# 56 - 173 Cholera and Other Vibrioses

### 173 Cholera and Other Vibrioses

Treatment for shigellosis must be adapted to the clinical context, 
with the recognition that the most fragile patients are children 
<5 years, who represent two-thirds of all cases worldwide and 
are the group most at risk of severe complications. There are few 
data on the use of quinolones in children, but Shigella dysentery 
is an accepted indication. The half-life of ciprofloxacin is longer 
in infants than in older individuals. The ciprofloxacin dose gener­
ally recommended for children is 30 mg/kg per day in two divided 
doses. Adults living in areas with high standards of hygiene are 
likely to develop milder, shorter-duration disease, whereas infants 
in endemic areas can develop severe, sometimes fatal, dysentery. In 
the former setting, treatment will remain minimal and bacteriologic 
proof of infection will often come after symptoms have resolved; 
in the latter setting, antibiotic treatment and more aggressive mea­
sures, possibly including resuscitation, are often required. 
REHYDRATION AND NUTRITION
Shigella infection rarely causes significant dehydration, particularly 
in industrialized countries. It is recommended that rehydration 
should be oral unless the patient is comatose or in shock. Because of 
the improved effectiveness of reduced-osmolarity oral rehydration 
solutions, WHO and UNICEF now recommend a standard solu­
tion of 245 mOsm/L (sodium, 75 mmol/L; chloride, 65 mmol/L; 
glucose [anhydrous], 75 mmol/L; potassium, 20 mmol/L; citrate, 
10 mmol/L). In shigellosis, the coupled transport of sodium and 
glucose may be variably affected, but oral rehydration therapy 
remains the easiest and most efficient form of rehydration, espe­
cially in severe cases.
Nutrition should be started as soon as possible, keeping in mind 
that in developing countries, malnutrition remains the primary 
indicator of the risk of diarrhea-related death. Early refeeding is 
safe, well tolerated, and clinically beneficial. Because breast-feeding 
reduces diarrheal losses and the need for oral rehydration in infants, 
it should be maintained in the absence of contraindications (e.g., 
maternal HIV infection). 
NONSPECIFIC, SYMPTOM-BASED THERAPY
Antimotility agents have been implicated in prolonged fever in 
volunteers with shigellosis. These agents are suspected of increasing 
the risk of toxic megacolon and are thought to have been respon­
sible for HUS in children infected by EHEC strains. For safety 
reasons, it is better to avoid antimotility agents in bloody diarrhea. 
TREATMENT OF COMPLICATIONS
There is no consensus regarding the best treatment for toxic mega­
colon. The patient should be assessed frequently by both medical 
and surgical teams. Anemia, dehydration, and electrolyte deficits 
(particularly hypokalemia) may aggravate colonic atony and should 
be actively treated. Nasogastric aspiration helps to deflate the colon. 
Parenteral nutrition has not been proven to be beneficial. Fever 
persisting beyond 48–72 h raises the possibility of local perforation 
or abscess. Most studies recommend colectomy if, after 48–72 h, 
colonic distention persists. However, some physicians recommend 
continuation of medical therapy for up to 7 days if the patient seems 
to be improving clinically despite persistent megacolon without 
perforation. Intestinal perforation, either isolated or complicating 
toxic megacolon, requires surgical treatment and intensive medical 
support.
Rectal prolapse must be treated as soon as possible. With the 
health care provider using surgical gloves or a soft warm wet cloth 
and the patient in the knee-chest position, the prolapsed rectum 
is gently pushed back into place. If edema of the rectal mucosa is 
evident, making reduction difficult, it can be osmotically reduced 
by application of gauze impregnated with a warm solution of satu­
rated magnesium sulfate. Rectal prolapse often relapses but usually 
resolves along with the resolution of dysentery.
HUS must be treated by water restriction, including discontinu­
ation of oral rehydration solutions and potassium-rich nutrition. 
Hemofiltration or peritoneal dialysis is often required.

■
■PREVENTION
Hand washing after defecation or handling of children’s feces and 
before handling of food is recommended. Stool decontamination (e.g., 
with sodium hypochlorite), together with a cleaning protocol for medi­
cal staff as well as for patients, has proven useful in limiting the spread 
of infection during Shigella outbreaks. Ideally, patients should have a 
negative stool culture before their infection is considered cured. Recur­
rences are rare if therapeutic and preventive measures are correctly 
implemented. Protection against fly intrusion in commonly infested 
sites such as kitchens and latrines is strongly advised in endemic areas.

