiting, watery
diarrhea, and abdominal pain. The rotavirus vaccine, available as either a two- or
three-dose vaccine series depending on the
brand, is now recommended for infants as
DRUGTOPICS.COM | JUNE 2016 | DrugTopics
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CONTINUING EDUCATION
M A NAG E M E N T OF AC U T E A N D CH RON IC DI A R R H E A
CDAD can be further stratified by its etiology
as being community- or hospital-acquired
or by its level of severity (Table 3).35-36 AlTYPE OF
TREATMENT
OPTIONS
though CDAD is primarily hospital acquired,
INFECTION
up to one-third of cases may be community
Mild to moderate
acquired, which is defined as a new infecMetronidazole 500 mg by mouth every 8 h for 10-14 days
severity
tion occurring in a patient who has not been
in a healthcare facility overnight in the past
Vancomycin 125 mg by mouth every 6 h for 10-14 days or fidaxomicin
Severe severity
three months.35,37 C difficile is a common
200 mg by mouth twice daily for 10 days
cause of nosocomial infections, with risk
factors for infection including immunosupVancomycin
500
mg
by
mouth
4
times
daily
+
intravenous
metronidazole
Severe complicated 500 mg every 8 h + vancomycin 500 mg per rectum in cases of complete
pression, treatment with chemotherapy, GI
severity
ileus
surgery, advanced patient age, presence of
severe underlying disease or chronic kidney
Same as initial preferred therapy for the stratified disease severity or
First recurrence
disease, environmental contamination, and
fidaxomicin 200 mg by mouth twice daily for 10 days
use of medications such as proton pump
inhibitors and antibiotics. FluoroquinoVancomycin
pulse
or
tapered
dose;
fi
daxomicin
200
mg
by
mouth
twice
Second recurrence daily for 10 days; alternative therapy; stool transplant
lones, clindamycin, cephalosporins, and
aminopencillins are the antibiotics most
Source: Refs 35-36
commonly associated with CDAD.35 Prevention of CDAD focuses on proper hygiene
a standard vaccination procedure in the US. Bacterial diarrhea
Use of this vaccine has led to a reduction Bacteria are another common cause of and antibiotic stewardship.
in emergency department visits and hos- acute gastroenteritis in the US; ETEC and
pitalizations. These vaccines (Rotarix and Vibrio cholera are the leading causes of
RotaTeq) should not be used in patients watery diarrhea. Dysentery is commonly
with an allergy to the vaccine, patients with caused by nontyphoid Salmonella spesevere combined immunodeficiency syn- cies, Shigella species, and Campylobacter
drome (bubble boy disease), or patients species. Diarrhea can be caused by either
with intussusception.33
the bacteria themselves or by toxins the
Norovirus, also known as the Norwalk- bacteria produce. Antibiotic therapy is reclike virus, is the principle cause of gastro- ommended for severe cases of diarrhea,
enteritis in the US and is the leading cause febrile dysentery, culture-positive bacterial
of viral gastroenteritis worldwide, with out- diarrhea, and moderate-to-severe traveler’s
Management of CDAD is focused on
breaks occurring on cruise ships, in dor- diarrhea (TD), with the preferred agent spe- proper rehydration, cessation of causative
mitories, in restaurants, and in healthcare cific to each causative organism.30
antibiotic therapy as appropriate, and inifacilities as some examples.31,34 Norovirus
Clostridium difficile. Clostridium difficile tiation of pharmacologic treatment with
outbreaks tend to occur during the winter is an anaerobic gram-positive bacillus that metronidazole, vancomycin, or fidaxomicin.
months by similar modes of transmission is both toxin and spore forming. It is the Medications that inhibit GI motility should
as rotavirus. The infection lasts approxi- causative organism of C difficile associated be avoided if CDAD is suspected because
mately two to three days in immunocom- diarrhea (CDAD), which is spread via the of the potential for toxic megacolon.36
petent hosts but may last weeks to years fecal-oral route.35 According to the IDSA
Metronidazole is a nitroimidazole anin immunocompromised individuals.34 No- and Society for Healthcare Epidemiology of tibiotic used for the management of a
rovirus infection is associated with muscle America guidelines, CDAD is defined by the number of parasitic and anaerobic condiaches, abdominal cramps, nausea, vomit- presence of diarrhea and histopathologic tions.38 Metronidazole is associated with
or colonoscopic findings of pseudomem- GI side effects such as nausea, diarrhea,
ing, and watery diarrhea.
