Recent advances in clinical science

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MANAGEMENT OF INFECTIOUS
DIARRHOEA
296 A C Casburn-Jones, M J G Farthing

Gut 2004; 53:296–305. doi: 10.1136/gut.2003.022103

I
nfectious diarrhoea is the most common cause of diarrhoea worldwide and is the leading cause
of death in childhood. Gastrointestinal infections have their major impact in the developing
world. In the developed world, despite improvements in public health and economic wealth,
the incidence of intestinal infection remains high and continues to be an important clinical
problem.
During the past 10 years there have been some major improvements in our knowledge base
regarding the treatment of infectious diarrhoea. Oral rehydration therapy (ORT) remains central
to case management but advances have been made by the introduction of hypotonic solutions and
there is early evidence that resistant starch may be the substrate of the future. The search for
antisecretory drugs continues, with real progress having been made by the introduction of a new
class of drugs, the enkephalinase inhibitors. Other new drugs are in the early phases of
development. The role of antimicrobial agents in the management of infective diarrhoea
continues to be clarified with the emergence of new agents and simplified treatment regimens.
Probiotics are popular with diarrhoea sufferers and have been shown to have some efficacy but
further scrutiny is required to determine the magnitude of their effects.

c INTRODUCTION

Infectious diarrhoea is the most common cause of diarrhoea worldwide and is responsible for
more deaths than gastrointestinal cancers, peptic ulcer, or inflammatory bowel disease.
Diarrhoeal disease is the leading cause of childhood death and the second most common cause
of death worldwide.
Gastrointestinal infections have their major impact in the developing world: diarrhoeal diseases
are responsible, directly or indirectly, for approximately three million deaths each year among
children under five years of age—that is, 1 every 10 seconds. There are an estimated 1.8 billion
episodes of childhood diarrhoea per year and virtually all of these acute diarrhoeal episodes are
related to infectious agents. In some parts of Africa preschool children may suffer up to seven
attacks of acute diarrhoea annually, although the average worldwide is approximately three
episodes per year.
In the developed world, despite improvements in public health and economic wealth, the
incidence of intestinal infection remains high and continues to be an important clinical problem,
although mortality has fallen sharply in recent decades. In England, 1 in 5 people has an
intestinal infection each year, of whom 1 in 6 presents to a general practitioner. Many of these
cases are not reported to the Health Protection Agency that has now incorporated the Public
Health Laboratory Service.1 In England and Wales, the incidence of gastrointestinal infections
appears to have stabilised since the mid-1990s. Salmonella isolates have decreased by 37% since
1998, reaching the lowest recorded annual total since 1985. This may be attributed to the
introduction of vaccination of chicken flocks against salmonella. Laboratory reporting of
Campylobacter jejuni reached a peak in 1998 and has slowly fallen by 7.5% in 2000 (fig 1). However,
intestinal infections are increasing generally in the western world, notably foodborne infections,
such as Salmonella spp, Campylobacter jejuni, and enterohaemorraghic Escherichia coli (EHEC), and
waterborne infections such as Giardia intestinalis and Cryptosporidium parvum. However, reductions
in foodborne campylobacter, listeria, and yersinia have been recently reported by the Centers for
Disease Control and Prevention in the United States.
See end of article for authors’
affiliations
_________________________ CAUSES OF INFECTIOUS DIARRHOEA
There are vast numbers of bacteria, viruses, and parasites that can cause diarrhoeal disease.2 New
Correspondence to:
Professor M J G Farthing, St enteropathogens continue to be discovered; the microorganisms listed in table 1 are the most
George’s Hospital Medical clinically significant agents. Infectious diarrhoea presents clinically as one of three major clinical
School, Cranmer Terrace,
London SW17 0RE, UK;
syndromes.
[email protected] c Acute watery diarrhoea, which usually resolves within 5–10 days.
_________________________ c Diarrhoea with blood (dysentery).

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60

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Cryptosporidium
c decreased absorption of fluid, electrolytes, and sometimes
50 Rotavirus
nutrients that can involve the small and large intestine.
Lab reports (1000s)

