Diarrhea in Adults

Authors: Juan-Pablo Caeiro, M.D., Herbert L. DuPont, M.D.

Updated 2014 Apr 24 03:14:00 PM: review of acute infectious diarrhea in

immunocompromised adults (N Engl J Med 2014 Apr 17)

WGO practice guideline on acute diarrhea in adults and children (National Guideline
Clearinghouse 2014 Mar 24) view update

review of acute diarrhea (Am Fam Physician 2014 Feb 1)

Acute diarrhea is one of the most common medical complaints in any population. All
practitioners seeing patients with the syndrome should have a working knowledge of: the
common causes of illness; when to perform a microbiologic assessment; when to initiate
empiric antimicrobial treatment; and when to use symptomatic therapy only. In all patients
with acute diarrhea, attention to fluid and salt intake is important.

EPIDEMIOLOGY
Global Burden
Acute diarrhea is an important cause of morbidity and mortality worldwide being responsible
for 1.6 to 2.5 million deaths per year in children less than 5 years of age. Diarrhea is the 7th
most important cause of death in low-and-middle-income countries after ischemic heart
disease, cerebrovascular disease, HIV/AIDS, perinatal conditions and chronic obstructive
lung disease (15).
A recent survey looking at acute diarrhea in the community in the U.S. demonstrated that
approximately 0.72 episodes of acute diarrhea developed per person-year resulting in nearly
200 million cases of illness per year. In the study 41 million individuals with acute diarrhea
sought medical attention, 6.6 million persons furnished a stool for testing and 3.6 million
were admitted to the hospital. Comparative rates of diarrhea by world region are provided
in Table 1.

Definitions and Syndromes in Infectious Diarrhea

Acute diarrhea can be defined as the new onset of passage of three or more unformed stools
in a 24-hour time period as passage of an increase number of stools of decreased form
compared with the normal state. In either case the duration is less than 14 days. Acute
diarrhea is frequently associated with one or more enteric symptoms like nausea, vomiting,
increase in abdominal gas, abdominal pain or cramps, tenesmus (intense urge with straining
but minimal or no bowel movement), fecal urgency, or passage of stools containing gross
blood and mucus (7).
Most cases of acute diarrhea are caused by enteric infection by a viral, bacterial or parasitic
pathogen. In Table 2 the important causes of infectious diarrhea are listed.

Categories of Infectious Diarrhea

Secretory Diarrhea
Non-inflammatory, secretory diarrhea usually presents with the passage of voluminous
watery stools associated with the presence of abdominal cramps and pain without important
levels of fever. The classical cause of secretory diarrhea is Vibrio cholerae O1, the causative
agent of cholera, but the syndrome can be caused by nearly any enteropathogen. The osmotic
gap, stool versus serum has been used in to differentiate secretory from non-secretory
diarrhea. The osmotic gap is determined as follows: Na+ and K+ concentrations found in the
stool and multiplying this by 2 with this number subtracted from 290 (the expected plasma
osmolality). In secretory diarrhea the osmotic gap is <125, usually <50.
Gastroenteritis
Gastroenteritis is a syndrome characterized by nausea and vomiting with or without watery
diarrhea generally caused by ingested viral agents or preformed toxins of Staphylococcus
aureus or Bacillus cereus. Clinical criteria have been proposed to differentiate outbreaks of
gastroenteritis due to viruses from those due to other causes. Diarrhea due
toStaphylococcus spp.,Bacillus cereus and Clostridium perfringens toxins presents with
shorter incubation period, typically <10 hours, more vomiting, and shorter duration of illness.
Inflammatory Diarrhea (Colitis and or Proctitis)
Acute inflammatory diarrhea refers to acute diarrhea secondary to an infectious agent
infecting the distal gut resulting in mucosal inflammation and inflammatory markers in
stools. Typically the patient with colitis passes many small volume stools that may be grossly
bloody. In the case of diarrhea/dysentery caused by Campylobacter jejuni and Shigella spp,
patients often have fever with temperatures of 38.5 C (101.3F). A similar syndrome can be
seen in enteric infection caused by Salmonella, invasive E. coli,Aeromonas, noncholera Vibrio spp or Entamoeba histolytica. Shigatoxin-producing E. coli (STEC) also
referred to as enterohemorrhagic E. coli (EHEC) cause foodborne outbreaks of inflammatory
diarrhea with little or no fever.
A complication of receptive anal intercourse in a gay male is proctitis caused by one of four
enteropathogens showing sexual transmission: Neisseria gonorrheae, Chlamydia
trachomatis, Herpes simplexor Treponema pallidum.
Persistent Diarrhea
When diarrhea lasts more than 14 days, it is considered to be persistent. The etiologic agents
are likely to be different in these cases (8). The most important group of pathogens is the
intestinal protozoa, including Giardia, Cryptosporidium and E. histolytica. Other well known
parasitic causes of persistent diarrhea are Cyclospora, Isospora and Microsporidium. The
bacterial enteropathogens can be implicated in a subset of persistently ill patients. In Table
3 the causes of persistent diarrhea and diagnostic tests are provided. A small percent of
patients with protracted diarrhea will be suffering from the poorly defined, Brainerd diarrhea.
This illness was first described in 1983 in Brainerd Minnesota. It is characterized by

