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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cholera: Clinical features, diagnosis, treatment, and

prevention
Authors: Regina LaRocque, MD, MPH, Jason B Harris, MD, MPH
Section Editor: Stephen B Calderwood, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2022. | This topic last updated: Mar 22, 2022.

INTRODUCTION

Cholera is an acute secretory diarrheal illness caused by toxin-producing strains of the gram-
negative bacterium Vibrio cholerae. Severe cholera is characterized by profound fluid and
electrolyte losses in the stool and the rapid development of hypovolemic shock, often within 24
hours from the initial onset of vomiting and diarrhea. Administration of appropriate
rehydration therapy reduces the mortality of severe cholera from over 10 percent to less than
0.5 percent [1].

This topic discusses the epidemiology, clinical manifestations, diagnosis, treatment, and
prevention of cholera. The microbiology and pathogenesis of V. cholerae and infections caused
by non-O1/O139 V. cholerae strains are discussed elsewhere. (See "Cholera: Microbiology and
pathogenesis" and "Infections due to non-O1/O139 Vibrio cholerae".)

The general approaches to acute diarrhea among adults and children in inadequately resourced
settings are also discussed elsewhere. (See "Approach to the adult with acute diarrhea in
resource-limited countries" and "Approach to the child with acute diarrhea in resource-limited
countries".)

ETIOLOGIC AGENT

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V. cholerae is a diverse species and includes pathogenic and non-pathogenic variants. Only
cholera toxin-producing (toxigenic) strains of V. cholerae are associated with cholera. V. cholerae
is classified serologically; of over 200 serological groups identified, only 2 (V. cholerae O1 and
O139) have caused cholera epidemics. This is discussed in detail elsewhere. (See "Cholera:
Microbiology and pathogenesis", section on 'Microbiology'.)

EPIDEMIOLOGY

Cholera is vastly underreported, and precise measurements of the morbidity and mortality
attributable to V. cholerae infection are lacking. However, there are an estimated 3 million cases
of diarrheal illness and approximately 100,000 deaths worldwide caused by V. cholerae annually
[2].

Global distribution — Cholera primarily occurs in settings where there is inadequate access to
clean water and sanitation. Cholera is endemic in approximately 50 countries (defined as having
reported cholera cases in at least three of the five past years), mostly in Africa and Asia [2]. In
addition, epidemics due to V. cholerae have occurred throughout Africa, Asia, the Middle East,
South and Central America, and the Caribbean and can be extensive [3]. As an example, the
strain implicated in the 2010 outbreak in Haiti was subsequently associated with outbreaks in
the neighboring countries of Dominican Republic, Cuba, and Mexico [4].

Cases in resource-rich settings are generally imported from travel to endemic or epidemic
settings [5].

Transmission — V. cholerae infection is primarily acquired by ingesting contaminated food or

water. In endemic regions, V. cholerae in the water are an important reservoir of the organism.
Because V. cholerae can live on chitinous plankton [6], filtration of water through coarse cloth
can reduce the incidence of cholera in endemic areas [7]. (See 'Preventing transmission' below.)

While exposure to environmental V. cholerae is important, direct person-to-person transmission

is also thought to play a role in transmission. Individuals with severe cholera can excrete as
many as 1010 to 1012 organisms per liter of stool. Organisms that were recently shed from
infected individuals appear to be transiently more infectious than organisms isolated from the
aquatic environment [8]. Mathematical models suggest that person-to-person transmission of
human-shed, hyper-infectious V. cholerae is essential for the rapid propagation of cholera that is
observed during epidemics [9]. (See "Cholera: Microbiology and pathogenesis", section on
'Hyperinfectivity'.)

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Endemic versus epidemic infection — Patterns of cholera transmission and infection differ
between historically endemic areas and areas experiencing cholera epidemics.

In areas of high endemicity, the incidence of V. cholerae infection follows a seasonal distribution,
with peaks before and after rainy seasons [3]. Superimposed epidemics may also occur, and
mathematical models suggest these epidemics are dependent on fluctuations in population-
based immunity and climate [10]. In areas of high endemicity, the incidence of cholera is
highest in children younger than five years, likely reflecting the lack of protective immunity [11].

In areas with more limited immunity in the population, massive epidemics may occur, with
similar attack rates in children and adults. The cholera epidemic in Haiti is an example of the
consequences of the introduction of V. cholerae into a naïve population. A V. cholerae O1 variant
El Tor strain was introduced into Haiti from South Asia possibly via United Nations stabilization
forces [12,13]. Within two years, 604,634 cases of infection, 329,697 hospitalizations, and 7436
deaths from cholera were reported in Haiti [14].

Even in endemic regions, breakdowns in safe water, hygiene, and health services can contribute
to epidemic transmission of cholera. In Yemen, where public health and healthcare
infrastructure has been devastated by years of warfare, two rapidly sequential outbreaks
occurred at the end of 2016 and the middle of 2017. The second of these outbreaks amounts to
the world's worst cholera outbreak to date, with approximately 500,000 cases of suspected
cholera and 2000 associated fatalities recorded within only four months [15].

Other major outbreaks have occurred in Sierra Leone, the Democratic Republic of Congo (DRC),
Nigeria, Angola, Vietnam, Pakistan, and Zimbabwe. Experience from such outbreaks
demonstrates that fatality rates in epidemic cholera are consistently higher than 1 percent,
particularly in the early stages of an epidemic and in rural areas [16]. As an example, in the
2008 to 2009 cholera outbreak in Zimbabwe, which involved nearly 100,000 people, the case
fatality rate was over 4 percent [17].

