602 PRACTICE GUIDELINES nature publishing group

CME

ACG Clinical Guideline: Diagnosis, Treatment, and

Prevention of Acute Diarrheal Infections in Adults
Mark S. Riddle, MD, DrPH1, Herbert L. DuPont, MD2 and Bradley A. Connor, MD3

Acute diarrheal infections are a common health problem globally and among both individuals in the United States
and traveling to developing world countries. Multiple modalities including antibiotic and non-antibiotic therapies
have been used to address these common infections. Information on treatment, prevention, diagnostics, and the
consequences of acute diarrhea infection has emerged and helps to inform clinical management. In this ACG Clinical
Guideline, the authors present an evidence-based approach to diagnosis, prevention, and treatment of acute diarrhea
infection in both US-based and travel settings.

Am J Gastroenterol 2016; 111:602–622; doi:10.1038/ajg.2016.126; published online 12 April 2016

INTRODUCTION supplements previously published Infectious Disease Society of

Acute diarrheal infection is a leading cause of outpatient visits, America (IDSA) (5), and World Gastroenterology Organiza-
hospitalizations, and lost quality of life occurring in both domes- tion guidelines (6). This guideline is structured into five sections
tic settings and among those traveling abroad. The Centers for of clinical focus to include epidemiology and population health,
Disease Control and Prevention has estimated 47.8 million cases diagnosis, treatment of acute disease, evaluation of persisting
occurring annually in the United States, at an estimated cost symptoms, and prevention. To support the guideline development,
upwards of US$150 million to the health-care economy (1,2). a comprehensive literature search on acute diarrheal infection in
Acute diarrhea can be defined as the passage of a greater number adults was performed across multiple databases. A medical library
of stools of decreased form from the normal lasting <14 days. information specialist searched the Ovid MEDLINE and EMBASE
Some definitions require an individual to present with an abrupt databases for relevant articles on 18 February 2015, using the fol-
onset 3 or more loose or liquid stools above baseline in a 24-h lowing main terms (with synonyms and closely related words):
period to meet the criteria of acute diarrhea. Persistent diarrhea “diarrhea” AND “acute disease,” “infectious diarrhea”, “dysentery,”
is typically defined as diarrhea lasting between 14 and 30 days, or “acute gastroenteritis.” The searches were limited to English
with chronic diarrhea generally considered as diarrheal symptoms language articles published in the past 10 years and excluded
lasting for greater than a month. Acute diarrhea of infectious etio- case reports, and child or animal studies. Details of the search
logy is generally associated with other clinical features suggest- methodologies are provided in the Appendix. Additional articles
ing enteric involvement including nausea, vomiting, abdominal were obtained from review of references from retrieved articles, as
pain and cramps, bloating, flatulence, fever, passage of bloody well as articles that were known to authors.
stools, tenesmus, and fecal urgency. Acute diarrheal infection is Each section presents key recommendations followed by a
also often referred to as gastroenteritis, and some acute gastro- summary of the evidence (Figure 1 and Table 1). The GRADE
intestinal infections may cause a vomiting predominant illness system was used to grade the strength of our recommendations
with little or no diarrhea. and the quality of the evidence (7). The strength of a recommenda-
This guideline provides recommendations for the diagnosis, tion is graded as “strong,” when the evidence shows the benefit of
management, and prevention of acute gastrointestinal infec- the intervention or treatment clearly outweighs any risk, and as
tion focusing primarily on immune-competent adult individuals “conditional,” when uncertainty exists about the risk–benefit ratio.
and does not consider Clostridium difficile-associated infections, The quality of the evidence is graded as follows: “high,” if further
which has recently been reviewed in a separate American College research is unlikely to change our confidence in the estimate of the
of Gastroenterology (ACG) Clinical Guideline (3). It replaces a effect; “moderate,” if further research is likely to have an important
previously published ACG Guideline on the same topic (4), and impact and may change the estimate; “low,” if further research is

1
Enteric Diseases Department, Naval Medical Research Center, Silver Spring, Maryland, USA; 2University of Texas Health Science Center at Houston, Houston,
Texas, USA; 3Weill Medical College of Cornell University, New York, New York, USA. Correspondence: Mark S. Riddle, MD, DrPH, Enteric Diseases Department,
Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA. E-mail: [email protected]
Received 23 November 2015; accepted 16 March 2016

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 Clinical Guideline: Acute Diarrheal Infections 603

Passage of !3 unformed stools in 24 h plus an enteric symptom (nausea, vomiting, abdominal pain/cramps, tenesmus, fecal
urgency, moderate to severe flatulence)

Oral fluid therapy: for all cases, hydrate through fluid and salt intake
Food: soups, broths, saltine crackers, broiled and baked foods

Watery diarrhea Dysenteric diarrhea (passage of grossly bloody stools)

Mild illness* Moderate-to-severe illness* Severe illness* with fever

No or low-grade fever
(!101°F) in a single case
("100°F)
(not outbreak)

Hydration Travel-
Non-travel-associated
only, may use associated
loperamide 4 mg
initially to Microbiologic assessment, Non-travel- Travel-
control No or then anti-microbial agent associated associated
Antibiotic
stooling therapy low-grade Fever directed to cause for all but
(Table 4) fever (≥101°F) STEC infection
*Illness severity: (≤100°F)
Severe —total Empiric
disability due to treatment,
diarrhea; Moderate Azithromycin
= able to function Consider 1 g in single
<72 h !72 h Consider
but with forced "48 h of dose OR 500 mg
duration duration microbiologic
change in activities loperamide once daily
assessment
due to illness; therapy for 3 days
Mild = no change
in activities

Persistent diarrhea (14 – 30 days) should be worked up by culture and/or culture-independent microbiologic
assessment, then treatment with anti-microbial agent directed to cause

Figure 1. Approach to empiric therapy and diagnostic-directed management of the adult patient with acute diarrhea (suspect infectious etiology).

very likely to change the estimate; “very low,” if an effect is very survey in which 12,755 persons (median age 40 years) were in-
uncertain (8). terviewed (9). Overall, 6% reported having experienced an acute
diarrheal illness at some point during the 4 weeks preceding the
interview (overall annualized rate, 0.72 episodes per person-year;
EPIDEMIOLOGY AND PUBLIC HEALTH 15–24, 1.1 episodes per person-year; 25–44, 1.7 episodes per
CONSIDERATIONS person-year; 45–64, 1.2 episodes per person-year). A follow-up
Recommendation survey where 3,568 respondents (median age 51) were asked at
1. Diagnostic evaluation using stool culture and culture- random about illness in the previous 7 days or previous month
independent methods if available should be used in situa- found that recall bias had an important effect on estimates of
tions where the individual patient is at high risk of spreading acute gastrointestinal illness (10). Using a 7-day exposure win-
disease to others, and during known or suspected outbreaks. dow, the estimated incidence of acute diarrhea was 1.6 episodes
(Strong recommendation, low level of evidence) per person-year, compared with 0.9 episodes per person-year if
asked about illness within the preceding month. Other popula-
Summary of evidence. Surprisingly, there are few published tion-based studies from Canada and western European countries
studies that describe the overall incidence of acute diarrhea using varied methodologies estimate annual incidence between
(including infectious and non-infectious causes) in the United 0.1 to 3.5 episodes per person-year (11).
States. In 1998, the Foodborne Diseases Active Surveillance Network Specifically focusing on infectious causes of acute diarrheal
(FoodNet) conducted a random population-based telephone illness, in 2011 the Centers for Disease Control and Prevention

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604 Riddle et al.

