Guideline For The Antibiotic Use in Acute Gastroenteritis: Special Article

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Infect Chemother.

2019 Jun;51(2):217-243
https://doi.org/10.3947/ic.2019.51.2.217
pISSN 2093-2340·eISSN 2092-6448

Special Article Guideline for the Antibiotic Use in


Acute Gastroenteritis

Youn Jeong Kim1,*, Ki-Ho Park2,*, Dong-Ah Park3,*, Joonhong Park4,*,


Byoung Wook Bang5,*, Seung Soon Lee6,*, Eun Jung Lee7,*, Hyo-Jin Lee8,*,
Sung Kwan Hong9,*, and Yang Ree Kim 8

Division of Infectious Diseases, Department of Internal Medicine, Incheon St. Mary's Hospital, College of
1

Medicine, The Catholic University of Korea, Seoul, Korea


Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Kyung
2

Hee University School of Medicine, Seoul, Korea


Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare
3

Collaborating Agency, Seoul, Korea


Department of Laboratory Medicine, Daejeon St. Mary's hospital, College of Medicine, The Catholic
4

University of Korea, Daejeon, Korea


Division of Gastroenterology, Department of Internal Medicine, Inha University College of Medicine,
5

Incheon, Korea
Division of Infectious Diseases, Department of Internal Medicine, Hallym University Chuncheon Sacred
6

Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea


Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Seoul
7

Received: May 30, 2019 Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
Division of Infectious Diseases, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of
8

Corresponding Author: Medicine, The Catholic University of Korea, Uijeongbu, Korea


Yang Ree Kim, MD, PhD Division of Infectious Diseases, Department of Internal Medicine, CHA Bundang Medical Center, CHA
9

Division of Infectious Diseases, Department University, Seongnam, Korea


of Internal Medicine, Uijeongbu St. Mary's
Hospital, College of Medicine, The Catholic
University of Korea, 271 Cheonbo-ro,
Uijeongbu, Gyeonggi-do 11765, Korea.
ABSTRACT
Tel: +82-31-820-3798
Fax: +82-31-820-3334 Acute gastroenteritis is common infectious disease in community in adults. This
E-mail: [email protected] work represents an update of ‘Clinical guideline for the diagnosis and treatment of
gastrointestinal infections’ that was developed domestically in 2010. The recommendation
*These authors contributed equally to this
manuscript. of this guideline was developed regarding the following; epidemiological factors, test for
diagnosis, the indications of empirical antibiotics, and modification of antibiotics after
Copyright © 2019 by The Korean Society of confirming pathogen. Ultimately, it is expected to decrease antibiotic misuse and prevent
Infectious Diseases and Korean Society for
antibiotic resistance.
Antimicrobial Therapy
This is an Open Access article distributed
Keywords: Infectious diarrhea; Traveler's diarrhea; Antibiotic
under the terms of the Creative Commons
Attribution Non-Commercial License (https://
creativecommons.org/licenses/by-nc/4.0/)
which permits unrestricted non-commercial
use, distribution, and reproduction in any
INTRODUCTION
medium, provided the original work is properly
cited. Gastroenteritis refers to infection in the stomach and intestines, and most cases of acute
gastroenteritis present as acute-onset diarrhea. Diarrhea is usually defined as passage
ORCID iDs of abnormally liquid or unformed stools at an increased amount and frequency. When
Yang Ree Kim
diarrhea is caused by a source of infection and is accompanied by nausea, vomiting, and
https://orcid.org/0000-0002-3585-3690
abdominal pain, it is referred to as infectious diarrhea. However, the microorganism
Conflict of Interest causing the infection is rarely confirmed in clinic. Diarrhea is defined as acute if it lasts for
No conflicts of interest. 14 days or less, which is the case for most infectious diarrhea. In patient samples collected

https://icjournal.org 217
Guideline for the Antibiotic Use in Acute Gastroenteritis

through ‘Sentinels in acute infectious diarrhea surveillance’ in Korea conducted by the


Korea Centers for Disease Control and Prevention (KCDC), bacterial pathogens were
isolated from 11.5 - 23.7% of samples between 2012 and 2016. In 2017, bacteria tested in the
surveillance project (Salmonella spp., Escherichia coli, Shigella spp., Vibrio parahaemolyticus, Vibrio
cholerae, Campylobacter spp., Clostridium perfringens, Staphylococcus aureus, Bacillus cereus, Listeria
monocytogenes, and Yersinia enterocolitica) were isolated in 1,376 of 9,344 samples collected at
70 participating institutions, thus at a rate of 14.7%, which showed that bacteria do not
account for a high number of cases of acute diarrhea. In general, acute gastroenteritis
improves spontaneously and does not require antibiotic treatment. Inappropriate use of
antibiotics may cause antibiotic-associated diarrhea or other complications and may also
lead to antibiotic resistance in the long term. Although the Korean Society for Antimicrobial
Therapy published ‘Clinical guideline for the diagnosis and treatment of gastrointestinal
infections’ in 2010, updates are required to reflect recent changes. Therefore, this guideline
was developed in order to provide clinical recommendations based on the newest evidence
on empirical antibiotic therapy for suspected acute gastroenteritis, which is commonly seen
in clinic, and on targeted antibiotic treatment for cases with confirmed bacterial growth,
with an ultimate aim to decrease antibiotic misuse and to prevent the rise of antibiotic-
resistant bacterial strains.

DEVELOPMENT OF CLINICAL GUIDELINE


1) Committee on clinical guideline
The committee comprised one chairperson (Yang Ree Kim, College of Medicine, The
Catholic University of Korea) and six committee members (Youn Jeong Kim, College of
Medicine, The Catholic University of Korea; Ki-Ho Park, Kyung Hee University School
of Medicine; Seung Soon Lee, Hallym University College of Medicine; Eun Jung Lee,
Soonchunhyang University College of Medicine; Hyo-Jin Lee, College of Medicine, The
Catholic University of Korea; and Sung Kwan Hong, CHA University College of Medicine)
recommended by the Korean Society for Antimicrobial Therapy and the Korean Society of
Infectious Diseases, one member (Byoung Wook Bang, Inha University College of Medicine)
recommended by the Korean Society of Gastroenterology, one member (Joonhong Park,
College of Medicine, The Catholic University of Korea) recommended by the Korean Society
of Clinical Microbiology, and one expert in clinical guidelines (Dong-Ah Park, National
Evidence-Based Healthcare Collaborating Agency).

2) Target and scope of the guideline


The present guideline is for community-acquired infectious diarrhea and traveler's diarrhea
in adults with the exception of Clostridioides difficile infection and immune-suppressed
patients. Moreover, the guideline focused on the use of antibiotics in treatment. Although
antidiarrheal agents and probiotics were included, intravenous hydration was excluded. The
guideline was designed so that various specialists, resident physicians, government officials,
and general practitioners treating acute gastroenteritis patients at hospitals and clinics of
various sizes can easily refer to the guideline.

3) Selection of key questions


The committee selected a total of 10 key questions, and questions on intervention were
organized based on the populations of interest, intervention, comparison and outcome
(PICO) format.

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Guideline for the Antibiotic Use in Acute Gastroenteritis

4) Literature search and selection of clinical guidelines


To search for guidelines on antibiotic use in acute gastroenteritis published after 2010,
‘acute gastroenteritis’, ‘acute colitis’, ‘infectious colitis’, ‘infectious diarrhea’, ‘travelers’
diarrhea’, ‘food-borne’, and ‘water-borne’ were used as the keywords for search; ‘guideline’
and ‘recommendation’ were used as keywords to search for guidelines and were combined
with other keywords through AND. The search was conducted on MEDLINE and EMBASE,
which are international electronic databases, on KoreaMed and KMbase, which are Korean
electronic databases, and on NGC, GIN, and KoMGI, which are databases on clinical practice
guidelines. Two committee members independently selected clinical guidelines and came
to an agreement. First, unrelated literature was excluded based on a review of titles and
abstracts, and second, guidelines that satisfied the selection criteria were selected. The
exclusion criteria were established based on a mutual agreement (Fig. 1).

5) Evaluation of clinical guidelines and review of recency


For the four clinical guidelines selected through the aforementioned process, two committee
members (per guideline) evaluated the quality of the guidelines through K-AGREE II and
calculated the scores for each domain (Table 1). The guidelines that had scores above 50% in
Domain 3, Rigor of Development, were selected. The clinical guideline on gastrointestinal
diseases developed in 2010 did not have a high score in Rigor of Development; however,
as it is the only guideline developed in Korea, it was used for adaptation. After reviewing
the recency of the guidelines selected for adaptation, additional evidence was collected on
PubMed and KoreaMed for each key question.

Identification Records identified through databases searching (n = 930)


• PubMed (n = 114)
• KoreaMed (n = 339)
• Ovid-EMBASE (n = 291)
• KMBASE (n = 3)
• NGC (n = 166)
• GIN (n = 17)

Screening Records after duplicates removed (n = 880)

Records excluded by abstract screening (n = 873)

Eligibility Full-text guidelines assessed for eligibility (n = 7)

Records excluded according to selection criteria (n = 3)


1. P: When guidelines are for patients other than the target patients of the key questions (n = 0)
2. I: When guidelines are not related to the key questions (n = 0)
3. O: When appropriate results were not reported (n = 0)
4. Publication format: When the publication is not a guideline (n = 2)
5. When recommendations were not made (n = 2)
6. When guidelines are not evidence-based (n = 1)
7. When guidelines were in another language than English or Korean (n = 1)
8. When guidelines were published in duplicates (n = 0)
9. When the original guidelines could not be retrieved (n = 0)

Included Guidelines included for evaluation (n = 4)

Figure 1. Search strategies and details for each database.