Other potential causes of viral gastro- branous colitis or a stool test positive for metallic taste, and abdominal discomfort.
enteritis may include (but are not limited toxigenic C difficile or its related toxins.36 Major drug interactions include disulfiram
to) coronavirus and adenovirus; however,
PAUSE AND PONDER
information about these causes is beyond
the scope of this review. As these infecWhich patient-specific factors would help you decide
tions are viral in nature, management is
which therapy to use for the treatment of CDAD?
focused on supportive care with fluids and
electrolytes.
TABLE 3
Preferred Management of C Difficile Infection
Although CDAD
is primarily hospital
acquired, up to onethird of cases may be
community acquired.”
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and alcohol. The use of alcohol while taking metronidazole can lead to a reaction
similar to that seen with disulfiram, which
may include nausea, vomiting, headache,
and abdominal cramps. As such, patients
should abstain from alcohol while they are
taking metronidazole and for three days
after treatment. Vancomycin is a bactericidal glycopeptide antibiotic that works by
inhibiting the formation of the bacterial cell
wall.39 Because this agent has minimal
systemic absorption, orally administered
vancomycin is indicated only for the management of CDAD and enterocolitis secondary to Staphylococcus aureus, and routine
monitoring of vancomycin levels is unnecessary. The most common adverse effects
of vancomycin are nausea, abdominal pain,
flatulence, diarrhea, and vomiting. Vancomycin-resistant Enterococcus is a concern
with overuse of oral vancomycin therapy.
Zar et al completed a prospective, randomized, double-blind, placebo-controlled
trial comparing metronidazole 250 mg by
mouth four times daily to vancomycin 125
mg by mouth four times daily for 10 days in
patients stratified by CDAD disease severity.40 In patients with mild disease, 90% of
patients taking metronidazole (37/41) and
98% of those taking vancomycin (39/40)
achieved clinical cure (P = 0.36). For those
with severe disease, a significant difference was found between the two groups,
with 76% (29/38) achieving clinical cure in
the metronidazole group compared to 97%
(30/31) in the vancomycin group (P = 0.02),
suggesting the benefit of preferential use
of vancomycin in this population. No significant difference was found in the rate of
relapse between the two groups (14% in
the metronidazole group; 7% in the vancomycin group; P = 0.27). This led the IDSA to
recommend that mild to moderate disease
should be managed with oral metronidazole
therapy, whereas vancomycin should be
used for severe CDAD (Table 3).35-37
Fidaxomicin is a macrocyclic antibiotic
indicated for the management of CDADassociated diarrhea in patients at least 18
years of age. This agent maintains bactericidal activity by inhibiting RNA synthesis.
The FDA-approved dose is 200 mg by
mouth twice daily for 10 days.41 The most
common side effects associated with fidaxomicin include GI adverse effects such as
nausea and diarrhea. Because of its high
cost, fidaxomicin is not used as a first-line
agent. In studies comparing fidaxomicin
with vancomycin, fidaxomicin was found
to be noninferior to vancomycin for clinical
cure rates but was associated with significantly lower rates of recurrence.42
The first recurrence of CDAD can be
managed with the same preferred therapy,
whereas a second recurrence may be managed with pulsed or tapered dose vancomycin. Alternative management strategies,
including stool transplants, may also be
considered at this point.