Table 1. Summary and strength of recommendations

Epidemiology and public health

1. Diagnostic evaluation using stool culture and culture-independent methods if available should be used in situations where the individual patient is at high
risk of spreading disease to others, and during known or suspected outbreaks. (Strong recommendation, low level of evidence)
Diagnosis
2. Stool diagnostic studies may be used if available in cases of dysentery, moderate–severe disease, and symptoms lasting >7 days to clarify the etiology of
the patient’s illness and enable specific directed therapy.(Strong recommendation, very low level of evidence)
3. Traditional methods of diagnosis (bacterial culture, microscopy with and without special stains and immunofluorescence, and antigen testing) fail to
reveal the etiology of the majority of cases of acute diarrheal infection. If available, the use of FDA-approved culture-independent methods of diagnosis can
be recommended at least as an adjunct to traditional methods. (Strong recommendation, low level of evidence)
4. Antibiotic sensitivity testing for management of the individual with acute diarrheal infection is currently not recommended. (Strong recommendation, very
low level of evidence)
Treatment of acute disease
5. The usage of balanced electrolyte rehydration over other oral rehydration options in the elderly with severe diarrhea or any traveler with cholera-like
watery diarrhea is recommended. Most individuals with acute diarrhea or gastroenteritis can keep up with fluids and salt by consumption of water, juices,
sports drinks, soups, and saltine crackers. (Strong recommendation, moderate level of evidence)
6. The use of probiotics or prebiotics for the treatment of acute diarrhea in adults is not recommended, except in cases of postantibiotic-associated illness.
(Strong recommendation, moderate level of evidence)
7. Bismuth subsalicylates can be administered to control rates of passage of stool and may help travelers function better during bouts of mild-to-moderate
illness. (Strong recommendation, high level of evidence)
8. In patients receiving antibiotics for traveler’s diarrhea, adjunctive loperamide therapy should be administered to decrease duration of diarrhea and
increase chance for a cure. (Strong recommendation, moderate level of evidence)
9. The evidence does not support empiric anti-microbial therapy for routine acute diarrheal infection, except in cases of TD where the likelihood of bacterial
pathogens is high enough to justify the potential side effects of antibiotics. (Strong recommendation, high level of evidence)
10. Use of antibiotics for community-acquired diarrhea should be discouraged as epidemiological studies suggest that most community-acquired diarrhea is
viral in origin (norovirus, rotavirus, and adenovirus) and is not shortened by the use of antibiotics. (Strong recommendation, very low-level evidence)
Evaluation of persisting symptoms
11. Serological and clinical lab testing in individuals with persistent diarrheal symptoms (between 14 and 30 days) are not recommended. (Strong recom-
mendation, very low level of evidence)
12. Endoscopic evaluation is not recommended in individuals with persisting symptoms (between 14 and 30 days) and negative stool work-up. (Strong
recommendation, very low level of evidence)
Prevention
13. Patient level counseling on prevention of acute enteric infection is not routinely recommended but may be considered in the individual or close contacts
of the individual who is at high risk for complications. (Conditional, very low level of evidence)
14. Individuals should undergo pretravel counseling regarding high-risk food/beverage avoidance to prevent traveler’s diarrhea. (Conditional, very low level
of evidence)
15. Frequent and effective hand washing and alcohol-based hand sanitizers are of limited value in preventing most forms of traveler’s diarrhea but may be
useful where low-dose pathogens are responsible for the illness as for an example during a cruise ship outbreak of norovirus infection, institutional outbreak,
or in endemic diarrhea prevention. (Conditional recommendation, low level of evidence)
Prophylaxis
16. Bismuth subsalicylates have moderate effectiveness and may be considered for travelers who do not have any contraindications to use and can adhere
to the frequent dosing requirements. (Strong recommendation, high level of evidence)
17. Probiotics, prebiotics, and synbiotics for prevention of TD are not recommended. (Conditional recommendation, low level of evidence)
18. Antibiotic chemoprophylaxis has moderate to good effectiveness and may be considered in high-risk groups for short-term use. (Strong recommenda-
tion, high level of evidence)
TD, traveler’s diarrhea.

updated the estimates of infectious gastroenteritis caused by a States caused 9.4 million episodes of diarrheal illness, 55,961 hos-
myriad of viruses, bacteria, and parasites (1,2). Based on empirical pitalizations, and 1,351 deaths. In addition, unspecified agents
modeling of active, passive, and outbreak surveillance data ~47.8 resulted in 71,878 hospitalizations and 1,686 deaths, caused ~38.4
million foodborne-related illnesses occur annually (one out of million episodes of domestically acquired foodborne illnesses. In
every six persons) in the United States. Furthermore, it was esti- addition to domestically acquired infections, over 44 million US
mated each year that 31 major pathogens acquired in the United residents traveled abroad to non-Canadian and non-European

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 Clinical Guideline: Acute Diarrheal Infections 605

destinations in 2014 (12), resulting in roughly 4 to 17 million cases authorities in compliance with both voluntary and mandatory
of traveler’s diarrhea (TD) based on 10–40% attack rates (13). In state requirements on reportable events.
addition to the significant burden of the acute illness associated Finally, with the advent of growing availability and increasing
with these infections, recent evidence suggests that these patho- use of culture-independent technologies in clinical laboratories
gens are linked with chronic health sequelae, including functional (discussed in detail later), an emerging concern is the potential
gastrointestinal disorders, reactive arthritis, hemolytic uremic syn- impact on replacement of culture-based methods for the afore-
drome, and Guilliane Barré syndrome (14–20). The cost of acute mentioned public health utilization (26). Current public health
and chronic illness attributable to these infections is estimated to and control strategies rely on isolate recovery, specimen pres-
be upwards of US$145 billion to the US economy (21–23). ervation, and partnerships with clinical laboratories. Although
In light of these data, acute diarrheal illness is considered a major culture-independent methods provide a promise for more sensi-
public health issue against which control efforts are needed. While tivity of pathogen identification (leading to more accurate disease-
this guideline is primarily focused on the diagnosis, prevention, burden estimates), they do so with a detrimental impact on the
and treatment of acute diarrhea in the individual, it is appropri- advanced characterization and typing, which is needed in outbreak
ate to specifically address the importance of diagnosis of the indi- investigation and resistance monitoring efforts. As such, and until
vidual in the context of population health improvement. Public new methods have evolved in which genotypic advanced charac-
health surveillance and response in the field of acute diarrhea terization platforms are widely available, it is recommended that
include strategies of infection control, anti-microbial stewardship, culture-based and culture-independent testing be used in parallel
outbreak investigation, as well as food and water safety interven- when practicable to support public health purposes.
tions and regulatory policy (24). The individual patient–medical
encounter is the interface and provides critical input on which the
success of these control strategies are built. There are significant DIAGNOSIS
data gaps and limitations with current burden of disease estimates Recommendations
that are due to limitations in the current reporting structure (2,25). 2. Stool diagnostic studies may be used if available in cases of
Important multipliers for which there is significant uncertainty dysentery, moderate-to-severe disease, and symptoms lasting
in published burden of disease models include the underreport- >7 days to clarify the etiology of the patient’s illness and
ing multiplier (which adjusts data reported to health departments enable specific directed therapy. (Strong recommendation,
as part of routine public health surveillance for the number of very low level of evidence)
infected people who seek treatment and test positive for a specific 3. Traditional methods of diagnosis (bacterial culture, micro-
infectious agent), and the pathogen fraction multiplier (which is scopy with and without special stains and immunofluores-
used to attribute a proportion of all episodes of gastroenteritis to cence, and antigen testing) fail to reveal the etiology of the
particular pathogens) (25). Improvement of estimates, which is majority of cases of acute diarrheal infection. If available,
required to make important policy decisions, benefits from more the use of Food and Drug Administration-approved culture-
certain data that comes from better reporting. From an outbreak independent methods of diagnosis can be recommended
investigation perspective, culture-based testing and reporting (and at least as an adjunct to traditional methods. (Strong recom-
advanced isolate characterization) is needed to provide sufficient mendation, low level of evidence)
information to distinguish among strains or serotypes and perhaps 4. Antibiotic sensitivity testing for management of the individual
identify virulence characteristics and susceptibility to anti-micro- with acute diarrheal infection is currently not recommended.
bial agents that relies on testing individual cases (26). Established (Strong recommendation, very low level of evidence)
networks such as FoodNet and Pulsenet have demonstrated
the importance of active surveillance for examining trends in Summary of the evidence. The commonly accepted statement
specific diseases over time, evaluating impact of food safety policy, that specific investigation is not normally required in the majority
as well as identifying and responding to large common source of cases of acute watery diarrhea because it is usually self-limiting
outbreaks (27). and resolves without specific treatment may under inform the
However, a comprehensive laboratory evaluation and advanced ability to provide a more rapid resolution of symptoms with
characterization work-up is neither practicable nor cost-effective appropriate directed therapy and potentially prevent postinfec-
for every patient presenting with an acute diarrheal infection (28). tious sequelae (29). Historical guidelines for diagnostic testing
No formal cost-effectiveness studies on the optimization of testing (ACG, IDSA) seem to be too restrictive in the current environ-
and reporting has been reported and these would be challenging ment of new diagnostic methods and enhanced ability to target
to conduct. However, public health fundamentals would strongly therapy (4,5).
support individual patient testing and reporting in a number of Evidence supporting the use of diagnostic testing to support
situations. These include diarrhea outbreaks among workers who clinical management may be different in higher-resource settings
prepare and handle food, health-care workers, daycare (adult and than they would be, for example, in the traveler who is in an area
child) attendees/employees, and residents of institutional facilities with limited access to adequate medical care or diagnostics (30).
(3). Additionally, if testing is conducted for individual clinical rea- Appropriate microbial identification may be helpful in tailor-
sons, the results of these tests should be reported to public health ing therapy as in antibiotics for bacterial pathogens, supportive

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606 Riddle et al.

Table 2. FDA-approved laboratory tests for enteric pathogens

Manufacturer Test system Platform Pathogens detected Detection time (h) FDA-approved Date-approved

Type No.