NGC, national guideline clearinghouse; GIN, guidelines international network.

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Guideline for the Antibiotic Use in Acute Gastroenteritis

Table 1. Score for each domain in quality evaluation


Domain Evaluative criteria Guideline Aa Guideline Bb Guideline Cc Guideline Dd
1 Scope and Purpose 96% 78% 69% 79%
2 Stakeholder Involvement 57% 70% 52% 57%
3 Rigor of Development 87% 63% 73% 52%
4 Clarity of Presentation 93% 100% 100% 99%
5 Applicability 47% 22% 39% 15%
6 Editorial Independence 94% 100% 94% 48%
a
Shane AL, Mody RK, Crump JA, Tarr PI, Steiner TS, Kotloff K, Langley JM, Wanke C, Warren CA, Cheng AC, Cantey
J, Pickering LK. 2017 Infectious Diseases Society of America clinical practice guidelines for the diagnosis and
management of infectious diarrhea. Clin Infect Dis 2017;65:e45-80.
b
Riddle MS, Connor BA, Beeching NJ, DuPont HL, Hamer DH, Kozarsky P, Libman M, Steffen R, Taylor D, Tribble
DR, Vila J, Zanger P, Ericsson CD. Guidelines for the prevention and treatment of travelers' diarrhea: a graded
expert panel report. J Travel Med 2017;24:S63-80.
c
Riddle MS, DuPont HL, Connor BA. American College of Gastroenterology(ACG) clinical guideline: diagnosis,
treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol 2016;111:602-22.
d
The Korean Society of Infectious Diseases, Korean Society for Chemotherapy, The Korean Society of Clinical
Microbiology. Clinical guideline for the diagnosis and treatment of gastrointestinal infections. Infect Chemother
2010;42:323-61.

6) P
 reparation of the guideline and determination of the grade of
recommendation
For each key question, the initial draft of the guideline included the actual guideline, grade of
recommendation, and background. The committee members prepared the initial draft based on
tables comparing the four selected guidelines and relevant evidence for each key question and
also considered evidence that was used in review of recency. After the initial draft was prepared,
the grade of recommendation and the background for the recommendations were described.
The overall quality of evidence used for recommendations for each key question was evaluated
as ‘high’, ‘moderate’, ‘low’, and ‘very low’. When the key question had no supporting evidence,
when evidence could be assumed based on expert agreement, and when recommendations were
absolutely necessary despite a lack of evidence, the level of evidence of the recommendations
was categorized as ‘expert opinion’. The grade of recommendation was evaluated as ‘strong
recommendation (strong)’ or ‘weak recommendation (weak)’ upon consideration of the balance
of desirable and undesirable outcome, quality of evidence, belief in patient value and preference,
cost of treatment, and use of resources. The committee held meetings to discuss and reach
agreement on the recommendations and grade of recommendation.

(1) Grade of recommendation


① Strong: It is best that most or all individuals receive the services outlined in the
recommendation. The benefit clearly outweighs the cost or risk, or the cost or risk
clearly outweighs the benefit.
② Weak: It may not be best for all individuals to receive the services outlined in the
recommendation. The decision should be made based on patient value, preference, and
circumstances. The level of evidence is low, or there is no clear difference in risks and
benefits.

(2) Level of evidence


① High: Almost no other study will change the level of trust in the estimates of the effects.
② Moderate: Other studies may influence the committee's trust in the estimates of the
effects, and the level of trust may also change.
③ Low: Other studies may significantly influence the committee's trust in the estimates of
the effects, and the level of trust may also change.
④ Very low: The committee does not trust the calculated estimates of the effects.

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Guideline for the Antibiotic Use in Acute Gastroenteritis

⑤ Expert opinion: Although there is no supporting evidence, the committee has


determined through official expert meetings that the recommendation is clinically
appropriate at present.

7) Review by external experts


Through a meeting held on January 11, 2019, opinions on the guideline was gathered
from physicians with their own clinical practice and specialists in infectious diseases,
gastroenterology, and clinical microbiology. The guideline was also reviewed and approved
by the Korean Academy of Family Medicine, Korean Society of Infectious Diseases, Korean
Society of Gastroenterology, Korean Society of Clinical Microbiology, and Korean Society for
Antimicrobial Therapy.

8) Limitations and future tasks of the guideline


The guideline was developed based on Korean and international clinical practice guidelines
and recent literature available at the time of development. If new drugs are developed or if
significant changes are observed in antibiotic resistance of pathogenic bacteria, the guideline
may be updated.

9) Support
The guideline was supported as a Policy Research Project by the KCDC in 2018 (research
project number 2018-E2803-00). The committee members who participated in developing
this guideline were not influenced by any means by government organizations, academic
societies, pharmaceutical companies, or other for-profit institutions.

SUMMARY OF GUIDELINE
Recommendation Grade of Level of
recommendation evidence
(KQ1) What clinical and epidemiological characteristics are associated with the diagnosis and treatment of adult patients with suspected acute infectious diarrhea?
1 Thoroughly investigate epidemiological characteristics, including clinical manifestation and history of Strong Moderate
exposure.
2 If diarrhea is observed in patients who work at childcare services, long-term residences, restaurants, Strong High
group meal services, or swimming pools or those who work with close patient contact, investigate the
possibility of group outbreaks.
3 If fever or bloody diarrhea is also present, test for Salmonella, Shigella, and Campylobacter. Strong Low
4 Enteric fever should only be considered ① if fever and diarrhea or fever alone is present, ② if the patient Strong Moderate
traveled to other countries with ongoing epidemics of enteric fever, and ③ if the patient consumed food
prepared by individuals who were recently exposed to the pathogen in an area with an ongoing epidemic
5 If there is a clinical possibility of Shiga toxin-producing bacteria, such as epidemiological possibility and Strong Moderate
afebrile bloody diarrhea or abdominal pain, Shiga toxin should be tested.
6 If large amounts of ‘rice water-like’ diarrhea are present with travel history in the past three days to areas Strong Low
with the ongoing cholera epidemic, conduct stool tests for cholera.
7 If diarrhea persists for more than 14 days in travelers, parasitic infections should be evaluated. Strong Moderate
8 If patients used antibiotics within 8 - 12 weeks of the onset of diarrhea, C. difficile should be tested. Strong Moderate
9 Evaluate for extraintestinal complications of the infection. Strong Moderate
(KQ2) Which tests are helpful in identifying the pathogen in adult patients with suspected acute infectious diarrhea?
(KQ2-1) Is stool test necessary for the diagnosis of acute infectious diarrhea? Which tests are appropriate?
1 If bloody or mucoid stool, severe abdominal pain or tenderness, or diarrhea with septic findings are Strong Moderate
present, conduct stool test to test for Salmonella, Shigella, Campylobacter, Yersinia, C. difficile, and
Shiga toxin-producing E. coli (STEC).
2 Although acute watery diarrhea or uncomplicated traveler’s diarrhea in adults improves within days Low Expert opinion
without antibiotics in most cases, consider non-culture tests in addition to traditional stool tests when
pathogens should be identified.
3 Conduct stool tests for Vibrio, norovirus, and rotavirus upon consideration of symptoms or Strong Moderate
epidemiological relevance.
(continued to the next page)

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Guideline for the Antibiotic Use in Acute Gastroenteritis