Campylobacters
40 Salmonellas

Shigellas Increased intestinal secretion

30
Intestinal secretory processes can be activated by infection
20
with bacteria and viruses. Secretory enterotoxins are the
major cause of increased intestinal secretion in infective 297
10 diarrhoea. Cholera toxin (CT) is the ‘‘prototype’’ enterotoxin
and its mechanism of action has been extensively researched;
0
77 79 81 83 85 87 89 91 93 95 97 99 01 it is the paradigm for enterotoxin mediated diarrhoea. CT
Year switches on secretion without any macro- or microscopic
damage to the enterocyte. Other secretory enterotoxins have
Figure 1 Laboratory reporting of selected gastrointestinal pathogens also been well characterised and include the closely related
in England and Wales (source: Health Protection Agency). E coli heat labile toxin (LT) and the structurally distinct E coli
heat stable toxin (ST).3 Since the discovery of these toxins,
c Persistent diarrhoea with or without evidence of intestinal other prosecretory enterotoxins have been discovered.
malabsorption; persistence is defined as diarrhoea that Intracellular mediators and other accessory mechanisms of
has continued for more than 14 days enterotoxin action are summarised in table 2.
The clinical syndromes of infectious diarrhoea can be a useful Other more recently discovered enterotoxins have been less
but sometimes unreliable indicator of the likely pathogen well characterised. Accessory cholera enterotoxin increases
responsible. The reason for the latter is shown in table 1, as short circuit current in Ussing chambers, although its precise
there can be considerable overlap between the major mode of action has not been defined. Zonular occludens
syndromes. For example, dysenteric pathogens do not always toxin, which is produced by V cholerae O1, increases the
cause bloody diarrhoea; the initial phase of shigella infection permeability of the small intestine by interacting with the
can present as watery diarrhoea. The presence of blood in the cytoskeleton and altering the structure of intercellular tight
stool almost always indicates an invasive enteropathogen, junctions.
excluding misdiagnosis due to exacerbation of bleeding It is now evident that secretory diarrhoea may be mediated
haemorrhoids. by other mechanisms of secretion, as well as the classical
enterocyte interaction. Multiple extracellular factors regulate
DIARRHOEA MECHANISMS epithelial ion transport—paracrine, immunological, neural,
Infectious diarrhoea occurs as a result of two major and endocrine factors; there is extensive overlap and inter-
disturbances in normal intestinal physiology: play between these systems that a single superregulatory
c increased intestinal secretion of fluid and electrolytes, system has been termed PINES (paracrine-immuno-neuro-
predominantly in the small intestine; and endocrine system). Secretory diarrhoea may be mediated by a

Table 1 Causes of infectious diarrhoea

Acute watery Persistent
Enteropathogen diarrhoea Dysentery diarrhoea

Viruses
Rotavirus + 2 2
Enteric adenovirus (types 40, 41) + 2 2
Calicivirus + 2 2
Astrovirus + 2 2
Cytomegalovirus + + +
Bacteria
Vibrio cholera and other vibrios + 2 2
Enterotoxigenic E coli (ETEC) + 2 2
Enteropathogenic E coli (EPEC) + 2 +
Enteroaggregative E coli (EAggEC) + 2 +
Enteroinavsive E coli (EIEC) + + 2
Enterohaemorraghic E coli (EHEC) + + 2
Shigella spp + + +
Salmonella spp + + +
Campylobacter spp + + +
Yersinia spp + + +
Clostridium difficile + + +
Mycobacterium tuberculosis 2 + +
Protozoa
Giardia intestinalis + 2 +
Cryptosporidium parvum + 2 +
Microsporidia + 2 +
Isospora belli + 2 +
Cyclospora cayetanensis + 2 +
Entamoeba histolytica + + +
Balantidium coli + + +
Helminths
Strongyloides stercoralis 2 2 +
Schistosoma spp 2 + +

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Table 2 Bacterial enterotoxins and their mechanisms of action
Enterotoxin Signal transduction Accessory pathways

Cholera toxin family

Cholera toxin cAMP ENS, 5-HT
E coli heat labile toxin I (LT-I) cAMP ENS
E coli heat labile toxin II (LT-II) cAMP ?
298 Salmonella enterotoxin cAMP ?
Shigella enterotoxin (ShET I+II) cAMP ?
Heat stable toxin family
E coli heat stable toxin (STa) cGMP ENS
Enteroaggregative E coli heat stable toxin 1 (EAST-1) cGMP ?
Yersinia enterocolitica heat stable toxin (Y-ST) cGMP ?
V cholera non-O1 heat stable toxin (NAG-ST) cGMP ?
Other enterotoxins
Accessory cholera enterotoxin ? ?
Clostridium difficile toxin A Ca++ Cytoskeleton
Enteroinvasive E coli toxin ? ?
Plesiomonas shigelloides LT+ST ? ?
Aeromonas hydrophila enterotoxin ? ?