Although several live attenuated oral and subunit parenteral vaccine 
candidates have been produced and are undergoing clinical trials, no 
vaccine against shigellosis is currently available. Especially given the 
rapid progression of antibiotic resistance in Shigella and its increasing 
recognition as a cause of child stunting, a vaccine is urgently needed. 
Most recent evidence indicates that synthetic polysaccharide conjugate 
vaccines (based on chemically synthesized, concatenated lipopolysac­
charide O-side chain mimics) elicit high levels of protective IgG anti­
bodies, hence promising protection. Protection would be particularly 
important for children <3 years, the population most susceptible to 
severe forms of shigellosis.
■
■FURTHER READING
Arena ET et al: Bioimage analysis of Shigella infection reveals targeting 
of colonic crypts. Proc Natl Acad Sci USA 112:E3282, 2015.
Bennish ML, Wojtyniak BJ: Mortality due to shigellosis: Community 
and hospital data. Rev Infect Dis 13(Suppl 4):S245, 1991.
Cohen D et al: Safety and immunogenicity of a synthetic carbohydrate 
CHAPTER 173
conjugate vaccine against Shigella flexneri 2a in healthy adult volun­
teers: A phase 1, dose-escalating, single-blind, randomised, placebocontrolled study. Lancet Infect Dis 21:546, 2021.
Cossart P, Sansonetti PJ: Bacterial invasion: The paradigms of 
enteroinvasive pathogens. Science 304:242, 2004.
Kotloff KL et al: The incidence, aetiology, and adverse clinical conse­
Cholera and Other Vibrioses 
quences of less severe diarrhoeal episodes among infants and children 
residing in low-income and middle-income countries: A 12-month 
case-control study as a follow-on to the Global Enteric Multicenter 
Study (GEMS). Lancet Glob Health 7:E568, 2019.
Mani S et al: Status of vaccine research and development for Shigella. 
Vaccine 34:2887, 2016.
Niyogi SK: Shigellosis. J Microbiol 43:133, 2005.
Phalipon A, Sansonetti PJ: Shigella’s ways of manipulating the host 
intestinal innate and adaptive immune system: A tool box for sur­
vival? Immunol Cell Biol 85:119, 2007.
Traa BS et al: Antibiotics for the treatment of dysentery in children. 
Int J Epidemiol 39:i70, 2010.
World Health Organization: Guidelines for the control of shigel­
losis, including epidemics due to Shigella dysenteriae type 1. WHO 
Library Cataloguing-in-Publication Data. www.who.int/cholera/
publications/shigellosis/en/.
Matthew K. Waldor, Edward T. Ryan

Cholera and Other 

Vibrioses
Members of the genus Vibrio cause several important infectious 
syndromes. Classic among them is cholera, a devastating diarrheal 
disease caused by Vibrio cholerae that has been responsible for seven 
global pandemics and much suffering over the past two centuries. 
Epidemic cholera remains a significant public-health concern in the

developing world today. Other vibrioses caused by other Vibrio spe­
cies include syndromes of diarrhea, soft tissue infection, or primary 
sepsis. All Vibrio species are highly motile, facultatively anaerobic, 
curved, gram-negative rods with one or more flagella. In nature, vib­
rios most commonly reside in tidal rivers and bays under conditions of 
moderate salinity. They proliferate in the summer months when water 
temperatures exceed 20°C, and the illnesses they cause also increase in 
frequency during the warm months.

CHOLERA
■
■DEFINITION
Cholera is an acute diarrheal disease that can, in a matter of hours, 
result in profound, rapidly progressive dehydration and death. Accord­
ingly, cholera gravis (the severe form) is a much-feared disease, par­
ticularly in its epidemic presentation. Fortunately, prompt aggressive 
fluid repletion and supportive care can obviate the high mortality that 
is historically associated with cholera. Although the term cholera has 
occasionally been applied to any severely dehydrating secretory diar­
rheal illness, whether infectious in etiology or not, it now refers to dis­
ease caused by V. cholerae serogroup O1 or O139—i.e., the serogroups 
with epidemic potential.
■
■MICROBIOLOGY AND EPIDEMIOLOGY
The species V. cholerae is classified into >200 serogroups based on the 
carbohydrate constituents of their lipopolysaccharide (LPS) O anti­
gens. Although some non-O1 V. cholerae serogroups (strains that do 
not agglutinate in antisera to the O1 group antigen) have occasionally 
caused sporadic outbreaks of diarrhea, serogroup O1 was, until the 
emergence of serogroup O139 in 1992 (see below), the exclusive cause 
of epidemic cholera. The O1 serogroup is further subdivided into two 
serotypes, termed Inaba and Ogawa. Two biotypes of V. cholerae O1, 
classic and El Tor, have been described, but the former is thought to 
be extinct.
PART 5
Infectious Diseases
Yearly incidence rate
per 100.000 inhabitants, 2020–2022
0–0.1
No reported case
0,1–1
1–10
10–100
100–1000
FIGURE 173-1  World distribution of cholera in 2020–2022. WHO, World Health Organization. (Reproduced with permission from Dr. M. Piarroux, Université de la Méditerranée, France.)

