Acute Diarrheal Infections in Adults

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nature publishing group02

TheAmerican Journal ofGASTROENTEROLOGY VOLUME 111 |MAY 2016 www.amjgastro.com

PRACTICE GUIDELINES

INTRODUCTION

Acute diarrheal inection is a leading cause o outpatient visits,

hospitalizations, and lost quality o lie occurring in both domes-

tic settings and among those traveling abroad. Te Centers or

Disease Control and Prevention has estimated 47.8 million cases

occurring annually in the United States, at an estimated cost

upwards o US$150 million to the health-care economy (1,2).

Acute diarrhea can be dened as the passage o a greater number

o stools o decreased orm rom the normal lasting


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Clinical Guideline: Acute Diarrheal Infections

2016 by the American College of Gastroenterology TheAmerican Journal ofGASTROENTEROLOGY

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very likely to change the estimate; very low, i an effect is very

uncertain (8).

EPIDEMIOLOGY AND PUBLIC HEALTH

CONSIDERATIONS

Recommendation

1. Diagnostic evaluation using stool culture and culture-

independent methods i available should be used in situa-

tions where the individual patient is at high risk o spreading

disease to others, and during known or suspected outbreaks.

(Strong recommendation, low level o evidence)

Summary of evidence. Surprisingly, there are ew published

studies that describe the overall incidence o acute diarrhea

(including inectious and non-inectious causes) in the United

States. In 1998, the Foodborne Diseases Active Surveillance Network

(FoodNet) conducted a random population-based telephone

survey in which 12,755 persons (median age 40 years) were in-

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;

1524, 1.1 episodes per person-year; 2544, 1.7 episodes per

person-year; 4564, 1.2 episodes per person-year). A ollow-up

survey where 3,568 respondents (median age 51) were asked atrandom about illness in the previous 7 days or previous month

ound that recall bias had an important effect on estimates o

acute gastrointestinal illness (10). Using a 7-day exposure win-

dow, the estimated incidence o acute diarrhea was 1.6 episodes

per person-year, compared with 0.9 episodes per person-year i

asked about illness within the preceding month. Other popula-

tion-based studies rom Canada and western European countries

using varied methodologies estimate annual incidence between

0.1 to 3.5 episodes per person-year (11).

Specically ocusing on inectious causes o acute diarrheal

illness, in 2011 the Centers or Disease Control and Prevention

Passage of3 unformed stools in 24 h plus an enteric symptom (nausea, vomiting, abdominal pain/cramps, tenesmus, fecalurgency, moderate to severe flatulence)

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

Watery diarrhea

Mild illness* Moderate-to-severe illness*No or low-grade fever

(100F)

Microbiologic assessment,

then anti-microbial agent

directed to cause for all butSTECinfection

Non-travel-associatedTravel-

associatedHydration

only, may useloperamide 4 mg

initially tocontrol

stoolingAntibiotic

therapy(Table 4)

No orlow-grade

fever

(100F)

Fever(101F)


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States caused 9.4 million episodes o diarrheal illness, 55,961 hos-

pitalizations, and 1,351 deaths. In addition, unspecied agents

resulted in 71,878 hospitalizations and 1,686 deaths, caused ~38.4

million episodes o domestically acquired oodborne illnesses. In

addition to domestically acquired inections, over 44 million US

residents traveled abroad to non-Canadian and non-European

updated the estimates o inectious gastroenteritis caused by a

myriad o viruses, bacteria, and parasites (1,2). Based on empirical

modeling o active, passive, and outbreak surveillance data ~47.8

million oodborne-related illnesses occur annually (one out o

every six persons) in the United States. Furthermore, it was esti-

mated each year that 31 major pathogens acquired in the United

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, moderatesevere disease, and symptoms lasting >7 days to clarify the etiology of

the patients 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 travelers 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 travelers 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 travelers 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, travelers diarrhea.


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destinations in 2014 (12), resulting in roughly 4 to 17 million cases

o travelers diarrhea (D) based on 1040% attack rates (13). In

addition to the signicant burden o the acute illness associated

with these inections, recent evidence suggests that these patho-

gens are linked with chronic health sequelae, including unctional

gastrointestinal disorders, reactive arthritis, hemolytic uremic syn-

drome, and Guilliane Barr syndrome (1420). Te cost o acute

and chronic illness attributable to these inections is estimated to

be upwards o US$145 billion to the US economy (2123).

In light o these data, acute diarrheal illness is considered a major

public health issue against which control efforts are needed. While

this guideline is primarily ocused on the diagnosis, prevention,

and treatment o acute diarrhea in the individual, it is appropri-

ate to specically address the importance o diagnosis o the indi-

vidual in the context o population health improvement. Public

health surveillance and response in the eld o acute diarrhea

include strategies o inection control, anti-microbial stewardship,

outbreak investigation, as well as ood and water saety interven-

tions and regulatory policy (24). Te individual patientmedicalencounter is the interace and provides critical input on which the

success o these control strategies are built. Tere are signicant

data gaps and limitations with current burden o disease estimates

that are due to limitations in the current reporting structure (2,25).

Important multipliers or which there is signicant uncertainty

in published burden o disease models include the underreport-

ing multiplier (which adjusts data reported to health departments

as part o routine public health surveillance or the number o

inected people who seek treatment and test positive or a specic

inectious agent), and the pathogen raction multiplier (which is

used to attribute a proportion o all episodes o gastroenteritis to

particular pathogens) (25). Improvement o estimates, which isrequired to make important policy decisions, benets rom more

certain data that comes rom better reporting. From an outbreak

investigation perspective, culture-based testing and reporting (and

advanced isolate characterization) is needed to provide suffi cient

inormation to distinguish among strains or serotypes and perhaps

identiy virulence characteristics and susceptibility to anti-micro-

bial agents that relies on testing individual cases (26). Established

networks such as FoodNet and Pulsenet have demonstrated

the importance o active surveillance or examining trends in

specic diseases over time, evaluating impact o ood saety policy,

as well as identiying and responding to large common source

outbreaks (27).

However, a comprehensive laboratory evaluation and advancedcharacterization work-up is neither practicable nor cost-effective

or every patient presenting with an acute diarrheal inection (28).

No ormal cost-effectiveness studies on the optimization o testing

and reporting has been reported and these would be challenging

to conduct. However, public health undamentals would strongly

support individual patient testing and reporting in a number o

situations. Tese include diarrhea outbreaks among workers who

prepare and handle ood, health-care workers, daycare (adult and

child) attendees/employees, and residents o institutional acilities

(3). Additionally, i testing is conducted or individual clinical rea-

sons, the results o these tests should be reported to public health

authorities in compliance with both voluntary and mandatory

state requirements on reportable events.