Risk factors — Cholera is associated with poverty and lack of access to safe food, water, and
adequate sanitation [18]. Large cholera epidemics often occur in populations impacted by
natural disaster or human conflict [19]. These associations reflect the underlying mode of
transmission via contaminated food and water. For example, drinking un-boiled or untreated
water is a commonly identified risk factor for cholera, while use of soap is associated with a
lower likelihood of infection [20]. In some, primarily foodborne cholera outbreaks, risk factors
may include consumption of specific foods, including rice products, or specific vegetables or
fruits [21]. In areas where cholera occurs sporadically, most cases are associated with shellfish
consumption.

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Other risk factors for V. cholerae infection and cholera reflect the biological interaction between
the host and pathogen, including blood group O (associated with more severe cholera),
hypochlorhydria (lowers the dose needed to cause infection), retinol deficiency [22-26].
Breastfeeding has been consistently shown to be protective against cholera [27,28]. (See
"Cholera: Microbiology and pathogenesis", section on 'Host susceptibility'.)

CLINICAL MANIFESTATIONS

Infection with V. cholerae results in a spectrum of disease, ranging from asymptomatic intestinal
colonization to severe diarrhea [29]. Abdominal discomfort, borborygmi, and vomiting are other
common symptoms, particularly in the early phases of disease. Among those with severe
disease, most complications are related to the substantial volume and electrolyte loss from
diarrhea. Fever is uncommon.

The clinical manifestations of cholera caused by V. cholerae O1 versus O139 are

indistinguishable.

Incubation period — Cholera has a typical incubation period of one to two days [30-32].
However, the incubation period of cholera varies with host susceptibility and inoculum size and
can range from several hours to as long as three to five days.

Diarrhea — While mild cases of V. cholerae infection may be clinically indistinguishable from
other causes of diarrheal illness, the profound and rapid loss of fluid and electrolytes mark
severe cholera as a clinically distinct entity. Cholera stools may contain fecal matter and bile in
the early phases of disease [3]. However, the characteristic symptom of severe cholera ("cholera
gravis") is the passage of profuse "rice-water" stool, a watery stool with flecks of mucous (
picture 1). It typically has a fishy odor. The diarrhea is usually painless, without tenesmus. In
adults, stool output can reach as high as 1 liter per hour in the most severe cases. In children,
the maximal rate of stool excretion in severe cholera is typically between 10 and 20 cc/kg/hour
[33]. This rate of fluid loss is not typically observed in other causes of diarrheal illness.

In addition, compared with other causes of childhood diarrheal illness, stool from cholera
patients contains a higher concentration of sodium, as well as significant amounts of potassium
and bicarbonate ( table 1).

In patients treated with proper rehydration, diarrhea is most severe during the first two days
and ends after four to six days [34-36]. The total volume loss over the course of illness may be
up to 100 percent of body weight [35].

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Other gastrointestinal symptoms — Vomiting, frequently with watery emesis, is common,

and may begin either before or after the onset of diarrhea. Patients may have abdominal
cramping but typically do not have the frank abdominal pain classically associated with
dysentery.

Manifestations of hypovolemia and electrolyte loss — Because of the rapid fluid and
electrolyte loss characteristic of diarrhea associated with severe cholera, hypovolemia and
electrolyte abnormalities are the most important sequelae. Severe hypovolemia may occur
within hours of the onset of symptoms. In the early stages of the cholera epidemic in Haiti, the
median time between onset of symptoms and death in individuals who died before
presentation to a cholera treatment center was 12 hours [37].

Cholera patients with severe hypovolemia may have sunken eyes, dry mouth, cold clammy skin,
decreased skin turgor, or wrinkled hands and feet (also known as "washer woman's hands").
Patients are frequently apathetic and lethargic. Acidosis from loss of stool bicarbonate as well
as lactic acidosis from poor perfusion may result in Kussmaul breathing (deep respirations
reflecting compensatory hyperventilation). The peripheral pulse is rapid and thready initially,
and it may become difficult to palpate as blood pressure drops. Muscle cramping and weakness
due to loss of potassium and calcium are common.

Laboratory testing of cholera patients may reveal hypokalemia, hyponatremia or hypernatremia

(although cholera is most often associated with isonatremic dehydration), hypocalcemia, and
acidosis.

Renal failure with acute tubular necrosis may occur as urine output decreases. In children,
depletion of glycogen stores and inadequate gluconeogenesis can lead to symptoms of severe
hypoglycemia or even coma.

Additional complications — Pneumonia has been described as a frequent comorbidity among

children with cholera, potentially from aspiration in the setting of vomiting, and has been
associated with mortality [38]. Blood stream invasion by the organism is rare. Fever is also
infrequent, so the presence of an elevated temperature should prompt consideration of a
concurrent infection or complication.

"Cholera sicca" is an unusual form of the disease in which fluid accumulates in the intestinal
lumen; circulatory collapse and even death can occur in the absence of diarrhea.

In general, there are no long-term complications of cholera when it is appropriately treated.

However, like other causes of childhood diarrheal illness, cholera may contribute to the
development of chronic enteropathy and malnutrition in young children.
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Mortality — The mortality of cholera in untreated patients may reach 50 to 70 percent [39,40].
Administration of appropriate rehydration therapy can reduce the mortality of severe cholera to
less than 0.5 percent [1]. In areas where cholera is endemic, the mortality risk is increased in
children (10 times greater than in adults) [41,42]. Although earlier studies had suggested a high
risk of fetal death associated with cholera during pregnancy (up to 50 percent during the third
trimester), more recent studies have reported a lower, but still elevated, risk (approximately 8
percent) [43,44].