explosive diarrhea that may last for months. The incubation period is about 10 to 30 days and
the illness duration approximately 16 months. It has been associated with consumption of
milk in outbreak settings. It has been associated with consumption of mild in outbreak
settings. Other causes of protracted diarrhea are post-infectious irritable bowel syndrome and
small bowel overgrowth syndrome from dysmotility of the small bowel. Non-infectious
causes of persistent diarrhea include inflammatory bowel diseases (Crohns disease and
ulcerative colitis), celiac and tropical sprue, and colorectal malignancy. Table 4 shows a
suggested initial work up for patients presenting with persistent diarrhea.

Special Settings
Day Care Centers
Infants attending day care centers may be exposed to enteropathogens secondary to
environmental contamination when a day care center child develops diarrhea (11). The most
common causes of diarrhea outbreaks in day care centers are the low-inoculum pathogens
including Shigella, Giardia, Cryptosporidium and Rotavirus. Immunity develops in high-risk
day care centers by repeated exposure to prevalent enteric pathogens.
Clostridium Difficile Diarrhea
Clostridium difficile is an emerging pathogen of increasing importance. The important risk
factors are underlying comorbidity including advanced age, receipt of antibiotics or proton
pump inhibitors. Currently an epidemic of toxinotype III binary toxigenic C. difficile strain is
being seen with greater importance throughout the U.S., Canada and Europe (4,19). The
disease produced byC. difficileis showing a number of important changes. A high percentage
of cases are being admitted to the hospital with the infection. Recurrence rate after treatment
is high often in excess of 30% in most studies.
Travelers Diarrhea
Travelers diarrhea is defined as acute diarrhea acquired by persons during international trips,
usually occurring in someone from an industrialized regions during visits to developing
tropical and semitropical countries. Travelers diarrhea is frequently caused by a bacterial
pathogen (9). Poor sanitation of the host country is an important factor associated with enteric
disease. The most important vehicle for transmission is food with water and ice being less
important.
Post-Infectious Irritable Bowel Syndrome
Post-infectious irritable bowel syndrome develops in 3-30% of patients with bacterial
diarrhea (14). The severity of initial infection seems to be the most relevant predictor of
irritable bowel syndrome. There is a possible role of serotonin, inflammatory cytokines, and
mast cells in the PI-IBS. Low-grade chronic mucosal inflammation exists in post-infectious
irritable bowel syndrome. These changes lead to alteration of small bowel motility and
bacterial overgrowth associated with bloating and abdominal discomfort. Most patients with
post-infectious irritable bowel syndrome have diarrhea predominant disease and the

psychiatric overlay is at a lower frequency than seen in infectious irritable bowel patients
without an antecedent enteric infection.