The natural habitat of V. cholerae is coastal salt water and brack­
ish estuaries, where the organism lives in close relation to plankton. 
V. cholerae can also exist in freshwater in the presence of adequate 
nutrients and warmth. Humans become infected incidentally but, once 
infected, can act as vehicles for spread. Ingestion of water contaminated 
by human feces is thought to be the most common means of acquisi­
tion of V. cholerae. However, consumption of contaminated food and 
human-to-human transmission also contribute to spread. There is 
no known animal reservoir. Although the infectious dose is relatively 
high, it is markedly reduced in hypochlorhydric persons, in those using 
antacids, and when gastric acidity is buffered by a meal. Cholera is 
predominantly a pediatric disease in endemic areas, but it affects adults 
and children equally when newly introduced into a population. In 
endemic areas, the burden of disease is often greatest during “cholera 
seasons” associated with high temperatures, heavy rainfall, and flood­
ing, but cholera can occur year-round.
Cholera is native to the Ganges delta on the Indian subcontinent. 
Since 1817, seven global pandemics have occurred. The current 
(seventh) pandemic—the first due to the El Tor biotype—began in 
Indonesia in 1961 and spread in serial waves throughout Asia as V. 
cholerae El Tor displaced the endemic classic biotype, which is thought 
to have caused the previous six pandemics. In the early 1970s, El Tor 
cholera erupted in Africa, causing major epidemics before becoming a 
persistent endemic problem. Currently, >95% of cholera cases reported 
annually to the World Health Organization (WHO) are from Africa 
and Asia (Fig. 173-1), but the true burden and distribution of cholera 
are unknown because the diagnosis is often syndromic and many 
countries with endemic cholera do not report cholera to the WHO. 
In 2022 and 2023, large outbreaks involving more than 10,000 cases 
per country were being reported every few weeks to the World Health 
Organization. It is possible that >1–4 million cases of cholera occur 
yearly (of which only ~400,000 are reported to the WHO) and that 
these cases result in >20,000–140,000 deaths annually (of which <2000 
are reported to the WHO).
Imported cases only

After a century without cholera in Latin America, the current 
cholera pandemic reached Central and South America in 1991. Fol­
lowing an initial explosive spread that affected millions, the burden 
of disease has markedly decreased in Latin America. In 2010, a severe 
cholera outbreak began in Haiti, a country with no recorded history of 
this disease. Several lines of evidence indicate that cholera was likely 
introduced into Haiti by United Nations security forces from Asia, 
raising the possibility that asymptomatic carriers of V. cholerae play an 
important role in transmitting cholera over long distances. In 2016, an 
outbreak of cholera began in Yemen in the setting of a civil war and 
population displacement and the breakdown of health infrastructure. 
The recent history of cholera has been punctuated by such severe 
outbreaks, especially among impoverished or displaced persons. These 
outbreaks are often precipitated by war or other circumstances that 
lead to the breakdown of public-health measures. Such was the case in 
the camps for Rwandan refugees set up in 1994 around Goma, Zaire; in 
2008–2009 in Zimbabwe; in 2015 in South Sudan and the Democratic 
Republic of the Congo; and in 2022 in Lebanon and the Syrian Arab 
Republic.
Sporadic endemic infections due to V. cholerae O1 strains related to 
the seventh-pandemic strain have been recognized along the U.S. Gulf 
Coast of Louisiana and Texas. These infections are typically associated 
with the consumption of contaminated, locally harvested shellfish. 
Occasionally, cases in U.S. locations remote from the Gulf Coast have 
been linked to shipped-in Gulf Coast seafood.
In October 1992, a large-scale outbreak of clinical cholera caused 
by a new serogroup, O139, occurred in southeastern India. The organ­
ism appears to be a derivative of El Tor O1 but has a distinct LPS and 
an immunologically related O-antigen polysaccharide capsule. (O1 
organisms are not encapsulated.) After an initial spread across 11 
Asian countries, V. cholerae O139 has once again been almost entirely 
replaced by O1 strains. The clinical manifestations of disease caused 
by V. cholerae O139 are indistinguishable from those of O1 cholera. 
Immunity to one, however, is not protective against the other.
■
■PATHOGENESIS
In the final analysis, cholera is a toxin-mediated disease. The watery 
diarrhea characteristic of cholera is due to the action of cholera toxin, 
a potent protein enterotoxin elaborated by the organism in the small 
intestine. The toxin-coregulated pilus (TCP), so named because its 
synthesis is regulated in parallel with that of cholera toxin, is essential 
for V. cholerae to survive and multiply in (colonize) the small intestine. 
Production of cholera toxin, TCP, and several other virulence factors 
are coordinately regulated by ToxR. This protein modulates the expres­
sion of genes coding for virulence factors in response to environmental 
signals via a cascade of regulatory proteins. Additional regulatory 
processes, including bacterial responses to the density of the bacterial 
population (in a phenomenon known as quorum sensing), modulate 
the virulence of V. cholerae.
Once established in the human small bowel, the organism produces 
cholera toxin, which consists of a monomeric enzymatic moiety (the 
A subunit) and a pentameric binding moiety (the B subunit). The B 
pentamer binds to GM1 ganglioside, a glycolipid on the surface of 
epithelial cells that serves as the toxin receptor and makes possible 
the delivery of the A subunit to its cytosolic target. The activated A 
subunit (A1) irreversibly transfers ADP-ribose from nicotinamide 
adenine dinucleotide to its specific target protein, the GTP-binding 
regulatory component of adenylate cyclase. The ADP-ribosylated G 
protein upregulates the activity of adenylate cyclase; the result is the 
intracellular accumulation of high levels of cyclic adenosine mono­
phosphate (AMP). In intestinal epithelial cells, cyclic AMP inhibits 
the absorptive sodium-transport system in villus cells and activates 
the secretory chloride-transport system in crypt cells, and these events 
lead to the accumulation of sodium chloride in the intestinal lumen. 
Because water moves passively to maintain osmolality, isotonic fluid 
accumulates in the lumen. When the volume of that fluid exceeds 
the capacity of the rest of the gut to resorb it, watery diarrhea results. 
Unless the wasted fluid and electrolytes are adequately replaced, shock 
(due to profound dehydration) and acidosis (due to loss of bicarbonate) 

follow. Although perturbation of the adenylate cyclase pathway is the 
primary mechanism by which cholera toxin causes excess fluid secre­
tion, cholera toxin also enhances intestinal secretion via prostaglandins 
and/or neural histamine receptors.