DIAGNOSIS

Most cases of cholera are presumptively diagnosed based on clinical suspicion in patients who
present with severe acute watery diarrhea. The diagnosis can be confirmed by isolation of V.
cholerae from stool cultures performed on specific selective media. Rapid tests such as stool
dipsticks or darkfield microscopy can support the diagnosis in settings where stool culture is
not readily available. (See 'Diagnostic studies' below.)

However, because of the morbidity of severe cholera, the variable availability of diagnostic
testing in endemic and epidemic settings, and the general applicability of fluid resuscitation to
other causes of severe watery diarrhea, management of cholera should be initiated on the basis
of clinical suspicion. (See 'Treatment' below.)

When to suspect cholera — Cholera is a potential cause of any case of severe watery diarrhea
with or without vomiting, especially in patients who develop rapid and severe volume depletion.
Whereas many different microbial pathogens can lead to volume-depleting diarrhea in children,
V. cholerae is the primary etiology in adults with such a presentation.

Specifically, according to the World Health Organization, cholera should always be suspected
when a patient five years or older develops severe volume depletion from acute watery
diarrhea, even in an area where cholera is not known to be endemic [45]. In endemic areas,
cholera should be suspected in patients two years or older with severe acute watery diarrhea.

In resource-rich settings where cholera is rare, epidemiologic clues that might increase the
suspicion of V. cholerae in a patient with watery diarrhea include travel to endemic areas or
areas where cholera outbreaks are occurring or ingestion of undercooked or raw shellfish.

Diagnostic studies

Stool culture — A definitive diagnosis of cholera is based on isolation of the organism from
clinical samples, which also permits a determination of the antibiotic susceptibility profile. V.

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cholerae can be isolated from stool using selective media such as thiosulfate citrate bile sucrose
(TCBS) agar or taurocholate tellurite gelatin agar (TTGA). Once cultured, V. cholerae can be
identified by biochemical tests; serogroup and serotype can be assigned by testing with specific
antibodies [46]. In settings such as the United States, where cholera is a sporadic illness, the
clinical microbiology laboratory should be informed of a suspicion of cholera so that
appropriate selective media can be used. These selective media are not routinely used for stool
culture.

The recovery of viable V. cholerae from clinical specimens can be enhanced by enrichment in
alkaline peptone water [46]. V. cholerae can also persist in a number of standard transport
media, including Cary-Blair media, while being transported to a central laboratory from field
settings.

Rapid tests and other tools

● Antigen detection − Several rapid antigen detection-based tests are commercially

available for diagnosis of cholera [47]. These include immunochromatographic lateral flow
devices (dipsticks), such as Crystal VC, which detect the presence of the O1 or O139
antigen in watery diarrheal stools, and Cholkit, which detects only the O1 antigen. In one
meta-analysis including 20 studies representing 8 different commercial rapid tests, the
combined sensitivity was 90 percent (95% CI 86-93) and the specificity was 86 percent (95%
CI 81-90), relative to bacterial culture (the diagnostic gold standard); there was variation
across individual studies [47].

The sensitivity of culture is diminished among individuals who no longer shed viable
bacteria in the stool; negative stool culture may be observed in the setting of antibiotic
administration and/or coinfection with lytic bacteriophage [48,49]. The apparent
diminished specificity of antigen-based dipstick tests (bacterial culture used as the
diagnostic gold standard) may reflect of the limits of bacterial culture. To account for this,
one study evaluated the performance of Cholkit, Crystal VC, microbial culture, and
polymerase chain reaction (PCR) using a Bayesian latent class modeling approach; the
sensitivity of Cholkit and Crystal VC were 98 percent (95% CI 88-100 percent for both), with
specificities of 97 percent (95% CI 89-100 percent) and 98 percent (95% CI 92-100 percent),
respectively [50].

● Molecular tests − Molecular testing for V. cholerae (eg, PCR), including tests that use dried
fecal spots, is also feasible; however, thus far practical use of molecular tests has been
limited to epidemiologic research and surveillance [51].

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● Darkfield microscopy − Darkfield microscopy of rice-water stools (at 400x magnification)

can also be used to evaluate for the presence of highly motile Vibrios, whose shooting
star-like motion can be inhibited by the subsequent addition of specific antibodies [52].
Darkfield microscopy is quite specific for V. cholerae but lacks sufficient sensitivity to be
used reliably for diagnosis.

ADDITIONAL EVALUATION

Further clinical evaluation of the patient with suspected or confirmed cholera includes an
assessment of the degree of volume depletion ( table 2), as this determines the management
strategy. (See 'Assessment of fluid loss' below.)

Laboratory testing is generally not needed, although serum electrolyte and glucose testing may
be helpful to identify extreme abnormalities in patients who have ileus, confusion, seizure, or
no urine output in response to fluid replacement. (See "Approach to the adult with acute
diarrhea in resource-limited countries", section on 'Clinical assessment' and "Approach to the
child with acute diarrhea in resource-limited countries", section on 'Clinical assessment'.)

DIFFERENTIAL DIAGNOSIS

A variety of pathogens can cause acute watery diarrhea ( table 3). In resource-limited
settings, where cholera most commonly occurs, rotavirus and cryptosporidium are frequent
causative pathogens among infants and young children, whereas enterotoxigenic Escherichia
coli predominates among older children and adults.

There are no signs or symptoms that can unequivocally distinguish cholera from other
infectious causes of severe watery diarrhea. However, as above, suspicion for cholera should be
raised if watery diarrhea is accompanied by severe and rapid volume depletion or occurs in an
outbreak setting.

TREATMENT

Aggressive volume repletion is the mainstay of treatment for cholera. Replacement fluids can
be given orally, except in the cases of severe volume depletion or shock, in which rapid fluid
repletion is warranted and intravenous fluids should thus be given. Antibiotics are an adjunctive
therapy for patients with some to severe volume depletion and may be of particular use in

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epidemic settings. Ensuring adequate nutrition is important for all patients, and children may
additionally benefit from supplementation of certain micronutrients.