Finally, with the advent o growing availability and increasing

use o culture-independent technologies in clinical laboratories

(discussed in detail later), an emerging concern is the potential

impact on replacement o culture-based methods or the aore-

mentioned public health utilization (26). Current public health

and control strategies rely on isolate recovery, specimen pres-

ervation, and partnerships with clinical laboratories. Although

culture-independent methods provide a promise or more sensi-

tivity o pathogen identication (leading to more accurate disease-

burden estimates), they do so with a detrimental impact on the

advanced characterization and typing, which is needed in outbreak

investigation and resistance monitoring efforts. As such, and until

new methods have evolved in which genotypic advanced charac-

terization platorms are widely available, it is recommended that

culture-based and culture-independent testing be used in parallel

when practicable to support public health purposes.

DIAGNOSIS

Recommendations

2. Stool diagnostic studies may be used i available in cases o

dysentery, moderate-to-severe disease, and symptoms lasting

>7 days to clariy the etiology o the patients illness and

enable specic directed therapy. (Strong recommendation,

very low level o evidence)

3. raditional methods o diagnosis (bacterial culture, micro-

scopy with and without special stains and immunouores-

cence, and antigen testing) ail to reveal the etiology o the

majority o cases o acute diarrheal inection. I available,the use o Food and Drug Administration-approved culture-

independent methods o diagnosis can be recommended

at least as an adjunct to traditional methods. (Strong recom-

mendation, low level o evidence)

4. Antibiotic sensitivity testing or management o the individual

with acute diarrheal inection is currently not recommended.

(Strong recommendation, very low level o evidence)

Summary of the evidence. Te commonly accepted statement

that specic investigation is not normally required in the majority

o cases o acute watery diarrhea because it is usually sel-limiting

and resolves without specic treatment may under inorm the

ability to provide a more rapid resolution o symptoms withappropriate directed therapy and potentially prevent postinec-

tious sequelae (29). Historical guidelines or diagnostic testing

(ACG, IDSA) seem to be too restrictive in the current environ-

ment o new diagnostic methods and enhanced ability to target

therapy (4,5).

Evidence supporting the use o diagnostic testing to support

clinical management may be different in higher-resource settings

than they would be, or example, in the traveler who is in an area

with limited access to adequate medical care or diagnostics (30).

Appropriate microbial identication may be helpul in tailor-

ing therapy as in antibiotics or bacterial pathogens, supportive


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examination o stool allowed recognition o viral agents o acute

diarrhea but was expensive and not widely available. Enzyme

immunoassays and serologic studies are available but suffer rom

these limitations as well (35).Diagnostics to determine specic microbial etiologies have

advanced in the past number o years. It is now possible using

culture-independent molecular techniques to rapidly and simul-

taneously identiy a multitude o bacterial, protozoan, and viral

diarrheal pathogens including some not commonly identied in

clinical laboratories (36).

Diarrheal disease by denition has a broad range o potential

pathogens particularly well suited or multiplex molecular test-

ing. Several well-designed studies show that molecular testing

now surpasses all other approaches or the routine diagnosis o

diarrhea. Molecular diagnostic tests can provide a more compre-

hensive assessment o disease etiology by increasing the diagnosticyield compared with conventional diagnostic tests (Table 2). Tey

are also aster, providing results in hours rather than days (37). Te

new diagnostics best applicability is or the clinician in practice,

seeing one patient at a time rather than in the public health setting,

e.g., in outbreak investigations. One potential drawback o molec-

ular technologies is the need to predene the particular microbes

being sought. In addition the signicance o an identied organism

may not be clear as these molecular technologies, which involve

nucleic acid amplication, are limited to our existing knowledge

o a microbes genome and do not discriminate between viable and

non-viable organisms. As a result they can detect microbes at non-

pathogenic levels. Given the high rates o asymptomatic carriage o

enteropathogens, this can be a considerable problem. o conoundmatters, urther multiplex techniques are more commonly associ-

ated with increased detection o mixed inections and the relative

importance o each pathogen may be unclear (3847).

Beore bacterial culture is discarded entirely, it is important to

acknowledge that multiplex molecular diagnostics do not yield

isolates that can be orwarded to public health laboratories. Speci-

mens collected or culture-independent testing may, in some cases,

be incompatible with culture because o the collection methods

or media that are used or collection. And, a strict reliance on

culture-independent diagnostics would limit our ability to detect

new causes o diarrheal disease (26,4851). Te uture may hold a

therapies, and avoidance o antibiotics or viral pathogens or

more specic anti-microbials or parasitic protozoan etiologies.

As symptoms o acute diarrhea are protean, attempts to diagnose

etiologic agents or classes are subjective at best and raught withimprecision due to overlap in symptoms. Although eatures o

the clinical presentation may be useul in distinguishing bacterial

rom protozoan causes, they are ofen an unreliable indicator o

the likely pathogen responsible. As with any syndromic disorder,

there can be considerable overlap in symptoms caused by various

agents (31). Despite efforts in recent years to educate travelers to

recognize acute bacterial diarrhea (as opposed to protozoan) or

purposes o sel-treatment, this approach is at best empiric, and

although may be suitable or travelers in remote destinations, it

does not translate well to the individual with community acquired

diarrhea (29).

Conventional diagnostic approaches to diarrheal diseaserequire multiple procedures: bacterial culture, microscopy with

and without stains or immunouorescence and stool antigen tests

or detection o protozoa, and or detecting viral agents, electron

microscopy, or antigen-based tests. Routine clinical laboratory

detection o bacterial pathogens requires the use o differential

culture media, which select or the growth o certain bacteria but

may ail to detect other bacteria, especially in the setting o anti-

biotic use. Culture methods are laborious and time consuming,

with results ofen not available or 48 to 72 h (32). Historically, a

decision to obtain a stool culture in an individual with diarrhea has

ofen been guided by the nding o ecal leukocytes or the presence

o stool lactoerrin (4,33). Although the latter is a more sensitive

predictor o a positive stool culture, using these markers to guideurther diagnostic studies has been proven to be imprecise and

probably unnecessary.

Microscopy has been the principal diagnostic tool in parasitology

or over 350 years. Te limitations o this method are that it is labor

and time intensive, requires technical expertise, and lacks sensitiv-

ity and reproducibility. Multiple specimens are ofen required to

reduce the day-to-day variability in parasite shedding (34).

When enteric viruses were identied as agents o acute diarrheal

inection, commercial diagnostic tests were unavailable. A reliance

on distinct characteristics o the clinical illness, ofen in the appro-

priate setting, was the standard o practice. Electron microscopical

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


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combination approach where culture specimens that have yielded

a positive result by culture-independent testing are then submitted

to public health laboratories or subtyping and sensitivity analy-

sis. A second specimen may need to be submitted i specimens

are incompatible with cultures such as dry ecal swab specimens

(5254).

Despite an increasing number o reports worldwide o resistance

to various antibiotics among bacterial enteropathogens, the clini-

cal impact o this has yet to be maniest in a signicant enough way

to warrant anti-microbial susceptibility testing across the board,

especially in the individual patient. In general, there appears to be

a low ailure rate with the use o empiric anti-microbial therapy,

especially with the uoroquinolones and macrolides (5562).

Anti-microbial susceptibility testing will continue to have a role in

the outbreak setting and or ongoing surveillance o local trends in

resistance patterns and mechanisms (6365).