The V. cholerae genome is composed of two circular chromo­
somes. Lateral gene transfer has played a key role in the evolution 
of epidemic V. cholerae. The genes encoding cholera toxin 
(ctxAB) are part of the genome of a bacteriophage, CTXΦ. The recep­
tor for this phage on the V. cholerae surface is the intestinal coloniza­
tion factor TCP. Because ctxAB is part of a mobile genetic element 
(CTXΦ), horizontal transfer of this bacteriophage may account for the 
emergence of new toxigenic V. cholerae strains. Many of the other genes 
important for V. cholerae pathogenicity, including the genes encoding 
the biosynthesis of TCP, accessory colonization factors, and virulence 
regulators, are clustered together in the V. cholerae pathogenicity 
island. Similar clustering of virulence genes is found in other bacterial 
pathogens. It is believed that pathogenicity islands are acquired by 
horizontal gene transfer. V. cholerae O139 is probably derived from an 
El Tor O1 strain that acquired the genes for O139 O-antigen synthesis 
by horizontal gene transfer.
■
■CLINICAL MANIFESTATIONS
Individuals infected with V. cholerae O1 or O139 exhibit a range of 
clinical manifestations. Some individuals are asymptomatic or have 
only mild diarrhea; others present with the sudden onset of explosive 
and life-threatening diarrhea (cholera gravis). The reasons for the 
range in signs and symptoms of disease are incompletely understood 
but include the level of preexisting immunity, blood type (persons 
with type O blood are at greatest risk of severe disease if infected, 
whereas those with type AB are at least risk), and nutritional status. In 
a nonimmune individual, after a 24- to 48-h incubation period, chol­
era characteristically begins with the sudden onset of painless watery 
diarrhea that may quickly become voluminous. Patients often vomit. 
In severe cases, volume loss can exceed 250 mL/kg in the first 24 h. If 
fluids and electrolytes are not replaced, hypovolemic shock and death 
may ensue. Fever is usually absent. Muscle cramps due to electrolyte 
disturbances are common. The stool has a characteristic appearance: a 
nonbilious, gray, slightly cloudy fluid with flecks of mucus, no blood, 
and a somewhat fishy, inoffensive odor. It has been called “rice-water” 
stool because of its resemblance to the water in which rice has been 
washed (Fig. 173-2). Clinical symptoms parallel volume contraction: 
CHAPTER 173
Cholera and Other Vibrioses 
FIGURE 173-2  Rice-water cholera stool. Note floating mucus and gray watery 
appearance. (Courtesy of Dr. A. S. G. Faruque, International Centre for Diarrhoeal 
Disease Research, Dhaka; with permission.)

at losses of <5% of normal body weight, thirst develops; at 5–10%, pos­
tural hypotension, weakness, tachycardia, and decreased skin turgor 
are documented; and at >10%, oliguria, weak or absent pulses, sunken 
eyes (and, in infants, sunken fontanelles), wrinkled (“washerwoman”) 
skin, somnolence, and coma are characteristic. Complications derive 
exclusively from the effects of volume and electrolyte depletion and 
include renal failure due to acute tubular necrosis. Thus, if the patient 
is adequately treated with fluid and electrolytes, complications are 
averted and the process is self-limited, resolving in a few days.

