THERAPY IN PRACTICE Pediatr Drugs 2003; 5 (3): 151-165

1174-5878/03/0003-0151/$30.00/0

© Adis International Limited. All rights reserved.

Treatment of Infectious Diarrhea in Children

Nure H. Alam and Hasan Ashraf
International Centre for Diarrhoeal Disease Research, Centre for Health and Population Research, Dhaka, Bangladesh

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
1.1 What is Diarrhea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
1.2 What is Dysentery/Invasive Diarrhea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
1.3 What is Not Diarrhea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
1.4 What is Persistent Diarrhea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
2. Acute Watery Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.2 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.3 Mechanisms of Watery Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.3.1 Secretory Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.3.2 Osmotic Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.4 Consequences of Watery Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
2.5 Management of Acute Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2.5.1 Prevention of Dehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2.5.2 Rehydration Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2.6 Feeding During and After Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3. Invasive Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.1 Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.2 Campylobacter Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.3 Salmonella Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.4 Amebiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.5 Escherichia coli Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4. Persistent Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.1 Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
4.2 Management of Persistent Diarrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
4.2.1 Rehydration Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
4.2.2 Antimicrobial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
4.2.3 Nutritional Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
5. Role of Drugs in the Management of Diarrheal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.1 Antimicrobial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
5.2 Antimotility Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.3 Antisecretory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.4 Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
5.5 Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
5.6 Unabsorbed Carbohydrates (Short Chain Fatty Acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
5.7 Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Abstract Diarrheal diseases remain an important cause of childhood morbidity and death in developing countries,
although diarrheal deaths have significantly declined in recent years, mostly due to successes in the implemen-
tation of oral rehydration therapy (ORT), which is the principal treatment modality.
Diarrhea may occur for varied reasons; however, most episodes of diarrhea in developing countries are
infectious in origin. Three clinical forms of diarrhea (acute watery diarrhea, invasive diarrhea, and persistent
diarrhea) have been identified to formulate a management plan. Acute diarrhea may be watery (where features
of dehydration are prominent) or dysenteric (where stools contain blood and mucus).
152 Alam & Ashraf

Rehydration therapy is the key to management of acute watery diarrhea, whereas antimicrobial agents play
a vital role in the management of acute invasive diarrhea, particularly shigellosis and amebiasis. In persistent
diarrhea, nutritional therapy, including dietary manipulations, is a very important aspect in its management, in
addition to rehydration therapy. Rehydration may be carried out either by the oral or intravenous route, depend-
ing upon the degree of dehydration. Oral rehydration salts (ORS) solution (World Health Organization formula)
is recommended for ORT. Intravenous fluid is recommended for initial management of severe dehydration due
to diarrhea, followed by ORT with ORS solution for correction of ongoing fluid losses. Antimicrobial therapy
is beneficial for cholera and shigellosis. Antiparasitic agents are indicated only if amebiasis and giardiasis are
present.
Appropriate feeding during diarrhea is recommended for nutritional recovery and to prevent bodyweight
loss. Antidiarrheal agents do not provide additional benefit in the management of infectious diarrhea. Although
some probiotics have been shown to be beneficial in the treatment of acute diarrhea due to rotavirus, their use
in the treatment of diarrhea is yet to be recommended, even in developed countries. The children of developing
countries might benefit from zinc supplementation during the diarrheal illness, but its mode of delivery and cost
effectiveness are yet to be decided.

In the early 1980s, diarrhea was the leading cause of child
mortality, accounting for 4.6 million deaths annually worldwide,
excluding China and Latin America.[1] Efforts to control diarrhea
over the past decades have been based on multiple, potentially
powerful interventions implemented more or less simultan-
eously. Oral rehydration therapy (ORT) was introduced in 1979
and rapidly became the cornerstone of the program for the control
of diarrheal diseases. Improved case management and disease
awareness over the decades have contributed significantly to the
control of diarrheal diseases, and the annual number of deaths
attributable to diarrhea among children <5 years of age has fallen
from the estimated 4.6 million in 1980 to about 1.5 million to-
day.[2]
The objective of this article is to discuss the existing guide-
lines for the management of infectious diarrhea in children, and
whether the antidiarrheal drugs tested so far have any beneficial
effect. Three clinical forms of diarrhea (acute watery diarrhea,
invasive diarrhea, and persistent diarrhea) are described under
separate headings. The role of some antidiarrheal agents tested
has also been discussed separately. To discuss other forms of
chronic diarrhea of specific etiology (e.g. celiac disease, tropical
sprue, cystic fibrosis, ulcerative colitis, Crohn’s disease, etc.) is
beyond the scope of this article and readers may refer to the lit-
erature to obtain further information on these specific areas.
1. Definition
fed, may normally pass as many as 8–10 semi-formed stools daily
that do not constitute diarrhea. Again, a recent change in charac-
ter of stools should be given adequate attention in recognition of
diarrhea.
1.2 What is Dysentery/Invasive Diarrhea?
Dysentery is usually defined as diarrhea characterized by the
presence of visible blood in the stools, which is usually associated
with abdominal cramps and fever. Gross blood in stools is the
most reliable sign; its presence facilitates early recognition by
mothers and health workers, and identifies a clinically severe
form of the disease, although many cases of invasive diarrhea
may not present with visible blood, particularly in young infants.
In such cases, stool microscopy would disclose the invasive na-
ture of the illness through the presence of pus cells, erythrocytes,
and macrophages.
1.3 What is Not Diarrhea?
The following are often erroneously considered to be diar-
rhea: (i) passage of frequent formed stools; (ii) passage of pasty
stools in a breast-fed infant; (iii) passage of a stool during or
immediately after feeding due to initiation of gastro-colic reflex;
and (iv) passage of frequent, loose greenish yellow stools on the
third and fourth days of life.

1.4 What is Persistent Diarrhea?

1.1 What is Diarrhea?
Diarrhea is defined as the passage of three or more abnor-
mally loose or watery stools per 24 hours. However, recent
change in consistency and character of the stools is more impor-
tant rather than the number of stools. During the initial 2–3
months of life, infants, particularly those who are being breast-
Most episodes of acute diarrhea resolve within 7 days; pro-
gressively smaller proportions persist beyond 14, 21, or 28 days.
The delineation of persistent diarrhea as a subgroup distinct from
acute diarrhea is, as such, arbitrary. The most commonly used
clinical definition is an acute episode of presumed infectious eti-
ology that lasts for more than 14 days. The 14-day cut-off for