Foodborne or Waterborne Gastroenteritis and Diarrhea

Food is an important vehicle for enteropathogens in all regions of the world. It is estimated
that 76 million persons suffer from foodborne diseases each year in the United States (17).
The illness leads to 325,000 hospitalizations and 5000 deaths per year. While
enterotoxigenic E. coli (ETEC) is the most important etiologic agent in travelers diarrhea,
the organism occasionally causes foodborne outbreaks in the United States.
Enterotoxigenic E. coli has caused extensive outbreaks of diarrhea secondary to
contamination of recreational lakes or water parks whereCryptosporidiumis also implicated in
outbreak disease. Surveillance data from the CDC demonstrated that 50% of waterborne
gastroenteritis outbreaks related to treated water were due toCryptosporidiumand 25% of
waterborne outbreaks from freshwater were due to ETEC and 25% were due to noroviruses.
Gastroenteritis in Cruise Ships
The incidence of diarrhea among passengers on international cruises is low but outbreaks of
norovirus gastroenteritis are showing outbreaks on a small number of ships. Eradication of
Norwalk virus from the affected ships is difficult due to resistance to disinfection and in view
of the low inoculum required to produce gastroenteritis.
Diarrhea in the Immunosuppressed Host
Before highly active anti-retroviral therapy, diarrhea was a frequent problem in patients with
advanced AIDS. Chronic diarrhea and wasting remain important in the African form of AIDS
where anti-retroviral therapy is substandard. Some anti-HIV drugs may cause diarrhea, such
as nelfinavir, atovaquone and clindamycin. In advanced untreated AIDS, virtually any
enteropathogen can produce diarrhea. Persons with AIDS remain at greater risk of diarrhea
than non-AIDS patients.
The most common enteropathogens causing infection leading to diarrhea in patients with
AIDS are a group of parasites
includingCryptosporidium, Microsporidium, Isospora and Cyclospora. Less common but
important causes of diarrhea in patients with AIDS include the bacterial
enteropathogens: Campylobacter, Shigella, Salmonella, C. difficile and Mycobacterium
avium complex. The major viral pathogens leading to diarrhea in advanced AIDS are HIV
which deplete intestinal immunity leading to mucosal atrophy and malnutrition
and Cytomegalovirus which causes colitis. The important pathogens leading to diarrhea in
HIV/AIDS are listed in Table 5.
Cancer and Organ Transplantation
Patients having undergone solid-organ transplantation (SOT) with immunosuppression
experience a high rate of diarrhea. In a study of renal transplant patients with diarrhea of 7
days duration related were found to have enteric infection secondary to Campylobacter
jejuni, Salmonellaspp.,Clostridium difficile, noroviruses, CMV, small bowel bacterial

overgrowth, and secondary to immunosuppressive drugs including mycophenolate mofetil,

tacrolimus, and cyclosporine.
It is estimated that 10% to 40% of liver transplant recipients develop diarrheal disease. CMV
infection andClostridium difficilediarrhea and colitis are frequent complications. Colitis may
appear in the absence of prior antimicrobial therapy.

DIAGNOSIS
Use of the Laboratory in Acute Endemic and Epidemic Diarrhea
The Infectious Diseases Society of America (IDSA) advocates the performance of laboratory
studies of any diarrhea lasting more than a day when associated with fever, passage of bloody
stools, or in a patient with systemic illness (13).
We would recommend obtaining stool samples for laboratory studies in patients with diarrhea
in the following situations: outbreak settings, in immunocompromised patients, persons with
severe disease requiring hospitalization and in travelers with persistent diarrhea.
Fecal Inflammatory Markers
The most sensitive marker of inflammation is fecal lactoferrin, which is a commercially
available assay. Finding 4+ lactoferrin in stools is an indication of mucosal inflammation.
Numerous fecal leukocytes are found microscopically when a patient has diffuse colonic
inflammation characteristically due to one of the
following: Shigella, Salmonella, Campylobacter and C. difficile. Fecal markers of
inflammation are not reliable indicators of specific enteric pathogens since they are
associated with pathologic process rather than a specific infection.
Stool Cultures
The conventional diagnostic enteric laboratory will routinely identify the presence
ofShigella, SalmonellaandCampylobacter. Most labs are able to look for E. coli 0157:H7 if
requested to look for this pathogen. The customary way to identifyE. coli0157:H7 is to
culture the stool on sorbitol containing MacConkey agar followed by serotyping. Since many
Shigatoxin-producingE. colido not belong to the 0157 serotype, complete evaluation for this
group of pathogens also involves examination of diarrhea stools for Shigatoxin by EIA.
The laboratory must be alerted to look for Vibrios and employ salt-containing media (TCBS)
when this group of bacteria is being sought. The two major indications for culturing
forVibriosare presence of shellfish- or seafood-associated dysenteric diarrhea where
conventional stools studies are negative or when cholera is suspected based on the finding of
profuse diarrhea with profound losses of fluid and dehydration. In the first case, noncholeraVibriosis being sought and in the second V. cholerae is the focus of the study followed
by testing for 01 serotype.
C. DifficileToxin Tests and Culture