These issues are discussed in detail below. The discussion is consistent with recommendations
from the World Health Organization (WHO), which are based upon the natural history and
pathophysiology of cholera as well as practical considerations from a public health standpoint
[45].

Fluid management — Fluid management of a patient with suspected or confirmed cholera is

guided by the level of volume depletion and an assessment of ongoing fluid losses.

Assessment of fluid loss — Volume status can be readily assessed through simple
examination of the mental status, eyes, mouth, skin, and pulse. The degree of volume depletion
can be categorized by WHO criteria of none (<5 percent of body weight), some (5 to 10 percent),
or severe (>10 percent) based on physical findings ( table 2). Cholera cots ( picture 2) are
inexpensive and useful for estimating continued volume losses in stool. In the absence of
cholera cots, continuing losses can be estimated as 10 to 20 mL/kg of body weight for each
stool or episode of vomiting.

Fluid resuscitation — The type and quantity of fluids to administer is determined by the level
of volume depletion and an assessment of ongoing fluid losses ( table 2). The entire
estimated fluid deficit should be replaced within three to four hours of presentation [45].

Detailed approaches to fluid repletion for adults ( algorithm 1) and children with acute
diarrhea are found elsewhere. (See "Approach to the adult with acute diarrhea in resource-
limited countries", section on 'Rehydration' and "Approach to the child with acute diarrhea in
resource-limited countries", section on 'Fluid and electrolytes'.)

Of note, while the general approach to volume repletion for severe cholera follows that for
watery diarrhea from other causes, the specifics of fluid management for cholera are distinct in
that patients with severe cholera present with more severe volume depletion (usually >5
percent), have more rapid fluid losses (typically 10 to 20 mL/kg/hour), and have proportionally
greater electrolyte losses in the stool than patients with non-cholera gastroenteritis [53,54]. For
these reasons, the most common errors in caring for patients with cholera include
underestimating the amount of fluid needed to correct volume depletion and replace ongoing
losses, or the use of incorrect, non-isotonic fluids to replace stool losses.

● Patients with some volume depletion — Oral rehydration solution (ORS) should be used
for volume repletion ( table 4), as it is as effective as and more practical than
intravenous fluid repletion in this setting (see "Oral rehydration therapy", section on
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'Efficacy'). In 2002, WHO recommended the use of a reduced osmolar ORS, which has
been demonstrated to decrease stool output, vomiting, and the need for supplemental
intravenous fluids [55]. Among patients with cholera, subclinical hyponatremia is common
with this WHO recommended ORS formulation, but rates of symptomatic hyponatremia
do not appear to be significantly increased [56]. A rice-based ORS that includes rice
powder instead of glucose has also been demonstrated to reduce the duration of diarrhea
and stool losses in severe cholera but is more tedious to prepare [57]. Types of ORS are
discussed in detail elsewhere ( table 1). (See "Oral rehydration therapy", section on
'Commercial and standard ORS'.)

Of note, patients with profound vomiting or continuing stool losses in the setting of
severe cholera can rapidly progress to severe dehydration if only ORS is provided, and
intravenous therapy in conjunction with ORS may thus be warranted for these patients.
Other indications for intravenous volume repletion in patients without severe volume
depletion include an inability to drink because of vomiting or mental status changes.

● Patients with severe volume depletion or hypovolemic shock — Intravenous fluids should
be urgently administered to rapidly restore circulation. An initial fluid volume of 100 mL/kg
should be given over three hours (or five hours for infants), with 30 mL/kg given over the
first half-hour (or first hour for infants). In patients with cholera, intravenous Ringer's
lactate is the best commercially available intravenous solution for this purpose as it
includes potassium and sodium bicarbonate, which are both lost in cholera stools (
table 1). However, locally-prepared fluids, such as "Dhaka solution," containing glucose
and more potassium than Ringer's lactate are available in some cholera-endemic regions
and can address potential complications of severe cholera including hypokalemia,
hypoglycemia, and metabolic acidosis.

Patients with severe cholera typically require an average of 200 mL/kg of isotonic oral or
intravenous fluids in the first 24 hours of therapy and may require more than 350 mL/kg [45].
Adherence to current standards of fluid management reduces the mortality of severe cholera to
less than 0.2 percent [58]. However, access to appropriate rehydration therapy is an important
obstacle, particularly during cholera epidemics. For this reason, a community-based response
and the strategic use of decentralized treatment centers (ie, oral rehydration points) to improve
access to therapy are crucial to the successful management of cholera outbreaks [59].

Continued monitoring — Volume status should be assessed through physical exam on an

ongoing basis ( table 2), more frequently for more severe volume depletion. The rate of fluid
repletion can be increased if volume depletion is not improving. Once the fluid volume to

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replace the estimated initial deficit has been administered, patients should then be managed
based on the estimated degree of residual volume depletion from ongoing losses.

Antibiotic therapy — Antibiotics are an adjunctive therapy for patients with cholera and
moderate to severe volume depletion. Several studies have demonstrated that in such patients,
effective antibiotics for cholera ( table 5) can shorten the duration of diarrhea, reduce the
volume of stool losses by up to 50 percent, and lessen the duration of shedding of V. cholerae to
one to two days [60]. As they can decrease shedding of an infectious organism, it is logical that
antibiotics would play a particularly important role in interrupting cholera outbreaks, although
this has not been directly demonstrated [61]. Antibiotics can be administered once the initial
volume deficit is corrected and vomiting has ceased.