© Adis International Limited. All rights reserved. Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea
defining persistent diarrhea, although arbitrary, is supported by
observations of a significantly high fatality rate when diarrhea
extends for ≥2 weeks. Persistent diarrhea is usually described in
children <5 years of age, and excludes specific disease entities
with known pathophysiology, such as celiac disease, tropical
sprue, cystic fibrosis, Crohn’s disease, ulcerative colitis etc.
2. Acute Watery Diarrhea
2.1 Pathophysiology
The human intestine (both large and small) is a tube within
which a large amount of water and electrolytes is delivered (in
the form of drinks and through secretion); however, most of this
is absorbed by processes of transport and exchange. Normally,
absorption and secretion of water and electrolytes occur through-
out the intestine. In a healthy adult, about 9 liters of fluid enters
the lumen of the small intestine everyday; about 2 liters ingested
by mouth and 7 liters secreted as salivary, gastric, pancreatico-
biliary, and intestinal secretions. In the small intestine, water and
electrolytes are simultaneously absorbed by the villus cells and
secreted by the crypt cells of the intestinal epithelium, resulting
in a bi-directional flow of water and electrolytes between the
intestinal lumen and the blood. Since fluid absorption is normally
greater than secretion, the net result is fluid absorption. Any
change in the bi-directional flow of water and electrolytes in the
small intestine (i.e. decreased absorption, increased secretion, or
both) results in either reduced net absorption or actual net secre-
tion, causing an increased volume of fluid entering the colon. The
capacity of the small intestine to absorb a balanced electrolyte
solution is about 18 liters, and that of a normal colon is 3.8 liters
daily.[3] Glucose and other actively absorbed nonelectrolytes
stimulate small intestinal fluid absorption, but the absorptive ca-
pacity of the colon cannot be enhanced by glucose.[3] Diarrhea
ensues when the volume delivered to the large intestine exceeds
the absorptive capacity of the colon.
2.2 Etiology
The important pathogens responsible for causing watery di-
arrhea in children in developing countries include rotavirus, en-
terotoxigenic E. coli, V. cholerae 01, V. cholerae 0139, and other
noncholera vibrios. Other less common agents are: enteropatho-
genic E. coli, enteroadherent E. coli, Campylobacter jejuni and
Cryptosporidium spp. (especially in immunocompromised pa-
tients). However, children of developed countries experience di-
arrhea mainly due to viruses, especially rotavirus.[4]
© Adis International Limited. All rights reserved.
153
2.3 Mechanisms of Watery Diarrhea
2.3.1 Secretory Diarrhea
The secretory diarrheas are typically caused by Vibrio
cholerae 01, V. cholerae 0139, enterotoxigenic Escherichia coli,
and sometimes V. cholerae non-01. After passing through the
gastric acid barrier, they colonize the lower part of the small
intestine, where they produce enterotoxins. For example, after
becoming attached to the small intestine, V. cholerae 01 liberates
cholera toxin (CT). CT is a protein molecule (molecular weight
84 000 Daltons) that consists of five B-subunits arranged in a
circular fashion and linked noncovalently to the A subunit con-
taining 2 peptides, A1 and A2, linked by a disulfide bond. First,
an irreversible binding occurs between the B-subunits of the toxin
molecule and GM1 monosialogangliosides, the cell surface re-
ceptor for CT. Following this, the A subunit penetrates into the
cell membrane and the active part (A1) is split off, which in turn
stimulates the activity of the enzyme adenylate cyclase through
cleavage of nicotinamide adenine dinucleotide. This increases
cellular concentration of cyclic-AMP, which inhibits or blocks
the chloride-linked neutral sodium absorption from the intestinal
lumen by the villus cells (but not the glucose- or other carrier-
mediated sodium absorption) and directly stimulates chloride se-
cretion by the crypt cells into the intestinal lumen. The net effect
is a massive outpouring of fluid and electrolytes, resulting in
classical secretory diarrhea.[5]
2.3.2 Osmotic Diarrhea
The permeability of the small intestinal mucosa allows rapid
movement of water and electrolytes to maintain the osmotic bal-
ance between the intraluminal contents and extracellular fluid.
Presence of poorly absorbed, osmotically active substance will
cause an increase in the intraluminal osmolality, resulting in
movement of water from the extracellular fluid into the gut lu-
men, causing diarrhea. Osmotic diarrhea may occur due to inges-
tion of purgatives (e.g. magnesium sulphate), or the presence of
lactose or glucose in conditions associated with poor absorption.
Rotavirus causes patchy damage to the small intestinal epi-
thelium, resulting in blunting of the villi. This is associated with
some reduction in the activity of lactase and other disaccharid-
ases, leading to reduced absorption of carbohydrates; however,
this is of less clinical significance because a large area still re-
mains intact for absorptive function. The intestinal morphology
and absorptive capacity returns to normal within 2–3 weeks.
2.4 Consequences of Watery Diarrhea
Stools of patients with watery diarrhea contain large amounts
of sodium, chloride, potassium, and bicarbonate ions. The effects
of watery diarrhea are due to this loss of water and electrolytes.
Pediatr Drugs 2003; 5 (3)
154
Additional amounts of water and electrolytes are lost in the pre-
sence of vomiting and fever. These combined losses cause dehy-
dration, base-deficit acidosis, and potassium depletion. Dehydra-
tion is the most dangerous consequence and needs immediate
attention as it leads to hypovolemia, circulatory collapse, and
death if not efficiently managed.
2.5 Management of Acute Diarrhea
Patients with diarrhea should first be assessed quickly to
determine the nature and pattern of diarrhea, the degree of dehy-
dration (no signs of dehydration, some or severe dehydration),
and the presence of any other associated conditions, such as pneu-
monia and malnutrition, in order that appropriate treatment can
be initiated without delay.
Modified World Health Organization (WHO) guidelines (ta-
ble I) for the assessment of dehydration are presented in this
article. These guidelines, developed in a workshop, proved to be
simple, easily learnt, and were validated in two multicenter stud-
ies[6,7] of reduced osmolarity oral rehydration salts (ORS) solu-
tion. They are being practiced in the treatment center of the In-
ternational Centre for Diarrheal Disease Research, Bangladesh
(ICDDR,B).
Although most patients with infectious diarrhea can be
treated at an outpatient clinic or at home, some patients will still
need hospitalization, mainly for intravenous rehydration. There
are no established admission criteria for acute diarrhea. Thus,
indications depend on the individual expert opinion and clinical
judgment. Indications for hospitalization of children with acute
diarrhea were elaborated in a recent report.[9] Severe dehydration,
neurologic involvement, toxic state/shock, severe vomiting, and
suspected surgical disease were labeled as an absolute indication,
while neonatal age, febrile infant <6 months of age with mucus
and blood in the stools, bloody diarrhea, immunodeficiency, mal-
Table I. Clinical assessment of dehydration, as provided in the World Health Organization treatment guidelines[8]
Assessment Diagnosis
no dehydration
Diagnostic criteria No significant signs/symptoms
Signs/symptoms
Condition Normal
Eyes Normal
Mucosa Normal
Thirst Normal
Skin turgor Normal
Radial pulse Normal
Bodyweight loss 0–4%
a The patients are unable to swallow; not a refusal to drink.
© Adis International Limited. All rights reserved.
Alam & Ashraf
nutrition, and parents unable to manage the problem, were la-
beled as relative indications.
The three essential parts in the effective clinical management
of acute diarrhea are: prevention of dehydration, if the patient is
not already dehydrated; prompt rehydration therapy by oral or
intravenous fluids when dehydration is present, followed by
maintenance therapy; and maintaining the patient’s usual diet
during and after diarrhea.
2.5.1 Prevention of Dehydration
Many patients with diarrhea do not show early evidence of
dehydration during their illness. While such patients may not
require the standard ORS solution, they should drink larger quan-
tities of appropriate fluids at home to account for the ongoing
losses of fluids and electrolytes, in addition to their normal daily
requirements. Mothers should be taught how to treat diarrhea at
home by giving the child increased amounts of fluids and contin-
uing feeding, and should also be educated to recognize signs of
dehydration that should prompt them to bring their children to a
healthcare facility. In the healthcare facility, the physician must
assess the child’s need for hospital care. ORT, if initiated early
at home to prevent dehydration,[10,11] might substantially de-
crease the number of visits to treatment facilities, and also overall
deaths from diarrheal diseases. The authors refer readers to treat-
ment plan A in the WHO guidelines[8,12] for further information.
2.5.2 Rehydration Therapy
Fluids are administered to dehydrated patients with acute
diarrhea in two phases, the rehydration and maintenace phases:
Rehydration Phase
The degree of dehydration should be clinically assessed ac-
cording to the presence of symptoms and signs that reflect the
magnitude of fluid loss, which in turn forms the basis for estimat-
ing the amount of fluid to be administered. After assessment of
some dehydration severe dehydration
At least two signs/symptoms, including Criteria for ‘some dehydration’ plus one
one key (*) sign present of these key (*) signs/symptoms present
Irritable/less active* Lethargic/comatose*
Sunken
Dry
Thirsty* Unable to drink*a
Reduced*
Uncountable/absent*
5–9% ≥10%
Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea
dehydration, patients should be rehydrated using the WHO guide-
lines as follows:[8,12] plan C for patients with severe dehydration
(rapid correction with intravenous fluids); plan B for some dehy-
dration (rehydration with ORS solution at a health center); and
plan A for patients without any sign of dehydration (treatment at
home to prevent dehydration).[8,12]
Rehydration therapy can usually be carried out with an ORS
solution, the formulation of which has recently been recom-
mended by WHO and the United Nations Children’s Fund (UNI-
CEF) [sodium 75 mmol/L, potassium 20 mmol/L, chlorine 65
mmol/L, citrate 10 mmol/L, glucose 75 mmol/L, osmolarity 245
mosmol].[13] The newly recommended ORS solution is advanta-