variety of secretagogues, including prostaglandins, 5-hydroxy- duration of time allowed for digestion and contact with the
tryptamine (5-HT), substance P, and vasoactive intestinal epithelium, and therefore any alteration in small intestinal
peptide (VIP). Neuronal pathways are involved in the and whole gut transit times may result in impaired
amplification of the effects of enterotoxins.4 absorption.
CT has been shown to release 5-HT from enterochromaffin Epithelial injury in the small intestine and colon occurs in
cells, which is thought to then activate the afferent limb of a association with many enteropathogens—bacteria, parasites,
neuronal reflex.4–6 The effector limb of the neuronal reflex is and viruses. The nature of the injury can occur at many
likely to complete the neuronal pathway by releasing the levels; from discrete damage to the microvillus membrane
neurotransmitter VIP.5 This binds to specific receptors on the during the attachment of E coli and Cryptosporidium parvum, to
basolateral membrane and activates adenylate cyclase-cAMP the mucosal inflammatory response to invasive pathogens—
intracellular secretory pathways. Interneurones propagate the for example, Shigella spp, Salmonella spp, and Entamoeba
secretory effects of CT distally in the small intestine. The histolytica, usually involving the release of cytolethal cytotox-
importance of 5-HT in mediating CT induced secretory ins resulting in epithelial cell loss and ulceration. Rotavirus,
diarrhoea has been confirmed by the use of 5-HT2 and another invasive enteropathogen, directly invades the epithe-
5-HT3 receptor antagonists, which decrease secretion in the lial cells in the middle and upper portion of the villus, with
rat and human intestine.6 7 Substance P antagonists also rapid epithelial cell death and acute villous trophy. Invasive
reduce CT induced fluid secretion in mammalian small enteropathogens also produce an acute inflammatory
intestine, suggesting that it may be a key neurotransmitter in response within the mucosa, recruiting proinflammatory
the sensory afferent limb or interneurone of the neuronal mediators such as prostaglandins and leukotrienes, resulting
reflex.8 Hence CT affects the epithelium directly but also in both impaired intestinal absorption and the initiation of a
recruits other components in PINES, including enteric prosecretory state in the intestine.3 Invasive enteropathogens
neurones, enterochromaffin cells, and multiple mediators to also promote the synthesis and release of chemokines, such
produce a complex secretory response. There may also be as interleukin (IL)-8, by intestinal epithelial cells. IL-8 is a
distant effects in the small intestine9 and a reflex secretory known potent chemoattractant for polymorphonuclear leu-
response in the colon.10 LT and ST also activate neural cocytes that enhance the inflammatory cascade and produce
secretory reflexes but 5-HT does not appear to be involved in further mucosal and epithelial damage by release of reactive
the secretory pathway of these toxins.11 oxygen species. Neutrophils also release 59-AMP, which is a
Rotavirus has been assumed to elicit diarrhoea by dam- potent secretatgogue acting though the adenosine A2
aging absorptive cells but evidence is emerging that rotavirus receptor on the apical membrane of intestinal epithelial cells.
intestinal infection can evoke fluid and electrolyte secretion In the clinical setting, these two pathophysiological
by activation of the enteric nervous system.12 disturbances—secretory diarrhoea, and secondly, impairment
of epithelial transport processes with enteropathogenic
Decreased intestinal absorption invasion and epithelial cell injury—often coexist. Shigella,
The other major mechanism by which enteric pathogens salmonella, and campylobacter produce a secretory diarrhoea
cause diarrhoea is impaired intestinal absorption. This is in the small intestine in the early phase of the illness, most
usually accompanied by macroscopic and microscopic injury likely as a result of enterotoxin activity, but then invade the
to the intestine.13 Diarrhoea due to impaired intestinal epithelium of the distal ileum and colon to produce an
absorption can be due to: (i) impaired epithelial transport inflammatory ileocolitis. At this stage there will be epithelial
processes—that is, impaired fluid, electrolyte, and nutrient cell loss and impaired absorption of fluid and electrolytes.
absorption in the small intestine; (ii) osmotic diarrhoea due
to the appearance of incompletely absorbed nutrients in the DIAGNOSIS OF INFECTIOUS DIARRHOEA
colon; or (iii) impaired water and sodium reabsorption by the The majority of intestinal infections are self limiting in
colon due to direct involvement of the colonic absorptive immunocompetant individuals so one could argue that
process. Intestinal absorption is also dependent on the making a specific diagnosis is unnecessary. This is certainly