(Continued)
Recommendation Grade of Level of
recommendation evidence
4 If there is a risk or suspicion of an outbreak of diarrhea, conduct stool tests. Strong Moderate
5 Since traditional stool tests (culture, microscopic analysis, and antigen analysis) often cannot identify Strong Very low
pathogens responsible for acute diarrheal diseases, consider the molecular diagnosis.
6 Since panel-based multiplex molecular analysis for diarrhea detects DNA regardless of the survival of Strong Low
microorganisms, consider clinical situations in interpreting the results.
(KQ2-2) Is stool leukocyte or lactoferrin test helpful in the clinical diagnosis of acute infectious diarrhea in adults?
1 Stool leukocyte or lactoferrin test is not recommended in identifying the cause of acute infectious Strong Moderate
diarrhea.
(KQ2-3) Are laboratory tests (complete blood count, chemistry, serology, culture) helpful in diagnosing acute infectious diarrhea or predicting complications?
1 Blood cultures are helpful in diagnosing patients with suspected infectious diarrhea in the following Strong Moderate
cases:
① patients with septic findings, ② suspected enteric fever, ③ systemic infectious symptoms, ④
immune-suppressed patients, ⑤ high-risk situations, such as hemolytic anemia, ⑥ patients with fever
of unclear etiology who have travel history to areas with endemic enteric fever or contact history with
individuals who traveled to area with endemic enteric fever.
2 Widal test is not recommended for diagnosis of pathogens causing enteric fever Strong Moderate
3 If infectious diarrhea is suspected, total white cell count and differential count may be helpful in Weak Low
determining whether it is bacterial.
4 Repeat hemoglobin, platelet count, electrolytes, blood urea nitrogen/creatinine to detect early findings Strong High
of hemolytic uremic syndrome or renal damage may help in predicting complications in patients infected
with E. coli 0157 or other STEC. Moreover, peripheral blood smear to confirm red blood cell fragments is
helpful when the hemolytic uremic syndrome is suspected.
(KQ2-4) Is computed tomography (CT) helpful in diagnosing or predicting complications of acute infectious diarrhea?
1 CT may be helpful in diagnosing complications, such as aortitis, infectious aneurysm, peritonitis, Weak Low
intestinal perforation, and toxic megacolon, when fever continues despite appropriate antibiotic
treatment in elderly patients with invasive Salmonella enterica or Yersinia infections or when patients
have atherosclerosis.
2 CT may be helpful in differential diagnosis of acute infectious diarrhea and non-infectious diarrhea. Weak Low
(KQ2-5) Is endoscopy helpful in diagnosis of infectious diarrhea?
1 Endoscopy is not recommended in most acute and chronic infectious diarrhea patients. Strong Very low
2 Endoscopy or sigmoidoscopy should be considered in acute diarrhea patients without improvement, in Strong Low
persistent unexplained diarrhea in acquired immune deficiency syndrome patients, persistent diarrhea in
patients who have anal sexual intercourse, and persistent diarrhea in patients with recent travel history.
3 Duodenal aspiration may be considered when Giardia, Strongyloides, Cystoisospora, or Microsporidia Weak Low
infection is suspected.
(KQ3) What are indications for empirical antibiotic therapy for acute infectious diarrhea and which antibiotics should be used?
1 In general, antibiotic treatment is not recommended for most cases of acute watery diarrhea. Strong Low
2 Empirical antibiotic therapy can be considered in the following cases: ① Weak ① Expert opinion
① If bloody or mucoid stool and fever, or Shigellosis symptoms (frequent scant bloody stools, fever, ② Low ② Low
cramping abdominal pain, and tenesmus) are present and ② in traveler’s diarrhea accompanied by high
fever above 38.5℃ or septic findings.
3 Antibiotic treatment is recommended for immune-suppressed patients with bloody diarrhea. Strong Low
4 For empirical antibiotic therapy, use fluoroquinolone antibiotics or azithromycin upon consideration of Strong High
the distribution and antibiotic sensitivity of pathogens in local communities or areas where the patient
traveled.
5 Rifaximin may be used for suspected infection with non-invasive bacteria without bloody diarrhea. Low Low
6 The use of antibiotics is not recommended for patients with suspected STEC infection. Strong Moderate
(KQ4) How should antibiotics be modified when the bacterial strain causing acute infectious diarrhea is identified?
1 When the bacteria and antimicrobial susceptibility results are identified, antibiotics should be modified Strong High
accordingly.
2 For infectious diarrhea caused by Campylobacter, the use of azithromycin is recommended. Strong High
3 For nontyphoidal salmonellosis, antibiotic treatment is not recommended with the exception of infants Weak Low
less than 3 months of age, patients over 50 with suspected atherosclerosis, immune-suppressed
patients, patients with valvulopathy, and patients with significant joint diseases.
4 Azithromycin, ciprofloxacin, or ceftriaxone is recommended for shigellosis. Strong High
5 Doxycycline is recommended for Vibrio cholerae infections, and ciprofloxacin, azithromycin, and Strong High
ceftriaxone may also be used.
(KQ5) Do anti-diarrheal agents decrease the duration of symptoms in acute infectious diarrhea?
1 Bismuth subsalicylates provide symptomatic improvement by regulating the amount of stool in mild or Strong High
moderate acute diarrhea.
2 Loperamide is helpful in shortening the duration of symptoms of acute watery diarrhea in otherwise Weak Moderate
healthy adults.
(continued to the next page)

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Guideline for the Antibiotic Use in Acute Gastroenteritis

(Continued)
Recommendation Grade of Level of
recommendation evidence
3 Loperamide should not be used for children below the age of 18. Strong Moderate
4 Loperamide should be avoided when there is a possibility of toxic megacolon or when fever continues. Strong Low
5 Loperamide may improve symptoms in traveler’s diarrhea with appropriate antibiotic treatment. Strong Moderate
(KQ6) Do probiotics decrease the duration of symptoms in acute infectious diarrhea?
1 Probiotics decrease the symptoms and duration of acute infectious diarrhea in otherwise healthy adult Weak Moderate
and pediatric patients.
2 Probiotics are not recommended to prevent traveler’s diarrhea. Weak Low

RECOMMENDATIONS FOR EACH KEY QUESTION


KQ1. What clinical and epidemiological characteristics are associated with the diagnosis and treatment of adult patients with
suspected acute infectious diarrhea?
Recommendation Grade of Level of
recommendation evidence
1 Thoroughly investigate epidemiological characteristics, including clinical manifestation and history of exposure. Strong Moderate
2 If diarrhea is observed in patients who work at childcare services, long-term residences, restaurants, group Strong High
meal services, or swimming pools or those who work with close patient contact, investigate the possibility of
group outbreaks.
3 If fever or bloody diarreha is also present, test for Salmonella, Shigella, and Campylobacter. Strong Low
4 Enteric fever should only be considered ① if fever and diarrhea or fever alone is present, ② if the patient trav- Strong Moderate
eled to other countries with ongoing epidemics of enteric fever, and ③ if the patient consumed food prepared
by individuals who were recently exposed to the pathogen in an area with an ongoing epidemic
5 If there is a clinical possibility of Shiga toxin-producing bacteria, such as epidemiological possibility and afe- Strong Moderate
brile bloody diarrhea or abdominal pain, Shiga toxin should be tested.
6 If large amounts of ‘rice water-like’ diarrhea are present with travel history in the past three days to areas with Strong Low
ongoing cholera epidemic, conduct stool tests for cholera.
7 If diarrhea persists for more than 14 days in travelers, parasitic infections should be evaluated. Strong Moderate
8 If patients used antibiotics within 8 - 12 weeks of the onset of diarrhea, C. difficile should be tested. Strong Moderate
9 Evaluate for extraintestinal complications of the infection. Strong Moderate

Infectious diarrhea has different causes and incidence in different countries based on the
level of public health, lifestyle, and diet. Korea has a surveillance system on gastrointestinal
infections characterized by vomiting and diarrhea at 196 surveillance institutions including
tertiary hospitals, hospitals with more than 200 beds, and public hospitals. Of the 15,717
pathogens isolated in 2017, 9,276 cases were viral (59.0%), most of which were caused by
norovirus and rotavirus, and 6,373 were bacterial (40.5%) caused by Salmonella, Clostridium
perfringens, and Campylobacter; 68 were caused by protozoa (0.4%), most of which were caused
by Giardia lamblia [1]. In the United States, food-borne outbreaks were caused by norovirus in
most cases, followed by Salmonella, between 2009 and 2015 [2]. Enteric fever includes typhoid
fever caused by Salmonella enterica subspecies enterica serovar Typhi (Salmonella typhi) and
paratyphoid fever caused by Salmonella enterica subspecies enterica serovar Paratyphi (Salmonella
paratyphi) A, B, and C. Enteric fever is most common in Central Asia and South East Asia,
and is also observed in other Asian countries, Africa, Latin America, and Oceania [3]. The
most common serotype of Salmonella in Korea between 1998 and 2007 were Salmonella typhi,
Salmonella enterica subspecies enterica serovar Enteritidis (Salmonella enteritidis), and Salmonella
enterica subspecies enterica serovar Typhimurium (Salmonella typhimurium) [4]. Salmonella causes
food- or water-borne gastroenteritis in Korea. Although its incidence is on a decreasing
trend, typhoid fever introduced from other countries has increased owing to increases in
travels to other countries and foreign nationals living in Korea [5].

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Guideline for the Antibiotic Use in Acute Gastroenteritis

Since possible pathogens can be estimated based on epidemiological characteristics in


patients with suspected acute infectious diarrhea (Table 2), food consumption (undercooked
meat, eggs, shellfish, and milk), consumption of unsterilized water, contact with pets, contact
with other infected individuals, history of stay at group facility, travel history, underlying
diseases, sexual history, and occupation should be confirmed. Vibrio spp. and norovirus are
common causes of diarrhea after consumption of uncooked seafood or shellfish, and diarrhea
after consumption of uncooked meat or poultry may be caused by Shiga toxin-producing
Escherichia coli (STEC) (beef ), C. perfringens (beef and poultry), Salmonella (poultry), Campylobacter
(poultry), Yersinia (pork and pork intestine), Staphylococcus aureus (poultry). When patients
consumed unpasteurized milk, their diarrhea may be accountable to Salmonella, Campylobacter,
Yersinia enterocolitica, S. aureus toxin, Cryptosporidium, or STEC, and Salmonella or Shigella
contamination is common in eggs. Water can cause infectious diseases directly through
consumption or indirectly through contamination of food or dishes [2]. Consumption of
unsterilized water may lead to Campylobacter, Cryptosporidium, Giardia, Shigella, Salmonella,
or STEC infection, and Cryptosporidium or other water-borne infections are possible after
swimming at pools. In Korea, there was an outbreak of acute diarrhea in 67 patients that used
a pool in 2008; in six patients with severe diarrhea, norovirus was identified in three patients.
Since norovirus with a similar RNA sequence was also detected in samples of groundwater,
the outbreak was reported to have been caused by contaminated groundwater [6]. Diarrhea in
prisons can be accounted for by norovirus, C. difficile, Shigella, Cryptosporidium, Giardia, Salmonella,
STEC, and rotavirus, and diarrhea in childcare services may have been caused by rotavirus,