Laboratory data usually reveal an elevated hematocrit (due to hemo­
concentration) in nonanemic patients; mild neutrophilic leukocytosis; 
elevated levels of blood urea nitrogen and creatinine consistent with 
prerenal azotemia; normal sodium, potassium, and chloride levels; a 
markedly reduced bicarbonate level (<15 mmol/L); and an elevated 
anion gap (due to increases in serum lactate, protein, and phosphate). 
Arterial pH is usually low (~7.2).
■
■DIAGNOSIS
Cholera should be suspected when a patient ≥5 years of age develops 
acute watery diarrhea in an area known to have cholera or develops 
severe dehydration or dies from acute watery diarrhea, even in an area 
where cholera is not known to be present. The clinical suspicion of 
cholera can be confirmed by the identification of V. cholerae in stool; 
however, the organism must be specifically sought. With experience, it 
can be detected directly by dark-field microscopy on a wet mount of 
fresh stool, and its serotype can be discerned by immobilization with 
specific antisera. Laboratory isolation of the organism requires the use 
of a selective medium such as taurocholate–tellurite–gelatin (TTG) 
agar or thiosulfate–citrate–bile salts–sucrose (TCBS) agar. If a delay 
in sample processing is expected, Cary-Blair transport medium and/
or alkaline-peptone water-enrichment medium may be used as well. 
In endemic areas, there is little need for biochemical confirmation and 
characterization, although these tasks may be worthwhile in places 
where V. cholerae is an uncommon isolate. Standard microbiologic bio­
chemical testing for Enterobacteriaceae will suffice for identification 
of V. cholerae. All vibrios are oxidase-positive. Point-of-care antigendetection cholera dipstick assays are commercially available for use in 
the field or where laboratory facilities are lacking.
PART 5
Infectious Diseases
TREATMENT
Cholera
Death from cholera is due to hypovolemic shock; thus, treat­
ment of individuals with cholera first and foremost requires fluid 
resuscitation and management. In light of the level of dehydration 
(Table 173-1) and the patient’s age and weight, euvolemia should 
first be rapidly restored, and adequate hydration should then be 
maintained to replace ongoing fluid losses (Table 173-2). Admin­
istration of oral rehydration solution (ORS) takes advantage of the 
hexose-Na+ co-transport mechanism to move Na+ across the gut 
mucosa together with an actively transported molecule such as glu­
cose (or galactose); Cl– and water follow. This transport mechanism 
remains intact even when cholera toxin is active. ORS may be made 
by adding safe water to prepackaged sachets containing salts and 
sugar or by adding 0.5 teaspoon (i.e., half a small spoonful) of table 
TABLE 173-1  Assessing the Degree of Dehydration in Patients 
with Cholera
DEGREE OF DEHYDRATION
CLINICAL FINDINGS
None or mild, but diarrhea
Thirst in some cases; <5% loss of total body 
weight
Moderate
Thirst, postural hypotension, weakness, 
tachycardia, decreased skin turgor, dry mouth/
tongue, no tears; 5–10% loss of total body weight
Severe
Unconsciousness, lethargy, or “floppiness”; weak 
or absent pulse; inability to drink; sunken eyes 
(and, in infants, sunken fontanelles); >10% loss of 
total body weight

TABLE 173-2  Treatment of Cholera, Based on Degree of Dehydrationa
DEGREE OF DEHYDRATION, 
PATIENT’S AGE (WEIGHT)
TREATMENTb
None or Mild, but Diarrheac
<2 years
1/4–1/2 cup (50–100 mL) of ORS, to a maximum 
of 0.5 L/d
2–9 years
1/2–1 cup (100–200 mL) of ORS, to a maximum 
of 1 L/d
≥10 years
As much ORS as desired, to a maximum of 2 L/d
Moderatec,d
<4 months (<5 kg)
200–400 mL of ORS
4–11 months (5–<8 kg)
400–600 mL of ORS
12–23 months (8–<11 kg)
600–800 mL of ORS
2–4 years (11–<16 kg)
800–1200 mL of ORS
5–14 years (16–<30 kg)
1200–2200 mL of ORS
≥15 years (≥30 kg)
2200–4000 mL of ORS
Severec
All ages and weights
Undertake IV fluid replacement with Ringer’s 
lactate (or, if not available, normal saline). Give 
100 mL/kg in the first 3-h period (or the first 6-h 
period for children <12 months old); start rapidly, 
then slow down. Give a total of 200 mL/kg in the 
first 24 h. Continue until the patient is awake, can 
ingest ORS, and no longer has a weak pulse.
aAdapted from World Health Organization: Outbreak Response Field Manual, Global 
Task on Cholera Control; https://www.gtfcc.org/wp-content/uploads/2020/05/gtfcccholera-outbreak-response-field-manual-2024.pdf. bContinue normal feeding during 
treatment. cReassess regularly; monitor stool and vomit output. dVolumes of ORS 
listed should be given within the first 4 h.
Abbreviation: ORS, oral rehydration solution.
salt and 6 level teaspoons (i.e., 6 small spoonfuls) of table sugar to 
1 L of safe water. Potassium intake in bananas or green coconut 
water should be encouraged. A number of ORS formulations are 
available, and the WHO now recommends “low-osmolarity” ORS 
for treatment of individuals with dehydrating diarrhea of any cause 
(Table 173-3). If available, rice-based ORS is considered superior to 
standard ORS in the treatment of cholera. ORS can be administered 
via a nasogastric tube to individuals who cannot ingest fluid; how­
ever, optimal management of individuals with severe dehydration 
includes the administration of IV fluid and electrolytes. Because 
profound acidosis (pH <7.2) is common in this group, Ringer’s lac­
tate is the best choice among commercial products (Table 173-4); 
it must be used with additional potassium supplements, prefer­
ably given by mouth. The total fluid deficit in severely dehydrated 
patients (>10% of body weight) can be replaced safely within the 
first 3–4 h of therapy, half within the first hour. Transient muscle 
cramps and tetany are common. Thereafter, oral therapy can usually 
TABLE 173-3  Composition of World Health Organization ReducedOsmolarity Oral Rehydration Solution (ORS)a,b
CONSTITUENT
CONCENTRATION, mmol/L
Na+

K+

Cl–

Citratec

Glucose

Total osmolarity

aContains (per package, to be added to 1 L of drinking water): NaCl, 2.6 g; 
Na3C6H5O7·2H2O, 2.9 g; KCl, 1.5 g; and glucose (anhydrous), 13.5 g. bIf prepackaged 
ORS is unavailable, a simple homemade alternative can be prepared by combining 
3.5 g (~1/2 teaspoon) of NaCl with either 50 g of precooked rice cereal or 6 
teaspoons of table sugar (sucrose) in 1 L of drinking water. In that case, potassium 
must be supplied separately (e.g., in orange juice or coconut water). c10 mmol of 
citrate per liter, which supplies 30 mmol of HCO3/L.