TREATMENT OF ACUTE DISEASEOral rehydration

Recommendation

5. Te usage o 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 uids and salt by consumption o water,

juices, sports drinks, soups, and saltine crackers. (Strong

recommendation, moderate level o evidence)

Summary of the evidence. One o the most signicant advances in

the past century was development o a balanced sodium-glucosesolution that allows optimal absorption o electrolytes and water.

Availability o oral rehydration solution (ORS) has reduced inant

mortality in developing countries by at least 50% (66). Te ma-

jor value o ORS is treatment o dehydrating orms o diarrhea

in inants and young children in developing countries. ORS may

not reduce diarrhea and the objective o ORS therapy is not to

shorten illness. In D dehydration is not common and mortal-

ity occurs only very rarely. Among otherwise healthy people, the

risk o atality during a bout o diarrhea is most common or the

elderly whether traveling or remaining in a nursing home. More

than 80% o deaths in the United States associated with diarrhea

occur in the elderly (67). For inants and the elderly with severe

D and in anyone who develops prouse cholera-like watery diar-rhea, balanced ORS and medical evaluation are advised. In non-

elderly adult travelers with diarrhea, the objectives are generally

improving symptoms and getting the people back to scheduled

activities. A previous study o D management in young adults

ailed to identiy clinical or laboratory benet o balanced ORS

therapy in patients treated with loperamide (68). For most oth-

erwise healthy adults with D, ormal ORS is not needed as they

can keep up with uid losses by taking in salty soups, ruit juices,

and carbohydrates to provide the glucose-sodium cotransport

(69). Popular carbonated sof drinks provide uids and almost

no sodium or potassium, while ruit juices (e.g., apple juice)

provide high levels o potassium and carbohydrate, but low levels

o sodium and chicken broth is heavy in sodium (70,71). ravelers

with diarrhea should keep up with uids and electrolytes through

diet to be certain they are regularly passing urine and have moist

mucous membranes.

In severe diarrhea, a balanced ORS can usually be purchased

at a local pharmacy with sodium o 6075 mEq/l and glucose o

7590 mmol/l (72) with value in replacing uids and salt in dehy-

drating orms o diarrhea as studied in inants and children. Sports

drinks while not adequate alone to treat severe diarrhea can pro-

vide partial sodium and potassium replacement. More research is

needed to determine the optimal composition o available uid-

salt replacement beverages or travelers (73). New developments in

oral rehydration are underway, and i convenient without increas-

ing diarrhea and without complications, they may offer advantages

in the treatment o more severe orms o D by preventing symp-

toms associated with mild orms o dehydration or rank dehydra-

tion in cholera-like orms o diarrhea (74).

Probiotics and prebiotics

Recommendation

6. Te use o probiotics or prebiotics or treatment o acute

diarrhea in adults is not recommended, except in cases o

postantibiotic-associated illness. (Strong recommendation,

moderate level o evidence)

Summary of the evidence. As our understanding o the impor-

tance o the human microbiome in health and disease has ad-

vanced, interest in the use o nonpathogenic bacteria and yeast,

as well as nutrients that enhance the growth o avorable microbes

in our bodies producing enhanced colonization resistance hasalso expanded (75). Probiotics are dened as live microorgan-

isms, which, when administered in adequate amounts, coner

health benets on the host. For a microorganism to be considered

a probiotic, it must exhibit non-pathogenic properties, be viable

in delivery vehicles, be stable in acid and bile, adhere to target

epithelial tissue, persist within the gastrointestinal tract, produce

anti-microbial substances, modulate the immune system, and

inuence metabolic activities (76). Postulated mechanisms o

action o probiotics include colonization resistance a barrier

effect that prevents attachment or colonization o microorganisms.

Probiotics supposedly act by prohibiting pathogen attachment,

enhancing the immune response and by assisting in re-establish-

ing the microora (77). Prebiotics are non-digestible ood ingre-dients that are ermentable in the colon and stimulate potentially

health-promoting bacteria, chiey bidobacteria and/or lacto-

bacilli, conerring a benecial shif in the microbial equilibrium

o the host gut ora (78). Bidobacteria as well as lactobacilli

appear to have important unctions in the ecophysiology o the

colonic microbiota. Tese organisms have been associated with

an increased resistance to inection and diarrheal disease (79,80).

Prebiotics when combined with probiotics orm synbiotics.

Synbiotic ormulations have been tested in animal models with

benecial effects on reducing adherence o pathogenic bacteria to

the jejunum and colonic mucosa (81).


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signicantly reduced the duration o diarrhea (mean difference

24.8 h; 95% condence interval (CI): 15.933.6 h; n=4,555, 35 trials),

and the stool requency on day 2 (mean difference 0.80 stools;

0.51.1; n=2,751, 20 trials). Effect sizes did not differ between

studies carried out in developed or developing countries.

Table 3describes six adult randomized controlled trials identi-ed in the 2010 Cochrane Review and no additional randomized

controlled trials have subsequently been published. Tese studies

include two different probiotics (ve studies with the single

product EnterococcusLAB SF68 and one study with Sacchromyces

boulardii). Tese studies were conducted in a variety o countries,

clinical settings, and used different eligibility, treatment regimens,

and primary clinical endpoints. While heterogeneity in studies is

ound, one product, EnterococcusLAB SF68, had one end point,

diarrhea lasting greater than 4 days, which was combinable and

reported in the Cochrane review. Among the our studies with

similar product and end point (8487), in the probiotic arms

With respect to treatment o inectious diarrhea, it is theorized

that by enhancing intestinal colonization by specic organisms there

would be a reduction in the environmental niche or the offending

pathogen through production o acids, hydrogen peroxide, or other

anti-microbial substances, increase o mucus production, and gut

barrier deense, as well as competition or nutrients or adhesionreceptors, antitoxin action, and stimulation o the immune system

(82). In 2010, a Cochrane systematic review was published on the

topic o probiotics and treatment o intestinal inection (83). In this

review, they identied 63 randomized and quasi-randomized con-

trolled trials comparing specic probiotic agent(s) compared with a

placebo or no-treatment with acute diarrhea o presumed inectious

etiology. Between 1966 and 2010, 63 studies including 8,014 sub-

jects met the eligibility criteria. Only six o these trials were among

adults (8489). Among the pediatric studies, mostly o which were

conducted among developing world populations and varied greatly

with respect to settings, organisms tested and dosage, probiotics

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

Study

author

Year Location Clinical

setting

N Eligibility Intervention Outcomes Ref.

Bruno 1981 Italy In-patient 49 Acute enteritis

(non-typhoid)

EnterococcusLAB SF68

(Bioflorin: 7510^6 three

times daily for 10 days).Placebo comparator

[P] diarrhea 4 days:

EXP 2/25 vs. PLAC 11/24

[P] diarrhea 3 days:EXP 6/25 vs. 17/24

(84)

Bruno 1983 Italy In-patient 21 Acute febrile

enteritis

(non-typhoid)



times daily for 10 days).