Luminex GPP xTAG B, V, P 15 <5 Yes 15/01/13

Hologic/Gen-Probe ProGastro SSCS — B 4 4 Yes 22/01/13
BD Diagnostics EBP BD MAX B 4 3–4 Yes 02/04/13
Biofire Diagnostics GI Panel FilmArray B, V, P 22 1–2 Yes 05/05/14
Nanosphere EP Verigene B 6 2 Yes 24/06/14
B, bacteria; FDA, Food and Drug Administration; P, parasite; V, viral.

therapies, and avoidance of antibiotics for viral pathogens or examination of stool allowed recognition of viral agents of acute
more specific anti-microbials for parasitic protozoan etiologies. diarrhea but was expensive and not widely available. Enzyme
As symptoms of acute diarrhea are protean, attempts to diagnose immunoassays and serologic studies are available but suffer from
etiologic agents or classes are subjective at best and fraught with these limitations as well (35).
imprecision due to overlap in symptoms. Although features of Diagnostics to determine specific microbial etiologies have
the clinical presentation may be useful in distinguishing bacterial advanced in the past number of years. It is now possible using
from protozoan causes, they are often an unreliable indicator of culture-independent molecular techniques to rapidly and simul-
the likely pathogen responsible. As with any syndromic disorder, taneously identify a multitude of bacterial, protozoan, and viral
there can be considerable overlap in symptoms caused by various diarrheal pathogens including some not commonly identified in
agents (31). Despite efforts in recent years to educate travelers to clinical laboratories (36).
recognize acute bacterial diarrhea (as opposed to protozoan) for Diarrheal disease by definition has a broad range of potential
purposes of self-treatment, this approach is at best empiric, and pathogens particularly well suited for multiplex molecular test-
although may be suitable for travelers in remote destinations, it ing. Several well-designed studies show that molecular testing
does not translate well to the individual with community acquired now surpasses all other approaches for the routine diagnosis of
diarrhea (29). diarrhea. Molecular diagnostic tests can provide a more compre-
Conventional diagnostic approaches to diarrheal disease hensive assessment of disease etiology by increasing the diagnostic
require multiple procedures: bacterial culture, microscopy with yield compared with conventional diagnostic tests (Table 2). They
and without stains or immunofluorescence and stool antigen tests are also faster, providing results in hours rather than days (37). The
for detection of protozoa, and for detecting viral agents, electron new diagnostics’ best applicability is for the clinician in practice,
microscopy, or antigen-based tests. Routine clinical laboratory seeing one patient at a time rather than in the public health setting,
detection of bacterial pathogens requires the use of differential e.g., in outbreak investigations. One potential drawback of molec-
culture media, which select for the growth of certain bacteria but ular technologies is the need to predefine the particular microbes
may fail to detect other bacteria, especially in the setting of anti- being sought. In addition the significance of an identified organism
biotic use. Culture methods are laborious and time consuming, may not be clear as these molecular technologies, which involve
with results often not available for 48 to 72 h (32). Historically, a nucleic acid amplification, are limited to our existing knowledge
decision to obtain a stool culture in an individual with diarrhea has of a microbes’ genome and do not discriminate between viable and
often been guided by the finding of fecal leukocytes or the presence non-viable organisms. As a result they can detect microbes at non-
of stool lactoferrin (4,33). Although the latter is a more sensitive pathogenic levels. Given the high rates of asymptomatic carriage of
predictor of a positive stool culture, using these markers to guide enteropathogens, this can be a considerable problem. To confound
further diagnostic studies has been proven to be imprecise and matters, further multiplex techniques are more commonly associ-
probably unnecessary. ated with increased detection of mixed infections and the relative
Microscopy has been the principal diagnostic tool in parasitology importance of each pathogen may be unclear (38–47).
for over 350 years. The limitations of this method are that it is labor Before bacterial culture is discarded entirely, it is important to
and time intensive, requires technical expertise, and lacks sensitiv- acknowledge that multiplex molecular diagnostics do not yield
ity and reproducibility. Multiple specimens are often required to isolates that can be forwarded to public health laboratories. Speci-
reduce the day-to-day variability in parasite shedding (34). mens collected for culture-independent testing may, in some cases,
When enteric viruses were identified as agents of acute diarrheal be incompatible with culture because of the collection methods
infection, commercial diagnostic tests were unavailable. A reliance or media that are used for collection. And, a strict reliance on
on distinct characteristics of the clinical illness, often in the appro- culture-independent diagnostics would limit our ability to detect
priate setting, was the standard of practice. Electron microscopical new causes of diarrheal disease (26,48–51). The future may hold a

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 Clinical Guideline: Acute Diarrheal Infections 607

combination approach where culture specimens that have yielded provide high levels of potassium and carbohydrate, but low levels
a positive result by culture-independent testing are then submitted of sodium and chicken broth is heavy in sodium (70,71). Travelers
to public health laboratories for subtyping and sensitivity analy- with diarrhea should keep up with fluids and electrolytes through
sis. A second specimen may need to be submitted if specimens diet to be certain they are regularly passing urine and have moist
are incompatible with cultures such as dry fecal swab specimens mucous membranes.
(52–54). In severe diarrhea, a balanced ORS can usually be purchased
Despite an increasing number of reports worldwide of resistance at a local pharmacy with sodium of 60–75 mEq/l and glucose of
to various antibiotics among bacterial enteropathogens, the clini- 75–90 mmol/l (72) with value in replacing fluids and salt in dehy-
cal impact of this has yet to be manifest in a significant enough way drating forms of diarrhea as studied in infants and children. Sports
to warrant anti-microbial susceptibility testing across the board, drinks while not adequate alone to treat severe diarrhea can pro-
especially in the individual patient. In general, there appears to be vide partial sodium and potassium replacement. More research is
a low failure rate with the use of empiric anti-microbial therapy, needed to determine the optimal composition of available fluid-
especially with the fluoroquinolones and macrolides (55–62). salt replacement beverages for travelers (73). New developments in
Anti-microbial susceptibility testing will continue to have a role in oral rehydration are underway, and if convenient without increas-
the outbreak setting and for ongoing surveillance of local trends in ing diarrhea and without complications, they may offer advantages
resistance patterns and mechanisms (63–65). in the treatment of more severe forms of TD by preventing symp-
toms associated with mild forms of dehydration or frank dehydra-
tion in cholera-like forms of diarrhea (74).
TREATMENT OF ACUTE DISEASE
Oral rehydration Probiotics and prebiotics
Recommendation Recommendation
5. The usage of balanced electrolyte rehydration over other oral 6. The use of probiotics or prebiotics for treatment of acute
rehydration options in the elderly with severe diarrhea or any diarrhea in adults is not recommended, except in cases of
traveler with cholera-like watery diarrhea is recommended. postantibiotic-associated illness. (Strong recommendation,
Most individuals with acute diarrhea or gastroenteritis moderate level of evidence)
can keep up with fluids and salt by consumption of water,
juices, sports drinks, soups, and saltine crackers. (Strong Summary of the evidence. As our understanding of the impor-
recommendation, moderate level of evidence) tance of the human microbiome in health and disease has ad-
vanced, interest in the use of nonpathogenic bacteria and yeast,
Summary of the evidence. One of the most significant advances in as well as nutrients that enhance the growth of favorable microbes
the past century was development of a balanced sodium-glucose in our bodies producing enhanced colonization resistance has
solution that allows optimal absorption of electrolytes and water. also expanded (75). Probiotics are defined as live microorgan-
Availability of oral rehydration solution (ORS) has reduced infant isms, which, when administered in adequate amounts, confer
mortality in developing countries by at least 50% (66). The ma- health benefits on the host. For a microorganism to be considered
jor value of ORS is treatment of dehydrating forms of diarrhea a probiotic, it must exhibit non-pathogenic properties, be viable
in infants and young children in developing countries. ORS may in delivery vehicles, be stable in acid and bile, adhere to target
not reduce diarrhea and the objective of ORS therapy is not to epithelial tissue, persist within the gastrointestinal tract, produce
shorten illness. In TD dehydration is not common and mortal- anti-microbial substances, modulate the immune system, and
ity occurs only very rarely. Among otherwise healthy people, the influence metabolic activities (76). Postulated mechanisms of
risk of fatality during a bout of diarrhea is most common for the action of probiotics include “colonization resistance” a barrier
elderly whether traveling or remaining in a nursing home. More effect that prevents attachment or colonization of microorganisms.
than 80% of deaths in the United States associated with diarrhea Probiotics supposedly act by prohibiting pathogen attachment,
occur in the elderly (67). For infants and the elderly with severe enhancing the immune response and by assisting in re-establish-
TD and in anyone who develops profuse cholera-like watery diar- ing the microflora (77). Prebiotics are non-digestible food ingre-
rhea, balanced ORS and medical evaluation are advised. In non- dients that are fermentable in the colon and stimulate potentially
elderly adult travelers with diarrhea, the objectives are generally health-promoting bacteria, chiefly bifidobacteria and/or lacto-
improving symptoms and getting the people back to scheduled bacilli, conferring a beneficial shift in the microbial equilibrium
activities. A previous study of TD management in young adults of the host gut flora (78). Bifidobacteria as well as lactobacilli
failed to identify clinical or laboratory benefit of balanced ORS appear to have important functions in the ecophysiology of the
therapy in patients treated with loperamide (68). For most oth- colonic microbiota. These organisms have been associated with
erwise healthy adults with TD, formal ORS is not needed as they an increased resistance to infection and diarrheal disease (79,80).
can keep up with fluid losses by taking in salty soups, fruit juices, Prebiotics when combined with probiotics form synbiotics.
and carbohydrates to provide the glucose-sodium cotransport Synbiotic formulations have been tested in animal models with
(69). Popular carbonated soft drinks provide fluids and almost beneficial effects on reducing adherence of pathogenic bacteria to
no sodium or potassium, while fruit juices (e.g., apple juice) the jejunum and colonic mucosa (81).