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true for most viral diarrhoeas and many bacterial diarrhoeas. significant increase in mucosal inflammatory cells and an
From the microbiological and public health perspective, a increase in 5-HT containing enterochromaffin cells, both of
specific diagnosis is helpful. The major challenge facing the which are thought to contribute to symptom production.
gastroenterologist is to decide whether an episode of Persistent diarrhoea is usually accompanied by weight loss
diarrhoea is infectious or due to another cause, such as a and possibly other clinical features of macro- and micro-
functional bowel disorder or inflammatory bowel disease. nutrient deficiency. There are a few specific clinical stigmata
of some tropical causes of persistent diarrhoea. Larvae currens 299
Clinical history is an erythematous pruritic migrating weal associated with
The clinical history is valuable in deciding whether intestinal strongyloidiasis. Hepatomegaly may accompany intestinal
infection is a likely cause of diarrhoea. Some individuals are schistosomiasis.
more susceptible to intestinal infection and can often be Rigid sigmoidoscopy may be helpful in confirming the
identified by taking a careful history (table 3). Food and presence of proctocolitis; it can be extremely difficult to
water are important vehicles for infection, as previously distinguish between proctocolitis secondary to infection or
discussed, in both the third world and the developed world. A non-specific inflammatory bowel disease, and hence the
careful history of oral intake may be crucial in identifying the specificity of sigmoidoscopic appearance is generally poor. It
source. Major outbreaks of giardiasis and cryptosporidiosis is important to note that a normal rectum does not exclude
have been well documented in North America and Europe infective colitis or non-specific inflammatory bowel disease.
following contamination of water supplies. Swimming in
seawater, freshwater, and swimming pools is also a risk Specific investigations
factor for intestinal infection. Foodborne diarrhoeal disease Specific investigation is not normally required in the majority
occurs either as a true infection in which the enteropatho- with acute watery diarrhoea as this is usually self limiting,
gens are consumed or as ingestion of preformed toxin.
and resolves without specific treatment. Patients with bloody
diarrhoea (dysentery) or persistent diarrhoea do require
Physical examination further investigation. The general approach is to start with
Physical examination is unhelpful in forming a specific the simplest, least invasive, ‘‘economically competitive’’ test,
diagnosis of infectious diarrhoea. However, it is vitally
progressing in a hierarchical way to more invasive and
important in assessing the individual’s hydration status and
expensive investigations.
in identifying other causes and risk factors for diarrhoea. c Stool microscopy and culture
Assessment of hydration status is particularly important in Stool microscopy and culture is the first line investigation.
infants, young children, and the elderly. Specific clinical Three stool samples should be examined under the light
criteria have been established to formally assess the hydra-
microscope for parasites by an experienced observer, and
tion state in infants and young children and provide helpful
then cultured for bacterial enteropathogens. Detection of
clinical guidance on the replacement volume of fluid required
parasites with standard microscopy is labour intensive and
and the most appropriate route of administration.14 Most
insensitive. Special stains are required to enhance detection
useful indicators for assessing hydration and for monitoring
of cysts and spores. Microscopy is vital for the diagnosis of
of rehydration in infants are anterior fontanelle, systolic
Entamoeba histolytica, Giardia intestinalis, Cryptosporidium
blood pressure, skin elasticity, ocular tension, and urine flow.
parvum, and Cyclospora cayetanensis. Newer antigen detection
Painful swollen joints may accompany intestinal infection,
assays have been developed that increase the sensitivity of
Yersinia enterocolitica, and C jejuni as part of Reiter’s syndrome.
the examination for giardia and cryptosporidium. In addi-
Guillain-Barré syndrome may develop as a result of C jejuni
tion, commercially available enzyme immunoassays are able
intestinal infection, which is now known to be the
to distinguish between E histolytica and the non-pathogenic
commonest cause of this syndrome. The haemolytic uraemic
but microscopically indistinguishable E dispar. C difficile
syndrome is an important although uncommon complication
requires confirmation by detection of toxin A in faeces by
of dysenteric shigellosis and EHEC infection. There is good
enzyme linked immunosorbent assay (ELISA). Faecal antigen
evidence that intestinal infections may initiate a functional
ELISAs are also available for rotavirus.
bowel disorder such as irritable bowel syndrome (IBS). Some
c Serodiagnosis
patients with so-called post-infective IBS have a mild but
Antibody testing is useful to confirm or support other tests in
a limited number of infections. Specific serum antibodies are
Table 3 Special risk groups for infectious diarrhoea present in 80–90% of patients in invasive amoebiasis.
Risk factors Groups at risk Antibodies are useful in Y enterocolitica, but a result can take
up to 10–14 days. ELISA kits are widely available for the
Age Infants
Young children diagnosis of strongyloides and schistosomiasis: they are often
The elderly used as first line screening tests for these infections,
Non-immune host defence-gastric The elderly
especially in travellers returning from endemic areas.
acid Hypo- and achlorhydria
Patients on acid inhibitory drugs c Abdominal imaging
Congenital immunodeficiency Plain abdominal radiograph is usually performed in those
Immunodeficiency HIV/AIDS
Cancer and cancer chemotherapy
who are severely unwell with abdominal pain to exclude
Undernutrition bowel perforation and for assessing the severity and extent of
Increased exposure to Travellers infectious colitis.
enteropathogens Contaminated food and water
Antibiotics Especially the elderly and cancer Transabdominal ultrasound can detect bowel wall thicken-
patients ing, enlarged lymph nodes, pneumatosis, abdominal tuber-
culosis, and complications such as amoebic liver abscesses.
c Endoscopy