geous because the requirement for unscheduled intravenous fluid
is significantly less, i.e. there is less ORT failure and less vomit-
ing, particularly in children with noncholera diarrhea.[13] One
disadvantage noted was the occurrence of more asymptomatic
hyponatremia, especially in cholera.
In some conditions ORT may be contraindicated, or the pa-
tients are unable to drink (e.g. painful oral condition, lethargy,
severe vomiting, paralytic ileus etc.). In such cases, intravenous
therapy is needed, initially until the dehydration is corrected. The
ORS solution can then be initiated as soon as patients are able to
drink. The vast majority of patients with diarrheal dehydration
can be treated successfully with ORT; however, success of ORT
may also depend upon the experience of the treating nurses and
physicians. ORT may not be effective in some conditions, such
as severe dehydration, high rate of purging (>10 ml/kg/h), per-
sistent vomiting (>3 times/h), inability or refusal to drink, glu-
cose malabsorption, incorrect preparation of ORS solution, and
abdominal distension (ileus).
Children with severe dehydration should initially be rehy-
drated using an appropriate intravenous fluid; 30 ml/kg of body-
weight should be administered over 1 hour in infants <1 year of
age, and 30 minutes in older children and adults.[8,12] The remain-
ing 70 ml/kg is to be infused over 5 hours in infants <1 year of
age, and 2.5 hours in older children and adults. For severely mal-
nourished children, rehydration should be slow, over 8–10 hours,
to avoid overhydration or heart failure.[14,15] Ongoing loss of fluid
in stools during this period should also be replaced.
The preferable intravenous infusion solution used in dehy-
drating diarrhea is either Ringer’s Lactate (sodium 130 mmol/L,
potassium 4 mmol/L, chlorine 109 mmol/L, lactate 28 mmol/L)[8,12]
or Cholera Saline (sodium 133 mmol/L, potassium 13 mmol/L,
chlorine 98 mmol/L, lactate 48 mmol/L)[16] where available. Nor-
mal saline (0.9% sodium chloride) can be used as a life-saving
measure when the above solutions are not available; however, in
such cases it would be important to start ORS solution as soon as
© Adis International Limited. All rights reserved.
155
the patient is able to drink; this is required for replenishment of
other important electrolytes, such as potassium and bicarbonate.
Maintenance Phase
This phase is for the replacement of ongoing losses of water
and electrolytes due to continuing diarrhea; its purpose is to pre-
vent dehydration. ORS solution is adequate for maintenance ther-
apy and the main advantage of ORS solution is that it can be used
alone to rehydrate ≥95% of patients with mild or moderate diar-
rheal dehydration.[12] In patients with severe dehydration follow-
ing rehydration with intravenous fluids, ORT should be instituted
as soon as they are able to drink. The disadvantages of intraven-
ous therapy include high cost, the need for trained personnel for
its administration, lack of availability in rural or inaccessible
areas, high risk of local or systemic infections when nonsterile
techniques or materials are used, and the chances of over- or
underhydration when too much or inadequate amount of fluid is
administered, respectively. On the other hand, ORT is effective,
simpler, less expensive, comforting to mothers and children, and
allows mothers active participation in the process of management
of their children.
2.6 Feeding During and After Diarrhea
To prevent growth faltering, good nutrition must be main-
tained, both during and after an episode of diarrhea. Maintaining
the patient’s usual diet is an integral part in the management of
patients with acute diarrhea, and there is no physiologic basis for
‘resting’ the bowel during or following a bout of acute diarrhea.
In fact, fasting during diarrhea has been shown to impair the
ability of the small intestine to absorb a variety of nutrients. Sixty
percent or more of nutrients are absorbed during acute and per-
sistent diarrhea.[17,18] Grading diet during diarrhea, starting with
one-fourth strength and gradually moving up to full strength is
unnecessary.[19] In general, the foods that should be given during
diarrhea are the same as those the child should receive when
he/she is well. It has also been observed that children breast-fed
throughout the illness, and fed soon after initial rehydration, tend
to gain more weight on recovery compared with those who are
not fed, or fed restricted amounts of food.[20] Thus, breast-feeding
should continue throughout episodes of diarrhea, and normal
feeding should be initiated as soon as initial rehydration is ac-
complished.
Children on mixed diets, e.g. cows’ milk, cooked cereal, and
vegetables, do not have increased stool output. However, those
taking only animal milk or formula may have some increase in
stool volume. Food is usually well tolerated during diarrhea, the
major exception being clinically significant intolerance of lactose
and, occasionally, protein in animal milk. This is unusual in acute
Pediatr Drugs 2003; 5 (3)
156
diarrhea, but can be a significant problem in children with per-
sistent diarrhea.
3. Invasive Diarrhea
Invasive diarrhea is caused by infection due to pathogens
having an ability to invade the mucosa of the distal small intestine
and colon, producing local and systemic inflammatory response,
with ulceration of mucosa and hemorrhage, which clinically man-
ifests as dysentery. Some invasive pathogens, such as Entamoeba
histolytica, Shigella spp., and Salmonella spp., have the ability
to invade the blood stream or may be carried by the lymphatic
system to systemic circulation to affect distant organs, e.g. liver,
spleen, central nervous system, and joints. The important patho-
gens that cause invasive diarrhea, mainly in developing countries,
include: Shigella spp., Campylobacter spp., Salmonella spp., En-
tamoeba histolytica, enteroinvasive E. coli, and enterohemorrha-
gic E. coli.[21]
3.1 Shigellosis
Shigella species are the cause of approximately 10% of acute
diarrhea in children aged 5 years or younger, but is also an im-
portant cause of diarrhea in older children and adults.[12] It is the
most common cause of dysentery (visible blood in the stool) in
developing countries. Shigella is classified under four species or
groups, each of which, with the exception of S. sonnei, has several
serotypes as follows: Group A – S. dysenteriae; Group B – S.
flexneri; Group C – S. boydii; Group D – S. sonnei. The infective
dose of Shigella is very low; only 10 bacteria may cause infection
in healthy adults. The transmission of shigellosis often occurs by
person-to-person contact, as the infective dose is low. Food- and
water-borne transmission can also occur, and the incubation per-
iod is 1–7 days. The convalescent, carrier state usually ceases
within 4 weeks of onset of the illness, even without therapy, and
a chronic carrier state extending for more than 1 year is rare.
Shigella species multiply in the small intestine where they
liberate the enterotoxin that is initially believed to be responsible
for watery diarrhea. They finally settle in the colon where they
enter and multiply into the colonic epithelium, spread to adjacent
cells, and cause cell death, leading to shallow ulcerations of the
gut. Most patients develop anorexia, fever, abdominal pain, and
tenesmus, starting a day or two after they are exposed to the
bacterium. The diarrhea is often bloody, particularly when due to
S. dysenteriae type 1 (S. shiga); however, blood may be absent
in neonates and small infants. Shigellosis generally has a self-
limited course and the diarrhea usually resolves within 5–7 days.
Severe infections with high fever may be associated with seizures
in children <2 years of age. A classical patient with shigellosis
© Adis International Limited. All rights reserved.
Alam & Ashraf
appears acutely ill, febrile, exhausted, and often has toxemia. The
abdomen is tender over the inflamed colon, or there may be dif-
fuse tenderness. The patient may present with various degrees of
rectal prolapse, which is more common in malnourished children;
third degree rectal prolapse commonly occurs in severely mal-
nourished children.[22]
Antimicrobial therapy plays a central role in the case man-
agement of shigellosis, and treatment options have changed
markedly over the years due to the increasing resistance of Shi-
gella organisms to standard antibacterials.[23] Eradication of this
invasive organism by effective therapy shortens the duration of
illness and hastens early recovery.[24,25] Of all Shigella species,
S. dysenteriae type 1 is the most virulent serotype, and the sero-
type associated with epidemics in many developing countries. It
is also the most efficient in acquiring resistance, and epidemics
are often caused by strains resistant to agents in common use for
treatment of shigellosis. Currently, most strains are resistant to
ampicillin, trimethoprim-sulfamethoxazole and, recently, nali-
dixic acid.[26,27]
3.2 Campylobacter Infections
There are many species of Campylobacter, but only some are
pathogens in humans, e.g. C. jejuni, C. coli, C. laridis, C. fetus,
C. pylori, etc.[28] Most Campylobacter-infected diarrhea illness
in humans is caused by only one species – C. jejuni. It was the
most common invasive pathogen isolated from the 2% surveil-
lance sampling during the year 2000 at the Dhaka Hospital of the
ICDDR,B - Centre for Health and Population Research (Faruque
ASG, personal communication). It is also the most common bac-
terial cause of diarrheal illness in the US.[29] The incubation per-
iod is 2–7 days, and it affects both the small and large intestine.
A very small number of Campylobacter organisms (<500) can
cause illness in humans. Most people who become ill get diar-
rhea, cramping, abdominal pain and fever within 2–5 days of
exposure to the organism. The diarrhea may be bloody, and can
be accompanied by nausea and vomiting. The illness typically
lasts 1 week. The organism produces two types of toxin: a heat
labile-like enterotoxin that activates cyclic AMP and causes fluid
secretion resulting in watery diarrhea; and a cytotoxin that causes
bloody diarrhea.
All persons infected with Campylobacter species will re-
cover without any specific treatment. In persons with compro-
mised immunity, Campylobacter occasionally spreads to the
bloodstream and may cause serious life-threatening infection. Pa-
tients should drink plenty of fluids as long as diarrhea lasts. In
more severe cases (e.g. persistent diarrhea, prolonged dysenteric
illness, severe malnutrition etc.), antibacterials such as erythro-
Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea
mycin or a fluoroquinolone can be used to shorten the duration
of symptoms if given early in the illness.
3.3 Salmonella Infections