Traveler’s diarrhea. TD affects individuals who live in developed countries and
travel to less developed or more tropical
areas of the world.43 Afflicted patients experience at least three loose stools within
a one-day period accompanied by at least
one of the following symptoms: elevated
temperature, cramping or pain in the abdomen, urgency to defecate, stools containing
mucus or blood, nausea, or vomiting.43,44
It is estimated that one in two people who
travel to developing areas will experience diarrhea.45 TD develops within the first seven
days of the trip and often runs its course in
seven days or fewer without medication.43,44
However, one in five patients with TD may
experience symptoms significant enough
to limit activities, and one in 100 patients
may experience severe illness requiring
hospital admission.43
Bacteria cause eight of 10 cases of TD;
therefore, bacterial pathogens will be the
focus of this review.43,46 The most frequently
implicated bacteria are ETEC, followed by
other common pathogens such as Shigella
species, Campylobacter, Aeromonas species, Salmonella species, and Plesiomonas species, with prevalence varying by
location.43,44,46 Other important causative
agents include parasites such as Giardia
(comprising approximately 10% of TD cases)
and viruses such as norovirus and rotavirus (comprising <10% of TD cases).43,44,46
Information about the management of viral
diarrhea can be found in the “infectious diarrhea” section of this article.
TD is transmitted by the consumption
of food or beverages contaminated with
pathogenic bacteria.47 Commonly implicated food carriers include salads, raw
vegetables, unpeeled fruits, and seafood
or meat products that are not thoroughly
cooked.43 Activities such as hiking and
camping are particularly risky because of
the limited ability to properly clean and
cook foods.43 Travelers should be aware of
the possibility of contracting TD based on
the region to which they will be venturing.
Mexico, Central and South America, Africa,
most of Asia, and the Middle East are considered to be the highest risk.44 Conversely,
the lowest risk regions are Australia, New
Zealand, North and West Europe, Canada,
and Japan.45 Timing of travel is an important
consideration, as most cases of TD occur
during hot and rainy seasons.43
Antibiotics are
the mainstay of
pharmacologic therapy
for TD and should be
initiated after a patient
passes three or more
unformed stools in 24
hours.”
Patients may consult a pharmacist regarding strategies to prevent TD before travel. Antibiotic prophylaxis is very effective but
is generally not recommended because of
increased risk of adverse effects and antibiotic resistance.44 Furthermore, changes to
normal GI flora precipitated by antibiotic use
may in fact increase a patient’s susceptibility to infection by more virulent pathogens.44
Additionally, antibiotic prophylaxis may lead
patients to have a false sense of protection
and be less cautious when selecting food
and beverages.46
Bismuth subsalicylate has been shown
to decrease the risk of TD by half when
used prophylactically.44 However, patients
must take two tablets four times daily, and
pill burden limits the usefulness of this regi-
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men. Patients should be counseled that the
most effective strategies for preventing TD
are proper hand hygiene and selection of
foods and beverages. Before eating, patients should clean their hands thoroughly
with soap and water or alcohol-containing
sanitizers if clean water is not available.44
Travelers should seek fruits and vegetables that can be peeled or that have been
rinsed with clean water. They should only
eat meals that have been recently cooked.
Beverages should be bottled if possible or
boiled before consumption if not bottled.45
If a patient does contract TD, the first
step is to adequately replace fluids and
electrolytes.44 Parents traveling with young
children should be counseled to carry ORT.
ORT must be prepared by combining the
contents of the packet with a specified
amount of sterile water.44 Many patients,
especially children, may find the salty taste
of ORT to be unpleasant; however, ORT
should be replaced with more palatable
sports drinks only in cases of mild diarrhea.