Table 2. Epidemiologic factors associated with pathogens of diarrhea


Epidemiological factors Possible pathogens
Food-related Food at hotel or restaurant Norovirus, nontyphoidal Salmonella, Clostridium
perfringens, Bacillus cereus, Staphylococcus aureus,
Campylobacter, ETEC, STEC, Listeria, Shigella, Cyclospora
cayetanensis, Cryptosporidium
Unpasteurized milk Salmonella, Campylobacter, Yersinia enterocolitica, S.
aureus toxin, Cryptosporidium, STEC, Brucella (goat milk
products), Mycobacterium bovis, Coxiella burnetii
Raw or uncooked meat or poultry STEC (meat), C. perfringens (meat, poultry), Salmonella
(poultry), Campylobacter (poultry), Yersinia (pork, pork
intestine), S. aureus (poultry), Trichinella (pork, wild
animal meat)
Fruits or vegetables STEC, nontyphoidal Salmonella, Cyclospora,
Cryptosporidium, Norovirus, Hepatitis A, Listeria
monocytogenes
Uncooked eggs Salmonella, Shigella
Shellfish Vibrio, Norovirus, Hepatitis A, Plesiomonas
Exposure or Consumption of unsterilized water Campylobacter, Cryptosporidium, Giardia, Shigella,
contact Salmonella, STEC, Plesiomonas shigelloides
Swimming at a pool Cryptosporidium
Prisons Norovirus, C. difficile, Shigella, Cryptosporidium, Giardia,
STEC, Rotavirus
Childcare services Rotavirus, Cryptosporidium, Giardia, Shigella, STEC
Recent antibiotic use C. difficile, multi-drug-resistant Salmonella
Travel history to areas with poor Escherichia coli (enteroaggregative, enterotoxigenic,
public health enteroinvasive), Shigella, Salmonella Typhi, nontyphoidal
Salmonella, Campylobacter, Vibrio cholerae,Entamoeba
histolytica, Giardia, Blastocystis, Cyclospora,
Cystoisospora, Cryptosporidium
Contact with pets that have diarrhea Campylobacter, Yersinia
Contact with pig stool Balantidium coli
Contact with poultry Non-typhoidal Salmonella
Visits to farms or zoos STEC, Cryptosporidium, Campylobacter
ETEC, enterotoxigenic E. coli; STEC, Shiga toxin-producing E. coli.

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Guideline for the Antibiotic Use in Acute Gastroenteritis

Cryptosporidium, Giardia, Shigella, or STEC. C. difficile may be accountable if the patient has
recent history of antibiotic use. Infectious diarrhea is caused by different common bacteria
in patients of different ages; for infants of 6 - 18 months, rotavirus is common, whereas
nontyphoidal Salmonella is common for patients younger than 3 months or patients older than
50 with atherosclerosis. Shigella should be considered first for patients aged 1 - 7 years, and
Campylobacter should be considered for young adults. Traveler's diarrhea is a common disease
associated with travelling and is observed in 30 - 70% of travelers depending on the area and
season; it is most commonly caused by E. coli, Campylobacter jejuni, Shigella, and Salmonella.
South East Asia, Central Asia, India, Africa, Mexico, and Latin America are high-risk areas of
traveler's diarrhea.

Although causative bacteria may not cause significant differences in clinical manifestations
of acute diarrhea, possible pathogens may be considered based on characteristic symptoms
(Table 3). Salmonella, Campylobacter, Yersinia, or Shigella should be considered first if persistent
fever and systemic symptoms are present [7]. Yersinia has symptoms similar to those of
acute appendicitis, thus necessitating differential diagnosis [7, 8]. Rotavirus and norovirus
often cause watery diarrhea, and Shigella, C. jejuni, Salmonella, STEC, and enteroinvasive E. coli
(EIEC) often cause bloody diarrhea [7]. For food-related outbreaks, the possible pathogen
can be estimated based on the incubation period. Short incubation periods of 1 - 6 hours
are estimated to have been caused by consumption of toxins, so S. aureus or Bacillus cereus
producing emetic toxin is suspected. C. perfringens or B. cereus producing diarrheal toxin
are suspected for incubation periods of 8 - 16 hours, and Enterotoxigenic E. coli (ETEC),
Salmonella, Shigella, and Vibrio cholerae may be suspected for incubation periods of 16 - 72 hours
[7, 8]. If there is a travel history to areas with cholera epidemics with large amounts of ‘rice
water-like’ diarrhea, the possibility of cholera should be considered. Since 1990, around 10
cases of cholera have been reported annually in Korea; in 2017, all five cases were introduced
from other countries (four from the Philippines and one from India) [9].

STEC is highly toxic and can cause a hemolytic uremic syndrome in young children and
elderly patients. Moreover, it is important in the perspective of public health as it spreads
easily. It can cause infections in small numbers below 102 colonies, so infections may arise
easily secondary to contaminated food or environment [7]. Although STEC O157:H7 is the
most common serotype that causes infections in humans worldwide, non-O157 STEC can
also cause symptoms. In 2011, there were outbreaks of enteritis caused by STEC O104:H4 in
Germany and France; of the 3,816 cases in Germany, 22% had hemolytic uremic syndrome
[10, 11]. According to 20 years of epidemiological investigation of STEC O157:H7 between

Table 3. Clinical findings associated with pathogens of diarrhea


Clinical findings Possible pathogens
Bloody diarrhea STEC, Shigella, Salmonella, Campylobacter, Entamoeba
histolytica, non-cholera Vibrio, Yersinia, Balantidium coli,
Plesiomonas
Chronic diarrhea Cryptosporidium, Giardia lamblia, Cyclospora cayetanensis,
Cystoisospora belli, Entamoeba histolytica
Abdominal pain STEC, Salmonella, Shigella, Campylobacter, Yersinia,
Non-cholera Vibrio, Clostridioides difficile
Severe abdominal pain and bloody diarrhea, STEC, Salmonella, Shigella, Campylobacter, Yersinia
mild or no fever enterocolitica
Abdominal pain with fever (similar to appendicitis) Yersinia enterocolitica, Yersinia pseudotuberculosis
Nausea and vomiting lasting ≤24 hours S. aureus toxin or Bacillus cereus (emetic toxin)
Vomiting, 2–3 days of non-bloody diarrhea Norovirus
STEC, Shiga toxin-producing E. coli.

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Table 4. Extraintestinal complications associated with pathogens of diarrhea


Clinical findings Possible pathogens
Postinfectious irritable bowel syndrome Campylobacter, Salmonella, Shigella, STEC, Giardia
Hemolytic uremic syndrome STEC, Shigella dysenteriae serotype 1
Erythema nodosum Yersinia, Campylobacter, Salmonella, Shigella
Guillain-Barre syndrome Campylobacter
Reactive arthritis (Reiter's syndrome) Salmonella, Shigella, Campylobacter, Yersinia, rarely Giardia,
Cyclospora cayetanensis
Intestinal perforation Salmonella, Campylobacter, Yersinia, Entamoeba histolytica
Aortitis, osteomyelitis Salmonella, Yersinia
STEC, Shiga toxin-producing E. coli.

1982 and 2002 in the United States, hemolytic uremic syndrome was found in 4% of 8,598
cases, with mortality of 0.5% [12]. Although research on STEC has been lacking in Korea,
a previous report suggested that STEC was identified in 0.19% of 17,148 diarrhea patients
in Kwangju between 2004 and 2018 [13]. Diarrhea appears approximately 2 - 12 days after
consumption of STEC, and symptoms vary between mild and bloody diarrhea, with around
90% of patients experiencing bloody stool [14]. The symptoms are often accompanied by
abdominal pain and generally start as non-bloody diarrhea and progress to be bloody 1-3 days
later; bloody diarrhea is more common in STEC O157:H7 infections than in non-O157 STEC
[15, 16]. Hemolytic uremic syndrome may arise in 5 - 13 days of diarrhea.

Although most cases of traveler's diarrhea improve spontaneously, 10% of patients may have
persistent diarrhea for several weeks to months. Here, parasitic infections, the most common
of which is Giardia, should be considered [17]. When afebrile bloody diarrhea and abdominal
pain are present after traveling to areas with epidemics of bacteria that produce Shiga toxin,
STEC infection can be suspected [18].

Extraintestinal complications (Table 4) of enteritis, such as the following, require caution:


Yersinia, Campylobacter, Salmonella, and Shigella may cause erythema nodosum; Campylobacter may
cause Guillain-Barre syndrome; STEC or Shigella dysenteriae serotype 1 may cause hemolytic
uremic syndrome; Salmonella, Shigella, Campylobacter, and Yersinia may cause reactive arthritis,
commonly referred to as Reiter's syndrome, or intestinal perforation; and Salmonella and
Yersinia may cause aortitis or osteomyelitis. Postinfectious irritable bowel syndrome is
also a well-known complication of infectious enteritis. This should be considered when
patients present with chronic diarrhea or abdominal pain after infectious diarrhea or
traveler's diarrhea [19, 20]; the condition is characterized by persistent gastrointestinal
symptoms even after loss of infectious causes, owing to persistent, permanent changes to
gastrointestinal functions after infectious enteritis. Although the symptoms improve in most
cases within one year, they sometimes persist for several years, in which case assessment by a
gastroenterologist is necessary. A study reported that irritable bowel syndrome developed in
9.2% of patients with bacterial enteritis confirmed through cultures within three months and
in 12.3% of the patients within six months [21].