The diagnosis ofC. difficilediarrhea/colitis is based on finding toxin A or toxin B in stool

samples or by culturing the organism from stool. The most sensitive tests appear to be
anaerobic culture followed by PCR or cell culture cytotoxicity for toxin B (2). The most
widely used test is enzyme-linked immunosorbent assay for toxins A and or B.
Parasite Studies
The major indications for parasite tests are when diarrhea is persistent, when diarrhea occurs
in an infant attending a DCC, in an adult gay male with diarrhea or when diarrhea
complicates immunosuppression. A well trained and experienced laboratory technician is
needed for direct microscopic identification of parasites in stools using the trichrome stain.
Modified acid fast staining is used for identification
of Cryptosporidium, Isospora and Cyclospora. A sensitive and reproducible commercial EIA
is available for Giardia, Cryptosporidiumand Entamoeba histolytica. The laboratory needs to
be alerted if cryptosporidiosis, cyclosporiasis or isosporiasis are being considered as a
modified acid-fast stain is needed to detect the organisms in the stools.
Rotavirus Antigen
Rotavirus is the principal cause of gastroenteritis in an infant 2 years of age or less. There are
a number of commercial EIAs available for detection of rotavirus. Each is sensitive and
accurate for diagnosis of group A rotaviruses.
Upper Endoscopy, Sigmoidoscopy or Colonoscopy
It may be necessary to endoscopically evaluate for the cause of diarrhea in patients with
persistent symptoms and negative stool evaluation for enteropathogens. In the setting of acute
diarrhea sigmoidoscopy or colonoscopy have a restricted role. They may be appropriated
when patient presents with acute and severe inflammatory diarrhea of unclear cause, often to
help clarify the presence or absence of C. difficile colitis. Colonoscopy and biopsies have
been demonstrated to be useful in patients with diarrhea and HIV infection with CD4 count
of less than 100 cells and negative stool culture for enteropathogens (3) and in HIV infected
patients with CD4 count of more than 100 with associated weight loss.

EMPIRIC THERAPY
(SEE THE ALGORITHM, FIGURE 1)

ORT/IV Fluids
It is well proven the effect of oral rehydration solution to prevent childhood mortality from
diarrhea in developing countries. WHO and UNICEF have approved a new low osmolarity
ORS-UNIPAC ($0.05 per generic sachet) for the treatment of dehydration associated with
diarrhea in both children and adults.
Reduced-osmolarity ORS has been shown to decrease vomiting, stool output, duration of
illness, and the need for unscheduled intravenous fluids compare with standard WHO ORS.

There may be an increase risk of transient and asymptomatic hyponatremia in adults with
cholera drinking the new formulation. See Table 6 for comparison the old and new
formulation.
Oral rehydration solution packets like Ceralyte may be available at stores selling products for
outdoor recreation camping or at travel medicine clinics. Pedialyte is available in various
forms in most retail stores.

Symptomatic Treatment
Loperamide is a synthetic opiate that exerts its effects on intestinal smooth muscles resulting
in retardation of the movement of the luminal column giving more time for fluid and salt
absorption. Loperamide has some minimal antisecretory effects. The drug may produce
rebound constipation and is contraindicated in persons with inflammatory diarrhea and/orC.
difficilediarrhea and colitis due to risk of toxic megacolon.
Loperamide doses are as follow: 4mg orally first dose, then 2mg orally after each loose stool
with a maximum of 8 mg per day.
Racecadotril is an enkephalinase inhibitor. Enkephalins are endogenous opioids with proabsorptive and antisecretory function in the small intestine. Racecadotril has proven to be
effective in clinical trials in children and adults (16). While not licensed in U.S. it has been
approved in other countries. SP 303 is another antisecretory drug working through an effect
of blockade of intestinal chloride channels (5). It is not currently licensed in the U.S. although
is available as Normal Stool Formula over the internet. Racecadotril and SP 303 should not
produce rebound constipation an advantage over loperamide.
Bismuth subsalicylate (BSS) is an antisecretory agent reducing diarrhea by approximately
40% compared with placebo. While the salicylate is the active antisecretory component in the
treatment of acute diarrhea, BSS is an effective preventive in travelers diarrhea through the
antibacterial effects of the bismuth moiety of the product (10).