Placebo comparator


EXP 1/10 vs. PLAC 7/11


EXP 3/10 vs. PLAC 7/11

(85)

Buydens 1996 Belgium In-patient and

outpatient

185 Acute watery

diarrhea




Placebo comparator


EXP 7/93 vs. PLAC 61/92


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)

(86)

Hochter 1990 Germany Outpatient 92 Acute diarrhea

(exclusion;

no antibiotics)

S. boulardii(600 mg/day

for 2 days then 300 mg/day

on days 3 to 7. Placebo

comparator

Mean (s.d.) freq. on day 3:

EXP 2.4 (2.1) vs. PLAC 3.0

(2.8)

(89)

Mitra 1990 Bangladesh Not described 183 V. cholera

(n=114) or

ETEC (n=41)

infection

Streptococcus faecium

SF68 containing 110(9)

of live SF68 or capsules of

placebo containing killed

SF68 (non-placebo) once

every 8 h for 3 days.

V. cholera

Duration (h): EXP 80 vs.

PLAC 80, P=0.96

Cumulative volume 48 h

(ml/kg body wt)

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

(88)

Wunderlich 1989 Switzerland andLichtenstein

Not described 78 Acute diarrhea(exclusions not

stated)

EnterococcusLAB SF68(Bioflorin: 22510^6 three


Placebo comparator

[P] diarrhea 4 days:EXP11/40 vs. PLAC 23/38


EXP 19/40 vs. PLAC 27/38

(87)

ETEC, enterotoxigenic E. coli; EXP, active treatment group; [P], probability; PLAC, placebo group; s.d., standard deviation.


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21/168 (12.5%) compared with 102/165 (62%) in the placebo arms

had diarrhea lasting greater than 4 days. When combined, these

studies achieved a 79% effi cacy (relative risk: 0.21, 95% CI: 0.08

0.52) or this outcome with substantial heterogeneity (2=0.56;

22=10.47, d..=3 (P=0.01); I2=71%). However, theoretical saety

concerns raised about this product limits urther recommendation

(90). Te one study with S. boulardiidid not appear to coner any

advantage in the primary or secondary outcomes evaluated (89).

Based on the current evidence, there are not enough studies,

which would support the recommended use o any particular

probiotic product or treatment in acute adult diarrhea inection.

Although a statistically signicant summary treatment effect was

observed or EnterococcusLAB SF68, heterogeneity in results does

not allow or generalization, theoretical saety concerns, and no

recent studies with this product have been reported. Recommen-

dations on use o probiotics in pediatric populations have recently

been published (91).

A single study o polyphenol-based prebiotic has been described

in the treatment o acute diarrhea in children and adults seekingtreatment at community health centers in Managua, Nicaragua

(92). No diarrhea case denition (e.g., requency or duration) or

inclusion was reported; however, exclusion critieria included those

with high ever, vomiting, severe dehydration, and bloody stools. A

remarkable treatment effect on mean time to last unormed stools

among the treatment group compared with placebo was reported

(prebiotic: 10.5 h vs. placebo: 54 h, P


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Summary of evidence. Te evidence or the use o anti-microbial

therapy is strongly supported or cases o D (Table 4lists accept-

able regimens). Numerous studies have demonstrated that anti-

biotics shorten the overall duration o moderate-to-severe D to

a little over 24 h (116). Te primary effi cacy parameter in most

clinical trials has been the time rom initiation o therapy until

the last unormed stool is passed (117). Anti-bacterial drugs have

been shown to reduce initiation o therapy until the last unormed

stool is passed in cases o D by 13 days compared with no

therapy or placebo (118121), and combination o an antibiotic

with loperamide urther shortens duration o illness (111). Fluoro-

quinolones such as ciprooxacin or levooxacin have been the

primary antibiotics o choice or most destinations (119,120,122),

although growing resistance to this class o antibiotics may change

this (123125). In addition, there is evidence that most Campy-

lobacter are uoroquinolone resistant and the use o macrolides

such as azithromycin or treatment is recommended (126).

Azithromycin was shown to be more effective than ciprooxacin

or all cases o D in travelers to Tailand, probably because o thehigh prevalence o Campylobacter in this region (127).

A review o nine randomized clinical trials and one Cochrane

review assessing uoroquinolone use or the treatment o D

(116,119,122,128131) ound overall reductions in diarrhea dura-

tion compared with placebo and evidence rom these studies

showed no serious harm associated with uoroquinolone use;

however, the literature on the use o ouroquinolones in all set-

tings has demonstrated risks o development o Clostridium

diffi cile inection and risks or tendonopathies and arthropathies

(132). For all antibiotics, either single-dose therapy or treatment

or up to 3 days is usually suffi cient to allow resolution o symp-

toms. Studies show that once daily therapy is as effective as 3-daytherapies or D due to noninvasive pathogens, which comprise

the majority o cases (120,121). A 3-day therapy is recommended

or patients presenting with ever or dysentery. Enteric inection

by Shigella dysenteriaeappears to be an exception, insoar as 5 days

passed watery stools not to exceed 8 mg per day. Loperamide is

not given or more than 48 h. Te most valuable use o loperamide

in the sel-treatment o D is as a combination drug with anti-

bacterial drugs where the antimotility drug quickly reduces the

number o diarrhea stools passed while the antibiotic cures the

enteric inection (29,111).

A common complaint o loperamide therapy in acute diarrhea

is post-treatment constipation. It is important to use the lowest

dose o loperamide to provide antidiarrheal effects without the

post-treatment constipation effects o the drug. Antimotility drugs

have been associated with intestinal complications such as toxic

dilatation o the colon or prolonged illness when used in bacte-

rial inammatory (112,113), although the association is rare and

i it occurs it is seen with otherwise untreated diarrhea caused by

the highly inammatory bacterial pathogens. When inamma-

tory orms o colitis are also treated with anti-microbial drugs, this

potentiation is very unlikely to occur (113).

Adsorbent drugs such as kaolin, pectin, charcoal, and attapulgite

do have an effect on orm o stools passed, but the number o stoolspassed and duration o post-treatment diarrhea are not shortened

(114,115) and are not recommended.

Antibiotic therapy

Recommendation

9. Te evidence does not support empiric anti-microbial therapy

or routine acute diarrheal inection, except in cases o D

where the likelihood o bacterial pathogens is high enough to

justiy the potential side effects o antibiotics. (Strong recom-

mendation, high level o evidence)

10. Use o antibiotics or community-acquired diarrhea should

be discouraged as epidemiological studies suggest that mostcommunity-acquired diarrhea is viral in origin (norovirus,

rotavirus, and adenovirus) and is not shortened by the use

o antibiotics. (Strong recommendation, very low level

evidence)

Table 4. Acute diarrhea antibiotic treatment recommendations

Antibiotica Dose Treatment duration

Levofloxacin 500 mg by mouth Single dosebor 3-day course

Ciprofloxacin 750 mg by mouth or Single doseb

500 mg by mouth 3-day course

Ofloxacin 400 mg by mouth Single dosebor 3-day course

Azithromycinc,d 1,000 mg by mouth or Single doseb

500 mg by mouth 3-day coursed

Rifaximine 200 mg by mouth three times daily 3-days

ETEC, Enterotoxigenic Escherichia coli.aAntibiotic 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.bIf symptoms are not resolved after 24 h, complete a 3-day course of antibiotics.cUse empirically as first line in Southeast Asia and India to cover fluoroquinolone-resistant Campylobacteror in other geographical areas if Campylobacteror resistant

ETEC are suspected.dPreferred regimen for dysentery or febrile diarrhea.eDo not use if clinical suspicion for Campylobacter, Salmonella, Shigella, or other causes of invasive diarrhea.