Salmonella spp. represent a large group of organisms having
more than 40 serogroups and over 2000 serotypes, about 6–10 of
which account for salmonella gastroenteritis. Salmonella spp.
can be broadly classified as typhoidal and nontyphoidal. S. typhi
and S. paratyphi A and B cause enteric fever and are classified
under typhoidal Salmonella, while the others are collectively
called nontyphoidal Salmonella, and are responsible for gastro-
enteritis and satellite infections. Typhoid fever may or may not
be associated with diarrhea. Salmonella enteritis is common in
industrialized countries where dairy products and canned foods
are frequently consumed. Salmonella gastroenteritis usually
presents as acute watery diarrhea, cramps, and fever, and may
present as dysentery in about 5% of patients. Oral rehydration is
effective in most patients, except for those presenting with severe
dehydration who require initial intravenous rehydration.
Salmonella infections usually resolve within 5–7 days and
often do not require specific drug treatment. However, there are
conditions where antimicrobial therapy using an appropriate
agent is indicated, e.g. dysenteric presentation, infection in small
infants, hosts with compromised immunity, etc. Globally, the
strains are currently resistant to ampicillin, chloramphenicol and
trimethoprim-sulfamethoxazole.[30]
3.4 Amebiasis
Several species of the protozoan parasite of the genus Enta-
moeba infect humans, but E. histolytica is the only species known
to cause disease. The other (nonpathogenic) species are important
because they may be confused with E. histolytica in stool micro-
scopy, which is frequently applied in their diagnosis. Infection
by E. histolytica occurs by ingestion of mature cysts in food,
water, or hands contaminated with feces. Excystation occurs in
the small intestine and trophozoites are released, which then mi-
grate to the large intestine. The trophozoites multiply by binary
fission and produce cysts, which are passed in the feces. The cysts
can survive days, or even weeks, in the external environment and
are responsible for transmission. Trophozoites can also be elim-
inated in diarrheal stools, but are rapidly destroyed once outside
the body, and if ingested do not survive the passage through the
acidic gastric environment. In many patients, the trophozoites
remain confined to the intestinal lumen (noninvasive infection)
and these individuals act as asymptomatic carriers, passing cysts
in their stool. In some patients the trophozoites invade the intes-
tinal mucosa (intestinal disease) or through the bloodstream to
© Adis International Limited. All rights reserved.
157
extraintestinal sites, such as the liver[31,32] and lungs[33] (extra-
intestinal disease), with resultant pathogenic manifestations.
It has been established that the invasive and noninvasive
forms represent two separate species; E. histolytica and E. dispar,
respectively. However, not all persons infected with E. histolytica
will have invasive disease. These two species are morphologi-
cally indistinguishable. Worldwide, the incidence of amebiasis is
higher in developing countries. In industrialized countries, risk
groups include male homosexuals, travelers, recent immigrants,
and institutionalized populations. On average, only 1/10 (10%)
of people infected with E. histolytica become sick.[12] The symp-
toms are often quite mild and can include loose stools, stomach
pain, and stomach cramping. Amebic dysentery is a severe form
of amebiasis associated with blood in the stools, stomach pain,
and fever.
3.5 Escherichia coli Infection
Enteroinvasive E. coli is not a common pathogen; however,
it can cause sporadic food-borne cases and outbreaks of diarrhea
in all ages worldwide. These organisms are similar to Shigella
spp., both biochemically and serologically and, like Shigella spp.,
they are able to penetrate and multiply within the colonic epithe-
lial cells and cause dysentery.
A newly recognized enteropathogen, E. coli serotype 0157,
0111:117, is a cause of sporadic hemorrhagic colitis in North
America where improperly cooked meat has served as the major
vehicle of transmission. The illness is characterized by the onset
of acute cramps, fever and watery diarrhea that may rapidly prog-
ress to bloody diarrhea. Enterohemorrhagic E. coli produces a
cytotoxin, which is responsible for edema and diffuse bleeding
in the colon, as well as hemolytic uremic syndrome in chil-
dren.[34]
4. Persistent Diarrhea
In developing countries, children <3 years of age may have
as many as 10 diarrhea episodes per year, although a rate of 3–4
per year has been commonly reported.[35] The majority of attacks
are of relatively short duration (<7 days) and can be treated easily
and effectively by ORT, maintaining the patient’s usual diet, and
antibiotics where indicated (e.g. cholera, shigellosis). Diarrhea
sometimes lasts longer than usual; these ‘persistent’ diarrhea
cases are associated with a deterioration of nutritional status and
present a substantial risk of death. Relatively few studies have
addressed the issue of its description, treatment, and prevention,
and its reported incidence varies widely in different regions. Us-
ing the above definitions, studies in several developing countries
have observed that overall, 3–20% of acute diarrhea episodes in
Pediatr Drugs 2003; 5 (3)
158
children <5 years of age become persistent.[35] Episodes of per-
sistent diarrhea, although fewer in number than those of acute
diarrhea, are more likely to have severe consequences, such as
increased mortality and malnutrition.
4.1 Etiology and Pathophysiology
The etiology and pathogenesis of persistent diarrhea is com-
plex and multifactorial, and infective, nutritional, and allergic
factors are usually associated with its causation. There is no spe-
cific microbial cause. Most pathogens causing acute diarrhea
might also cause persistent diarrhea, with the notable exception
being V. cholerae. Bacteria that are isolated more frequently in
persistent diarrhea include enteroaggregative E. coli; however,
Cryptosporidium spp. may also be important in severely under-
nourished and/or immunodeficient children. Undernutrition de-
lays the repair of damaged intestinal epithelium, causing diarrhea
to be prolonged, which is also suggested by epidemiologic
data.[36] Allergies to animal proteins, especially cows’ milk pro-
tein, are also responsible for sustained damage to intestinal mu-
cosa and prolongation of diarrhea. It has been postulated that the
ingestion of cows’ milk protein during and after diarrhea, espe-
cially in early infancy, leads to absorption of intact protein, sen-
sitization, and secondary damage to the epithelium.[37]
Irrespective of its cause, persistent diarrhea is associated
with extensive changes in the bowel mucosa, particularly flatten-
ing of the villi and reduced production of disaccharidase en-
zymes, causing reduced absorption of nutrients and perpetuation
of the illness after elimination of the original infectious cause.
Young age (<1 year), malnutrition, and impaired cell-mediated
immunity have been identified as risk factors for the development
of persistent diarrhea in children.[35]
4.2 Management of Persistent Diarrhea
Despite the passage of several loose stools per day, the ma-
jority of patients with persistent diarrhea remain well hydrated;
such children can be treated at home. Children with persistent
diarrhea with one or more of the following features should be
treated in a hospital: <4 months of age, presence of dehydration,
severe malnutrition, and presence of systemic infection.
4.2.1 Rehydration Therapy
The principles of fluid and electrolyte replacement have been
well established for acute diarrhea and do not differ in persistent
diarrhea. The aim of treatment is to restore the initial fluid deficit
and replace ongoing stool-related fluid losses until the diarrhea
stops. In most patients this can be done with the use of standard
ORS solution. On the basis of the presence of signs of dehydra-
tion (table I), fluids should be given according to the WHO-
© Adis International Limited. All rights reserved.
Alam & Ashraf
recommended diarrhea treatment plans A, B, or C as appropri-
ate[8,12] (discussed earlier in section section 2.5.2).
4.2.2 Antimicrobial Agents
Antimicrobial agents are not usually indicated, except in
some cases of specific enteric infection, such as those that are due
to Shigella, Salmonella, and Vibrios species, where eradication
therapy is indicated in acute, as well as persistent, diarrhea. Anti-
microbial therapy is also indicated in associated nonenteric in-
fection, such as urinary tract, respiratory tract and ear infection.
Antiparasitic agents should also be prescribed for amebiasis and
giardiasis.
4.2.3 Nutritional Management
Breast-Milk
It is recommended that breast-feeding should be continued,
and even encouraged, during episodes of persistent diarrhea.
Other Foods
In prescribing other foods (to partially or fully weaned chil-
dren), the algorithmic approach recommended by WHO[38] is fol-
lowed by most treatment centers, including ICDDR,B. This be-
gins with a diet that is simple, locally available, cheap, and
culturally acceptable, and also devoid of common dietary com-
ponents that are responsible for continuing mucosal injury or
malabsorption, such as lactose and cows’ milk protein. In
ICDDR,B, a low-lactose formula (diet A – cows’ milk, sugar, and
rice powder mixture containing 67 Kcal/100ml) is used as the
initial diet for 5–7 days. If there is no improvement, a lactose and
cows’ milk protein-free diet (diet B – rice powder, egg albumin,
and glucose mixture of 70 Kcal/100ml) is initiated. A small pro-
portion (5–10%) of patients may not recover from diarrhea with
these diets, in which case a chicken-based diet is advised that is
free from cows’ milk and complex carbohydrates (diet C – minced
chicken meat, glucose, and vegetable oil mixture containing 60
Kcal/100ml). These formulations (table II) might be used by oth-
ers, or can be modified according to their local culture and the
availability of foods.
Vitamins and Minerals
All patients with persistent diarrhea should get supplemental
vitamins and minerals (retinol [vitamin A], folic acid, zinc, etc.),
at about twice the dose of the recommended daily allowance, for
2–3 weeks, to help mucosal repair and improve intestinal func-
tions, as well as to replace the existing deficiency, if any. As a
guide, one recommended daily allowance for a child aged 1 year
is folic acid 50μg, zinc 10mg, and retinol 400μg.[8,39] Other vita-
mins and minerals, including pyridoxine (vitamin B6), cyanoco-
balamin (vitamin B12), ascorbic acid (vitamin C), ergocalciferol
(vitamin D2), tocopherol (vitamin E), phytomenadione (vitamin
Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea 159