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608 Riddle et al.

Table 3. Randomized double-blind placebo-controlled trials evaluating probiotics in treatment effectiveness of acute diarrhea

Study Year Location Clinical N Eligibility Intervention Outcomes Ref.

author setting

Bruno 1981 Italy In-patient 49 Acute enteritis Enterococcus LAB SF68 • [P] diarrhea ≥4 days: (84)
(non-typhoid) (Bioflorin: ≥75×10^6 three EXP 2/25 vs. PLAC 11/24
times daily for 10 days). • [P] diarrhea ≥3 days:
Placebo comparator EXP 6/25 vs. 17/24
Bruno 1983 Italy In-patient 21 Acute febrile Enterococcus LAB SF68 • [P] diarrhea ≥4 days: (85)
enteritis (Bioflorin: ≥75×10^6 three EXP 1/10 vs. PLAC 7/11
(non-typhoid) times daily for 10 days). • [P] diarrhea ≥3 days:
Placebo comparator EXP 3/10 vs. PLAC 7/11
Buydens 1996 Belgium In-patient and 185 Acute watery Enterococcus LAB SF68 • [P] diarrhea ≥4 days: (86)
outpatient diarrhea (Bioflorin: ≥75×10^6 three EXP 7/93 vs. PLAC 61/92
times daily for ≥6 days). • [P] diarrhea ≥3 days:
Placebo comparator EXP 57/93 vs. PLAC 88/92
• Mean (s.d.) freq. on day 3:
EXP 1.1(0.3) vs. PLAC 2.5 (1.3)
Hochter 1990 Germany Outpatient 92 Acute diarrhea S. boulardii (600 mg/day • Mean (s.d.) freq. on day 3: (89)
(exclusion; for 2 days then 300 mg/day EXP 2.4 (2.1) vs. PLAC 3.0
no antibiotics) on days 3 to 7. Placebo (2.8)
comparator
Mitra 1990 Bangladesh Not described 183 V. cholera Streptococcus faecium V. cholera (88)
(n=114) or SF68 containing 1×10(9) • Duration (h): EXP 80 vs.
ETEC (n=41) of live SF68 or capsules of PLAC 80, P=0.96
infection placebo containing killed • Cumulative volume 48 h
SF68 (non-placebo) once (ml/kg body wt)
every 8 h for 3 days. EXP 395.5 vs. PLAC 286.5,
P=0.13
ETEC
• Duration (h): EXP 24 vs.
PLAC 24, P=0.62
• Cumulative volume 48 h
(ml/kg body wt)
EXP 57.5 vs. PLAC 76.4,
P=0.42
Wunderlich 1989 Switzerland and Not described 78 Acute diarrhea Enterococcus LAB SF68 • [P] diarrhea ≥4 days: (87)
Lichtenstein (exclusions not (Bioflorin: 225×10^6 three EXP11/40 vs. PLAC 23/38
stated) times daily for 7 days). • [P] diarrhea ≥3 days:
Placebo comparator EXP 19/40 vs. PLAC 27/38
ETEC, enterotoxigenic E. coli; EXP, active treatment group; [P], probability; PLAC, placebo group; s.d., standard deviation.

With respect to treatment of infectious diarrhea, it is theorized significantly reduced the duration of diarrhea (mean difference
that by enhancing intestinal colonization by specific organisms there 24.8 h; 95% confidence interval (CI): 15.9–33.6 h; n=4,555, 35 trials),
would be a reduction in the environmental niche for the offending and the stool frequency on day 2 (mean difference 0.80 stools;
pathogen through production of acids, hydrogen peroxide, or other 0.5–1.1; n=2,751, 20 trials). Effect sizes did not differ between
anti-microbial substances, increase of mucus production, and gut studies carried out in developed or developing countries.
barrier defense, as well as competition for nutrients or adhesion Table 3 describes six adult randomized controlled trials identi-
receptors, antitoxin action, and stimulation of the immune system fied in the 2010 Cochrane Review and no additional randomized
(82). In 2010, a Cochrane systematic review was published on the controlled trials have subsequently been published. These studies
topic of probiotics and treatment of intestinal infection (83). In this include two different probiotics (five studies with the single
review, they identified 63 randomized and quasi-randomized con- product Enterococcus LAB SF68 and one study with Sacchromyces
trolled trials comparing specific probiotic agent(s) compared with a boulardii). These studies were conducted in a variety of countries,
placebo or no-treatment with acute diarrhea of presumed infectious clinical settings, and used different eligibility, treatment regimens,
etiology. Between 1966 and 2010, 63 studies including 8,014 sub- and primary clinical endpoints. While heterogeneity in studies is
jects met the eligibility criteria. Only six of these trials were among found, one product, Enterococcus LAB SF68, had one end point,
adults (84–89). Among the pediatric studies, mostly of which were diarrhea lasting greater than 4 days, which was combinable and
conducted among developing world populations and varied greatly reported in the Cochrane review. Among the four studies with
with respect to settings, organisms tested and dosage, probiotics similar product and end point (84–87), in the probiotic arms

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 Clinical Guideline: Acute Diarrheal Infections 609

21/168 (12.5%) compared with 102/165 (62%) in the placebo arms Summary of the evidence. Medical treatment is not required in
had diarrhea lasting greater than 4 days. When combined, these patients with non-severe, non-cholera-like diarrhea. Non-anti-
studies achieved a 79% efficacy (relative risk: 0.21, 95% CI: 0.08– biotic anti-diarrheal drugs have been shown to reduce the number
0.52) for this outcome with substantial heterogeneity (Τ2=0.56; of stools passed in cases of diarrhea allowing the ill people to con-
χ22=10.47, d.f.=3 (P=0.01); I2=71%). However, theoretical safety tinue their planned schedule. The drugs with value in controlling
concerns raised about this product limits further recommendation symptoms with reduced rate of stooling are the antisecretory and
(90). The one study with S. boulardii did not appear to confer any antimotility drugs. Intestinal secretion is the major pathophysio-
advantage in the primary or secondary outcomes evaluated (89). logic mechanism leading to watery diarrhea in some forms of
Based on the current evidence, there are not enough studies, acute diarrheal infection including TD. The antisecretory drugs
which would support the recommended use of any particular that have been evaluated and shown to have value for therapy
probiotic product for treatment in acute adult diarrhea infection. in secretory forms of diarrhea are BSS (95), zaldaride maleate
Although a statistically significant summary treatment effect was (96), and crofelemer (97). It is the salicylate part of BSS that has
observed for Enterococcus LAB SF68, heterogeneity in results does antisecretory anti-diarrheal properties (98). BSS will reduce the
not allow for generalization, theoretical safety concerns, and no stools passed by ~40% (95). Crofelemer is a cystic fibrosis trans-
recent studies with this product have been reported. Recommen- membrane regulator chloride-channel blocker and is effective
dations on use of probiotics in pediatric populations have recently in some forms of diarrhea including TD and AIDS-associated
been published (91). diarrhea (99). Zaldaride is a calmodulin-inhibiting drug that
A single study of polyphenol-based prebiotic has been described has antisecretory properties related to intracellular concentra-
in the treatment of acute diarrhea in children and adults seeking tions of calcium (100). The drug significantly shortened the
treatment at community health centers in Managua, Nicaragua stools passed in subjects studied with TD compared with placebo
(92). No diarrhea case definition (e.g., frequency or duration) for therapy (96,101,102). Racecadotril, a specific enkephalinase
inclusion was reported; however, exclusion critieria included those inhibitor that prevents degradation of the endogenous anti-
with high fever, vomiting, severe dehydration, and bloody stools. A secretory peptide neurotransmitter enkephalins that inhibit
remarkable treatment effect on mean time to last unformed stools cyclic nucleotide secretory pathways without effect on gut
among the treatment group compared with placebo was reported motility (103) and has been used successfully in pediatric diar-
(prebiotic: 10.5 h vs. placebo: 54 h, P<0.0001). While important rhea (104). While racecadotril was shown to be as effective as
methodological and analytic detail are missing, and understand- loperamide in the treatment of acute endemic diarrhea in adults
ing of potential mechanism of action is lacking, this product may (105), this antidiarrheal drug needs to be studied further in
warrant additional investigation in a well-designed clinical trial. diverse forms of diarrhea. Of the strictly antisecretory, only two
While evidence supporting therapy of probiotics in treatment agents are approved for use by the Food and Drug Administra-
of acute diarrheal infection is lacking, and few studies addressing tion in the United States, BSS for treatment of acute diarrhea
the effectiveness of probiotics in treatment of antibiotic-associated and crofelemer for HIV-associated diarrhea. The recommended
diarrhea (93), there is supporting evidence for the role of probiotics dose of BSS for therapy of acute diarrhea is 30 ml (525 mg) of
in prevention of acute diarrhea associated with antibiotic use (94). liquid formulation or two tablets (263 mg per tablet) chewed
The pooled results among 63 randomized controlled trials across well each 30–60 min not to exceed eight doses in 24 h. The drug
all population, setting, and probiotic types indicated a relative risk will produce black stools and black tongues from harmless
reduction of 0.58, with a number needed to treat of 13. Heteroge- bismuth sulfide salt.
neity and gaps in reporting of the studies, design, population, and The major antimotility drugs used for therapy of acute diarrhea
antibiotic associated class make clinical application of these results are loperamide and diphenoxylate. Of these, the most useful drug
to the individual patient clinical care challenging. Future research is loperamide, which has less central opiate effects. Another limi-
is needed to support directed therapy and effectiveness among tation of diphenoxylate is that it contains atropine, which has no
various patient populations, clinical indications, antibiotics, and antidiarrheal effectiveness and may produce objectionable side
probiotic strains, as well as further understanding the risk of effects. Loperamide works through two mechanisms, the most
adverse events associated with probiotic use for these indications. important being the production of segmental contraction of the
gut, which slows the intraluminal movement of fluids and allows
Non-antibiotic therapies greater absorption (106). A secondary effect appears to be inhi-
Recommendation bition of calmodulin leading to reduced mucosal secretion (107).
7. Bismuth subsalicylates (BSSs) can be administered to control Thus, the mechanisms of antidiarrheal effect of loperamide are
rates of passage of stool and may help travelers function indirect or direct inhibition of mucosal secretion and reduction
better during bouts of mild to moderate illness. (Strong in motility. In a comparative randomized trial in patients with TD,
recommendation, high level of evidence) loperamide reduced the number of diarrheal stools passed when
8. In patients receiving antibiotics for TD, adjunctive lopera- compared with BSS (108) and loperamide was shown to shorten
mide therapy can be administered to decrease duration of diarrhea in both children (109) and adults with acute diarrhea
diarrhea and increase chance for a cure. (Strong recommen- (110). The recommended dose of loperamide for therapy for adults
dation, moderate level of evidence) with diarrhea is 4 mg initially followed by 2 mg after subsequently