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6

o therapy appears to be superior to single-dose or 3-day therapy

(125). With increasing resistance to ampicillin and trimethoprim/

sulamethoxazole, azithromycin has been the treatment o choice

(133,134). Recently, however, Shigella sonnei has been ound to

have reduced susceptibility to azithromycin among isolates in the

United States (61).

Although no studies looked at the effi cacy o azithromycin vs.

placebo, there were our randomized controlled trials that com-

pared azithromycin to the ouroquinolones in the treatment o D

(118,127,135,136). No difference was noted in effi cacy between the

two treatment groups. Among adult student travelers to Mexico, a

single dose 1,000 mg azithromycin was comparable to levooxa-

cin 500 mg in shortening the duration o illness (22.3 vs. 21.5 h)

(118). Tree trials demonstrate that azithromycin was as effective

as a uoroquinolone in the treatment o D occurring in Tailand

or Mexico (118,125,127). Azithromycin was also shown to be

active in the treatment o diarrhea caused by Campylobacter

including uoroquinolone-resistant strains (125,137). Azithro-

mycin is effective against Shigella spp., as well as noninvasivediarrheagenic Escherichia coli (137,138). Looked at as a whole,

these studies suggest that azithromycin is as effective as the ouro-

quinolones in providing relie rom D. Anti-microbial resistance

patterns or azithromycin have been studied but results are incon-

clusive. One study showed that azithromycin had high activity

against D pathogens but another suggested that concentrations

needed to inhibit diarrheagenic E. colihave been increasing over

the past decades. (26) In vitrostudies showed increasing resistance

among Campylobacter isolates in Nepal and Tailand but clinical

ailures have not been reported (139).

Riaximin, a non-absorbable riamycin-derived antibiotic,

has been shown to be effective against diarrheagenic E. coli,which appear to be the most common bacterial pathogens in the

Western Hemisphere (140). In two studies evaluating riaximin

compared with placebo, riaximin was associated with a higher

percentage o travelers cured. A ollow-up study carried out on

a subset o patients with diarrhea because o EAEC showed the

200 mg dose administered three times a day was more effective

than placebo in decreasing median initiation o therapy until the

last unormed stool is passed (22 vs. 72 h) (141). wo additional

studies directly compared riaximin with ciprooxacin. Tere was

no signicant difference with respect to cure or treatment ailure

(142,143). Another study ailed to demonstrate overall advan-

tage when ciprooxacin was compared with riaximin in D in

Mexico, Guatemala, and India. However, a subgroup with inva-sive illness showed a reduced benet ollowing treatment with

riaximin (131).

While individual sel-treatment o D among travelers has been

common since the late 1980s, there are a ew microbe-specic con-

cerns with the use o empiric anti-bacterial therapy o D. Te rst

is that anti-bacterial drugs appear to complicate enteric disease

caused by Shiga-like toxin-producing E. coliby increasing the risk

o hemolytic uremic syndrome. Although this may occur more

commonly in children, a meta-analysis did not show an association

between anti-microbial therapy in adult patients with hemorrhagic

colitis due to E. coli0157:H7 and the subsequent development o

hemolytic uremic syndrome (144). Another theoretical concern

with antibiotic use is that or non-typhoidal Salmonella strains,

there may be prolonged intestinal carriage. A meta-analysis showed

that antibiotic therapy does not appear to reduce the length o

illness in immunocompetent adults and increases the period

during which Salmonella was detected in stool (144). Tis how-

ever would not necessarily be an argument against antibiotic use

as short-term carriage appears to be o limited clinical signicance

to those who are affected (145).

Another perhaps more legitimate concern is that treatment

with antibiotics will modiy the microbiota. Tis may result

in the development o C. diffi cile-associated diarrhea or colitis

(132,145). A recent publication reported patients who developed

C. diffi cile colitis ollowing treatment with ciprooxacin (146).

However, this does not appear to be a common adverse outcome

associated with treated D. We are becoming increasingly aware

that changes in an individuals gut microbiota may be associated

with international travel to certain destinations. In a recent study,

it was shown that antibiotic use or sel-treatment o D increasesa travelers risk o colonization by resistant bacteria namely

extended spectrum -lactamase-producing Enterobacteriaceae

and carbapenemase-producing Enterobacteriaceae. In this study,

travel itsel was associated with a 21% rate o colonization by

extended spectrum -lactamase-producing Enterobacteriac-

ceae, but remarkably 80% o travelers who sel-medicated with

antibiotics became colonized with these microorganisms, raising

the possibility that this might contribute to the spread o resistant

intestinal bacteria to the population at large in developed coun-

tries (147). Changes in ones gut microbiota might have conse-

quences with respect to an individuals susceptibility to inection

or postinectious consequences o intestinal inection as well, butthis is speculative at present (148). At present, the risk o acquired

extended spectrum -lactamase on the individual and commu-

nity vs. the potential negative consequences o untreated D has

raised awareness and interest in the development o more data to

inorm management decisions.

Te evidence is strong or anti-microbial treatment o specic

parasitic causes o acute diarrheal inection such as metronidazole,

tinidazole, or nitazoxanide or Giardia inections, metronidazole

or tinidazole or Entameba histolytica, nitazoxanide or Crypto-

sporidiosis, trimethoprim/sulamethoxasole or Cyclosporiasis or

Cystisosporiasis, albendazole or Enterocyotzooan bienusi, or iodo-

quinol or Diemtameba ragilis(149155). With the advent o new

molecular diagnostics, more specic diagnoses including parasiticetiologies may be made more promptly, guiding the targeted use o

anti-microbial therapy (both agent and duration o treatment) to

match a specic pathogen.

EVALUATION OF PERSISTING SYMPTOMS

Recommendations

11. Serological and clinical lab testing in individuals with persis-

tent diarrheal symptoms (between 14 and 30 days) is not

recommended. (Strong recommendation, very low level o

evidence)


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Riddle et al.


12

differential diagnoses such as celiac disease, Crohns disease, eosin-

ophilic gastroenteritis, and Whipples disease. Gastrointestinal

endoscopy and relevant serological assays may contribute to the

diagnosis and management i sustained or progressive weight loss

is a prominent eature, and upper endoscopy may be considered,

especially i empiric therapy and symptomatic measures have not

helped. Mucosal biopsies are recommended even when the endo-

scopic appearance is normal. Te diagnostic yield o colonoscopy

in patients ranges rom 7 to 32%, with IBD and microscopic coli-

tis being the most common diagnoses (164169). It has also been

seen that colonoscopy yields a noninectious diagnosis more ofen

than upper endoscopy (170172). A review o 18 primary stud-

ies looking at the diagnostic value o colonoscopy in patients with

chronic diarrhea, as well as a review o nine published guidelines

provides the basis or a colonoscopy recommendation in such

patients (165,167,168,173186).