TABLE 173-4  Electrolyte Composition of Cholera Stool and of 
Intravenous Rehydration Solution
CONCENTRATION, mmol/L
SUBSTANCE
NA+
K+
CL–
BASE
Stool
 
 
 
 
Adult

Child

Ringer’s lactate

4a

aPotassium supplements, preferably administered by mouth, are required to replace 
the usual potassium losses from stool.
be initiated, with the goal of maintaining fluid intake equal to fluid 
output. However, patients with continued large-volume diarrhea 
may require prolonged IV treatment to match gastrointestinal fluid 
losses. Severe hypokalemia can develop but will respond to potas­
sium given either IV or orally. In the absence of adequate staff to 
monitor the patient’s progress, the oral route of rehydration and 
potassium replacement is safer than the IV route.
Although not necessary for cure, the use of an antibiotic to which 
the organism is susceptible diminishes the duration and volume 
of fluid loss and hastens clearance of the organism from the stool. 
Adjunctive antibiotics should therefore be administered to patients 
with moderate or severe dehydration due to cholera. In many areas, 
macrolides such as erythromycin (adults, 250 mg orally four times 
a day for 3 days; children, 12.5 mg/kg per dose four times a day 
for 3 days) or azithromycin (adults, a single 1-g dose; children, a 
single 20-mg/kg dose) are the agents of choice. Increasing resistance 
to tetracyclines is widespread; however, in areas with confirmed 
susceptibility, tetracycline (nonpregnant adults, 500 mg orally four 
times a day for 3 days; children >8 years old, 12.5 mg/kg per dose 
four times a day for 3 days) or doxycycline (nonpregnant adults, a 
300-mg single dose; children >8 years old, a single dose of 4–6 mg/
kg) may be used. Similarly, increasing resistance to fluoroquino­
lones is being reported, but in areas with confirmed susceptibil­
ity, a fluoroquinolone such as ciprofloxacin may be used (adults, 
500 mg twice a day for 3 days; children, 15 mg/kg twice a day for 
3 days). Oral administration of supplemental zinc is associated 
with decreased volume and severity of diarrhea in young children, 
including in those with cholera. Children <6 months of age with 
cholera should be treated with 10 mg of zinc daily for 10 days; chil­
dren from 6 to <60 months of age should be treated with 20 mg of 
oral zinc daily for 10 days.
■
■PREVENTION
Provision of safe water and of facilities for sanitary disposal of feces, 
improved nutrition, and attention to food preparation and storage in 
the household can significantly reduce the incidence of cholera. In 
addition, precautions should be taken to prevent the spread of cholera 
via infected and potentially asymptomatic persons from endemic to 
nonendemic regions of the world (as was probably the case in the out­
break in Haiti; see “Microbiology and Epidemiology,” above).
Much effort has been devoted to the development of an effective 
cholera vaccine over the past few decades, with a particular focus on 
oral vaccine strains. In an attempt to maximize mucosal responses, 
two types of oral cholera vaccine have been developed: oral killed vac­
cines and live attenuated vaccines. Currently, three oral killed cholera 
vaccines have been prequalified by the WHO. BivWC (ShancholTM; 
Shantha Biotechnics, Hyderabad, India) contains both biotypes and 
serotypes of V. cholerae O1 and V. cholerae O139 without supplemen­
tal cholera toxin B subunit, but its manufacture is being terminated. 
A related vaccine is produced in South Korea (EuvicholTM, EuvicholPlusTM; Eubiologics, Seoul) and currently accounts for the vast majority 
of cholera vaccine available to global health control programs. WC-rBS 
(Dukoral®; Valneva, Sweden AB, Stockholm,) contains both biotypes 
and serotypes of V. cholerae O1 supplemented with 1 mg of recombi­
nant cholera toxin B subunit per dose. The vaccines are administered 

as a two- or three-dose regimen, with doses usually separated by 
14 days. They provide ~60–85% protection for the first few months. 
Booster immunizations of WC-rBS are recommended after 2 years for 
individuals ≥6 years of age and after 6 months for children 2–5 years of 
age. For BivWC, no formal recommendation regarding booster immu­
nizations exists. However, BivWC was associated with ~60% protection 
over 5 years among recipients of all ages in a study in Kolkata, India; 
the rate of protection among children ≤5 years of age approximated 
40%. In outbreak situations, even a single dose of BivWC can provide 
some protection: 40% and 63% adjusted protection for 6 months for all 
and severely dehydrating cholera, respectively—although there was no 
evidence of protection in children younger than 5 years of age. Models 
predict significant herd immunity when vaccination coverage rates 
exceed 50%. The killed vaccines have been safely administered among 
populations with high rates of HIV infection.