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610 Riddle et al.

passed watery stools not to exceed 8 mg per day. Loperamide is Summary of evidence. The evidence for the use of anti-microbial
not given for more than 48 h. The most valuable use of loperamide therapy is strongly supported for cases of TD (Table 4 lists accept-
in the self-treatment of TD is as a combination drug with anti- able regimens). Numerous studies have demonstrated that anti-
bacterial drugs where the antimotility drug quickly reduces the biotics shorten the overall duration of moderate-to-severe TD to
number of diarrhea stools passed while the antibiotic cures the a little over 24 h (116). The primary efficacy parameter in most
enteric infection (29,111). clinical trials has been the time from initiation of therapy until
A common complaint of loperamide therapy in acute diarrhea the last unformed stool is passed (117). Anti-bacterial drugs have
is post-treatment constipation. It is important to use the lowest been shown to reduce initiation of therapy until the last unformed
dose of loperamide to provide antidiarrheal effects without the stool is passed in cases of TD by 1–3 days compared with no
post-treatment constipation effects of the drug. Antimotility drugs therapy or placebo (118–121), and combination of an antibiotic
have been associated with intestinal complications such as toxic with loperamide further shortens duration of illness (111). Fluoro-
dilatation of the colon or prolonged illness when used in bacte- quinolones such as ciprofloxacin or levofloxacin have been the
rial inflammatory (112,113), although the association is rare and primary antibiotics of choice for most destinations (119,120,122),
if it occurs it is seen with otherwise untreated diarrhea caused by although growing resistance to this class of antibiotics may change
the highly inflammatory bacterial pathogens. When inflamma- this (123–125). In addition, there is evidence that most Campy-
tory forms of colitis are also treated with anti-microbial drugs, this lobacter are fluoroquinolone resistant and the use of macrolides
potentiation is very unlikely to occur (113). such as azithromycin for treatment is recommended (126).
Adsorbent drugs such as kaolin, pectin, charcoal, and attapulgite Azithromycin was shown to be more effective than ciprofloxacin
do have an effect on form of stools passed, but the number of stools for all cases of TD in travelers to Thailand, probably because of the
passed and duration of post-treatment diarrhea are not shortened high prevalence of Campylobacter in this region (127).
(114,115) and are not recommended. A review of nine randomized clinical trials and one Cochrane
review assessing fluoroquinolone use for the treatment of TD
Antibiotic therapy (116,119,122,128–131) found overall reductions in diarrhea dura-
Recommendation tion compared with placebo and evidence from these studies
9. The evidence does not support empiric anti-microbial therapy showed no serious harm associated with fluoroquinolone use;
for routine acute diarrheal infection, except in cases of TD however, the literature on the use of flouroquinolones in all set-
where the likelihood of bacterial pathogens is high enough to tings has demonstrated risks of development of Clostridium
justify the potential side effects of antibiotics. (Strong recom- difficile infection and risks for tendonopathies and arthropathies
mendation, high level of evidence) (132). For all antibiotics, either single-dose therapy or treatment
10. Use of antibiotics for community-acquired diarrhea should for up to 3 days is usually sufficient to allow resolution of symp-
be discouraged as epidemiological studies suggest that most toms. Studies show that once daily therapy is as effective as 3-day
community-acquired diarrhea is viral in origin (norovirus, therapies for TD due to noninvasive pathogens, which comprise
rotavirus, and adenovirus) and is not shortened by the use the majority of cases (120,121). A 3-day therapy is recommended
of antibiotics. (Strong recommendation, very low level for patients presenting with fever or dysentery. Enteric infection
evidence) by Shigella dysenteriae appears to be an exception, insofar as 5 days

Table 4. Acute diarrhea antibiotic treatment recommendations

Antibiotica Dose Treatment duration

Levofloxacin 500 mg by mouth Single doseb or 3-day course

Ciprofloxacin 750 mg by mouth or Single doseb
500 mg by mouth 3-day course
Ofloxacin 400 mg by mouth Single doseb or 3-day course
Azithromycinc,d 1,000 mg by mouth or Single doseb
500 mg by mouth 3-day coursed
Rifaximin e
200 mg by mouth three times daily 3-days
ETEC, Enterotoxigenic Escherichia coli.
a
Antibiotic regimens may be combined with loperamide, 4 mg first dose, and then 2 mg dose after each loose stool, not to exceed 16 mg in a 24-h period.
b
If symptoms are not resolved after 24 h, complete a 3-day course of antibiotics.
c
Use empirically as first line in Southeast Asia and India to cover fluoroquinolone-resistant Campylobacter or in other geographical areas if Campylobacter or resistant
ETEC are suspected.
d
Preferred regimen for dysentery or febrile diarrhea.
e
Do not use if clinical suspicion for Campylobacter, Salmonella, Shigella, or other causes of invasive diarrhea.