The antibiotic options for cholera include macrolides, fluoroquinolones, and tetracyclines. The
choice between them should be based on availability and local resistance patterns.

Tetracyclines are the antibiotic class for which there is greatest clinical experience, and several
trials have demonstrated the efficacy of tetracyclines [60,62]. In a randomized trial from
Bangladesh of 246 patients with severe volume depletion and culture confirmed tetracycline-
susceptible V. cholerae, a single high dose of doxycycline (300 mg) had similar efficacy as a two-
day course of tetracycline (500 mg every six hours) with respect to stool output, duration of
diarrhea, vomiting, and requirement for oral rehydration solution [63]. However, resistance to
tetracycline and doxycycline is common [39,64,65], so empiric use of these agents should be
limited to outbreak settings in which the causative isolate has documented susceptibility.

In regions where tetracycline resistance is common, fluoroquinolones and macrolides are

reasonable alternative agents, although resistance to fluoroquinolones is also growing in
endemic areas.

Fluoroquinolones at varying doses, including a single dose, have had at least comparable
efficacy as tetracyclines against both V. cholerae O1 and O139 in several trials [66-68]. In one
randomized trial that included 260 adult men with moderate to severe volume depletion in the
setting of V. cholerae O1 or O139 infection in Bangladesh, ciprofloxacin (1000 mg single dose)
was effective against both strains, and superior to doxycycline (300 mg single dose) in
eradicating organisms from stool [67]. In that study, 37 percent of the O1 isolates were resistant
to tetracycline. However, in Asia and Africa, fluoroquinolone resistance among Vibrio cholerae
O1 isolates has subsequently been described [69-71]. Between 2001 and 2004, the in vitro
susceptibility of V. cholerae O1 to ciprofloxacin in Bangladesh decreased, as reflected by a 10-
fold increase in the mean minimal inhibitory concentration [MIC] from 0.023 mcg/mL to 0.250
mcg/mL [69,71]. Multi-dose fluoroquinolone regimens (eg, given for three days) are associated

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with higher rates of clinical and bacteriologic response than single-dose regimens for isolates
that have decreased fluoroquinolone susceptibility (identified by resistance to nalidixic acid)
[72].

Macrolides are also effective in adults and children [69,71,73-75]. In a trial of 128 children with
cholera, erythromycin (12.5 mg/kg every six hours for three days) and azithromycin (20 mg/kg
single dose) had similar clinical and bacteriologic efficacy, although azithromycin was
associated with less vomiting. Some trials have demonstrated greater efficacy with macrolides
compared with fluoroquinolones, likely because of decreased susceptibility of V. cholerae strains
to the latter [71,73,75]. As an example, in a randomized trial of 195 men with severe cholera in
Bangladesh, single-dose azithromycin (1 gram) was superior to single-dose ciprofloxacin (1
gram) with regards to clinical efficacy (73 versus 27 percent ceased to have watery stool at 48
hours) and bacteriologic efficacy (78 versus 10 percent eradication of V. cholerae from stools at
48 hours) [71]. The median MIC to ciprofloxacin in this study was 11 to 83 times higher than
observed in previous studies at that site. Strains of V. cholerae O1 resistant to both erythromycin
and azithromycin have rarely been reported [76].

Most V. cholerae O139 strains and many O1 El Tor strains are resistant to trimethoprim-
sulfamethoxazole and furazolidone [65].

Nutrition and vitamins — As with other causes of acute diarrhea, adequate nutrition in
patients with cholera is important to prevent malnutrition and facilitate recovery of normal
gastrointestinal function [45]. Eating should resume as soon as possible after the initial fluid
deficit of cholera is corrected, and breastfeeding of infants should be encouraged in
conjunction with oral rehydration solution.

Among children who have acute diarrhea, zinc and vitamin A supplementation are also
important interventions. Zinc supplementation reduces the duration and volume of stool in
children with cholera [77]. This is discussed elsewhere. (See "Approach to the child with acute
diarrhea in resource-limited countries", section on 'Vitamins and minerals'.)

PREVENTION

Preventing transmission — A clean water supply and appropriate sanitation are the
cornerstones of cholera prevention. However, these can be difficult to achieve in resource-
limited settings. Over 2 billion people lack access to clean water or sanitation and are thus at
risk for waterborne diseases such as cholera [78]. Breastfeeding of young infants in endemic
settings protects against cholera and other enteric infections (see "Infant benefits of

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breastfeeding", section on 'Prevention of illnesses while breastfeeding'). Additionally, filtering

water through a sari cloth before drinking has been demonstrated to be effective in preventing
V. cholerae infection acquired from surface water sources [7].

Travelers to regions where cholera is endemic should follow the general precautions for the
prevention of travelers' diarrhea [79]. This includes avoidance of tap water, food from street
vendors, raw or undercooked seafood, and raw vegetables [80]. Water can be treated with
chlorine or iodine, by filtration, or by boiling [81]. (See "Travel advice", section on 'Food and
water'.)

Vaccines

For residents in endemic areas — WHO recommends the inclusion of oral cholera vaccines in
cholera control programs in endemic areas, in conjunction with other prevention and control
strategies [82]. WHO also recommends that oral cholera vaccines be considered as part of an
integrated control program in areas at risk for a cholera outbreak. The optimal use of cholera
vaccines after an outbreak remains an area of active investigation [83], although observational
data suggest that vaccination following the onset of an epidemic is effective in reducing the risk
of cholera [84], even if only a single dose can be given [85].