In the situation o chronic diarrhea and abdominal symptoms

occurring afer a bout o inectious diarrhea, a diagnosis o postin-

ectious irritable bowel syndrome must be considered (187).Postinectious irritable bowel syndrome requires a paradigm shif:

an external event, in this case a gastrointestinal inection, leads to

prolonged and permanent changes in gastrointestinal unction,

which do not appear to be directly mediated by the persistence

o an inectious agent. Tere appears to be a physiologic basis

or the apparent ailure to downregulate intestinal inammation

but there are no commercially available serologic or other diag-

nostic tests to conrm and the diagnosis rests on using conven-

tional criteria such as Rome III in patients who have been sick with

gastroenteritis or D.

PREVENTION

Counseling

Recommendations

13. Patient level counseling on prevention o acute enteric inec-

tion is not routinely recommended but may be considered

in the individual or close-contacts o the individual who is at

high risk or complications. (Conditional, very low level o

evidence)

14. Individuals should undergo pretravel counseling regarding

high risk ood/beverage avoidance to prevent D. (Condi-

tional, very low level o evidence)

Summary of evidence. Non-travel setting: One in six US citizensget sick rom a oodborne illness each year, and a majority o these

illness will be rom contaminated ood consumed in the United

States (e.g., non-travel associated) (1,2). Food saety is a major

public health effort that involves multiple Federal, State, and

local agencies including the Food and Drug Administration, US

Department o Agriculture, US Food Inspection Service, and state

and local health departments, all o which ocus on the potential

risks or large outbreaks associated with centralization o ood

processing and reliance on imported oods. However, to reduce

the burden o disease the responsibility o oodborne preven-

tion must not only include the producers on the arm, packaging

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 o evidence)

Summary of evidence

In the evaluation o the patient with persistent symptoms, a thor-

ough and directed history is essential. Relevant questions would

include travel history, the nature o the initial symptoms, onset

(sudden or gradual), duration, requency and characteristics o

bowel movements (particularly the presence o blood or mucus),

stool volume, tenesmus, pattern, association with particular

oods, use o antibiotics, and the presence or absence o other

associated symptoms such as nausea, vomiting, incontinence,

ever, and weight loss. Te answers to these questions may direct

urther investigations (156).

Among patients with persistent symptoms (between 14 and

30 days), the role o clinical laboratory studies and endoscopy

is uncertain and should be dictated by clinical suspicion anddisease severity, within the context o most likely etiologies. An

initial diagnostic evaluation in the patient with persistent symp-

toms should include tests or the presence o microbial pathogens.

Although stool culture and microscopy remain the initial diagnos-

tic tests, they both suffer rom limitations that may be addressed

by newer diagnostic methods. Even some o the newer methods,

such as enzyme-linked immunoassays and direct immunouores-

cence staining, which increase sensitivity, may not be able to dis-

tinguish, e.g., between the pathogen Entamoeba histolyticaand a

non-pathogenic but microscopically indistinguishable Entamoeba

dispar. (157). Singleplex and multiplex PCR assays or the detec-

tion o enteric microbial pathogens are more sensitive than culture,microscopy, or antigen detection (158160). In one study describ-

ing a real-time PCR assay designed to detect Giardia intestinalis,

the lower limit o detection was as little as 102 spores per ml o

stool as opposed to microscopy, which required >106spores per ml

o stool (161).7One study showed using PCR methods resulted in

a 22-old increase in the detection o Cryptosporidiumand Giardia

compared with conventional microscopy (162). Colonoscopy

has been considered in the evaluation o the patient with persis-

tent diarrhea. In a recent study looking at the diagnostic value

o endoscopy or the diagnosis o giardiasis or other intestinal

diseases in patients with persistent diarrhea returning rom tropical

or subtropical areas, lower endoscopy (colonoscopy or sigmoido-

scopy) yielded relevant diagnoses more ofen than upper endo-scopy (163). Tis study, however, suffers rom a small sample size

insoar as only 31 patients with persistent diarrhea were exam-

ined and thus the additional value o such procedures cannot be

recommended. In certain clinical situations such as postantibiotic

or hospital-acquired gastrointestinal illness, testing or Clostridium

diffi cilemay be recommended, as well as additional serologic and

clinical laboratory testing including a complete blood count, which

may be helpul in inorming an inectious cause in the absence o

revealing stool studies.

While not considered in these guidelines, the work-up o

chronic diarrhea is briey considered and should include the


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6

industries, stores, and restaurants but also penetrate down to the

individuals in the home who are buying and preparing oodthe

last step in the chain o oodborne illness prevention.

Te intervention o improving ood preparation in the home

has not been systematically studied. Te Centers or Disease

Control has recently responded through launching a new con-

sumer ood saety campaign to educate the public on the simple

message o clean, separate, cook, chill, and report. No recom-

mendations on counseling by providers have been provided. No

recommendations on counseling by providers have been recom-

mended. However, or vulnerable patient populations who are

at increased risk or severe disease and complications associated

with acute oodborne illness, including pregnant women, elderly,

and those with immune deciency due to HIV or immuno-

therapeutic, situational individual patient level counseling may

be appropriate.

Traveler setting:In the realm o travel medicine, Shlim reviewed

the evidence or the effectiveness o personal hygiene precautions

in prevention o D (188). In the eight studies identied in this2005 review, seven ound no correlation between the types o

ood selected by the traveler and the risk o acquiring travelers

diarrhea, whereas one showed a correlation between a ew

dietary lapses. Te summary rom this review provides the basis

or current recommendations where it was stated, Te sum total

o these errors leads to abundant opportunities or the spread

o enteric pathogens, whether rom employees hands, ies, or

contaminated meat and produce, with ample time available or

bacterial growth to reach inective levels. One could postulate

that boil it, cook it, peel it, or orget it would be good advice to

someone who was purchasing and preparing their own ood in a

sanitized kitchen but that it is inadequate or travelers aced withthe multiplicity o hygienic errors ound in the kitchens o many

destination countries.

Subsequent to this review there have been ew studies reported

on this topic. A recent report among travelers who attended a travel

clinic beore travel (exposed) and travelers to similar regions but

did not attend travel clinic (non-exposed) was reported (189). In

this study, 13 (4.3%) o those interviewed reported drinking unsae

water and this proportion was similar in those who attended or did

not attend travel clinic beore travel (exposed (n=7/150, 4.6%) and

non-exposed subjects (n=6/150; 4%) (P=0.78)). Forty-ve (15%) o

enrolled subjects ate some ood with elevated risk o travelers diar-

rhea (such as raw ruit or vegetables, drink with ice or ice cream);

this proportion was higher in the non-exposed people (n=36/150;24%) than in the people attending the ravel Clinic (n=9/150; 6%)

(P


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Riddle et al.