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Upper gastrointestinal endoscopy is useful in the investiga- Table 4 Major advances in the treatment of infectious
tion of patients with persistent diarrhoea, with or without diarrhoea
clinical features of intestinal malabsorption. Severe villous
Supportive therapy
atrophy in the second part of the duodenum can occur in Hypotonic oral rehydration solutions17–19
infections due to small intestinal protozoa—giardia, crypto- Resistant starch based ORS
20

sporidium, cyclospora, and the microsporidia. Changes in Antisecretory drugs

Racecadotril-enkephalinase inhibitor31–34
300 villous morphology can be confirmed by duodenal biopsy, Others in development
35 36

which may also reveal the presence of protozoal cysts or Antimicrobial chemotherapy
72
trophozoites. Duodenal fluid can also be aspirated during the Nitazoxanide, antiprotozoal agent
44 45 40 41
Ultrashort regimens: cholera , traveller’s diarrhoea
procedure—this is particularly helpful for the detection of Rifaximin, non-absorbed antibiotic42
Giardia intestinalis cysts and trophozoites and for the larvae of Probiotics
strongyloides. Rotavirus diarrhoea47 48
Antibiotic associated diarrhoea?49
Endoscopic examination of the colon and ileum is useful
following negative stool culture and microscopy in the ORS, oral rehydration solution.
presence of dysentery or persistent symptoms. This may be
helpful for distinguishing between infectious colitis and
inflammatory bowel disease, but the pathological features are Supportive therapy
not very reliable in the acute setting. Discrete ulceration can Fluid and electrolyte replacement
occur in amoebiasis and colonic tuberculosis and there are This is the cornerstone of treatment. Fluid and electrolyte
few distinguishing features that reliably differentiate these replacement via the oral route is usually sufficient unless the
infections from Crohn’s disease. Pseudomembranes in the person is vomiting and/or losses are very severe. Dehydration
colon are generally indicative of C difficile infection but can be occurs more quickly in infants and young children and
also found in ischaemic colitis. Colonic biopsies can detect E therefore early administration of an oral rehydration solution
histolytica, cytomegalovirus, and the ova of Schistosoma spp. (ORS) is advised to prevent severe dehydration and acidosis.
c Histology In severe dehydration in infants and young children,
If colonic mucosal biopsies are taken within the first 24– intravenous fluids are advisable. The acidosis that can occur
72 hours, histological features may be indicative of infection, in severe dehydration is corrected with fluid replacement
including mucosal oedema, straightening of the glands, and alone and does not require any specific bicarbonate therapy.
an acute inflammatory infiltrate.15 16 After this stage it can Food should be commenced as soon as the individual wishes
very difficult to distinguish between infectious colitis and to eat and drink normally. Breast feeding should be
non-specific inflammatory bowel disease. Biopsies can reveal continued in infants. In most cases in adults a formal ORS
the pseudomembranes of C difficile and the caseating is often not required but a recommended increase in oral
granulomata of tuberculosis. fluids with for example salty soups (sodium), fruit juices
(potassium), and a source of carbohydrates (salty crackers,
TREATMENT rice, bread, pasta, potatoes) to provide glucose for the
During the past 10 years there have been some major glucose-sodium cotransport.
improvements in our knowledge base regarding the treat-
ment of infectious diarrhoea. Oral rehydration therapy
Recommended oral replacement fluids are glucose-electrolyte
Major advances in the treatment of infectious solutions known collectively as oral rehydration solutions
diarrhoea (table 4) (ORS). ORT has been a life saving therapy for many patients
Oral rehydration therapy (ORT) remains central to case with severe diarrhoea. The scientific principle and rationale
management but advances have been made by the introduc- for this therapy is based on active carrier mediated sodium-
tion of hypotonic solutions and early evidence that resistant glucose cotransport.14
starch may be the substrate of the future. The search for The World Health Organisation (WHO) has for several
antisecretory drugs continues, with real progress having been decades recommended an ORS containing 90 mmol/l of
made by the introduction of a new class of drugs, the sodium. There has been some concern about the widespread
enkephalinase inhibitors. Other new drugs are in the early use of the 90 mmol/l ORS because of the small but significant
phases of development. The role of antimicrobial agents in risk of hypernatraemia. A lower sodium concentration of 50–
the management of infective diarrhoea continues to be 60 mmol/l is as effective as the previously recommended
clarified with the emergence of new agents and simplified 90 mmol/l and appears to be more efficacious in reducing
treatment regimens. The place of probiotics in the treatment faecal losses.17 The WHO in 2002 finally endorsed the use of a
and prevention of infectious diarrhoea continues to be low osmolality ORS (245 mosmol/kg) with a sodium con-
evaluated but studies to date suggest moderate efficacy. centration of 75 mmol/l.
There are four main approaches to the treatment of Although glucose has traditionally been the main substrate
infectious diarrhoea. for ORS, the possibility that efficacy may be increased by
c Supportive therapy—fluid and electrolyte replacement.
using complex substrates, such as cereals or defined glucose
c Antidiarrhoeal symptomatic treatment to reduce stool
polymers, has been explored extensively in the last few
frequency and any other symptoms such as abdominal
pain. decades. Replacing glucose with a glucose polymer such as
c Antisecretory drug therapy aimed at reducing faecal rice starch has the dual advantage of producing low
losses. osmolality solution18 while delivering an increased amount
c Specific therapy such as antimicrobial chemotherapy to of substrate in the form of rice starch polymer along with
reduce duration and severity of the illness. some protein, which will also drive active sodium absorption.