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 Clinical Guideline: Acute Diarrheal Infections 611

of therapy appears to be superior to single-dose or 3-day therapy hemolytic uremic syndrome (144). Another theoretical concern
(125). With increasing resistance to ampicillin and trimethoprim/ with antibiotic use is that for non-typhoidal Salmonella strains,
sulfamethoxazole, azithromycin has been the treatment of choice there may be prolonged intestinal carriage. A meta-analysis showed
(133,134). Recently, however, Shigella sonnei has been found to that antibiotic therapy does not appear to reduce the length of
have reduced susceptibility to azithromycin among isolates in the illness in immunocompetent adults and increases the period
United States (61). during which Salmonella was detected in stool (144). This how-
Although no studies looked at the efficacy of azithromycin vs. ever would not necessarily be an argument against antibiotic use
placebo, there were four randomized controlled trials that com- as short-term carriage appears to be of limited clinical significance
pared azithromycin to the flouroquinolones in the treatment of TD to those who are affected (145).
(118,127,135,136). No difference was noted in efficacy between the Another perhaps more legitimate concern is that treatment
two treatment groups. Among adult student travelers to Mexico, a with antibiotics will modify the microbiota. This may result
single dose 1,000 mg azithromycin was comparable to levofloxa- in the development of C. difficile-associated diarrhea or colitis
cin 500 mg in shortening the duration of illness (22.3 vs. 21.5 h) (132,145). A recent publication reported patients who developed
(118). Three trials demonstrate that azithromycin was as effective C. difficile colitis following treatment with ciprofloxacin (146).
as a fluoroquinolone in the treatment of TD occurring in Thailand However, this does not appear to be a common adverse outcome
or Mexico (118,125,127). Azithromycin was also shown to be associated with treated TD. We are becoming increasingly aware
active in the treatment of diarrhea caused by Campylobacter that changes in an individual’s gut microbiota may be associated
including fluoroquinolone-resistant strains (125,137). Azithro- with international travel to certain destinations. In a recent study,
mycin is effective against Shigella spp., as well as noninvasive it was shown that antibiotic use for self-treatment of TD increases
diarrheagenic Escherichia coli (137,138). Looked at as a whole, a traveler’s risk of colonization by resistant bacteria namely
these studies suggest that azithromycin is as effective as the flouro- extended spectrum β -lactamase-producing Enterobacteriaceae
quinolones in providing relief from TD. Anti-microbial resistance and carbapenemase-producing Enterobacteriaceae. In this study,
patterns for azithromycin have been studied but results are incon- travel itself was associated with a 21% rate of colonization by
clusive. One study showed that azithromycin had high activity extended spectrum β -lactamase-producing Enterobacteriac-
against TD pathogens but another suggested that concentrations ceae, but remarkably 80% of travelers who self-medicated with
needed to inhibit diarrheagenic E. coli have been increasing over antibiotics became colonized with these microorganisms, raising
the past decades. (26) In vitro studies showed increasing resistance the possibility that this might contribute to the spread of resistant
among Campylobacter isolates in Nepal and Thailand but clinical intestinal bacteria to the population at large in developed coun-
failures have not been reported (139). tries (147). Changes in one’s gut microbiota might have conse-
Rifaximin, a non-absorbable rifamycin-derived antibiotic, quences with respect to an individual’s susceptibility to infection
has been shown to be effective against diarrheagenic E. coli, or postinfectious consequences of intestinal infection as well, but
which appear to be the most common bacterial pathogens in the this is speculative at present (148). At present, the risk of acquired
Western Hemisphere (140). In two studies evaluating rifaximin extended spectrum β -lactamase on the individual and commu-
compared with placebo, rifaximin was associated with a higher nity vs. the potential negative consequences of untreated TD has
percentage of travelers cured. A follow-up study carried out on raised awareness and interest in the development of more data to
a subset of patients with diarrhea because of EAEC showed the inform management decisions.
200 mg dose administered three times a day was more effective The evidence is strong for anti-microbial treatment of specific
than placebo in decreasing median initiation of therapy until the parasitic causes of acute diarrheal infection such as metronidazole,
last unformed stool is passed (22 vs. 72 h) (141). Two additional tinidazole, or nitazoxanide for Giardia infections, metronidazole
studies directly compared rifaximin with ciprofloxacin. There was or tinidazole for Entameba histolytica, nitazoxanide for Crypto-
no significant difference with respect to cure or treatment failure sporidiosis, trimethoprim/sulfamethoxasole for Cyclosporiasis or
(142,143). Another study failed to demonstrate overall advan- Cystisosporiasis, albendazole for Enterocyotzooan bienusi, or iodo-
tage when ciprofloxacin was compared with rifaximin in TD in quinol for Diemtameba fragilis (149–155). With the advent of new
Mexico, Guatemala, and India. However, a subgroup with inva- molecular diagnostics, more specific diagnoses including parasitic
sive illness showed a reduced benefit following treatment with etiologies may be made more promptly, guiding the targeted use of
rifaximin (131). anti-microbial therapy (both agent and duration of treatment) to
While individual self-treatment of TD among travelers has been match a specific pathogen.
common since the late 1980s, there are a few microbe-specific con-
cerns with the use of empiric anti-bacterial therapy of TD. The first
is that anti-bacterial drugs appear to complicate enteric disease EVALUATION OF PERSISTING SYMPTOMS
caused by Shiga-like toxin-producing E. coli by increasing the risk Recommendations
of hemolytic uremic syndrome. Although this may occur more 11. Serological and clinical lab testing in individuals with persis-
commonly in children, a meta-analysis did not show an association tent diarrheal symptoms (between 14 and 30 days) is not
between anti-microbial therapy in adult patients with hemorrhagic recommended. (Strong recommendation, very low level of
colitis due to E. coli 0157:H7 and the subsequent development of evidence)

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612 Riddle et al.

12. Endoscopic evaluation is not recommended in individuals differential diagnoses such as celiac disease, Crohn’s disease, eosin-
with persisting symptoms (between 14 and 30 days) and ophilic gastroenteritis, and Whipple’s disease. Gastrointestinal
negative stool work-up. (Strong recommendation, very low endoscopy and relevant serological assays may contribute to the
level of evidence) diagnosis and management if sustained or progressive weight loss
is a prominent feature, and upper endoscopy may be considered,
Summary of evidence especially if empiric therapy and symptomatic measures have not
In the evaluation of the patient with persistent symptoms, a thor- helped. Mucosal biopsies are recommended even when the endo-
ough and directed history is essential. Relevant questions would scopic appearance is normal. The diagnostic yield of colonoscopy
include travel history, the nature of the initial symptoms, onset in patients ranges from 7 to 32%, with IBD and microscopic coli-
(sudden or gradual), duration, frequency and characteristics of tis being the most common diagnoses (164–169). It has also been
bowel movements (particularly the presence of blood or mucus), seen that colonoscopy yields a noninfectious diagnosis more often
stool volume, tenesmus, pattern, association with particular than upper endoscopy (170–172). A review of 18 primary stud-
foods, use of antibiotics, and the presence or absence of other ies looking at the diagnostic value of colonoscopy in patients with
associated symptoms such as nausea, vomiting, incontinence, chronic diarrhea, as well as a review of nine published guidelines
fever, and weight loss. The answers to these questions may direct provides the basis for a colonoscopy recommendation in such
further investigations (156). patients (165,167,168,173–186).
Among patients with persistent symptoms (between 14 and In the situation of chronic diarrhea and abdominal symptoms
30 days), the role of clinical laboratory studies and endoscopy occurring after a bout of infectious diarrhea, a diagnosis of postin-
is uncertain and should be dictated by clinical suspicion and fectious irritable bowel syndrome must be considered (187).
disease severity, within the context of most likely etiologies. An Postinfectious irritable bowel syndrome requires a paradigm shift:
initial diagnostic evaluation in the patient with persistent symp- an external event, in this case a gastrointestinal infection, leads to
toms should include tests for the presence of microbial pathogens. prolonged and permanent changes in gastrointestinal function,
Although stool culture and microscopy remain the initial diagnos- which do not appear to be directly mediated by the persistence
tic tests, they both suffer from limitations that may be addressed of an infectious agent. There appears to be a physiologic basis
by newer diagnostic methods. Even some of the newer methods, for the apparent failure to downregulate intestinal inflammation
such as enzyme-linked immunoassays and direct immunofluores- but there are no commercially available serologic or other diag-
cence staining, which increase sensitivity, may not be able to dis- nostic tests to confirm and the diagnosis rests on using conven-
tinguish, e.g., between the pathogen Entamoeba histolytica and a tional criteria such as Rome III in patients who have been sick with
non-pathogenic but microscopically indistinguishable Entamoeba gastroenteritis or TD.
dispar. (157). Singleplex and multiplex PCR assays for the detec-
tion of enteric microbial pathogens are more sensitive than culture,
microscopy, or antigen detection (158–160). In one study describ- PREVENTION
ing a real-time PCR assay designed to detect Giardia intestinalis, Counseling
the lower limit of detection was as little as 102 spores per ml of Recommendations
stool as opposed to microscopy, which required >106 spores per ml 13. Patient level counseling on prevention of acute enteric infec-
of stool (161).7 One study showed using PCR methods resulted in tion is not routinely recommended but may be considered
a 22-fold increase in the detection of Cryptosporidium and Giardia in the individual or close-contacts of the individual who is at
compared with conventional microscopy (162). Colonoscopy high risk for complications. (Conditional, very low level of
has been considered in the evaluation of the patient with persis- evidence)
tent diarrhea. In a recent study looking at the diagnostic value 14. Individuals should undergo pretravel counseling regarding
of endoscopy for the diagnosis of giardiasis or other intestinal high risk food/beverage avoidance to prevent TD. (Condi-
diseases in patients with persistent diarrhea returning from tropical tional, very low level of evidence)
or subtropical areas, lower endoscopy (colonoscopy or sigmoido-
scopy) yielded relevant diagnoses more often than upper endo- Summary of evidence. Non-travel setting: One in six US citizens
scopy (163). This study, however, suffers from a small sample size get sick from a foodborne illness each year, and a majority of these
insofar as only 31 patients with persistent diarrhea were exam- illness will be from contaminated food consumed in the United
ined and thus the additional value of such procedures cannot be States (e.g., non-travel associated) (1,2). Food safety is a major
recommended. In certain clinical situations such as postantibiotic public health effort that involves multiple Federal, State, and
or hospital-acquired gastrointestinal illness, testing for Clostridium local agencies including the Food and Drug Administration, US
difficile may be recommended, as well as additional serologic and Department of Agriculture, US Food Inspection Service, and state
clinical laboratory testing including a complete blood count, which and local health departments, all of which focus on the potential
may be helpful in informing an infectious cause in the absence of risks for large outbreaks associated with centralization of food
revealing stool studies. processing and reliance on imported foods. However, to reduce
While not considered in these guidelines, the work-up of the burden of disease the responsibility of foodborne preven-
chronic diarrhea is briefly considered and should include the tion must not only include the producers on the farm, packaging