Internationally licensed, commercial, oral cholera vaccines include:

● Bivalent killed whole-cell vaccine (eg, Shanchol, Shantha Biotechnics-Sanofi Pasteur, India;
or Euvichol, EuBiologics, Republic of Korea) – Contains killed whole cells of several biotypes
and serotypes of V. cholerae O1 and V. cholerae O139 without supplemental cholera toxin B
subunit. Its efficacy has been evaluated in several trials in India and Bangladesh [86-90].
Vaccine efficacy in these trials ranged from 53 to 67 percent and persisted five years
following vaccination; herd protection has also been demonstrated. In children ≤5 years
old, short-term efficacy was similar to that for older individuals, although was lower (42
percent) five years following vaccination. In situations in which the full vaccine series
cannot be given, even a single vaccine dose appears to provide protection for older
children and adults. In a randomized placebo-controlled trial, adjusted six-month vaccine
efficacy of a single dose of Shanchol was 40 and 63 percent for all and severely
dehydrating cholera, respectively, and protection was sustained over at least two years
[88,91]. However, there was no evidence of protection in children under five years of age.

Additionally, observational evidence suggests that when given shortly after the onset of a
cholera epidemic, vaccination with Shanchol can provide protection within the first several
months following administration. A case control study following a cholera outbreak in

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Guinea reported that two doses of Shanchol given as part of a nonselective mass
vaccination campaign were associated with an adjusted vaccine efficacy of 87 percent [84].

● WC-rBS (eg, Dukoral, Crucell, Sweden) – Contains killed whole cells of several biotypes and
serotypes of V. cholerae O1 in addition to recombinant cholera toxin B subunit. Its efficacy
has been evaluated in several studies, including two that occurred in outbreak settings in
Mozambique and Zanzibar [92,93]. In both studies, oral cholera vaccination was
undertaken prior to the outbreak, and in both studies, receipt of one or more doses of
vaccine was associated with 78 percent protection. Vaccination was equally effective in
children ≤5 years and in older persons [92]. Protection declines rapidly in young children
after six months but remains as high as 60 percent in older recipients for two to three
years. The WC-rBS vaccine also appears to provide herd immunity when high levels of
vaccine coverage are attained [94]. It is not effective against V. cholerae O139.

For travelers to high-risk areas — Most travelers to resource-limited settings are at low risk
for cholera, even if they are traveling to endemic or epidemic locations. Select travelers, such as
aid, refugee, and healthcare workers planning to work among displaced populations (eg, those
in crowded camps and urban slums) in endemic or epidemic settings, are at higher risk and
may benefit from pre-travel cholera vaccination. (See "Immunizations for travel", section on
'Indications'.)

In the United States, a live attenuated cholera vaccine CVD 103-HgR (Vaxchora) that prevents
cholera caused by serotype O1 is available for adult and pediatric travelers ≥2 years at high risk
of exposure [95]. The efficacy of the vaccine was demonstrated in a placebo-controlled trial of
197 healthy volunteers who underwent oral challenge with a V. cholerae O1 strain [96]. Efficacy
of a single vaccine dose against moderate to severe cholera (passage of over three liters of
loose stool) was 90 and 80 percent among those who received the oral challenge 10 days and
three months following vaccination, respectively. The vaccine was well tolerated without
increased rates of diarrhea, other gastrointestinal complaints, or fever. Clinical use of this
vaccine is discussed elsewhere. (See "Immunizations for travel", section on 'Cholera vaccine'.)

In other countries, such as Canada and Europe, the oral, inactivated whole cell recombinant
cholera toxin B subunit vaccine (Dukoral) discussed above is available for prevention of cholera
caused by serotype O1 in travelers. (See 'For residents in endemic areas' above.)

SOCIETY GUIDELINE LINKS

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Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Acute diarrhea in
adults" and "Society guideline links: Travel medicine".)

SUMMARY AND RECOMMENDATIONS

● Cholera is an acute secretory diarrheal illness caused by toxin-producing strains of the

gram-negative bacterium Vibrio cholerae. Strains of V. cholerae that do not produce toxin
do not cause cholera. V. cholerae is classified serologically, based on differences in the
structure of the O-antigen of lipopolysaccharide. Of over 200 serological groups identified,
only two (V. cholerae O1 and O139) have caused cholera epidemics. (See 'Etiologic agent'
above.)

● The precise burden of cholera is difficult to define, as the disease is vastly underreported.
Cholera primarily affects resource-limited settings where there is inadequate access to
clean water sources, as infection is most frequently acquired by the ingestion of food or
water contaminated with V. cholerae. Cholera is endemic in approximately 50 countries,
mostly in Africa and Asia, and has caused extensive epidemics throughout Africa, Asia, the
Middle East, South and Central America, and the Caribbean ( figure 1). Patterns of
cholera transmission and infection differ between historically endemic areas and areas
experiencing cholera epidemics. (See 'Epidemiology' above.)

● Infection with V. cholerae results in a spectrum of disease, ranging from asymptomatic

intestinal colonization to severe diarrhea. While mild cases of V. cholerae infection may be
clinically indistinguishable from other causes of watery diarrheal illness, the profound and
rapid loss of fluid and electrolytes mark severe cholera as a clinical entity distinct from
other causes. Significant hypovolemia and electrolyte abnormalities, which can occur
within a few hours of symptom onset, are the most important sequelae of severe cholera.
Abdominal discomfort, borborygmi, and vomiting are other common symptoms,
particularly in the early phases of disease. (See 'Clinical manifestations' above.)

● Most cases of cholera are presumptively diagnosed, based on consistent clinical

manifestations. Cholera is a potential cause of any case of severe watery diarrhea with or
without vomiting, especially in patients who develop rapid and severe volume depletion.
Whereas many different microbial pathogens can lead to volume depleting diarrhea in
young children, V. cholerae is the primary etiology in older individuals with such a
presentation. The diagnosis can be confirmed by isolation from stool cultures performed
on specific selective media. Rapid tests such as stool dipsticks or darkfield microscopy can

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support the diagnosis in settings where stool culture is not readily available. (See
'Diagnosis' above.)