ANTIBACTERIAL TREATMENT
A telephone survey in U.S. of diarrheal illness found that 12% of persons with acute diarrhea
had received an antimicrobial agent by their physician. This rate closely approximates the
frequency of bacterial enteric infection and associated diarrhea in the U.S.
Empiric antibacterial therapy is indicated in patients with fever who are passing gross mucus
and blood in stools. A second condition where empiric therapy is indicated is moderate to
severe travelers diarrhea since bacterial enteropathogens explain most of these cases.
Fluoroquinolones are the most frequently employed antibacterial drugs for infectious diarrhea
in adults. In a placebo controlled study ciprofloxacin was shown to be effective in decreasing
the duration of diarrhea in patients with severe community acquired diarrhea (defined as 4 or
more liquid stools per day for more than 3 days, associated with fever, vomiting or abdominal

pain). Norfloxacin, ofloxacin and levofloxacin are other fluoroquinolones that have shown to
reduce the duration of diarrhea and other symptoms.
Treatment of travelers diarrhea (Figure 2) is best initiated by the affected persons employing
self-therapy with antibacterial drugs taken with them on their trip. The three proven drugs in
this condition are rifaximin 200 mg TID for three days, or a fluoroquinolone taken daily for
three days. Azithromycin in a dose of 500 mg once a day for three days is the preferred
treatment for febrile dysentery due to the increasing importance of ciprofloxacin-resistant
Campylobacter (Table 2).

Specific Antimicrobial Agents

Rifaximin
Rifaximin is a non-absorbed (<0.4%) rifamycin antimicrobial drug that is effective in
reducing diarrhea caused by non-invasive bacterial enteropathogens. The drug is useful in the
treatment of travelers diarrhea where there is an absence of fever or dysentery. The drug has
been used as a chemoprophylactic agent in the prevention of travelers diarrhea (6).
Azithromycin
Azithromycin is an azalide antibiotic with activity against virtually all enteric bacterial
enteropathogens causing diarrhea including ciprofloxacin-resistant Campylobacter and
invasive Shigella.
Nitazoxanide
Nitazoxanide is effective and is approved for use in the treatment
of giardiasis and cryptosporidiosis. It has activity against Clostridium difficile and has been
successfully used in diarrhea and colitis due to the organism (18). It appears to have antiviral
action and has shortened the course of rotavirus gastroenteritis in children studied in Egypt
(20).
Bile Acid Resin
Bile acid sequestrants are generally not indicated for the treatment of acute diarrhea. They
may improve diarrhea in patients who suffer tropical-related diarrhea due to the toxic
dinoflagellate Pfiesteria piscida (1) .P. piscidamay be found in the south eastern coast of the
U.S. and the Gulf of Mexico. Bile acid malabsorption may cause chronic diarrhea that would
benefit by bile acid binding resin therapy.

Therapy of Persistent Diarrhea

While there are effective drugs in bacterial and in parasitic diarrhea, empiric therapy is not
recommended with search for an etiologic agent. Nitazoxanide is a broad-spectrum
antiparasitic agent with activity against a wide range of parasitic agents and against some
non-parasitic pathogens like Clostridium difficile and Rotavirus. If empiric treatment were
given to a patient with protracted diarrhea, nitazoxanide would be the preferred agent.
However, no placebo-controlled trial has been done in this situation.

The nitazoxanide dose is 500mg tablets taken with food twice a day for 3 days in adults (12).

Complications of Acute Infectious Diarrhea

Acute diarrhea is a self-limited entity the majority of the time. Rarely it can be trigger
complications outside the gastrointestinal tract. Table 7 shows the most significant
complications of diarrhea.

CONCLUSIONS
Acute diarrhea is common in all populations. The rate of illness in western countries
including the U.S. is surprisingly high relating to consumption of contaminated foods or
drink. While the rate of illness is higher in developing countries, the more impressive fact
relates to the high rate of death among infants living in areas with reduced hygiene and
common occurrence of malabsorption. Having a working knowledge of the important causes
of acute diarrhea and an approach to work-up and treatment of acute diarrhea is essential in
all primary care settings. Febrile dysenteric illness and moderate to severe travelers diarrhea
is generally treated with empirical antibacterial therapy. Other forms of diarrhea are best
managed after making an etiologic diagnosis through stool examination. We offer a flow
chart for management based on presenting symptoms.