Since other epidemiological data on infectious diarrhea are lacking outside of the sentinel
surveillance of gastrointestinal infections in Korea, more Korean research is warranted in
this regard.

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KQ2. Which tests are helpful in identifying the pathogen in adult patients with suspected acute infectious diarrhea?

KQ2-1. Is the stool test necessary for diagnosis of acute infectious diarrhea? Which tests are appropriate?
Recommendation Grade of Level of
recommendation evidence
1 If bloody or mucoid stool, severe abdominal pain or tenderness, or diarrhea with septic findings are present, Strong Moderate
conduct stool test to test for Salmonella, Shigella, Campylobacter, Yersinia, C. difficile, and Shiga toxin-
producing E. coli (STEC).
2 Although acute watery diarrhea or uncomplicated traveler’s diarrhea in adults improves within days without Low Expert
antibiotics in most cases, consider non-culture tests in addition to traditional stool tests when pathogens opinion
should be identified.
3 Conduct stool tests for Vibrio, norovirus, and rotavirus upon consideration of symptoms or epidemiological Strong Moderate
relevance.
4 If there is a risk or suspicion of outbreak of diarrhea, conduct stool tests. Strong Moderate
5 Since traditional stool tests (culture, microscopic analysis, and antigen analysis) often cannot identify Strong Very
pathogens responsible for acute diarrheal diseases, consider molecular diagnosis. Low
6 Since panel-based multiplex molecular analysis for diarrhea detects DNA regardless of the survival of Strong Low
microorganisms, consider clinical situations in interpreting the results.

In general, acute watery diarrhea improves spontaneously without particular treatment. Stool
tests are necessary when pathogens should be confirmed from a public health perspective
due to risks of further progression of the disease or risks of outbreaks.

Since it is difficult to identify responsible pathogens based on clinical symptoms of


infectious diarrhea, in vitro diagnostic tests should be conducted on stool samples to
identify the pathogens. In vitro tests of microorganisms include bacterial and viral culture,
parasite/parasitic egg smears, enzyme-based immunological assays such as viral antigen
test (norovirus and rotavirus), parasitic antigen test (Giardia and Entamoeba histolytica), and
bacterial toxin test (C. difficile), as well as recently introduced molecular microbiological tests.
Various pathogens can cause acute infectious diarrhea, and in vitro tests are limited in terms
of the complexity and cost. Therefore, only highly pathogenic bacteria, such as Salmonella,
Shigella, Campylobacter, Yersinia, C. difficile, STEC, and Vibrio et al., are selectively cultured,
and only certain viruses, such as norovirus and rotavirus, are tested in enzyme-based
immunological assays; here, although enzyme-based immunological assays take a short
amount of time, they have relatively low sensitivity and specificity [22].

For usual bacterial cultures, fresh stool is seeded onto culture media to detect Salmonella,
Shigella, and C. jejuni. Acute diarrhea caused by Y. enterocolitica, C. difficile, Vibrio, or STEC is
tested additionally when there is clinical suspicion. To detect Y. enterocolitica, samples are
seeded on cefsulodin-irgasan-novobiocin (CIN) medium for culture at room temperature;
samples are seeded on thiosulfate citrate bile salt sucrose (TCBS) medium for Vibrio and on
sorbitol-MacConkey medium for STEC. When diarrhea persists for more than two weeks,
Giardia is often responsible; for diagnosis, protozoa is confirmed in stool smear or cyst
antigens are confirmed through immunological assays. Bacteria that cause acute diarrhea
through toxins include ETEC, STEC, Clostridium botulinum, C. difficile, B. cereus, and S. aureus.
STEC and C. difficile can also be tested through commercialized immunological test or
molecular microbiological kits.

Fresh stool is preferred for bacterial tests for acute diarrhea, and rectal swabs may also be
used. Rectal swabs are transported in modified Stuart transport medium. All samples should
be delivered to the laboratory within two hours as delays in delivery may lead to drops in
stool pH, thus suppressing the growth of some bacteria including Shigella. If timely delivery

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to the laboratory is difficult, the samples may be refrigerated for a short period of time and
transported on ice. If samples should be delivered to over long distances to contracted testing
institutions, the samples should be deep-frozen on dry ice (−70°C).

Panel-based multiplex molecular analysis for diarrhea employs polymerase chain reaction
(PCR), which is widely used for molecular microbiological analyses, to use DNA from samples
to simultaneously test for various pathogens causing diarrhea, such as bacteria, viruses, and
parasites, and often has a higher sensitivity compared to conventionally used culture tests [23,
24]. Therefore, it is useful in detecting pathogens causing acute infectious diarrhea, which
are often not found easily through conventional stool culture [25, 26]. According to a previous
report, when multiplex molecular analysis and conventional diagnostic test were compared
for detection of viruses, bacteria, and parasites in 1,758 stool samples collected from 1,516
patients, molecular analysis identified pathogens in 530 samples (30%) whereas conventional
test identified pathogens in only 324 samples (18%) [22]. Another study comparing multiplex
molecular analysis and conventional tests (culture to identify bacteria and electron microscopy
to identify viruses) reported that molecular analysis identified pathogenic viruses in many
samples that were negative in electron microscopy and multiplex molecular analysis had high
sensitivity to many bacteria that were not detected in culture, including enteropathogenic E.
coli (EPEC hereafter), enteroaggregative E. coli (EAEC hereafter), and non-O157 STEC. Overall,
multiplex molecular analysis (60/135, 44.4%) identified pathogens in more than double of cases
identified by conventional tests (24/135, 17.8%) [23].

Recently, microfluidic devices that enable sample pre-processing, mixing, isolation, and
analysis to be performed on one chip have been developed and have been applied as nucleic
acid-based point-of-care assays, where the high sensitivity and specificity of nucleic acid
amplification are maintained with simultaneous nucleic acid extraction within short amounts
of time [27, 28]; these assays have been very useful in early diagnosis of infectious diarrhea.

However, since molecular tests identify the presence of DNA from microorganisms, they
cannot distinguish between live and dead bacteria. Therefore, the tests may come out as
positive even after treatment, and pathogenic colonies or normal gut flora may also lead to
positive results. For these reasons, clinical situations should be considered when interpreting
the results. Further research is also required on the cost-effectiveness and South Korean data
on the utility of panel-based multiplex molecular analysis.

KQ2-2. Is stool leukocyte or lactoferrin test helpful in clinical diagnosis of acute infectious diarrhea in adults?
Recommendation Grade of Level of
recommendation evidence
1 Stool leukocyte or lactoferrin test is not recommended in identifying the cause of acute infectious diarrhea. Strong Moderate

Most acute inflammatory diarrhea is caused by Campylobacter, C. difficile, enterohemorrhagic E.


coli (EHEC hereafter), EIEC, Salmonella, Shigella, and Yersinia, and non-inflammatory diarrhea
is caused by Clostridium food poisoning, ETEC, Staphylococcus, Vibrio cholerae, viruses (norovirus
and rotavirus), and parasites (Giardia and Cryptosporidium) [8]. Most pathogens causing non-
inflammatory diarrhea cause diarrhea through toxins but do not cause inflammation in
intestinal mucosa; therefore, leukocytes or occult blood is rarely found in stool. Although
stool leukocyte or lactoferrin test is not widely used in acute diarrhea patients in Korea, they
are screening tests used for diagnosis of intestinal inflammation abroad. Since neutrophils in
stool denature with time, the tests should be conducted in a timely manner. If stool leukocyte

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test is positive, it is highly likely that the diarrhea is of inflammatory origin, and the test is
often negative in viral, parasitic, or toxin-caused diarrhea. However, stool leukocytes are
only occasionally observed in inflammatory diarrhea, are not uniformly distributed, and
have limited sensitivity. Moreover, although stool smears are used for differential diagnosis
of invasive infections, the smears often result in false positives or negatives. Lactoferrin
does not denature during transport or pre-processing and can thus be used as an alternative
marker to stool leukocytes. However, since lactoferrin is also present in inflammatory
enteritis of non-infectious etiologies, differential diagnosis from infectious inflammatory
diarrhea is necessary [29], and it is not used commonly in clinical laboratories.

KQ2-3. Are laboratory tests (CBC, chemistry, serology, culture) helpful in diagnosing acute infectious diarrhea or predicting
complications?
Recommendation Grade of Level of
recommendation evidence
1 Blood cultures are helpful in diagnosing patients with suspected infectious diarrhea in the following cases: Strong Moderate
① septic findings, ② suspected enteric fever, ③ systemic infectious symptoms, ④ immune-suppressed
patients, ⑤ high-risk situations, such as hemolytic anemia, ⑥ patients with fever of unclear etiology who have
travel history to areas with endemic enteric fever or contact history with individuals who traveled to an area
with endemic enteric fever.
2 Widal test is not recommended for diagnosis of pathogens causing enteric fever Strong Moderate
3 If infectious diarrhea is suspected, total white cell count and differential count may be helpful in determining Weak Low
whether it is bacterial.
4 Repeat hemoglobin, platelet count, electrolytes, blood urea nitrogen/creatinine to detect early findings of Strong High
hemolytic uremic syndrome or renal damage may help in predicting complications in patients infected with
E. coli 0157 or other STEC. Moreover, peripheral blood smear to confirm RBC fragments is helpful when the
hemolytic uremic syndrome is suspected.