● Aggressive volume repletion is the mainstay of treatment for cholera. The type and
quantity of fluids to administer is determined by the level of volume depletion and an
assessment of ongoing fluid losses ( table 2). Replacement fluids can be given orally,
except in the cases of severe volume depletion or shock, in which rapid fluid repletion is
warranted and intravenous fluids should thus be given. Patients with severe cholera
typically require an average of 200 mL/kg of isotonic oral or intravenous fluids in the first
24 hours of therapy and may require more than 350 mL/kg. (See 'Fluid management'
above.)

● Antibiotics can shorten the duration of diarrhea, reduce the volume of stool losses, and
lessen the duration of V. cholera shedding. We suggest antibiotics for patients who have
moderate to severe volume depletion in the setting of suspected or documented cholera
(Grade 2B). We also suggest antibiotics for patients who have suspected or documented
cholera in the setting of an epidemic (Grade 2C). Antibiotics are usually given orally, after
initial rehydration and when the patient is no longer vomiting. The antibiotic options for
cholera include macrolides, fluoroquinolones, and tetracyclines ( table 5). The choice
between them should be based on availability and local resistance patterns. (See
'Antibiotic therapy' above.)

● As with other causes of acute diarrhea, adequate nutrition in patients with cholera is
important to prevent malnutrition and facilitate recovery of normal gastrointestinal
function. In addition, children with acute diarrhea may benefit from zinc and vitamin A
supplementation. (See 'Nutrition and vitamins' above.)

● A clean water supply and appropriate sanitation are the cornerstones of cholera
prevention. In addition, two oral cholera vaccines that are available internationally have
demonstrated protective efficacy of 60 to 80 percent in areas at high risk of outbreak.
These vaccines may be particularly useful as part of cholera prevention programs in
endemic areas or in areas at high risk for cholera epidemics. (See 'Prevention' above.)

Use of UpToDate is subject to the Terms of Use.

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Topic 2704 Version 35.0

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GRAPHICS

Rice-water stools of cholera

The passage of profuse "rice-water" stool is characteristic of severe

cholera. The stool is watery with flecks of mucous and has the
appearance of water in which rice has been washed.

Graphic 93210 Version 1.0

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Estimated electrolyte content of cholera stool and therapeutic fluids for

cholera

Millimoles/liter
Comment
Na+ K+ Cl– HCO3– Carbohydrate

Electrolyte losses in stools

Cholera stool, 130 20 100 45 -- Stool sodium losses

adult in cholera are
higher than in other
Cholera stool, 100 30 90 30 --
diarrheal illnesses.
child

Non-cholera 50 35 25 20 --
stool, child (ETEC)

Intravenous therapy

Lactated Ringer's 130 4 109 28 -- Lactated Ringer's

solution (LR) solution is
preferred over
normal saline
because it contains
Normal saline 154 0 154 0 -- potassium and
bicarbonate. 'Dhaka
solution' contains
Cholera saline 133 13 154 48 140
more potassium and
(Dhaka solution)
bicarbonate than
LR, and also
contains dextrose.

Oral rehydration therapy

ORS (WHO 2002) 75 20 65 10 75 (glucose) WHO ORS utilizes

(citrate) glucose as a
carbohydrate
Rice based ORS 75 20 65 10 27 grams rice source. Rice based
(eg, CeraORS (citrate) syrup solids ORS formulation
75®) have been found in
randomized trials to
Homemade ORS: ~75 0 ~75 0 ~75 reduce the duration
Half (1/2) of diarrhea and
teaspoon salt stool losses in
Six (6) severe cholera. A
teaspoons homemade
sugar preparation of ORS
1 liter of clean could be used in an
water
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water
emergency
scenario.

Graphic 93208 Version 1.0

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Assessment of severity of volume depletion among patients with acute

diarrhea

Moderate Severe
Examination Mild hypovolemia
hypovolemia hypovolemia

Look at:

Mental status Alert Restless, irritable Lethargic or

unconscious

Eyes Normal Sunken Very sunken and dry

Tears Present Absent Absent

Mouth/tongue Moist, slightly dry Dry Very dry

Thirst Increased thirst Thirsty, drinks eagerly Drinks poorly or not

able to drink

Feel:

Skin pinch Goes back rapidly Goes back slowly Goes back very slowly
(tenting)

Pulse Normal Rapid, weak Very fast, weak or

nonpalpable

Extent of volume loss

<5% of body weight From 5 to 10% of body >10% of body weight

weight

Estimated fluid deficit

<50 mL/kg 50-100 mL/kg >100 mL/kg

Adapted from: Swerdlow DL, Ries AA. JAMA 1992; 267:1495 and World Health Organization. The treatment of diarrhea: A
manual for physicians and other senior health workers, 4th revision. WHO/FCH/CAH/05.1. World Health Organization,
Geneva 2005. (Available at http://whqlibdoc.who.int/publications/2005/9241593180.pdf).

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Common pathogens causing diarrhea in adults in the developing world

Clinical
Common pathogens Comments
syndrome

Acute watery Enterotoxigenic Escherichia coli Most common cause of acute watery
diarrhea (ETEC) diarrhea

Vibrio cholerae O1 or O139

Norovirus Vomiting may be a prominent feature

Campylobacter species

Nontyphoidal Salmonella enterica

Aeromonas species

Enteroaggregative Escherichia coli

(EAEC)

Enterotoxigenic Bacteroides fragilis

Acute bloody Shigella species Most common cause of acute bloody

diarrhea diarrhea

Campylobacter species

Enteroinvasive Escherichia coli (EIEC)

Enterohemorrhagic Escherichia coli

(EHEC)

Nontyphoidal Salmonella enterica Rare

Entamoeba histolytica

Schistosoma mansoni

Courtesy of Regina C LaRocque, MD, MPH, and Mark Pietroni, MA, FRCP, FFPH, DTM&H.