14

is o no medical concern. Persons with underlying inammatory

bowel disease or HIV inection should not receive BSS because o

the ear o excessive absorption o this generally poorly absorbed

bismuth compound leading to bismuth encephalopathy (216).

Probiotic/prebiotic/synbiotics. Te use o probiotics, prebiotics,

and synbiotics to prevent acute diarrheal inection is an appealing

concept because o their ease o use and relative saety. Te data,

however, supporting their use in preventing inectious diarrhea

is not consistently strong and at this point we do not recommend

them or this purpose

Te preventive role o probiotics, prebiotics, and synbiotics in

acute diarrheal inection in adults is limited to studies in prospec-

tive travelers (217226). Tere are no published studies in the set-

ting o community-acquired diarrhea, in the outbreak setting or

example. Available studies suffer rom variability in age groups,

setting, causes o acute diarrhea, and probiotic strains. Although

most o the trials are o adequate quality, limitations include short

ollow-up and not estimating person-time analysis. Tere were alsolarge variations in the dosage o probiotics, requency o adminis-

tration, and ormulations used. Further variation was seen with

regard to timing and administration o these preparations relative

to a number o actors including travel and concurrent treatment

with anti-microbials (217). Although two meta-analyses suggest a

marginal benet o probiotics in prevention o D, both suggest

there is insuffi cient evidence or extrapolation to global recom-

mendations or their use (217,218).

Probiotics. In the past three decades, trials investigating the e-

ects o probiotics in the prevention o D have demonstrated

varying results (219). In one o the earlier studies, Enterococcusaeciumdid not prevent D. In a study by the same group, Saccha-

romyces boulardiigiven to 3,000 Austrian travelers in a placebo-

controlled manner resulted in a clinically modest dose-dependent

benet in D prevention, effects were most impressive in travelers

to North Arica and urkey (220). In a study o 756 Finnish travel-

ers to two separate destinations in urkey, a 41% diarrhea attack

rate was noted in the LactobacillusGG group vs. 46.5% in the pla-

cebo group, a very modest difference. However, the rate o protec-

tion was 39.5% at one location and almost nil at the other location

(221). In a US study o 245 travelers to various destinations those

taking LactobacillusGG experienced a 3.9% incidence o diarrhea

per day at risk vs. 7.4% in the placebo group. Using this novel

approach to protective effi cacy, they calculated a protection rateo 47% (222). Lactobacillus bulgaricusas well as Lactobacillus er-

mentumpreparations were ound to be ineffective in preventing

D (223,224) and there was no benecial effect seen with a nonvi-

able ormulation o Lactobacillus acidophilusin the prevention o

D in a randomized placebo-controlled trial in travelers to West

Arica and other destinations (227).

Prebiotics and synbiotics. Early work showed the prebiotic

Lactulose reduced intestinal carriage o Shigella but was in-

effective in treating Shigellainections (228). In a small study o

42 adult patients traveling to tropical countries (22 in the study

resembling endemic settings in the developing world than those

seen with typical travelers staying in clean hotels.

Prophylaxis

Recommendations

16. Bismuth subsalicylates have moderate effectiveness and may

be considered or travelers who do not have any contraindi-

cations to use and can adhere to the requent dosing require-

ments. (Strong recommendation, high level o evidence)

17. Probiotics, prebiotics, and synbiotics or prevention o

travelers diarrhea are not recommended. (Conditional

recommendation, low level o evidence)

18. Antibiotic chemoprophylaxis has moderate to good effective-

ness and may be considered in high-risk groups or short-

term use. (Strong recommendation, high level o evidence)

Summary of evidence. Traveler setting: Prevention o D is

challenging because o the ubiquitous exposures to individu-

als through contaminated ood, water, and generally unhygienicconditions among much o the developing world. ravelers are

requently counseled on preventive risk behaviors, but despite

a travelers best attention to such recommendations, evidence is

lacking that such precautions have any protective effect (188).

Although vaccines or many o the agents commonly associated

with D are under development, these are considered a long-term

solution and might likely suffer rom the lack o utilization as has

been seen with most travel-associated vaccines (202206). Alter-

native primary prevention strategies such as BSS, probiotics, and

antibiotics have been evaluated and are considered here.

Bismuth subsalicylate. BSS has been shown in several studies toreduce the requency o D when used during period o risk or

3 weeks (207209). While the salicylate portion o the drug pro-

vides antidiarrheal effects, it is the bismuth moiety that is active

when the molecule is used or chemoprophylaxis (210). BSS and

the bismuth reaction products ound in the gut have dose-respon-

sive activity against bacteria (211) and anti-viral properties (212).

Te drug provides at least 60% protection in a dose o 2.1 g per day

(207,208). Te recommended dose o BSS or D prevention is

two tablets our daily doses at mealtimes and at bedtime. Both the

dose and the interval o administration appear to be important as

2.1 and 1.05 g given two times a day led to reduced levels o pro-

tection, 41% and 35%, respectively (209). Te chemoprophylactic

dose o BSS leads to important absorption o salicylate and shouldnot be used when other salicylates are being taken. BSS does not

have the damaging effects on gastric mucosa as acetyl salicylic

acid effects and, in act, has intestinal mucosa-cytoprotective e-

ects (213,214).

BSS use has been shown to reduce the occurrence o D i taken

in proper daily dose or up to 3 weeks. Most authorities recom-

mend that chemoprophylaxis could be used or trips up to 2 weeks

(215). Chemoprophylaxis should not be used or longer trips.

Future travelers planning to use BSS chemoprophylaxis need to

be warned that during administration o the drug their stools and

tongues will turn black and that this harmless bismuth sulde salt


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6

group, 20 in the placebo group), the use o sodium butyrate and

short-chain atty acids as a prebiotic was evaluated or the preven-

tion o D (229). Noted was a signicant reduction in the occur-

rence o D in the prebiotic group (4.5%) vs. 40% in the placebo

group. Sodium butyrate has been established in animal studies

as a regulator o the intestinal environment. Limitations o the

study included sample size and lack o diversity among the travel-

ers. A double-blind, placebo-controlled trial o a novel galacto-

oligosaccharide mixture in 159 healthy travelers to countries

o low and high risk or D showed a signicant reduction in

diarrhea in the prebiotic group as compared with those who

consumed placebo (maltodextrin) (225). Tis particular ormu-

lation was studied because o earlier work showing this agent

increased bidobacerium numbers in the colonic content o

piglets and inhibited the attachment o enterohepatic E. coliand

Salmonella enterica yphimurium to H29 cells in vitro (230).

A randomized, double-blind, placebo-controlled trial o an oral

synbiotic AKSB, a combination o two probiotics (Enterococcus

aeciumand S. cervisiae) and a prebiotic (ructo-oligosaccharide),ailed to show benet (226).

For probiotics, prebiotics, and synbiotics alike the challenge has

been to nd the right ormulation or combination or the right

condition or individual. Mirroring the use o these agents in other

gastrointestinal diseases, a more thorough knowledge o the host

microbiome might be necessary beore appropriate trials can be

designed using specic agents or prevention.