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Cereal based ORS has only a significant advantage in cholera Another approach has been the development of an
but not in other diarrhoeal states.19 enkephalinase inhibitor, racecadotril, which has proabsorp-
Resistant starch is only partially hydrolysed in the small tive activity via its ability to potentiate endogenous enke-
intestine and approximately 30% enters the colon where it is phalins in the intestine.31 32 This is an effective agent for
degraded by colonic bacteria to short chain fatty acids that reducing stool weight and bowel frequency, it can be safely
promote sodium and water absorption. A randomised used in children, and does not cause rebound constipation,
controlled trial in cholera diarrhoea showed that a resistant which can be a problem with more commonly used 301
starch ORS was superior to the WHO-ORS and hypotonic antimotility antidiarrhoeal agents.33 34
glucose monomer ORS in its effectiveness in reducing faecal The thiazolidinone drug-like moieties which inhibit the
losses.20 cystic fibrosis transmembrane regulator protein may also
hold promise for the future.35 This protein is integral to the
Antidiarrhoeal therapy chloride channel on the apical membrane of the intestinal
There are two major classes of antidiarrhoeal agents useful epithelial cell that is an essential component of the secretory
for reducing stool frequency, abdominal cramps, and possibly process. Further clinical evaluation is required to determine
stool volume. whether this will be a valuable addition to the management
c Antimotility agents of secretory diarrhoea.
c Antisecretory agents SP 303, a naturally occurring polyphenolic polymer with
chloride channel blocking activity, has been shown to have
Antimotility agents antisecretory actions and in a double blind randomised
The most commonly used are the antimotility agents such as controlled trial reduced the duration of traveller’s diarrhoea
loperamide and a diphenoxylate-atropine combination. These by 29%.36 Further studies are required to determine whether
agents act by increasing intestinal transit time and enhancing this agent will find a place in the treatment regimens for this
condition.
the potential for reabsorption of fluid and electrolytes. They
Bismuth salicylate has been shown to be effective in the
have a modest effect on reducing faecal losses. Loperamide
treatment of traveller’s diarrhoea.37 It is an effective
may have some antisecretory activity but this contribution to
antidiarrhoeal, reducing the number of unformed stools by
its clinical efficacy is probably marginal. Loperamide is
approximately 50%; this is attributed to the antisecretory
usually the first line treatment in self therapy and no self
action of its salicylate moiety but it is also thought to have
respecting traveller is without a packet in his/her travel kit.
antibacterial and anti-inflammatory properties.38 It is not a
Loperamide has been studied in various randomised con-
popular drug of choice as a large number of tablets must be
trolled trials; it has failed to demonstrate any benefit over
taken (eight tablets), it has a delayed onset of action (up to
placebo in some trials,21 but a more recent trial has shown
four hours), it can interfere with the absorption of other
benefit.22 Loperamide combined with an antibiotic has been
medications such as doxycyline, and has some unpleasant
shown to be advantageous in some trials23 24 but of no benefit
side effects (tinnitus, black tongue).
in others.25 Antimotility agents are not recommended for
children and young infants due to the potential for central Antimicrobial therapy
nervous system side effects and the theoretical possibility of Antibiotic therapy for infectious diarrhoea is controversial.
respiratory depression. Antimotility agents are generally not Those with mild symptoms and those who are clearly
recommended in dysentery because of the risk of colonic improving probably do not need antibiotic treatment.
dilatation associated with infective colitis. However, there is However, there are certain infectious diarrhoeas in which
limited clinical evidence for this concern. Loperamide has treatment is recommended: dysenteric shigellosis, cholera,
been shown to be safe in the treatment of bacillary dysentery pseudomembranous enterocolitis, that due to parasites, and
if used in conjunction with an antibiotic.24 Antimotility sexually transmitted diseases. There are several diseases in
agents have also been thought to increase the faecal carriage which the indications are less clear but treatment is usually
of gut enteropathogens but there is little evidence that this is recommended: infection with the non-cholera vibrios,
the case. prolonged or protracted infection with yersinia, early in the
course of campylobacteriosis, aeromonas and plesiomonas
Antisecretory agents infections, and outbreaks of enteropathogenic E coli diarrhoea
There is an ongoing search for the ideal antisecretory agent— in nurseries. Patients should be treated if they are debilitated,
that is, a drug that will directly inhibit secretory processes particularly with malignancy, immunosuppressed, have an
within the enterocyte.26 27 Intracellular signalling mechan- abnormal cardiovascular system, have valvular, vascular, or
isms were an initial pharmacological target, especially those orthopaedic prostheses, have haemolytic anaemia (especially
related to calcium and the calcium binding protein calmo- if salmonellosis is involved), or are extremely young or old.
dulin. Zaldaride maleate, a calmodulin inhibitor, has been Treatment is also advised for those with prolonged symptoms
evaluated in phase III randomised controlled trials but future and those who relapse.
development was discontinued because of no additional There is a large body of evidence to show that antimicrobial
benefit compared with standard antidiarrhoeal agents.28 29 agents can reduce the severity and duration of some
Recent attention has focused on the enteric nervous system intestinal infections, especially in those bacteria and infec-
(ENS). It is now well established that the ENS is involved in tions that produce acute watery diarrhoea. Antimicrobials are
the promotion of intestinal secretion. A number of neuro- also useful in bacterial intestinal infections that cause
transmitters have been identified in the ENS, and many are systemic involvement. There are numerous antibiotics that
thought to be involved in intestinal secretion and are have been studied in the treatment of infectious diarrhoea,
therefore potential pharmacological targets for the treatment some empirical and some targeted. Intestinal infections can
of watery diarrhoea.30 be regarded in different categories depending on whether