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Cholera cots

These devices, in which patients may defecate directly into a collection

bucket, facilitate the rapid measurement of ongoing fluid losses and
management of epidemics. Inexpensive hand decontamination between
examinations may be facilitated by using a portable locally prepared hand
sanitizer with at least 60 percent ethanol or isopropenol and an emollient
such as 3 percent glycerol[1] .

Reference:

1. Boyce, JM, Pittet, D, Healthcare Infection Control Practices Advisory Committee,

HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Guideline for Hand Hygiene in
Health-Care Settings. Recommendations of the Healthcare Infection Control Practices
Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Society
for Healthcare Epidemiology of America/Association for Professionals in Infection
Control/Infectious Diseases Society of America. MMWR Recomm Rep 2002; 51:1,45, quiz
CE1-4.

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Approach to fluid management in adult with

hypovolemia

ORS: oral rehydration salts.

Courtesy of Regina C LaRocque, MD, MPH, and Mark Pietroni, MA, MBBChir, FRCP, DTM&H.

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Replacement fluid volume for patients with moderate volume depletion by

age and weight

Replacement fluid
Age Weight
volume

<4 months <5 kg 200 to 400 mL

4 to 12 months 5 to 8 kg 400 to 600 mL

1 to 2 years 8 to 11 kg 600 to 800 mL

2 to 4 years 11 to 16 kg 800 to 1200 mL

5 to 14 years 16 to 30 kg 1200 to 2200 mL

>14 years >30 kg 2200 to 4400 mL

Patients with moderate volume depletion are estimated to have lost 5 to 10 percent of their body
weight (ie, 50 to 100 mL of fluid per kg). The total fluid deficit should be repleted within the first
three to four hours of presentation.

If weight is known, 100 mL/kg of fluid can be administered. Ongoing losses, if severe, should be
incorporated into replacement phase. Fluids should never be restricted. For infants <6 months
receiving standard oral rehydration solutions (ORS), provide an additional 100 to 200 mL of water;
this is not needed for patients receiving hypo-osmolar ORS.

Data adapted from: World Health Organization. The treatment of diarrhea: A manual for physicians and other senior health
workers - 4th revision. World Health Organization, Geneva 2005. Available at:
http://whqlibdoc.who.int/publications/2005/9241593180.pdf.

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Oral antibiotics for suspected cholera

Typical
Class Antibiotic pediatric Adult dose Comment(s)
dose*

Tetracyclines Doxycycline 4 to 6 mg/kg 300 mg (single Antibiotic resistance

(single dose) dose) to all tetracyclines is
common[1] .

Tetracycline 50 500 mg 4 times per Empiric use is

mg/kg/day in day for 3 days appropriate in
4 equally epidemics caused by
divided documented
doses, for 3 susceptible isolates.
days Not recommended
for pregnant women
and children less
than 8 years of age.

Macrolides Azithromycin 20 mg/kg 1 g (single dose) Single dose

(single dose) azithromycin is
Erythromycin 40 500 mg 4 times per preferred therapy[2] .
mg/kg/day in day for 3 days Rare reports of
4 equally macrolide resistance.
divided
doses, for 3
days

Fluoroquinolones Ciprofloxacin 20 mg/kg 1 g (single dose) Reduced

(single dose) susceptibility to
In areas with
fluoroquinolones has
isolates that have
been reported in Asia
reduced
and Africa[2,4] .
susceptibility to
fluoroquinolones: Not recommended
for pregnant women
500 mg twice daily
and children less
for 3 days[3]
than 8 years of age.

* Not to exceed maximum dose.

References:

1. Yamamoto T, Nair GB, Albert MJ, et al. Survey of in vitro susceptibilities of Vibrio cholerae O1 and O139 to
antimicrobial agents. Antimicrob Agents Chemother 1995; 39:241.
2. Saha D, Karim MM, Khan WA, et al. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med
2006; 354:2452.
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3. Khan WA, Saha D, Ahmed S, et al. Efficacy of Ciprofloxacin for Treatment of Cholera Associated with Diminished
Susceptibility to Ciprofloxacin to Vibrio cholerae O1. PLoS One 2015; 10:e0134921.
4. Islam MS, Midzi SM, Charimari L, et al. Susceptibility to fluoroquinolones of Vibrio cholerae O1 isolated from
diarrheal patients in Zimbabwe. JAMA 2009; 302:2321.

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Global cholera cases reported to the World Health Organization

There were no data listed for 1996.

Reproduced with permission from: Global Health Observatory Data Repository. Cholera cases reported to WHO. World Health Organiz
Copyright © 2012 World Health Organization. Available at: https://www.who.int/health-topics/cholera#tab=tab_1 (Accessed on Novem

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Contributor Disclosures
Regina LaRocque, MD, MPH Grant/Research/Clinical Trial Support: CDC [Grant support]. Other Financial
Interest: CDC Foundation [Subcontractor]. All of the relevant financial relationships listed have been
mitigated. Jason B Harris, MD, MPH No relevant financial relationship(s) with ineligible companies to
disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Day Zero Diagnostics [Whole genome
sequencing for microbial identification and determination of antimicrobial susceptibility]. All of the
relevant financial relationships listed have been mitigated. Elinor L Baron, MD, DTMH No relevant
financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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