Antibiotics. Anti-microbial prophylaxis has been considered an

option to prevent inection. In 1985 issues surrounding prophy-

laxis were debated during an NIH-sponsored consensus meet-

ing, which concluded that routine antibiotic chemoprophylaxisshould not be used because o concerns about the development o

antibiotic resistance, the demonstrated effi cacy o empiric therapy

afer the development o symptoms, and the potential or un-

necessary side effects (231). Since that meeting, studies that have

examined the cost benet o chemoprophylaxis or the preven-

tion o D have recommended against prophylaxis except in

high-risk groups (232,233). While debate continues, the standard

practice and recommendation has remained unchanged or 20

years (234236).

wo recent developments are challenging the general recom-

mendation against use o chemoprophylaxis. First, postinectious

irritable bowel syndrome has been recognized as an important

chronic health consequence, occurring in a sizeable proportion othose who experience an episode o D, particularly among those

with bacterial inection and a more severe clinical presentation

(237239). Second, riaximin, a non-absorbable antibiotic, has

been developed and may provide a saer alternative or prophy-

laxis than uoroquinolones, which are known to be quite effective

but may have an unacceptable saety prole. Te high volume o

international travel and, consequently, the high number o people

at risk or acquiring D, postinectious irritable bowel syndrome

and other postinectious chronic health conditions, creates a

potentially large burden o illness that could be prevented with

the use o sae and effective chemoprophylaxis. However, saety

concerns associated with antibiotic use, o any class, is an impor-

tant consideration.

A recent systematic review summarized several studies show-

ing a comparative advantage o antibiotic chemoprophylaxis or

the prevention o D (240). Four riaximin studies included in

the meta-analysis had a total o 604 subjects. One o those studies

(DuPont et al.(241)) had three treatment arms (riaximin 200 mg

dosed once, two and three times a day) and one control arm

(placebo dosed three times a day). Tere was no observed signi-

cant difference o risk reduction among dosing regimens in the

Dupont et al.study, and the overall pooled DerSimonian and Laird

effect (relative risk) estimate or all studies combined was 0.33

(95% CI: 0.240.45), equating to a protective effi cacy o 67% (95%

CI: 5576%) avoring chemoprophylaxis (heterogeneity 2=3.09,

P=0.377; I2=3.1%). In terms o absolute risk reduction, pooled

DerSimonian and Laird summary estimates ound that riaximin

chemoprophylaxis decreased D attack rates by a mean o 22.1%

(95% CI: 6.337.9%) equating to a number needed to treat o 4.5

(95% CI: 2.615.9). With respect to riaximin chemoprophylaxis,two studies (Armstrong et al.(242) and Flores et al.(243)) did not

show that chemoprophylaxis with riaximin reached a statistically

signicant difference in preventing D compared with placebo

(242,243). In both studies the incidence o D in the control group

was relatively low (8/48 or 17% and 9/47 or 19%, respectively),

which could have explained the ndings given sample size calcula-

tions were based on the expected incidence o D to be 40%, and

thus recruitment may have been too small to detect the true effect

o riaximin in preventing D. Most recently, an effectiveness study

by Zanger et al.(244) reported moderate protection with riaximin

or up to 28 days to the South and Southeast Asian regions ( 244).

Effi cacy was noted to be higher in travelers to countries in SouthAsia (65%, 95% CI: 1577) compared with Southeast Asia, which

is likely attributed to differential (invasive) pathogen distributions

(no microbiology was conducted in the study). However, a study by

aylor et al.(245) suggests that riaximin may be effective against

shigellosis, which is a common invasive D pathogen (and also

associated with chronic health complications) (246). Tere were

no serious adverse drug-associated saety adverse events reported

among these published studies.

While no recent studies have been conducted, oroquinolones

consistently demonstrate a higher effectiveness in the prevention

o D with a summary pooled estimate o 88% (95% CI: 8093%)

protective effi cacy (240). Te emergence o uoroquinolone resist-

ance to commonly encountered D pathogens may be a actortoday i these studies were replicated (139,247,248). Furthermore,

relative to riaximin, the saety prole or oroquinolones is less

avorable given the association with tendonopathies and the sys-

temic broad-spectrum nature o this antibiotic with attendant

pressures on systemic drug-resistant pathogens o importance

(132).

Te evidence to date suggests moderate to good effi cacy o

riaximin and oroquinolones or chemoprophylaxis. How-

ever, until such studies are carried out, which adequately assess

the risk and benets o this strategy in reduction o acute and

chronic consequences while balance the negative consequences


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Riddle et al.


16

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o antibiotic use, recommendations or use in the traveler setting

should be restrictive and used in short durations. Te traveler

who is at high risk or D and susceptible to potentially serious

health consequences, or whose illness may critically impact the

intended purpose o travel, may benet rom antibiotic chemo-

prophylaxis.

ACKNOWLEDGMENTS

Tis guideline was produced in collaboration with the Practice

Parameters Committee o the American College o Gastroenterol-

ogy. Te Committee gives special thanks to Ganesh R. Veerappan,

who served as guideline monitor or this document. We thank

the Cornell University reerence librarian, Kevin Pain, or his

assistance and expertise in conducting the systematic review o

the literature and providing articles. We also are grateul to Lauren

Gerson or her support and direction in the development o this

guideline.

CONFLICT OF INTERESTGuarantor of the article:Mark S. Riddle, MD, DrPH.

Specic author contributions:All authors had an equal role in

reviewing the literature, developing the recommendations, critically

appraising the evidence, and drafing the manuscript. All authors

have approved the nal draf submitted.

Financial support:No nancial support was received by any o the

authors or development o these guidelines.

Potential competing interests (past 2 years):Mark S. RiddleSalix

Pharmaceuticals (research support and participated on advisory

boards), Romark (advisory board participant), Janssen Pharmaceuti-

cals (cooperative research and development agreement), Prometheus

Laboratories (cooperative research and development agreement);akeda Vaccines (advisory board and cooperative research and

development agreement); Limmaech Biologics (cooperative

research and development agreement); Herbert L. DuPontSalix

Pharmaceuticals (participated on advisory boards), PaxVax (DSMB

Board member), Romark (advisory board), GSK (consultant and

grant support through university), Sano Pasteur (grant support

through university), akeda (grant support through university); Seres

Health (grant support through university); Bradley A. ConnorSalix

Pharmaceuticals (advisory board participant), PaxVax (speakers

bureau), Romark (advisory board participant).

Copyright statement:One o the authors (Mark S. Riddle) is an

employee o the U.S. Government and is a military service member.

Tis work was prepared as part o offi cial duties. itle 17 U.S.C. 105provides that Copyright protection under this title is not available

or any work o the United States Government. itle 17 U.S.C. 101

denes a U.S. Government work as a work prepared by a military

service member or employee o the U.S. Government as part o that

persons offi cial duties.

DISCLAIMER

Te views expressed in this article do not necessarily reect the

offi cial policy or position o the Department o the Navy, Depart-

ment o Deense, nor the US Government. Tis is a partial US

Government work. Tere are no restrictions on its use.


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