When infectious diarrhea is suspected, blood culture may be helpful in identifying the
pathogen in patients with septic findings, patients with suspected enteric fever, and
suppressed patients with fever [30, 31]. Non-typhoidal Salmonella, Campylobacter, Shigella,
Listeria, non-cholera Vibrio, and Yersinia may cause invasive infections and infectious diarrhea
in many immune-suppressed patients, and blood culture may be employed to identify
the pathogen and test for antibiotic sensitivity [32-36]. In order to confirm bacteremia,
cultures of blood samples drawn from different sites should be conducted in 2-3 repeats. It
is advisable to collect 20ml of samples, and the cultures should be done prior to antibiotic
use [37]. Recently developed automated blood culture instruments, such as BacT/ALERT 3D
automated microbial detection system, perform automated reads of each culture bottle at
regular, short intervals to generate rapid test results; these instruments also have very high
sensitivity at 95 - 98%.

The Widal test detects agglutinin, which responds to Salmonella O (somatic) antigens and
H (flagella) antigens, for rapid serological diagnosis of enteric fever. Since it is cheap
and simple, it was widely used previously, but it is no longer recommended due to its
low specificity and sensitivity to enteric fever [30, 38]. The Widal test results should be
interpreted upon consideration of the past history of enteric fever, vaccination history,
and antigen levels in healthy individuals in community [39]. Increased vaccination against
enteric fever and other infections by S. enterica may decrease the specificity of Widal test,
and cross-reaction may also be observed in non-Salmonella infections (e.g., malaria, dengue
fever, and brucellosis) in areas with endemics of enteric fever [38, 40]. There also are
significant deviations in agglutinin levels in healthy populations in community; this is
because the level may change with time and vary depending on how endemic enteric fever
is in a given area [30].

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Peripheral total and differential white cell count may be helpful in diagnosing whether
infectious diarrhea is of bacterial, viral, or parasitic etiology. When infectious diarrhea is
caused by bacteria, total leukocyte and neutrophil count often increase. In bacterial sepsis,
total leukocyte and platelet count may decrease below the normal range. The leukemoid
reaction may be observed in shigellosis. If infectious diarrhea is of viral etiology, the
total white cell count may be within normal range with increases in lymphocyte fraction,
and eosinophil count may increase in parasitic infections. Monocytes may increase in
intracellular pathogenic infections such as Salmonella infections.

Since hemolytic uremic syndrome arises with time in infectious diarrhea, single complete
blood count (CBC) is not enough for evaluation of its risks. Hemoglobin levels close to
normal ranges may indicate dehydration. If platelet count decreases for 1 - 14 days from
the onset of diarrhea, the risk of hemolytic uremic syndrome increases. If platelet count
increases or stabilizes in patients in recovery, CBC monitoring can be discontinued. Patients
with increasing serum creatinine, blood pressure, and body fluid volume should be closely
monitored, and treatment for acute renal failure should be considered [41].

KQ2-4. Is computed tomography (CT) helpful in diagnosing or predicting complications of acute infectious diarrhea?
Recommendation Grade of Level of
recommendation evidence
1 CT may be helpful in diagnosing complications, such as aortitis, infectious aneurysm, peritonitis, intestinal Weak Low
perforation, and toxic megacolon, when fever continues despite appropriate antibiotic treatment in elderly
patients with invasive Salmonella enterica or Yersinia infections or when patients have atherosclerosis.
2 CT may be helpful in differential diagnosis of acute infectious diarrhea and non-infectious diarrhea. Weak Low

Although aortitis and infectious aneurysm are very rare, they often have unfavorable prognosis
and are caused by Gram-positive bacteria including Staphylococcus, Enterococcus, and Streptococcus
pneumoniae. However, they also may occur as complications of acute infectious diarrhea;
Salmonella infections may lead to abdominal aortitis, and the incidence is high in individuals
at high risks of atherosclerosis. CT enables rapid diagnosis of aortitis, aortic dissection,
and hematoma of vascular walls [42]. Yersinia infection may cause complications, including
bacteremia, mesenteric lymphadenitis, endocarditis, and infectious aneurysm, and these
complications are common in patients with diabetes, chronic liver disease, poor nutrition status,
and tumor, as well as in elderly patients. When bacteria are identified in blood cultures, CT may
be helpful in diagnosis of aortitis [35, 43]. Infectious abdominal aneurysm has been reported
following Campylobacter infection, particularly Campylobacter fetus infection. Although this is a very
rare condition, there is a high risk of rupture. Therefore, early diagnosis is very important for
prognosis, and surgical treatment is necessary along with antibiotic treatment [44].

Acute diarrhea may also be present in inflammatory bowel diseases and ischemic enteritis,
and CT may help in the differential diagnosis of these. On radiological findings, hyperplasia of
bowel walls may lead to ‘empty lumen sign’ in infectious diarrhea, as well as relatively less ‘fat
stranding’ compared to inflammatory bowel disease or ischemic enteritis. ‘Fat stranding’, ‘comb’
sign, fistula, or abscess may be found in inflammatory bowel diseases. Ischemic enteritis often
invades the sigmoid colon or splenic flexure, and mesenteric infiltration is a major radiological
finding. These CT findings may help in differential diagnosis of the cause of acute diarrhea [45].
Different changes in the intestinal wall thickness caused by inflammation may be observed
depending on the cause. If the infection invades the small intestine, the intestinal wall may be
normal on CT or may only show mild edema. Infection by E. coli O157 or enteritis caused by C.
difficile infection is characterized by severe hyperplasia of colon wall on CT [46-48].

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KQ2-5. Is endoscopy helpful in diagnosis of infectious diarrhea?


Recommendation Grade of Level of
recommendation evidence
1 Endoscopy is not recommended in most acute and chronic infectious diarrhea patients. Strong Very
Low
2 Endoscopy or sigmoidoscopy should be considered in acute diarrhea patients without improvement, in Strong Low
persistent unexplained diarrhea in acquired immune deficiency syndrome patients, persistent diarrhea in
patients who have anal sexual intercourse, and persistent diarrhea in patients with recent travel history.
3 Duodenal aspiration may be considered when Giardia, Strongyloides, Cystoisospora, or Microsporidia infection Weak Low
is suspected.

Although acute infectious diarrhea is common in healthy individuals, most cases do not
require tests or treatment as they recover spontaneously within short period. Likewise,
endoscopy to evaluate the cause of diarrhea is also not recommended [49]. Diarrhea is
categorized into acute (less than 14 days), persistent (14 - 29 days), and chronic (30 days
or longer) [50], and endoscopy is recommended for acute diarrhea without improvement,
persistent diarrhea of unclear etiology in AIDS patients, and persistent diarrhea associated
with anal sexual intercourse [29]. Endoscopy may also be helpful in persistent diarrhea after
traveling to tropical or subtropical regions.

Sigmoidoscopy is sufficient for differential diagnosis of acute diarrhea. Although


colonoscopy does not play a significant role in the diagnosis of acute infectious diarrhea and
is thus not recommended, it may be considered if other conditions, such as colon cancer,
are suspected. Even when colonoscopy is used, strong laxatives should be avoided whenever
possible, and the test should be done with light enema. Endoscopy may be used to confirm
inflammation state of colon mucosa and to differentially diagnose various types of enteritis
through biopsy at different sites [51, 52]; endoscopy is particularly useful in diagnosis of
CMV enteritis and C. difficile enteritis [53]. Moreover, intestinal juice may be aspirated during
endoscopy to obtain useful information for differential diagnosis of enteritis. A previous
study reported that bacterial culture of intestinal juice aspirated during endoscopy and stool
culture had a 91.2% concordance rate, thus suggesting that intestinal juice aspiration may be
useful in the diagnosis [54]. In general, endoscopy is more useful for differential diagnosis of
chronic diarrhea than acute diarrhea, and it is particularly helpful for diagnosis of Giardiasis,
celiac disease, Crohn's disease, Whipple's disease, and eosinophilic gastroenteritis [53].
Since acute infectious diarrhea is mostly caused by lower gastrointestinal tract infections,
gastroscopy is not recommended for this; however, gastroscopy may still be useful for a
subset of patients. If trophozoite is found in duodenal biopsy and aspiration, Giardiasis can
be diagnosed [55, 56], and duodenal aspiration is also useful for suspected Strongyloides,
Cystoisospora, or Microsporidia infection [57].