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 Clinical Guideline: Acute Diarrheal Infections 613

industries, stores, and restaurants but also penetrate down to the Hand washing
individuals in the home who are buying and preparing food—the Recommendation
last step in the chain of foodborne illness prevention. 15. Frequent and effective hand washing and alcohol-based hand
The intervention of improving food preparation in the home sanitizers are of limited value in preventing most forms of
has not been systematically studied. The Centers for Disease traveler’s diarrhea but may be useful where low-dose patho-
Control has recently responded through launching a new con- gens are responsible for the illness as for an example during
sumer food safety campaign to educate the public on the simple a cruise ship outbreak of norovirus infection, institutional
message of clean, separate, cook, chill, and report. No recom- outbreak, or in endemic diarrhea prevention. (Conditional
mendations on counseling by providers have been provided. No recommendation, low level of evidence)
recommendations on counseling by providers have been recom-
mended. However, for vulnerable patient populations who are Summary of evidence. Traveler setting: The evidence of hand
at increased risk for severe disease and complications associated washing and use of alcohol-based hand sanitizers in prevent-
with acute foodborne illness, including pregnant women, elderly, ing TD is mixed. Theoretically, they would be most effective in
and those with immune deficiency due to HIV or immuno- prevention of enteric infection caused by pathogens causing
therapeutic, situational individual patient level counseling may illness at low inoculum doses. Enteric pathogens can be divided
be appropriate. into three categories based on expected dose necessary to cause
Traveler setting: In the realm of travel medicine, Shlim reviewed diarrhea. The most contagious enteric pathogens are noroviruses
the evidence for the effectiveness of personal hygiene precautions and Shigella strains (190) because of low inoculum require-
in prevention of TD (188). In the eight studies identified in this ments plus stability in the environment (191). Hand washing
2005 review, seven found no correlation between the types of should be effective in reducing these highly communicable
food selected by the traveler and the risk of acquiring traveler’s pathogens and should be aggressively pursued in settings where
diarrhea, whereas one showed a correlation between a few one of these is likely to occur, e.g., during cruise-ship travel or
dietary lapses. The summary from this review provides the basis in a community or institutional outbreak due to one of these
for current recommendations where it was stated, “The sum total pathogens.
of these errors leads to abundant opportunities for the spread The expected dose for the diarrheagenic E. coli strains, the most
of enteric pathogens, whether from employees’ hands, flies, or common causes of TD, is high in the level of one million bacteria
contaminated meat and produce, with ample time available for or higher (192,193) with the infections nearly always a result
bacterial growth to reach infective levels. One could postulate of ingestion of contaminated foods where food has been
that “boil it, cook it, peel it, or forget it” would be good advice to improperly handled allowing propagation of the pathogen to
someone who was purchasing and preparing their own food in a diarrhea-causing levels. Effective hand washing or regular use of
sanitized kitchen but that it is inadequate for travelers faced with alcohol-based hand sanitizers could well be useful in preventing
the multiplicity of hygienic errors found in the kitchens of many TD if thoroughly pursued by persons preparing food eaten by
destination countries”. other travelers, but is unlikely to impact when done by the person
Subsequent to this review there have been few studies reported consuming the contaminated food.
on this topic. A recent report among travelers who attended a travel For cruise travelers regular hand washing can be useful in case
clinic before travel (‘exposed’) and travelers to similar regions but there is apparent or inapparent transmission of norovirus infec-
did not attend travel clinic (‘non-exposed’) was reported (189). In tion. Alcohol-based hand sanitizers often have anti-viral properties
this study, 13 (4.3%) of those interviewed reported drinking unsafe (194), although in one study hand washing with soap and water
water and this proportion was similar in those who attended or did was effective in removing norovirus from hands, while alcohol-
not attend travel clinic before travel (exposed (n=7/150, 4.6%) and based hand sanitizers were not (195). In a retrospective survey of
non-exposed subjects (n=6/150; 4%) (P=0.78)). Forty-five (15%) of protective measures against TD, regular use of alcohol hand sani-
enrolled subjects ate some food with elevated risk of traveler’s diar- tizers did not appear to offer any protection against either diarrhea
rhea (such as raw fruit or vegetables, drink with ice or ice cream); or respiratory tract infection in travelers (196). Again, this lack of
this proportion was higher in the non-exposed people (n=36/150; prevention of TD probably relates to the high inoculum require-
24%) than in the people attending the Travel Clinic (n=9/150; 6%) ments of the common forms of infection. This is in contrast to the
(P<0.0001). Fifty (16.7%) reported diarrhea or gastrointestinal established value of hand washing in preventing endemic pediat-
symptoms, 9 (6%) in the group of exposed subjects and 41 (27.3%) ric diarrhea in developing regions where lower inoculum patho-
in the non-exposed group (P<0.0001), suggesting some effect of gens are common (197,198). In developing regions the presence
pretravel counseling, although there could have been other factors of soap in homes is associated with reduced diarrhea rates in local
related to the self-selection of exposed (more cautious given their populations living in unhygienic areas (199). Alcohol-based hand
seeking out of pretravel counseling) and non-exposed travelers, disinfectant use in a public setting in Germany did provide protec-
which could explain these differences. tion against respiratory and diarrheal illness in a randomized study
In summary, the evidence of counseling effectiveness on TD risk in local non-traveling inhabitants (200). Hygiene including hand
reduction related to food and water indiscretion is mixed and lacks washing undoubtedly has a greater effect in preventing diarrhea
recent high-quality studies. in wilderness backpackers (201) who may have exposures more

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614 Riddle et al.