Oral live attenuated vaccines for V. cholerae O1 also are in develop­
ment. These strains have in common their lack of the genes encod­
ing cholera toxin. One such vaccine, CVD 103-HgR (VaxchoraTM; 
Emergent BioSolutions, Washington, DC), is derived from a classic 
strain of V. cholerae and has been approved by the U.S. Food and 
Drug Administration for use in travelers to cholera-endemic regions 
but is not prequalified by the WHO. The vaccine was 90% and 80% 
efficacious against severe cholera after experimental infection of 
North American volunteers 10 days and 90 days after vaccination, 
respectively. Vaxchora is approved for use in individuals 2–64 years of 
age; no recommendations concerning the timing or need for booster 
vaccinations are currently available. Other live attenuated vaccine can­
didate strains have been prepared from El Tor and O139 V. cholerae 
and have been tested in studies of volunteers. An advantage of live 
attenuated cholera vaccines is that they may induce more potent pro­
tection after a single oral dose. Conjugate and subunit cholera vaccines 
also are being developed.
CHAPTER 173
Recognizing that it may be decades before safe water and adequate 
sanitation become a reality for those most at risk of cholera, the WHO 
has recommended incorporation of cholera vaccination into compre­
hensive control strategies and has established an international stockpile 
of oral killed cholera vaccine to assist in outbreak responses. A global 
strategy on cholera control was launched in 2017 with the WHO 
hosting the secretariat of the Global Task Force on Cholera Control 
(GTFCC). This country-by-country approach aims to reduce cholera 
deaths by 90% and to eliminate cholera in as many as 20 countries by 
2030. Integral components of this strategy are advancing water, sanita­
tion, and hygiene (WASH) programs, as well as use of cholera vaccine. 
From 2016 to 2023, almost 300 million doses of cholera vaccine have 
been requested from the Global Vaccine Stockpile, and approximately 
150 million doses have been shipped to requesting countries for use 
in control programs. Due to vaccine shortages, cholera vaccines have 
most recently been almost solely used in reactive and not preventative 
campaigns, and are often given as single doses.
Cholera and Other Vibrioses 
OTHER VIBRIO SPECIES
The genus Vibrio includes several human pathogens that do not cause 
cholera. Abundant in coastal waters throughout the world, noncholera 
vibrios can reach high concentrations in the tissues of filter-feeding 
mollusks. As a result, human infection commonly follows the inges­
tion of seawater or of raw or undercooked shellfish (Table 173-5). 
Most noncholera vibrios can be cultured on blood or MacConkey agar, 
which contains enough salt to support the growth of these halophilic 
species. In the microbiology laboratory, the species of noncholera 
vibrios are distinguished by standard biochemical tests. The most 
important of these organisms are Vibrio parahaemolyticus and Vibrio 
vulnificus. Vibriosis causes an estimated 80,000 illnesses and 100 deaths 
in the United States every year.
The two major types of syndromes for which these noncholera vib­
rios are responsible are gastrointestinal illness (due to V. parahaemo­
lyticus, non-O1/O139 V. cholerae, V. mimicus, V. fluvialis, V. hollisae, and 

V. furnissii) and soft tissue infections (due to V. vulnificus, V. alginolyticus, 
and V. damselae). V. vulnificus is also a cause of primary sepsis in some 
immunocompromised individuals.

TABLE 173-5  Features of Selected Noncholera Vibrioses
ORGANISM
VEHICLE OR ACTIVITY
HOST AT RISK
SYNDROME
Vibrio parahaemolyticus
Shellfish, seawater
Normal
Gastroenteritis
 
Seawater
Normal
Wound infection
Non-O1/O139 Vibrio cholerae
Shellfish, travel
Normal
Gastroenteritis
 
Seawater
Normal
Wound infection, otitis media
Vibrio vulnificus
Shellfish
Immunosuppresseda
Sepsis, secondary cellulitis
 
Seawater
Normal, immunosuppresseda
Wound infection, cellulitis
Vibrio alginolyticus
Seawater
Normal
Wound infection, cellulitis, otitis
 