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antimicrobial therapy has been proven to be effective in for the treatment of traveller’s diarrhoea. This drug has been
clinical trials. Efficacy varies from being definitely effective to shown to be as effective as ciprofloxacin but with the
possible and/or doubtful efficacy. Efficacy is regarded as potential advantage of only minimal systemic absorption.42
reduction in duration of illness, severity, and complications Azithromycin is also a good choice for pregnant women
(see table 5). and children, for whom fluoroquinolones are not approved,
In cases where there is doubt about the efficacy of and for patients who cannot otherwise tolerate fluoroquino-
302 antibiotics, it may not be related solely to the potency of lones
the antibiotic but also to the study design. Administration of Cholera is treated with antibiotics—standard therapy is
the antibiotic may be delayed after the onset of symptoms. with tetracycline for three days but other agents are equally
When given relatively late in the natural history of the illness, as effective—doxycycline, trimethoprim-sulphamethoxzole,
additional benefits of therapy could be missed. norfloxacin, and ciprofloxacin.43 44 Single dose ciprofloxacin
has been shown to be as effective as three days of doxycy-
Acute watery diarrhoea line.45
In acute watery diarrhoea, treatment is largely supportive. Treatment of E coli O157:H7 is not recommended at present
Antibiotic therapy is controversial unless the illness is severe because current antibiotics do not appear to be helpful, and
or due to cholera. It is a widely held belief that in what is inconclusive data have suggested that the incidence of
generally a mild self limiting illness, antibiotic use is complications, including haemolytic uraemic syndrome,
unnecessary; the risk of antibiotic resistance is increased may be greater after antibiotic therapy. Antibiotics are not
and introduces the possibility of antibiotic side effects (for routinely recommended for use in children, and there is
example, Stevens Johnson syndrome or pseudomembranous concern that their use might increase the risk of haemolytic
colitis). uraemic syndrome secondary to EHEC infection.
In traveller’s diarrhoea, a major form of acute watery
diarrhoea, antimicrobial therapy is unequivocally effective; Probiotics
this is supported by many randomised controlled trials. In 1985, Gorbach identified a lactobacillus as a result of
Traveller’s diarrhoea is mainly due to bacterial enteropatho- screening bacteria in fermented milk products thought to be
gens (approximately 80%), the most frequently isolated being beneficial to human health.46 This lactobacillus species was
enterotoxigenic E coli; broad spectrum antibiotics have been acid and bile resistant, adhered to human intestinal epithelial
shown to be effective but there is increasing resistance to cells, and had growth characteristics necessary for commer-
trimethoprim-sulphamethoxazole and ampicillin and there- cial development. This strain, identified as Lactobacillus GG, is
fore these are less suitable for blind therapy. Quinolone one of several probiotics, a non-pathogenic organism, used to
antibiotics are now the treatment of choice; standard doses improve intestinal microbial balance. Following this discov-
for 3–5 days can reduce the severity and duration of illness by ery, multiple candidate microorganisms have been developed,
at least 50%.39 40 Similar efficacy has also been shown with but Lactobacillus GG remains the most common strain to be
single dose regimens.41 Recently, there has been renewed tested in controlled trials. In a multicentre trial, Lactobacillus
interest in a non-absorbed locally active antibiotic, rifaximin, GG was shown to reduce the duration of rotavirus episodes