resembling endemic settings in the developing world than those is of no medical concern. Persons with underlying inflammatory
seen with typical travelers staying in clean hotels. bowel disease or HIV infection should not receive BSS because of
the fear of excessive absorption of this generally poorly absorbed
Prophylaxis bismuth compound leading to bismuth encephalopathy (216).
Recommendations
16. Bismuth subsalicylates have moderate effectiveness and may Probiotic/prebiotic/synbiotics. The use of probiotics, prebiotics,
be considered for travelers who do not have any contraindi- and synbiotics to prevent acute diarrheal infection is an appealing
cations to use and can adhere to the frequent dosing require- concept because of their ease of use and relative safety. The data,
ments. (Strong recommendation, high level of evidence) however, supporting their use in preventing infectious diarrhea
17. Probiotics, prebiotics, and synbiotics for prevention of is not consistently strong and at this point we do not recommend
traveler’s diarrhea are not recommended. (Conditional them for this purpose
recommendation, low level of evidence) The preventive role of probiotics, prebiotics, and synbiotics in
18. Antibiotic chemoprophylaxis has moderate to good effective- acute diarrheal infection in adults is limited to studies in prospec-
ness and may be considered in high-risk groups for short- tive travelers (217–226). There are no published studies in the set-
term use. (Strong recommendation, high level of evidence) ting of community-acquired diarrhea, in the outbreak setting for
example. Available studies suffer from variability in age groups,
Summary of evidence. Traveler setting: Prevention of TD is setting, causes of acute diarrhea, and probiotic strains. Although
challenging because of the ubiquitous exposures to individu- most of the trials are of adequate quality, limitations include short
als through contaminated food, water, and generally unhygienic follow-up and not estimating person-time analysis. There were also
conditions among much of the developing world. Travelers are large variations in the dosage of probiotics, frequency of adminis-
frequently counseled on preventive risk behaviors, but despite tration, and formulations used. Further variation was seen with
a traveler’s best attention to such recommendations, evidence is regard to timing and administration of these preparations relative
lacking that such precautions have any protective effect (188). to a number of factors including travel and concurrent treatment
Although vaccines for many of the agents commonly associated with anti-microbials (217). Although two meta-analyses suggest a
with TD are under development, these are considered a long-term marginal benefit of probiotics in prevention of TD, both suggest
solution and might likely suffer from the lack of utilization as has there is insufficient evidence for extrapolation to global recom-
been seen with most travel-associated vaccines (202–206). Alter- mendations for their use (217,218).
native primary prevention strategies such as BSS, probiotics, and
antibiotics have been evaluated and are considered here. Probiotics. In the past three decades, trials investigating the ef-
fects of probiotics in the prevention of TD have demonstrated
Bismuth subsalicylate. BSS has been shown in several studies to varying results (219). In one of the earlier studies, Enterococcus
reduce the frequency of TD when used during period of risk for faecium did not prevent TD. In a study by the same group, Saccha-
3 weeks (207–209). While the salicylate portion of the drug pro- romyces boulardii given to 3,000 Austrian travelers in a placebo-
vides antidiarrheal effects, it is the bismuth moiety that is active controlled manner resulted in a clinically modest dose-dependent
when the molecule is used for chemoprophylaxis (210). BSS and benefit in TD prevention, effects were most impressive in travelers
the bismuth reaction products found in the gut have dose-respon- to North Africa and Turkey (220). In a study of 756 Finnish travel-
sive activity against bacteria (211) and anti-viral properties (212). ers to two separate destinations in Turkey, a 41% diarrhea attack
The drug provides at least 60% protection in a dose of 2.1 g per day rate was noted in the Lactobacillus GG group vs. 46.5% in the pla-
(207,208). The recommended dose of BSS for TD prevention is cebo group, a very modest difference. However, the rate of protec-
two tablets four daily doses at mealtimes and at bedtime. Both the tion was 39.5% at one location and almost nil at the other location
dose and the interval of administration appear to be important as (221). In a US study of 245 travelers to various destinations those
2.1 and 1.05 g given two times a day led to reduced levels of pro- taking Lactobacillus GG experienced a 3.9% incidence of diarrhea
tection, 41% and 35%, respectively (209). The chemoprophylactic per day at risk vs. 7.4% in the placebo group. Using this novel
dose of BSS leads to important absorption of salicylate and should approach to protective efficacy, they calculated a protection rate
not be used when other salicylates are being taken. BSS does not of 47% (222). Lactobacillus bulgaricus as well as Lactobacillus fer-
have the damaging effects on gastric mucosa as acetyl salicylic mentum preparations were found to be ineffective in preventing
acid effects and, in fact, has intestinal mucosa-cytoprotective ef- TD (223,224) and there was no beneficial effect seen with a nonvi-
fects (213,214). able formulation of Lactobacillus acidophilus in the prevention of
BSS use has been shown to reduce the occurrence of TD if taken TD in a randomized placebo-controlled trial in travelers to West
in proper daily dose for up to 3 weeks. Most authorities recom- Africa and other destinations (227).
mend that chemoprophylaxis could be used for trips up to 2 weeks
(215). Chemoprophylaxis should not be used for longer trips. Prebiotics and synbiotics. Early work showed the prebiotic
Future travelers planning to use BSS chemoprophylaxis need to Lactulose reduced intestinal carriage of Shigella but was in-
be warned that during administration of the drug their stools and effective in treating Shigella infections (228). In a small study of
tongues will turn black and that this harmless bismuth sulfide salt 42 adult patients traveling to tropical countries (22 in the study

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 Clinical Guideline: Acute Diarrheal Infections 615

group, 20 in the placebo group), the use of sodium butyrate and concerns associated with antibiotic use, of any class, is an impor-
short-chain fatty acids as a prebiotic was evaluated for the preven- tant consideration.
tion of TD (229). Noted was a significant reduction in the occur- A recent systematic review summarized several studies show-
rence of TD in the prebiotic group (4.5%) vs. 40% in the placebo ing a comparative advantage of antibiotic chemoprophylaxis for
group. Sodium butyrate has been established in animal studies the prevention of TD (240). Four rifaximin studies included in
as a regulator of the intestinal environment. Limitations of the the meta-analysis had a total of 604 subjects. One of those studies
study included sample size and lack of diversity among the travel- (DuPont et al. (241)) had three treatment arms (rifaximin 200 mg
ers. A double-blind, placebo-controlled trial of a novel galacto- dosed once, two and three times a day) and one control arm
oligosaccharide mixture in 159 healthy travelers to countries (placebo dosed three times a day). There was no observed signifi-
of low and high risk for TD showed a significant reduction in cant difference of risk reduction among dosing regimens in the
diarrhea in the prebiotic group as compared with those who Dupont et al. study, and the overall pooled DerSimonian and Laird
consumed placebo (maltodextrin) (225). This particular formu- effect (relative risk) estimate for all studies combined was 0.33
lation was studied because of earlier work showing this agent (95% CI: 0.24–0.45), equating to a protective efficacy of 67% (95%
increased bifidobacferium numbers in the colonic content of CI: 55–76%) favoring chemoprophylaxis (heterogeneity χ2=3.09,
piglets and inhibited the attachment of enterohepatic E. coli and P=0.377; I2=3.1%). In terms of absolute risk reduction, pooled
Salmonella enterica Typhimurium to HT29 cells in vitro (230). DerSimonian and Laird summary estimates found that rifaximin
A randomized, double-blind, placebo-controlled trial of an oral chemoprophylaxis decreased TD attack rates by a mean of 22.1%
synbiotic AKSB, a combination of two probiotics (Enterococcus (95% CI: 6.3–37.9%) equating to a number needed to treat of 4.5
faecium and S. cervisiae) and a prebiotic (fructo-oligosaccharide), (95% CI: 2.6–15.9). With respect to rifaximin chemoprophylaxis,
failed to show benefit (226). two studies (Armstrong et al. (242) and Flores et al. (243)) did not
For probiotics, prebiotics, and synbiotics alike the challenge has show that chemoprophylaxis with rifaximin reached a statistically
been to find the right formulation or combination for the right significant difference in preventing TD compared with placebo
condition or individual. Mirroring the use of these agents in other (242,243). In both studies the incidence of TD in the control group
gastrointestinal diseases, a more thorough knowledge of the host was relatively low (8/48 or 17% and 9/47 or 19%, respectively),
microbiome might be necessary before appropriate trials can be which could have explained the findings given sample size calcula-
designed using specific agents for prevention. tions were based on the expected incidence of TD to be 40%, and
thus recruitment may have been too small to detect the true effect
Antibiotics. Anti-microbial prophylaxis has been considered an of rifaximin in preventing TD. Most recently, an effectiveness study
option to prevent infection. In 1985 issues surrounding prophy- by Zanger et al. (244) reported moderate protection with rifaximin
laxis were debated during an NIH-sponsored consensus meet- for up to 28 days to the South and Southeast Asian regions (244).
ing, which concluded that routine antibiotic chemoprophylaxis Efficacy was noted to be higher in travelers to countries in South
should not be used because of concerns about the development of Asia (65%, 95% CI: 15–77) compared with Southeast Asia, which
antibiotic resistance, the demonstrated efficacy of empiric therapy is likely attributed to differential (invasive) pathogen distributions
after the development of symptoms, and the potential for un- (no microbiology was conducted in the study). However, a study by
necessary side effects (231). Since that meeting, studies that have Taylor et al. (245) suggests that rifaximin may be effective against
examined the cost benefit of chemoprophylaxis for the preven- shigellosis, which is a common invasive TD pathogen (and also
tion of TD have recommended against prophylaxis except in associated with chronic health complications) (246). There were
high-risk groups (232,233). While debate continues, the standard no serious adverse drug-associated safety adverse events reported
practice and recommendation has remained unchanged for 20 among these published studies.
years (234–236). While no recent studies have been conducted, floroquinolones
Two recent developments are challenging the general recom- consistently demonstrate a higher effectiveness in the prevention
mendation against use of chemoprophylaxis. First, postinfectious of TD with a summary pooled estimate of 88% (95% CI: 80–93%)
irritable bowel syndrome has been recognized as an important protective efficacy (240). The emergence of fluoroquinolone resist-
chronic health consequence, occurring in a sizeable proportion of ance to commonly encountered TD pathogens may be a factor
those who experience an episode of TD, particularly among those today if these studies were replicated (139,247,248). Furthermore,
with bacterial infection and a more severe clinical presentation relative to rifaximin, the safety profile for floroquinolones is less
(237–239). Second, rifaximin, a non-absorbable antibiotic, has favorable given the association with tendonopathies and the sys-
been developed and may provide a safer alternative for prophy- temic broad-spectrum nature of this antibiotic with attendant
laxis than fluoroquinolones, which are known to be quite effective pressures on systemic drug-resistant pathogens of importance
but may have an unacceptable safety profile. The high volume of (132).
international travel and, consequently, the high number of people The evidence to date suggests moderate to good efficacy of
at risk for acquiring TD, postinfectious irritable bowel syndrome rifaximin and floroquinolones for chemoprophylaxis. How-
and other postinfectious chronic health conditions, creates a ever, until such studies are carried out, which adequately assess
potentially large burden of illness that could be prevented with the risk and benefits of this strategy in reduction of acute and
the use of safe and effective chemoprophylaxis. However, safety chronic consequences while balance the negative consequences

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