KQ3. What are indications for empirical antibiotic therapy for acute infectious diarrhea and which antibiotics should be used?
Recommendation Grade of Level of
recommendation evidence
1 In general, antibiotic treatment is not recommended for most cases of acute watery diarrhea. Strong Low
2 Empirical antibiotic therapy can be considered in the following cases: ① If bloody or mucoid stool and fever, ① Weak ① Expert opinion
or Shigellosis symptoms (frequent scant bloody stools, fever, cramping abdominal pain, and tenesmus) are ② Low ① Low
present and ② in traveler's diarrhea accompanied by high fever above 38.5℃ or septic findings.
3 Antibiotic treatment is recommended for immune-suppressed patients with bloody diarrhea. Strong Low
4 For empirical antibiotic therapy, use fluoroquinolone antibiotics or azithromycin upon consideration of distribution Strong High
and antibiotic sensitivity of pathogens in local communities or areas where the patient traveled.
5 Rifaximin may be used for suspected infection with non-invasive bacteria without bloody diarrhea. Low Low
6 The use of antibiotics is not recommended for patients with suspected STEC infections. Strong Moderate

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Acute watery diarrhea is often viral in etiology (norovirus, rotavirus, and adenovirus). Even
when bacterial in etiology, the symptoms often improve spontaneously without treatment, and
treatment does not necessarily shorten the duration of symptoms. Considering the side effects
and cost of antibiotics as well as antibiotic resistance, antibiotic treatment does not offer much
benefit [58]. Therefore, antibiotic treatment is not recommended with the exception of special
cases, including immune-suppressed patients. Diarrhea can be classified as mild, moderate,
and severe. Mild diarrhea is defined as bearable and is characterized by three or less loose bowel
movements per day; patients can still travel or engage in other activities as scheduled. Moderate
diarrhea is characterized by four or more bowel movements per day, and patients travel or activity
plans are interfered by diarrhea. Severe diarrhea is defined as six or more bowel movements per
day, and it interferes with daily activities and prevents planned trips or other activities. All bloody
diarrhea is defined as severe [59]. When empirical antibiotic therapy was used for moderate
traveler's diarrhea, the treatment was found to decrease the duration of diarrhea by 1.5 days on
average [58, 60, 61], and by 16 - 30 hours for severe traveler's diarrhea [58].

Salmonella, Campylobacter, Shigella, and STEC are the most common pathogenic bacteria
causing acute bloody diarrhea. Multiple randomized controlled studies demonstrated that
empirical antibiotic therapy in these patients lead to 1-day reduction in the duration of
symptoms compared to placebo treatment. However, antibiotic treatment increases the time
for excretion of Salmonella, and can also cause the excretion of fluoroquinolone-resistant
Campylobacter. Therefore, considering the benefits and risks of treatment, empirical antibiotic
therapy is not recommended for most patients except immune-suppressed patients and
those with severe infections. Although no evidence supporting that antibiotic use is clearly
beneficial could be found, this guideline considered clinical environment in South Korea as
well as expert opinions for the following recommendation: antibiotic use can be considered
if bloody or mucoid stool and fever, or Shigellosis symptoms (frequent scant bloody diarrhea
fever, cramping abdominal pain, and tenesmus) are present and in traveler's diarrhea
accompanied by high fever above 38.5°C or septic findings (Fig. 2).

Selection of antibiotics for empirical antibiotic therapy of acute infectious diarrhea should
consider the distribution and antibiotic sensitivity of pathogens in local communities or areas
where the patient traveled. Although fluoroquinolone antibiotics, including ciprofloxacin
and levofloxacin, have been recommended for first-line therapy, resistance against these
antibiotics has increased recently. Moreover, fluoroquinolone antibiotics have risks of serious
side effects, such as ligament inflammation, ligament rupture, peripheral neuropathy, and
central nervous system side effects, and thus require caution.

In some areas, macrolides, such as azithromycin, is recommended due to increased


resistance of Campylobacter to fluoroquinolone. In Europe in 2012, Campylobacter infections
were three times more common than nontyphoidal Salmonella infections [62], and
ciprofloxacin resistance of Campylobacter was reported to be as high as 44% in some European
countries [63]. Fluoroquinolone resistance of Campylobacter has also been reported to be high
in Mexico (56%) and Thailand (>92%) [64, 65]. Considering these, macrolides including
azithromycin may be considered for empirical antibiotic therapy in areas where Campylobacter
is common and has high resistance to fluoroquinolone.

According to the KCDC's analysis of 3,526 samples isolated from infectious diarrhea patients
in 2014, Salmonella species accounted for 13.5%, and Campylobacter species accounted for
6.1% [66]. Moreover, 29% (63/218) of Campylobacter have been reported to be resistant to

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Three or more loose, watery bowel movements per day


+ nausea, vomiting, abdominal pain
Test and treatment
Suspected non-infectious causes
according to causes
Suspected infectious causes

- Bloody or mucoid stool + fever Watery diarrhea


- Shigellosis symptoms
Travel history

No Yes

Severe Mild - moderate Body temperature <38.5°C - Body temperature ≥38.5°C


- Septic signs

Consider stool tests

Symptomatic treatment
Stool tests (conventional tests
± Panel-based multiplex molecular analysis)
+ consider empirical antibiotic therapy

Figure 2. Algorithm for treatment of infectious diarrhea.


- Mild: Diarrhea is bearable, and the patient is capable of travelling or other activities as planned.
- Moderate: Diarrhea interferes planned travels or other activities.
- Severe: Diarrhea interferes with daily activities and prevents planned travels or other activities.

fluoroquinolones although this report was made from a single institution [67]. Therefore, the
percentage of Campylobacter and increase in fluoroquinolone resistance should be considered
in infectious diarrhea in South Korea, and the use of macrolides, such as azithromycin,
should also be considered.

Since rifaximin is a non-absorbable rifamycin derivative, it is relatively safe. It shortened the


duration of symptoms compared to placebo in a randomized controlled trial [68], and its
effects were comparable to those of fluoroquinolones [69, 70]. Rifaximin is often effective
against E. coli and less effective against invasive bacteria, such as Campylobacter, Salmonella,
and Shigella. In particular, resistance is an issue in Campylobacter. Therefore, rifaximin is not
recommended in areas where invasive bacteria are common or in patients with suspected
infection with invasive bacteria (bloody diarrhea) (Table 5).

Table 5. Empirical antibiotics in acute infectious diarrhea


Antibiotic Dose Duration
Ciprofloxacin 500 mg PO twice daily or 3 days
500 mg PO once daily 3 days
750 mg PO Single dose
Levofloxacin 500 mg PO 3 days
Azithromycin 500 mg PO 3 days
1,000 mg PO Single dose
Rifaximin 200 mg PO three times daily 3 days
PO, per os.

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In studies employing animal models and in vitro models of STEC infection, fluoroquinolone
and trimethoprim-sulfamethoxazole (TMP/SMX) antibiotics were associated with increased
secretion of Shiga toxin, but fosfomycin, azithromycin, and rifaximin did not increase
the excretion of Shiga toxin [71-73]. Recent meta-analyses of STEC patients did not show
a significant correlation between antibiotic use and hemolytic uremic syndrome [74,
75]. However, when the analysis was repeated only on studies with low risk of bias and
appropriate definition of the hemolytic uremic syndrome, the risk of hemolytic uremic
syndrome doubled when antibiotics were used [75]. Therefore, the use of antibiotics is not
recommended for patients with suspected or confirmed STEC infections.

For empirical antibiotic therapy, single administration or three-day regimen is recommended


for most uncomplicated cases. However, a previous study suggested that five-day regimen,
rather than single administration or three-day regimen, is more effective in gastroenteritis
caused by Shigella dysenteriae [76].

KQ4. How should antibiotics be modified when the bacterial strain causing acute infectious diarrhea is identified?
Recommendation Grade of Level of
recommendation evidence
1 When the bacteria and antimicrobial susceptibility results are identified, antibiotics should be modified Strong High
accordingly.
2 For infectious diarrhea caused by Campylobacter, the use of azithromycin is recommended. Strong High
3 For nontyphoidal salmonellosis, antibiotic treatment is not recommended with the exception of infants less Weak Low
than 3 months of age, patients over 50 with suspected atherosclerosis, immune-suppressed patients, patients
with valvulopathy, and patients with significant joint diseases.
4 Azithromycin, ciprofloxacin, or ceftriaxone is recommended for shigellosis. Strong High
5 Doxycycline is recommended for Vibrio cholerae infections, and ciprofloxacin, azithromycin, and ceftriaxone Strong High
may also be used.

Although multiple randomized controlled trials showed significant decreases in the duration
of symptoms of Campylobacter gastroenteritis with antibiotic treatment, the degree of
significance was not great. A meta-analysis showed that treatment with fluoroquinolone or
macrolide shortened the duration of symptoms by 1.32 days [77]. Azithromycin was more
effective in decreasing the excretion of bacteria than ciprofloxacin in diarrhea observed in
American soldiers deployed to Thailand; this finding seems to have been related to the high
Campylobacter prevalence and fluoroquinolone resistance in the area [78]. Since antibiotic use
increases recurrence and prolongs bacterial excretion in nontyphoidal salmonellosis, it is not
recommended in most cases [79]. According to a randomized controlled trial on pediatric
patients with Salmonella enteritis, bacteriological recurrence was observed in 53% of cases
treated with ampicillin or amoxicillin, but no recurrence was found in the placebo control
group. Moreover, 38% of patients with bacteriological recurrence had symptomatic recurrence
[79]. This seems to be because antibiotic treatment in this population of patients damages
the gut flora. In a meta-analysis on 767 patients in 12 studies, antibiotic treatment did not
yield significant benefit in symptomatic improvement and duration in adult nontyphoidal
salmonellosis patients who were otherwise healthy [80]. In cases where there is a high risk
of bacteremia or high risks of complications from gastrointestinal infection, antibiotics may
be used. When the KCDC analyzed 219 bacterial strains of nontyphoidal Salmonella clinically
isolated between 2006 and 2008, the resistance to ampicillin, nalidixic acid, ciprofloxacin, and
TMP/SMX was 49%, 50%, <1%, and 8%, respectively. The use of azithromycin, ciprofloxacin,
or ceftriaxone is recommended for shigellosis. Although TMP/SMX or ampicillin may be used
when isolated bacteria are sensitive, a Korean study reported a high resistance rate. In 67
strains of Shigella sonnei isolated in Jeollanam-do in 1999 - 2000, the resistance to trimethoprim,

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Guideline for the Antibiotic Use in Acute Gastroenteritis

sulfonamide, nalidixic acid, and ampicillin was 100%, 99%, 70%, and 49%, respectively, but no
resistance to cefotaxime or ciprofloxacin was observed [81] (Table 6).