Table II. Composition of different diets for patients with persistent diarrhea K), thiamine (vitamin B1), nicotinic acid, riboflavin (vitamin
B2), calcium pantothenate, biotin, calcium, phosphorus, magne-
Diet Aa
Whole milk powder 40g sium, iron, copper, iodine, selenium, manganese, cobalt, and moly-
Rice powder 40g bdenum, at about twice the dose of the recommended daily allow-
Sugar 25g ance, should also be supplemented in persistent diarrhea.[38,40]
Oil (soya) 25g Locally available commercial preparations of vitamin/mineral
Magnesium chloride 0.5g mixture are usually suitable for use.
Potassium chloride 1g
Calcium 2g
Cooking water Approximately 850ml 5. Role of Drugs in the Management of
Volume after cooking 1000ml Diarrheal Disease
Energy 67 Kcal/100ml Since the majority of episodes of diarrhea are caused by in-
Protein 1.4 g/100ml
testinal infections, drugs capable of significantly reducing stool
Osmolality 246 mosmol/L
volume and/or frequency would be useful in the treatment of
PER 8%
infectious enteritis. Unfortunately, such drugs have not yet been
FER 47%
developed. However, the potential roles of the following categor-
Diet Ba ies of drugs in the management of diarrheal diseases deserve
Rice powder 60g
discussion: antimicrobial agents, antimotility drugs, antisecretory
Egg white 100g (four egg whites)
drugs, immunotherapy, probiotics, unabsorbed carbohydrate,
Oil (soya) 30g
Glucose 35g
other agents.
Common salt (sodium chloride) 1g
Potassium chloride 1g 5.1 Antimicrobial Agents
Magnesium chloride 0.5g
Calcium 2g Currently, the most important aspects in the management of
Cooking water Approximately 850ml diarrheal diseases include prevention and treatment of dehydra-
Volume after cooking 1000ml tion, maintaining the patient’s usual diet, and antimicrobial ther-
Energy 70 Kcal/100ml apy for specific indications, if any. In the management of infec-
Protein 1.88 g/100ml tious disease, including infective diarrhea, antimicrobial therapy
Osmolality 315 mosmol/L is indicated to meet one or more of the following objectives: reduc-
PER 10%
tion in mortality, shortening the duration of illness, to prevent/
FER 47%
reduce transmission of infection, and to prevent or reduce com-
Diet Ca plications. Besides potential advantages, there are also concerns
Chicken, minced 180g
regarding the use of antimicrobial therapy, e.g. cost of therapy,
Oil (soya) 30g
adverse effects, development of resistance, and diversion of at-
Glucose 35g
tention from other important aspects, such as ORT and maintain-
Onion 20g
ing the patient’s usual diet (this may be a special problem in the
Common salt (sodium chloride) 1g
Potassium chloride 1g
management of patients with diarrhea where other therapies may
Magnesium chloride 0.5g be more important) .
Calcium 2g Appropriate use of antimicrobial agents requires making a
Cooking water 900ml diagnosis (infectious etiology) and having a clear understanding
Volume after cooking 1000ml of the role of antimicrobial therapy in their management. How-
Energy 60 Kcal/100ml ever, an etiologic diagnosis of infectious disease requires labora-
Protein 4.5 g/100ml tory confirmation, i.e. identification of infectious agents by direct
Osmolality 272 mosmol/L visualization by simple microscopy of stained specimen, or iso-
PER 32% lation and identification by culture of body fluids or tissues, or
FER 48% by other recently developed sophisticated techniques such as
a Preparation of the diets needs standard cooking: diets A and B need
enzyme-linked immunosorbent assay and polymerase chain re-
boiling for 5–7 minutes; diet C needs cooking for 25–30 minutes.
action. As mentioned earlier, this is often not possible for various
FER = fat energy ratio; PER = protein energy ratio. reasons, including cost and the lack of reliable laboratory facili-