REFERENCES
1. Balagani R, Wills B, Leikin JB. Cholestyramine improves tropical-related diarrhea. Am J
Ther 2006; 13(3): 281-282.[PubMed]
2. Barbut F,Kajzer C, Planas N, Petit JC. Comparison of three enzyme immunoassays, a
cytotoxicity assay, and toxigenic culture for diagnosis of Clostridium difficile-associated
diarrhea. J Clin Microbiol, 1993;31(4): 963-967.[PubMed]
3. Bini EJ, Cohen J. Diagnostic yield and cost-effectiveness of endoscopy in chronic human
immunodeficiency virus-related diarrhea. Gastrointest Endosc, 1998; 48(4): 354-361.
[PubMed]
4. Cheng AC, McDonald JR, Thielman NM. Infectious diarrhea in developed and developing
countries. J Clin Gastroenterol, 2005;39(9): 757-773.[PubMed]
5. DiCesare D, DuPont HL, Mathewson JJ, Ashley D, Martinez-Sandoval F, Pennington JE,
Porter SB. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the
symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J
Gastroenterol 2002;97(10): 2585-2588[PubMed]
6. DuPont HL,Jiang ZD, Okhuysen PC, Ericsson CD, de la Cabada FJ, Ke S, DuPont MW,
Martinez-Sandoval F.A randomized, double-blind, placebo-controlled trial of rifaximin to
prevent travelers' diarrhea. Ann Intern Med 2005;142(10):805-812.[PubMed]

7. DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters
Committee of the American College of Gastroenterology. Am J Gastroenterol 1997;
92(11):1962-1975.[PubMed]
8. DuPont HL, Capsuto EG. Persistent diarrhea in travelers. Clin Infect Dis 1996;22(1):124128.[PubMed]
9. DuPont HL, Ericsson CD. Prevention and treatment of traveler's diarrhea. N Engl J Med
1993;328(25): 1821-1827.[PubMed]
10. DuPont HL,Ericsson CD, Johnson PC, Bitsura JA, DuPont MW, de la Cabada
FJ. Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate. Jama
1987;257(10): 1347-1350.[PubMed]
11. Ekanem EE, DuPont HL, Pickering LK, Selwyn BJ, Hawkins CM. Transmission
dynamics of enteric bacteria in day-care centers. Am J Epidemiol 1983;118(4):562-572.
[PubMed]
12. Fox LM, Saravolatz LD. Nitazoxanide: a new thiazolide antiparasitic agent. Clin Infect
Dis 2005;40(8):1173-80.[PubMed]
13. Guerrant RL,Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Hennessy T,
Griffin PM, DuPont H, Sack RB, Tarr P, Neill M, Nachamkin I, Reller LB, Osterholm MT,
Bennish ML, Pickering LK; Infectious Diseases Society of America. Practice guidelines for
the management of infectious diarrhea. Clin Infect Dis 2001;32(3):331-351.[PubMed]
14. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome--a metaanalysis. Am J Gastroenterol 2006;101(8):1894-1899; quiz 1942.[PubMed]
15. Lopez AD,Mathers CD, Ezzati M, Jamison DT, Murray CJ.Global and regional burden of
disease and risk factors, 2001: systematic analysis of population health data. Lancet
2006;367(9524):1747-1757.[PubMed]
16. Matheson AJ, Noble S. Racecadotril. Drugs 2000;59(4):829-835; discussion 836-837.
[PubMed]
17. Mead PS,Slutsker L, Dietz V, McCaig LF, Bresee JS, Shapiro C, Griffin PM, Tauxe
RV. Food-related illness and death in the United States. Emerg Infect Dis 1999;5(5):607-625.
[PubMed]
18. Musher DM,Logan N, Hamill RJ, Dupont HL, Lentnek A, Gupta A, Rossignol
JF.Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis
2006;43(4):421-427.[PubMed]
19. Pepin J,Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, Leblanc M, Rivard
G, Bettez M, Primeau V, Nguyen M, Jacob CE, Lanthier L. Emergence of fluoroquinolones
as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study
during an epidemic in Quebec. Clin Infect Dis 2005; 41(9):1254-1260.[PubMed]

20. Rossignol JF,Abu-Zekry M, Hussein A, Santoro MG. Effect of nitazoxanide for treatment
of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Lancet
2006;368(9530):124-129.[PubMed]