Table 6. Recommended antibiotics by pathogen


Pathogen First-line antibiotics Second-line antibiotics
Campylobacter Azithromycin Ciprofloxacinb
Non-typhoidal Salmonella Usually not indicateda NA
Salmonella enterica Typhi or Ceftriaxone or ciprofloxacin Ampicillinb, TMP/SMXb, or azithromycin
Paratyphi
Shigella Azithromycin, ciprofloxacinb, or TMP/SMXb or ampicillinb
ceftriaxone
Vibrio cholerae Doxycycline Ciprofloxacin, azithromycin, or ceftriaxone
Non-choleraic Vibrio Noninvasive disease: usually not Noninvasive disease: usually not indicated
indicated
Invasive disease: ceftriaxone + Invasive disease: TMP/SMX +
doxycycline aminoglycoside
a
Ceftriaxone, ciprofloxacin, TMP/SMX, or amoxicillin may be used when there is a risk of invasive infections.
b
Has a high risk of resistance in South Korea and may be used based on sensitivity test results. Caution is required
when sensitivity is unknown (e.g., only positive PCR results).
NA, not available; TMP/SMX, trimethoprim-sulfamethoxazole.

KQ5. Do anti-diarrheal agents decrease the duration of symptoms in acute infectious diarrhea?
Recommendation Grade of Level of
recommendation evidence
1 Bismuth subsalicylates provide symptomatic improvement by regulating the amount of stool in mild or Strong High
moderate acute diarrhea.
2 Loperamide is helpful in shortening the duration of symptoms of acute watery diarrhea in otherwise healthy adults. Weak Moderate
3 Loperamide should not be used for children below the age of 18. Strong Moderate
4 Loperamide should be avoided when there is a possibility of toxic megacolon or when fever continues. Strong Low
5 Loperamide may improve symptoms in traveler's diarrhea with appropriate antibiotic treatment. Strong Moderate

Antidiarrheal agents include intestinal motility inhibitors, adsorbents, and intestinal


secretion inhibitors. Intestinal secretion or motility inhibitors may be helpful in decreasing
the frequency or duration of diarrhea for symptomatic improvement of acute infectious
diarrhea patients with moderate symptoms [82].

Bismuth subsalicylates, which are intestinal secretion inhibitors, decrease the frequency
of diarrhea and improve nausea and abdominal pain within 24 hours of treatment in acute
diarrhea patients. They are effective in improving the symptoms of traveler's diarrhea and
are particularly helpful in preventing symptoms in ETEC enteritis [83, 84]. Coformulations
with bismuth subnitrate are available in Korea for acute diarrhea patients. Racecadotril is
an enkephalinase-specific inhibitor, which is a secretion inhibitor that decreases diarrhea
without influence on intestinal motility. It is effective in diarrhea in pediatric patients and
had similar effects as loperamide in acute diarrhea in adults [85-87].

Loperamide inhibits intestinal motility to decrease the movement of intestinal contents and
promote the absorption, thereby decreasing diarrhea. It also suppresses the secretion of
intestinal mucosal secretion, which contributes to decreasing diarrhea [88, 89]. It shortens the
duration by 1 day, and decreases amount and frequency of watery diarrhea in otherwise healthy
adults. Meta-analyses have reported that side effects outweigh treatment effects in pediatric
patients, especially those younger than 3, patients with poor nutrition, patients with moderate
or severe dehydration, patients with systemic symptoms, and patients with bloody diarrhea.
Side effects include intestinal obstruction, abdominal distension, lethargy, and even death
[90]. Loperamide may be used with antibiotics for fast symptomatic improvement of traveler's

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Guideline for the Antibiotic Use in Acute Gastroenteritis

diarrhea. Although the treatment effects are not clear, it helps to decrease the symptoms and
is known to be relatively safe with few reports of side effects. When a meta-analysis compared
single use of antibiotics and combined use of loperamide (4 mg administration initially,
additional administration of 2 mg with each episode of diarrhea, up to 16 mg per day), clinical
improvement was greater in the combined treatment group 24 hours after the start of treatment,
and the duration of diarrhea was also shorter in the combined treatment group after treatment.
The treatment failure rate was also lower in the combined treatment group. In terms of the
safety, the two groups did not differ significantly without any major side effects. When the
effects of loperamide in traveler's diarrhea was compared to those of bismuth subsalicylates, the
effects were greater in the group receiving loperamide, and there was no significant difference
in side effects [61, 91, 92]. When loperamide is used in acute diarrhea, constipation may
arise. When used in severe intestinal inflammation, megacolon can arise, and the duration
of symptoms may increase. Therefore, the use of loperamide should be avoided when there
is a possibility of megacolon or when fever persists from severe inflammatory responses. In
particular, for enteritis caused by C. difficile or C. perfringens, loperamide should not be used as it
may lead to toxic megacolon or intestinal expansion. The side effects were more common when
loperamide was used on its own without appropriate antibiotic treatment [93-95].

Adsorbents, such as kaolin, pectin, charcoal, and attapulgite, do not decrease the frequency
or duration of diarrhea and, thus, are not recommended in infectious diarrhea [96, 97].

KQ6. Do probiotics decrease the duration of symptoms in acute infectious diarrhea?


Recommendation Grade of Level of
recommendation evidence
1 Probiotics decrease the symptoms and duration of acute infectious diarrhea in otherwise healthy adult and Weak Moderate
pediatric patients.
2 Probiotics are not recommended to prevent traveler's diarrhea. Weak Low

The World Health Organization defined probiotics as live microorganisms that are beneficial
for the host when administered in adequate amounts [98]. Theoretically, the administration of
beneficial bacteria in acute infectious diarrhea suppresses the proliferation of harmful bacteria
and thus treats or prevents acute infectious diarrhea. Many studies have been conducted on
probiotics in pediatric patients with acute bacterial diarrhea, and most studies found that
probiotics were effective in decreasing the duration and frequency of acute infectious diarrhea
[98, 99]. In a Cochrane analysis of 63 studies on 8,014 patients with acute infectious diarrhea,
most of whom were pediatric patients, the groups receiving probiotics had diarrhea for one day
less on average compared to control groups, and the frequency of bowel movements on day 2 of
administration was 0.8/day less in the probiotics groups than in the control groups. Lactobacillus
GG and Saccharomyces boulardii were the most commonly used probiotics in these studies [100].
However, since less studies have been conducted on adult patients than on pediatric patients with
acute infectious diarrhea, it is difficult to draw conclusion on the effects in adults. Moreover, as
many probiotics studies had different definition of diarrhea, cause of diarrhea, interpretation of
results, methods, and probiotic strains, it is difficult to compare their effects [101]. According to
research conducted on adults, when Enterococcus SF 68 was administered per os in 211 patients,
the duration of diarrhea was 1.69 days in the group receiving the treatment and 2.81 days in the
control group. At day 4 of treatment, diarrhea resolved in all patients in the treatment group
whereas it persisted in 15.2% of patients in the control group; in other words, probiotics were
found to decrease the duration of acute infectious diarrhea [102]. Similarly, when Enterococcus SF 68
was administered in 123 adult patients with acute diarrhea, diarrhea improved in 87.2% of patients

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Guideline for the Antibiotic Use in Acute Gastroenteritis

in the treatment group on day 4 of treatment, compared to 59.5% improvement observed in the
control group, and no side effects of probiotics were reported [103]. However, Mitra AK et al.
administered enterococcus SF 68 to 183 acute bacterial diarrhea patients for 3 days and observed
no decrease in the duration and frequency of bowel movement [104]. Although probiotics have
been covered by the public health insurance in South Korea for pediatric patients with acute
infectious diarrhea, antibiotic-associated diarrhea, and necrotizing enteritis since 2011, the
same coverage does not apply for adults (notice number 2011-74). Probiotics are known to be safe
with very little side effects, but caution is still required as cases of fungemia or bacteremia from
probiotics have been reported in immune-suppressed patients [105].

It is difficult to conclude that certain probiotic strains are superior to others in acute
infectious diarrhea. Since the effects of probiotics are strain-specific, it is also difficult to
apply the findings of a study to other closely related species [106]. Moreover, research on
dose-dependent effects is lacking, and the results indicated no correlation between dose and
treatment effects [107]. However, in five out of six studies where different doses of probiotics
were administered, dose-dependent increases in probiotics in stool were observed, indicating
a recovery in stool [107]. Research is also lacking in comparison of single and combined
therapy in acute infectious diarrhea [108].

Although research has been conducted to evaluate acute infectious diarrhea in adults in
the context of recent travels, it is difficult to interpret the results due to different research
environments, variability in probiotic strains, and short follow-up duration [12]. Moreover,
two meta-analyses showed preventive efficacy against traveler's diarrhea, the prophylactic use
of probiotics is not recommended due to insufficient evidence [109, 110].

SUPPLEMENTARY MATERIAL
Guideline Korean version.

Supplementary material can be found with this article on-line https://icjournal.org/src/sm/


ic-51-217-s001.pdf.

Supplementary

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