© Adis International Limited. All rights reserved. Pediatr Drugs 2003; 5 (3)
160
ties, including experienced technicians. Thus, empiric antimicro-
bial therapy in severe illness (suspected cholera, evidence of se-
vere colitis with toxicity, suspected sepsis, etc.) is required when
laboratory tests cannot be performed or when the results of lab-
oratory tests are awaited. It needs to be mentioned here that anti-
microbial therapy should not be delayed until availability of the
laboratory results, as the outcome of interest (resolution of dis-
ease, development of complications, or an adverse outcome) may
occur earlier than that.
Before selection of antimicrobial agents, the following fac-
tors should also be considered: proven efficacy of the antimicro-
bial agents against the etiologic agent, tolerability, availability,
cost, formulation (oral, intramuscular, intravenous, etc.), and
compliance. Assessment of the need and selection of the appro-
priate agent needs to be individualized to meet the specific re-
quirements of the patients; however, this is time consuming and
expensive, and requires well equipped laboratory facilities, sup-
ported by well experienced staff, particularly in developing coun-
tries where the magnitude of diarrheal disease is the greatest.
However, it may be possible to make some generalization when
a group of patients with similar infectious conditions, and coming
from the same community, are considered. Applications of this
method, which may not be perfect, require some knowledge and
understanding, such as prevalence and incidence of various in-
fectious agents causing diarrhea in the community, age-specific
susceptibility of the population, risk factors for infection and
death, seasonal variation in the incidences of infectious diseases,
assessment of host defense status (previous exposure, immuniza-
tion), nutritional status, and conditions that influence efficacy
and antimicrobial susceptibility of common pathogens.
Most infectious diarrheas have a self-limiting course, i.e.
they resolve over a period of time, during which supportive meas-
ures such as management of dehydration and maintaining the
patient’s usual diet are important. However, the course of the
illness and an adverse outcome may be significantly modified by
Table III. Antimicrobial treatment of cholera
Antimicrobial agent Recommended oral dosage
adults children
Tetracycline 500mg q6h for 3 days 12.5 mg/kg q6h for 3 days
Tetracycline 2.0g as a single dose, once only Not recommended
Doxycycline 300mg as a single dose, once only Not recommended
Erythromycin 500mg q6h for 3 days 12.5 mg/kg q6h for 3 days
Trimethoprim + 160mg of trimethoprim + 800mg of 5 mg/kg of trimethoprim + 25 mg/kg
sulfamethoxazole sulfamethoxazole q12h for 3 days of sulfamethoxazole q12h for 3 days
Furazolidone 100mg q6h for 3 days 1.25 mg/kg q6h for 3 days
Ciprofloxacin 1.0g as a single dose, once only Not recommended
qxh = every x hours.
© Adis International Limited. All rights reserved.
Alam & Ashraf
antimicrobial therapy for some specific etiologic diarrhea. Tak-
ing into consideration the risks and costs versus the benefits, the
WHO recommends routine use of antimicrobial agents for shigel-
losis, severe cholera, invasive intestinal amebiasis, and giardia-
sis.[8,12] Antimicrobial agents recommended for the above infec-
tious diarrheas are listed in table III and table IV.
5.2 Antimotility Drugs
The antimotility category of drugs includes the synthetic opi-
ates, such as diphenoxylate and loperamide. The mechanism of
action of these opiates is to reduce stool output, primarily by
affecting intestinal motility.
Although diphenoxylate is effective in relieving symptoms
of mild chronic diarrhea in adults, there is no clear evidence of
its usefulness in acute diarrhea in children or adults.[41] There is
evidence that the antimotility effects of diphenoxylate may actu-
ally worsen bacillary dysentery.[42] Potentially fatal adverse ef-
fects of diphenoxylate on the central nervous system are not un-
common;[43,44] therefore, there is no role for diphenoxylate in the
treatment of childhood diarrhea.
Loperamide has not been shown to reduce losses of fluid and
electrolytes in acute diarrhea.[45] The drug may have a modest effect
on the duration of diarrhea,[45] probably as a result of reduced gas-
trointestinal motility; however, this effect is dose-dependent[46,47]
and of questionable clinical importance. Abdominal distension
and potentially fatal paralytic ileus have been reported in infants
and young children treated with loperamide.[48-50] Toxic effects
on the central nervous system have most commonly been ob-
served in children <6 months of age. In conclusion, loperamide
has no place in the routine management of diarrhea in children.
5.3 Antisecretory Drugs
Of all enteric pathogens that produce acute diarrhea in hu-
mans, V. cholerae induces the most dramatic illness, and the di-
Comment
Not recommended for children <8 years of age, and
in pregnant women
Not recommended in children and pregnant women
Not recommended in children and pregnant women
Suitable for children and pregnant women
Suitable for children and pregnant women
Not recommended for children and pregnant women
Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea 161