Table 5 Antimicrobial therapy for acute infectious diarrhoea

Organism Efficacy of antimicrobial therapy Drug of choice Alternative choice

Bacteria
Vibrio cholerae Proven Tetracycline 500 mg qds 3 days. TMP-SMX, doxycyline, norfloxacin,
44 45 43
Ciprofloxacin 1000 mg single dose ciprofloxacin, 3 days
ETEC Proven Ciprofloxacin 500 mg bd 3–5 days39 Ciprofloxacin 500 mg single dose41
Norfloxacin 400 mg bd, 3–5 days40
EPEC Possible
EIEC Possible ?Same as Shigella spp
EHEC Controversial See text
50 51–55
Shigella spp Proven efficacy in dysenteric shigellosis TMP-SMX 2 tabs bd 5 days*. Short term quinolone. Cefixime
Ciprofloxacin 500 mg bd 5 days.51 Other 400 mg daily 5–7 days OR other third
quinolones—norfloxacin, fleroxacin, generation cephalosporins.
cinoxacin Nalidixic acid 1 g qds 5–7 days
Salmonella spp Doubtful efficacy in enterocolitis. Proven Ciprofloxacin 500 mg bd 10–14 days. 3rd TMP-SMX.53 Ampicillin, amoxycillin
efficacy in severe salmonellosis gen cephalosporins 10–14 days. Carrier
(dysentery, fever) state: norfloxacin 400 mg bd 28 days
56–59
Campylobacter spp Possible efficacy in campylobacter Erythromycin 250–500 mg qds 7 days Ciprofloxacin 500 mg bd 5–7 days.
enteritis. Proven efficacy in Azithromycin 500 mg od 3 days
campylobacter, dysentery/sepsis
60 61 60 61
Yersinia spp Doubtful efficacy in Yersinia enteritis. Ciprofloxacin 500 mg bd 7–10 days Tetracycline 250 mg qds 7–10 days
Proven efficacy in Yersinia septicaemia
Clostridium difficile Proven Metronidazole 400 mg tds 7–10 days62 Vancomycin 125 mg qds 7–10 days.62–64
65
Fusidic acid, teicoplanin
Protozoa
Cryptosporidium parvum Possible
Isospora belli Proven
Cyclospora cayetanensis Proven
66
Entamoeba histolytica Proven Metronidazole 750 mg tds 5 days. Paromomycin 25–35 mg/kg tds 7–
66 66
Diloxanide furoate 500 mg tds 10 days 10 days
Balantidium coli Proven Metronidazole 400 mg tds 10 days66 67 Tetracycline 500 mg qds 10 days66 67

Antimicrobial therapy is not indicated for acute viral diarrhoea such as that due to rotavirus, enteric adenoviruses, and small round structured viruses.
*TMP/SMX is of limited value because of resistance patterns.

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Table 6 Antimicrobial therapy of persistent infectious diarrhoea
Enteropathogen Antimicrobial therapy Alternative(s)

Protozoa
Giardia intestinalis Metronidazole 400 mg tds 7–10 days80 Tinidazole 2 g single dose80
71 14
Cryptosporidium parvum ?Paromomycin 500 mg qds ?Nitazoxanide
Cyclospora cayetanensis TMP-SMX 2 tabs bd 7 days79
Isospora belli TMP-SMX 2 tabs qds 10 days 303
Microsporidia
76
Encephalitozoon intestinalis ? Albendazole 400 mg bd ?Furazolidone 100 mg qds 20 days
73
14–28 days
Enterocytozoon bieneusi ? Atovaquone75
Entamoeba histolytica See table 5
Balantidium coli See table 5
Helminths
Strongyloides stercoralis Albendazole 400 mg od 3 days Thiabendazole 25 mg/kg bd 2–3 days
Schistosoma spp Praziquantel 2–3 doses on day 1 Ivermectin 100–200 mg/kg od 2 days
S mansoni, S haematobium Praziquantel 40 mg/kg/d
S japonicum Praziquantel 60 mg/kg/d
Virus
Cytomegalovirus Ganciclovir 5 mg/kg bd 14–21 days Foscarnet 60 mg/kg tds 14–21 days
maintenance therapy required

The treatment of other bacterial infections that can cause persistent diarrhoea (see table 1) can be found in table 5
(references).

but had no effect on bacterial diarrhoeas.47 A recent meta- sensitivity to many agents. Albendazole is effective in treating
analysis would support the view that probiotics can shorten E intestinalis but not very effective in treating E bieneusi.73 74
the duration of acute diarrhoeal illness in children by one Uncontrolled studies have shown the following agents to
day.48 Although meta-analysis also suggests that probiotics have some benefit in treating microsporidia: atovaquone,75
benefit antibiotic associated diarrhoea,49 further studies are furazolidone,76 furazolidone-albendazole,77 and thalidomide.78
required to provide a definitive answer. C cayetanensis infection can be treated effectively with TMP-
SMX.79
Dysentery
Antibiotics are recommended for the treatment of dysentery ACKNOWLEDGEMENTS
due to most organisms50–67 (table 5). However, antibiotic AC-J is supported by the Digestive Disorders Foundation, UK. This
review has been modified and updated from an earlier version
therapy for campylobacter56 57 and EHEC infection remains authored by MJGF in 2001 (see Farthing2).
controversial.68–70 In campylobacter infection there is good
evidence that antibiotics do not alter the natural course of the ..................
illness if antibiotics are started .4 days after the onset of Authors’ affiliations
symptoms. Randomised controlled trials are conflicting in A C Casburn-Jones, Department of Gastroenterology, University College
terms of efficacy of antibiotics if started early in the course of Hospital, London, UK
M J G Farthing, St George’s Hospital Medical School, London, UK
infection. One randomised controlled trial has shown that
erythromycin started early reduces the duration of illness in
children58 but a second study failed to confirm these
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