Seawater
Burned, other immunosuppressed
Sepsis
aEspecially with liver disease or hemochromatosis.
Source: Table 161-3 in Harrison’s Principles of Internal Medicine, 14th edition.
■
■SPECIES ASSOCIATED PRIMARILY WITH 
GASTROINTESTINAL ILLNESS
V. parahaemolyticus 
Widespread in marine environments, the 
halophilic V. parahaemolyticus is the leading seafood-borne bacterial 
cause of enteritis worldwide. This species was originally implicated 
in enteritis in Japan in 1953, accounting for 24% of reported cases in 
one study—a rate that presumably was due to the common practice 
of eating raw seafood in that country. In the United States, commonsource outbreaks of diarrhea caused by this organism have been linked 
to the consumption of undercooked or improperly handled seafood 
or of other foods contaminated by seawater. Since the mid-1990s, the 
incidence of V. parahaemolyticus infections has increased in several 
countries, including the United States. Serotypes O3:K6, O4:K68, and 
O1:K-untypable, which are genetically related to one another, account 
in part for this increase. Recent reports from China and Thailand 
suggest that serotype O10:K4 may be an emerging serotype. The 
enteropathogenicity of V. parahaemolyticus is associated with its abil­
ity to cause hemolysis via a thermostable direct hemolysin (Vp-TDH). 
Although the mechanisms by which the organism causes diarrhea are 
not fully defined, most V. parahaemolyticus genomes encode two type 
III secretion systems, which directly inject toxic bacterial proteins into 
host cells. The activity of one of these secretion systems is required for 
intestinal colonization and virulence in animal models. V. parahaemo­
lyticus should be considered a possible etiologic agent in all cases of 
diarrhea that can be linked epidemiologically to seafood consumption 
or to the sea itself. The incidence of V. parahaemolyticus infection in 
the United States has increased from 0.06 per 100,000 persons in 1996 
to 0.9 cases per 100,000 in 2019.
PART 5
Infectious Diseases
Infections with V. parahaemolyticus can result in two distinct gas­
trointestinal presentations. The more common of the two presenta­
tions (including nearly all cases in North America) is characterized 
by watery diarrhea, usually occurring in conjunction with abdominal 
cramps, nausea, and vomiting and accompanied in ~25% of cases by 
fever and chills. After an incubation period of 4 h to 4 days, symptoms 
develop and persist for a median of 3 days. Dysentery, the less common 
presentation, is characterized by severe abdominal cramps, nausea, 
vomiting, and bloody or mucoid stools. V. parahaemolyticus also causes 
rare cases of wound infection and otitis and very rare cases of sepsis.
Most cases of V. parahaemolyticus–associated gastrointestinal ill­
ness, regardless of the presentation, are self-limited. Fluid replacement 
should be stressed. Antimicrobial agents may be of benefit in moderate 
or severe disease. Doxycycline, fluoroquinolones, macrolides, or thirdgeneration cephalosporins are usually used. Deaths are extremely rare 
among immunocompetent individuals. Severe infections are associated 
with underlying diseases, including diabetes, preexisting liver disease, 
iron-overload states, or immunosuppression.
Non-O1/O139 (Noncholera) V. cholerae 
The heterogeneous 
non-O1/O139 V. cholerae organisms cannot be distinguished from V. 
cholerae O1 or O139 by routine biochemical tests but do not agglu­
tinate in O1 or O139 antiserum. Non-O1/O139 strains have caused 
several well-studied food-borne outbreaks of gastroenteritis and have 
also been responsible for sporadic cases of otitis media, wound 

infection, and bacteremia. Generally, non-O1/O139 V. cholerae strains 
do not produce cholera toxin and do not cause large epidemics of diar­
rheal disease. Like other vibrios, non-O1/O139 V. cholerae organisms 
are widely distributed in marine environments. In most instances, 
recognized cases in the United States have been associated with the 
consumption of raw oysters or with recent travel. The broad clinical 
spectrum of diarrheal illness caused by these organisms is probably due 
to the group’s heterogeneous virulence attributes.
The typical incubation period for gastroenteritis due to these organ­
isms is <2 days, and the illness lasts for ~2–7 days. Patients’ stools 
may be copious and watery or may be partly formed, less voluminous, 
and bloody or mucoid. Diarrhea can result in severe dehydration. 
Many cases include abdominal cramps, nausea, vomiting, and fever. 
Like those with cholera, patients who are seriously dehydrated should 
receive oral or IV fluids; the value of antibiotics is not clear.
Extraintestinal infections due to non-O1/O139 V. cholerae com­
monly follow occupational or recreational exposure to seawater. 
Around 10% of non-O1/O139 V. cholerae isolates come from cases 
of wound infection, 10% from cases of otitis media, 20% from cases 
of bacteremia (which is particularly likely to develop in patients with 
liver disease), and approximately 40% from stool. Extraintestinal infec­
tions should be treated with antibiotics. Information to guide antibiotic 
selection and dosing is limited, but most strains are sensitive in vitro to 
tetracycline, ciprofloxacin, and third-generation cephalosporins.
■
■SPECIES ASSOCIATED PRIMARILY WITH SOFT 
TISSUE INFECTION OR BACTEREMIA
(See also Chap. 134)
V. vulnificus 
Infection with V. vulnificus is rare, but this organism is 
the most common cause of severe Vibrio infections in the United States. 
Like most vibrios, V. vulnificus proliferates in the warm summer months 
and requires a saline environment for growth. In the United States, 
infections in humans typically occur in coastal states between May and 
October and most commonly affect men >40 years of age. V. vulnifi­
cus has been linked to two distinct syndromes: primary sepsis, which 
usually occurs in patients with underlying liver disease, and primary 
wound infection, which generally affects people without underlying 
disease. (Vulnificus is Latin for “wound maker.”) Some authors have 
suggested that V. vulnificus also causes gastroenteritis independent of 
other clinical manifestations. V. vulnificus is endowed with a number 
of virulence attributes, including a capsule that confers resistance to 
phagocytosis and to the bactericidal activity of human serum as well 
as a cytolysin. Measured as the 50% lethal dose in mice, the organism’s 
virulence is considerably increased under conditions of iron overload; 
this observation is consistent with the propensity of V. vulnificus to 
infect patients who have hemochromatosis.
Primary sepsis most often develops in patients who have cirrho­
sis or hemochromatosis. However, V. vulnificus bacteremia can also 
affect individuals who have hematopoietic disorders or chronic renal 
insufficiency, those who are using immunosuppressive medications 
or alcohol, or (in rare instances) those who have no known underly­
ing disease. After a median incubation period of 16 h, the patient 
develops malaise, chills, fever, and prostration. One-third of patients