Table IV. Antimicrobial treatment for shigellosis, amebiasis and giardiasis

Antimicrobial Recommended oral dosage Comment
agent adults children

Shigellosis
Ampicillin 500mg q6h for 5 days 25 mg/kg q6h for 5 days Can be safely used in children and pregnant women;
Shigella species are resistant in many areas
Trimethoprim + 160mg of trimethoprim + 800mg of 5 mg/kg trimethoprim + 25 mg/kg of Shigella species are resistant in many areas
sulfamethoxazole sulfamethoxazole q12h for 5 days sulfamethoxazole q12h for 5 days
Nalidixic acid 500mg q6h for 5 days 15 mg/kg q6h for 5 days Shigella dysenteriae type 1 is resistant in many areas
Pivmecillinam 400mg q6h for 5 days 15 mg/kg q6h for 5 days Can be safely used in children and pregnant women
Ceftriaxone 3g daily for 5 days 75–100 mg/kg od for 5 days Can be safely used in children and pregnant women
Ciprofloxacin 500mg q12h for 5 days Not recommended Not recommended for routine use in children and
pregnant women
Norfloxacin 800mg q12h for 5 days Not recommended Not recommended for routine use in children and
pregnant women

Amebic dysentery
Metronidazole 750mg tid for 5 days (10 days for 10 mg/kg tid for 5 days (10 days for
severe disease) severe disease)
Tinidazole 500mg od for 3 days Not recommended Not recommended for children <12 years of age

Giardiasis
Metronidazole 250mg tid for 5 days 5 mg/kg tid for 5 days
od = once daily; qxh = every x hours; tid = three times daily.

arrhea produced by this pathogen is a classical example of infec-
tive secretory diarrheas. Other noninfectious secretory diarrhea
will not be discussed in this review. The mechanism of fluid loss
in cholera has been discussed in section 2.3.2.[5] In experimental
animal studies, several drugs have been shown to have an anti-
secretory effect, some of which have been tested in patients.[51-58]
Although some have been shown to reduce stool volume, these
are not suitable for practical use because of adverse effects. Al-
though antisecretory drugs could potentially assist in the treat-
ment of patients with cholera, none have been shown to be ben-
eficial in routine clinical management to date.
Enkephalins, the endogenous opiate substances first discov-
ered in 1975, play an important physiologic role by acting as
neurotransmitters, most notably along the digestive tract where
they elicit intestinal antisecretory activity without affecting in-
testinal transit time or motility. However, activity is limited by
an enzyme (enkephalinase) present throughout the gastrointest-
inal tract. Racecadotril, an enkephalinase inhibitor, reinforces the
physiologic activity of endogenous enkephalins and shows intes-
tinal antisecretory activity without affecting the intestinal transit
time.[59-61] In addition to animal studies, some clinical studies[62-64]
have demonstrated the efficacy of racecadotril in acute noncholera
diarrhea compared with placebo and loperamide. A study was
recently conducted in adult patients with cholera to examine the
effect of racecadotril as an adjunct therapy to standard therapy
(rehydration and antimicrobial). However, the drug failed to show
any beneficial effect compared with placebo (Alam NH, unpub-
lished data).
Therefore, none of the antisecretory drugs have been recom-
mended in the routine management of acute diarrhea in children,
although racecadotril has been marketed in some countries in
Europe.
5.4 Immunotherapy
As a consequence of disappointing results from clinical trials
with various ‘antisecretory drugs’ and the absence of a suitable
rotavirus vaccine, there is scope for new approaches to address
the major global health problem of diarrhea in children. Admin-
istering hyperimmune bovine colostrums containing a very high
titer of antibodies against the pathogens presents a potentially
attractive immunologic approach to treating enteric infections.[65-67]
Although some intervention studies conducted in rotavirus-infected
diarrhea have shown positive results,[65-67] studies[68,69] in bacter-
ial diarrhea failed to prove their efficacy. Interpretation of the
mechanism of action in rotavirus diarrhea is notably speculative.
There is evidence that milk immunoglobulin concentrate neutral-
izes a very high dose of infectious rotavirus,[70] and the efficacy
has also shown to be dose- and time-dependent.[71] Hyperimmune
bovine colostrums given orally to patients infected with rotavirus
clear the rotavirus isolates that are excreted into feces earlier than
placebo.[65,66] However, more studies, including cost-effective
analysis, are required before a firm conclusion can be reached in