Beverages with high sugar content such as
fruit juice and cola have the potential to exacerbate diarrhea through osmotic effects
and should therefore be avoided. Antibiotics are the mainstay of pharmacologic
therapy for TD and should be initiated after
a patient passes three or more unformed
stools in a 24-hour period.46 Fluoroquinolones, specifically levofloxacin and ciprofloxacin, are the antibiotics of choice, and
a one-day course of these agents is usually
sufficient.44 In areas where resistance to
fluoroquinolones is increasing among TD
pathogens, azithromycin 500 mg may be
used for one to three days. Rifaximin is
not approved for empiric therapy but may
be used when the causative pathogen is
known to be noninvasive E coli. Antimotility
agents such as loperamide are generally
considered safe and effective when used
in conjunction with antibiotics to provide
additional symptom relief.44
Foodborne illness
There are approximately 9.4 million episodes, 56,000 hospitalizations, and more
than 1000 deaths due to foodborne illnesses each year in the US. These may
be caused by bacterial, parasitic, or viral
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DrugTopics | JUNE 2016 | DRUGTOPICS.COM
sources.47 The most common of these infectious etiologies include Salmonella species, Shigella species, S aureus, Campylobacter species, and norovirus; Salmonella
species are associated with the highest
annual rates of illnesses, hospitalizations,
and deaths.48 Symptoms of foodborne illness occur within hours to days of infection depending on the causative organism
and are short in duration.30 Foods commonly associated with foodborne illnesses
include meats, poultry, water, unpasteurized dairy products, and vegetables. An
assessment of foodborne illness causes
in the US from 1998 to 2008 found that
norovirus was associated with the most
outbreaks of foodborne illnesses. Produce
commodities, including fruits, vegetables,
and nuts, accounted for many of the illnesses (46%), and leafy vegetables accounted for more illnesses than any other
commodity (22%). Poultry-based infections
(19%) were primarily caused by Listeria
monocytogenes or Salmonella species.49
Preventive strategies include avoidance
of undercooked seafood or meat, prevention of cross-contamination, and avoidance
of unpasteurized dairy products.3 Treatment
strategies include supportive care with fluids and electrolytes. Foodborne illnesses
caused by Bacillus cereus, Clostridium perfringens, and S aureus do not benefit from
antimicrobial therapy management; the
management of other infectious causes of
foodborne illnesses has been discussed in
previous sections.
The pharmacist’s role and self-care
exclusions
When assessing a patient with diarrhea, pharmacists should first determine
whether a patient is in need of medical
evaluation, such as those patients at risk
for dehydration and other complications.
Patients who are at high risk for dehydration include those with diarrhea lasting
more than two days, diarrhea occurring
at least six times per day, those who are
experiencing frequent vomiting in addition
to diarrhea, and those with fever (temperature of at least 101.3°F/38.5°C).50 Individuals who are less than two years old
or older than 65 years should be referred
because of an increased risk of complications resulting in hospitalization or death.
Pregnant women, patients taking immunosuppressive medications, and those with
immunocompromising diseases should be
treated under the care of a provider. Patients who report severe pain in the abdomen and those who observe pus or blood
in the stool should be referred to rule out
more serious illnesses. Technicians may
play a role in collecting information about
patient symptoms and severity in preparation for referral to the pharmacist.
Those patients who are eligible for
self-care with OTC products should be
counseled that use of these agents is not
recommended beyond 48 hours after the
onset of acute diarrhea symptoms, regardless of when OTC products are initiated.17
Chronic and persistent diarrhea should be
further evaluated by a provider before continued use of self-care interventions.
Conclusion
Diarrhea is a common complaint with a
higher incidence of morbidity and mortality in patients at the extremes of age and
in immunosuppressed populations. Hydration is the primary treatment modality for
both noninfectious and infectious diarrhea.
Noninfectious diarrhea may be caused by
food intolerances, in which case patients
should be counseled to avoid the offending foods, or by IBS-D, for which newer
treatment modalities may be employed.
Other management options for noninfectious diarrhea include bismuth subsalicylate and loperamide. Infectious diarrhea
may be caused by bacterial, viral, or protozoal sources; the management of these
cases depends on the underlying cause
of infection. Preventive therapy for infectious diarrhea is focused on vaccinations
when appropriate, proper hand hygiene,
antibiotic stewardship, and proper food
preparation to prevent cross-contamination. Because loperamide monotherapy
has the potential to worsen disease and
cause complications, this treatment option
should be avoided in most cases of infectious diarrhea.