© Adis International Limited. All rights reserved. Pediatr Drugs 2003; 5 (3)
162
recommending use of hyperimmune bovine colostrums in the
management of diarrhea in children.
5.5 Probiotics
Probiotic is defined as a ‘live microbial food ingredient’ that
is beneficial to health. A number of health-related effects are
documented in association with probiotic therapy, such as allevi-
ation of symptoms of lactose intolerance, immune enhancement,
shortening of the duration of diarrhea, decreased mutagenicity of
intestinal contents, decreased fecal bacterial enzyme activity, and
prevention of the recurrence of superficial bladder cancer.[72] The
potential for probiotic therapy in acute infectious diarrhea has
recently been studied. A number of studies[73-76] have docu-
mented the beneficial effects of lactic acid bacteria on diarrhea,
particularly on rotavirus diarrhea. Some studies[77,78] have dem-
onstrated that ingestion of Bifidobacterium longum and Lactoba-
cillus casei strain GG reduced the duration of antibacterial-induced
diarrhea. Oral bacterial therapy reduced the stool frequency in
Pakistani children with acute, nonbloody diarrhea.[73] Similar re-
sults were also demonstrated by Isolauri et al.[74] and Shornikova
et al.[75] in the treatment of rotavirus diarrhea in Finnish children,
and Guarino et al.[76] demonstrated the reduction of duration of
diarrhea with rotavirus-positive and -negative ambulatory chil-
dren in Italy. The possible mechanism of bacterial effect of live
bacteria is augmentation of immune response.[79]
Although probiotics have been found to be beneficial in the
treatment of rotavirus diarrhea, the cost-effectiveness needs to be
defined. As it is the children of developed countries who mostly
experience rotavirus diarrhea, the use of probiotics may have
potential as an antidiarrheal agent in those countries; however,
more studies are needed before it is recommended for use as an
antidiarrheal agent in developing countries.
5.6 Unabsorbed Carbohydrates (Short Chain
Fatty Acids)
In recent years, considerable interest has been generated in
unabsorbed carbohydrates, such as dietary fibers and amylase
resistant starch, as a subject of research in health and disease. In
humans, these products are mainly fermented in the colon by the
resident bacterial flora producing short chain fatty acids
(SCFAs), such as acetate, propionate, and butyrate.[80] These
compounds serve as a metabolic fuel for the colonocytes,[81] stim-
ulate epithelial cell proliferation,[82] and exert a trophic effect on
colonic mucosa.[83] SCFAs are also absorbed through the co-
lon,[84,85] and their absorption is associated with stimulation of
sodium transport from the colon in several species, including
humans.[86-88] Thus, luminal SCFA levels in the colon may be a
© Adis International Limited. All rights reserved.
Alam & Ashraf
factor determining the clinical course of acute diarrheal dis-
eases.[89,90]
Cereal-based ORS solutions have been shown to reduce stool
volume by about 30–40% in cholera.[91] A part of the effect on
stool volume reduction might be attributed to SCFAs produced by
unabsorbed carbohydrates, including dietary fibers and amylase-
resistant starch in the colon. To improve glucose-containing
ORS, two recent studies have been conducted; one evaluating the
addition of amylase-resistant starch to WHO-ORS in the treat-
ment of adult cholera,[92] and the other[93] evaluating the addition
of soluble fibers, specifically partially hydrolyzed guar gum
(Benefiber®1) in the treatment of acute noncholera, watery diar-
rhea in children. In both studies, stool output and duration of
diarrhea were significantly reduced. In another study, Benefiber®
was added to a comminuted chicken-based diet in the treatment
of persistent diarrhea,[94] and a similar effect was observed. One
study[95] in the ICDDR,B assessed the effect of green banana- and
pectin-containing diets in the treatment of persistent diarrhea in
children. Both were found to reduce stool output, as well as the
duration of diarrhea in children with persistent diarrhea. In
Bangladesh, cooked green banana and half ripe wood apple are
traditionally used as antidiarrheal agents for hastening recovery
from diarrhea. The results of these studies support their use in the
treatment of diarrhea.
5.7 Other Agents
Zinc and folic acid, among others, are important agents con-
sidered to have antidiarrheal properties. Although these micro-
nutrients are recommended for routine use in the treatment of
persistent diarrhea,[8] their use in acute diarrhea is yet to be con-
sidered. A number of studies have evaluated the therapeutic ef-
fect of zinc supplementation in acute diarrhea and the findings
were reviewed in a recent report.[96] Zinc supplementation given
at a dosage of two recommended daily allowances per day (10–20
mg/day) for 14 days is efficacious in significantly reducing the
severity of diarrhea and duration of the episode. As the studies
were mostly carried out in developing countries, where many
children were undernourished, its use can only be recommended
in developing countries. The therapeutic effect of folic acid has
also been evaluated in the treatment of acute diarrhea in children.
Although some previous studies[97,98] have shown its beneficial
effect, a recent well designed study[99] failed to show any effect.
1 The use of tradenames is for product identification purposes only and
does not imply endorsement.
Pediatr Drugs 2003; 5 (3)
Treatment of Infectious Diarrhea
6. Conclusions
The management of dehydration (prevention and treatment)
and maintaining the patient’s usual diet during and after diarrhea
remain the mainstay in the management of diarrheal diseases,
irrespective of etiology, while antimicrobial therapy is indicated
for specific etiologic diarrheas. Antidiarrheal drugs, although
commonly used, have not been seen to provide any practical ben-
efit and most of them are contraindicated, particularly for use in
children.
While probiotics have potential as antidiarrheal agents in the
treatment of children in developed countries, zinc might be rec-
ommended for children in developing countries who have diar-
rhea. However, efforts should continue in search of effective,
well tolerated, and cheap antidiarrheal drugs.
For better management of diarrhea in children, every treat-
ment center can formulate their own treatment protocol according
to their needs, determined on the basis of epidemiologic knowl-
edge of the disease and sociocultural background, although most
centers in developing countries follow WHO recommended treat-
ment guidelines.
Acknowledgements
We thank Dr Mohammad Abdus Salam for reviewing the article.
No sources of funding were used to assist in the preparation of this
manuscript. The authors have no conflicts of interest that are directly relevant
to the content of this manuscript.
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Correspondence and offprints: Dr Nure H. Alam, Clinical Sciences Division,
ICDDR,B, GPO Box 128, Dhaka, 1000, Bangladesh.
E-mail: nhalam@icddrb.org

© Adis International Limited. All rights reserved. Pediatr Drugs 2003; 5 (3)