References are available online at
www.drugtopics.com/cpe. •
CONTINUING EDUCATION
T E ST QU E ST ION S
For Pharmacists
1. Which of the following medications for IBS-D
is only available through a Risk Evaluation and
Mitigation Strategy program?
a. Alosetron
b. Eluxadoline
c. Loperamide
d. Rifaximin
2. Which of the following medications for IBS-D is
a schedule IV controlled substance?
a. Alosetron
b. Eluxadoline
c. Loperamide
d. Rifaximin
3. Which of the following patients should be
referred for medical evaluation?
a. 45-year-old man with a 36-hour history of diarrhea
and a temperature of 101°F
b. 18-year-old woman with a three-day history of
diarrhea and a temperature of 99.6°F
c. 12-year-old boy with four loose stools occurring in
the past 24 hours and a temperature of 100.4°F
d. 56-year-old man with three loose stools and one
episode of vomiting in the past 18 hours and a
temperature of 98.5°F
4. Which of the following bacteria are most
commonly implicated in traveler’s diarrhea?
a. Enterotoxigenic Escherichia coli
b. Salmonella species
c. Shigella species
d. Campylobacter species
5. Which of the following is a cause of infectious
diarrhea?
a. Bacteria
b. Viruses
c. Protozoa
d. All of the above
6. In the management of noninfectious diarrhea,
which of the following OTC agents is associated
with tinnitus?
a. Bismuth subsalicylate
b. Loperamide
c. Pedialyte
d. Omeprazole
7. Which of the following antibiotics is commonly
associated with causing Clostridium difficile
associated diarrhea (CDAD)?
a. Fluoroquinolones
b. Cephalosporins
c. Amoxicillin
d. All of the above
8. In a patient with mild CDAD, which of the
following agents is considered first-line therapy?
a. Metronidazole
b. Vancomycin
c. Rifaximin
d. Fidaxomicin
9. Based on epidemiologic studies, which of the
following food substances was most commonly
associated with foodborne illnesses?
a. Fruits
b. Poutry
c. Leafy vegetables
d. Shellfish
10. Which of the following is the primary cause of
gastroenteritis in the United States?
a. Rotavirus
b. Norovirus
c. Salmonella species
d. Escherichia coli
For Pharmacy Technicians
1. Diarrhea is defined as which of the following:
a. The production of more than one stool per day
regardless of the patient’s baseline
b. The production of more than two stools per day
regardless of the patient’s baseline
c. An increase in stool frequency or a decrease in stool
consistency from baseline
d. A decrease in stool frequency or an increase in stool
consistency from baseline
2. Diarrhea can be classified by which of the
following means:
a. Etiology: Infectious versus noninfectious etiology
b. Duration: Acute, persistent, or chronic
c. Pathophysiologic mechanism: secretory, osmotic,
exudative, or motor
d. All of the above
3. Which of the following oral liquids is preferred
in patients most at risk for dehydration in the
outpatient setting?
a. Bottled water
b. Sports drinks
c. ORT (eg, Pedialyte)
d. None of the above, as dehydration is not a concern
4. Which of the following factors has the potential
to cause acute noninfectious diarrhea?
a. Overconsumption of fructose
b. Consumption of magnesium-containing antacids
c. Lactose intolerance
d. All of the above
5. Which of the following is a correctly matched
brand and generic OTC product for symptom
management of diarrhea?
a. Bismuth subsalicylate - Lactaid
b. Loperamide - Imodium
c. Loperamide – Pepto-Bismol
d. Bismuth subsalicylate - Imodium
6. At what point in time should patients be referred
for further evaluation when they are self-treating
for noninfectious diarrhea?
a. >48 hours after the first OTC dose
b. >48 hours after the onset of symptoms
c. One week after first OTC dose
d. One week after the onset of symptoms
7. Which of the following is an antibiotic used in
the treatment of IBS-D?
a. Rifaximin
b. Loperamide
c. Bismuth subsalicylate
d. Alosetron
8. Which of the following may put patients at the
highest risk for traveler’s diarrhea?
a. Drinking only bottled water
b. Traveling during cold and dry seasons
c. Traveling within the United States
d. Eating raw vegetables and unpeeled fruit
9. Which of the following diagnoses requires the
use of antibiotics for treatment?
a. Acute noninfectious diarrhea
b. Lactose intolerance
c. C difficile
d. None of the above
10. Which of the following medication classes is
associated with an increased risk of C difficile?
a. Proton pump inhibitors (eg, omeprazole)
b. B-lactam antibiotics (eg, amoxicillin)
c. Both A and B
d. None of the above
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