AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The appellation for cholera probably derives from the Greek word for the gutter of a roof, comparing the deluge of water following a rainstorm to that of the anus of an infected person. Cholera is an ancient disease caused by Vibrio cholerae O1 or, more recently, by V cholerae O139. The hallmark for the disease is profuse secretory diarrhea. Cholera can be spread as an endemic, epidemic, or pandemic disease. Despite all the major advances in research, the condition still remains a challenge to the modern medical world.

Throughout history, populations all over the world have sporadically been affected by devastating outbreaks of cholera. Records from Hippocrates (460-377 BC) and Galen (129-216 AD) describe an illness that might well have been cholera, and numerous hints indicate that a choleralike malady was also known in the plains of the Ganges River since antiquity.

The seventh pandemic of cholera, caused by V cholerae O1, biotype El Tor, began in 1961 and continues today. Reports also document endemics caused by biotype O139.

Cholera has been rare in industrialized nations for the last 100 years; however, the disease is still common in other parts of the world, including the Indian subcontinent and sub-Saharan Africa. The World Health Organization has reported cholera outbreaks in West Africa as recent as September 2005. In the United States, because of advanced water and sanitation systems, cholera is not a major threat, although everyone, especially travelers, should be aware of how the disease is transmitted and what can be done to prevent it.

Pathophysiology

The species V cholerae has been classified according to the carbohydrate determinants of its somatic O antigens. Approximately 140 serotypes have been defined and are classified broadly as those that agglutinate in antisera to the O1 group antigen (V cholerae O1) or those that do not agglutinate in antisera to the O1 group antigen (non-O1 V cholerae).

V cholerae exists in 2 biotypes, classic and El Tor, which are defined on the basis of their biochemical and other laboratory parameters. Each biotype has been divided further into 2 serotypes, Inaba and Ogawa. V cholerae O1 was the cause of most pandemics until a new strain, termed V cholerae O139 (non-O1 type), was recognized as a cause of epidemic in southern India and parts of Bangladesh in 1992.

Cholera is a toxin-mediated disease. The clinical features and epidemiologic manifestations of disease caused by cholera O139 are indistinguishable from those caused by O1 strains. Cholera toxin (CTX) is a potent protein enterotoxin elaborated by the organism in the small intestine. To reach the small intestine, however, the organism has to negotiate the normal defense mechanisms of the GI tract. Because the organism is not acid-resistant, it depends on its large inoculum size to bypass gastric acidity. Using its own properties, such as motility, chemotaxis, and elaboration of hemagglutinin/protease, the organism transcends the mucous layer of the small intestine.

Hemagglutinin/protease is both an agglutinin and a zinc-dependent protease, which cleaves the mucin and fibronectin as well as a subunit of CTX. Hemagglutinin/protease also may serve to facilitate the spread and excretion of vibrios within the intestine in stools by detaching them from the intestinal walls. After the vibrios negotiate these 2 barriers, they adhere to the intestinal wall mediated by toxin-coregulated pilus (TCP). The synchronous working of TCP, CTX, and a few other virulence factors all are regulated by toxR gene product, which is designated as the "master switch."

Once established, the organisms produce CTX that consists of subunits A and B. The B subunit is the binding subunit, and the A subunit is the enzymatic subunit. These 2 working in harmony, transfer adenosine diphosphate (ADP) and activate it to cyclic adenosine monophosphate (cAMP), which inhibits the absorptive sodium transport and activates the excretory chloride transport in the intestinal crypt cells, eventually leading to an accumulation of sodium chloride in the intestinal lumen.

The high osmolality in the intestinal lumen is balanced by water secretion that eventually overwhelms the lumen absorptive capacity and leads to diarrhea. Unless the wasted fluid and electrolytes are replaced adequately, shock (caused by profound dehydration) and acidosis (caused by loss of bicarbonate) follow.

The O139 Bengal strain of V cholerae has a very similar pathogenic mechanism except that it produces a novel O139 lipopolysaccharide (LPS) and an immunologically related O-antigen capsule. These 2 features enhance its virulence and increase its resistance to human serum in vitro and occasional development of O139 bacteremia.

Frequency

United States

In the United States, cholera has virtually been eliminated because of improved hygiene and sanitation systems.

A unique strain of V cholerae O1 that is related closely to, but distinguishable from, the strain of the seventh pandemic was recognized in Louisiana and along the Gulf of Mexico in 1973. Since then, this strain has become indigenous to the Gulf coast, although its environmental reservoirs and ecology remain unclear. With the current level of sanitation, epidemic spread of this organism is not expected.

Through 1991, 65 cases of diarrhea resulting from this endemic infection were reported to the Center for Disease Control (CDC). Most of these cases occurred in Louisiana. Through 1990, 42 cases of cholera occurred in travelers returning to the United States from abroad during the seventh pandemic. The frequency of cholera among international travelers returning to the United States has averaged 1 per 500,000 population, with a range of 0.05-3.7 per 100,000 population, depending on the countries visited.

International

Periodic global or pandemic spread of cholera from its endemic reservoir in the Indian subcontinent was recognized as characteristic of cholera as early as 1831, when the second pandemic reached England.

Of the 6 pandemics that occurred in the 19th century, 5 affected Europe and 4 reached the United States, causing more than 150,000 deaths in 1832 and 50,000 deaths in 1866. The seventh pandemic of cholera, and the first in the 20th century, began in 1961; by 1991, it had affected 5 continents. This was the first pandemic recognized to be caused by the El Tor biotype of V cholerae O1. After its spread in Asia in the 1960s, V cholerae O1 El Tor entered Africa in the early 1970s, causing epidemic cholera and establishing itself as a significant endemic infection. Cholera epidemics now occur regularly in Africa.

The number of patients with cholera worldwide is uncertain because most cases go unreported. The likely contributory factors are that (1) most cases occur in remote areas of developing countries where definitive diagnosis is not possible, (2) reporting systems often are nonexistent in such areas, (3) the stigma of reporting cholera has direct consequences on commercial trade and tourism, and (4) many countries with endemic cholera do not report at all.

In 1990, fewer than 30,000 cases were reported to the WHO. Reported cases increased more than 10-fold with the beginning of the Latin American epidemic in 1991. In 1994, the number of cases (384,403) and countries (94) reporting cholera was the largest ever registered at the WHO. Even Europe experienced a 30-fold increase in cholera from 1993-1994, with reported cases increasing from 73 to 2,339 and deaths increasing from 2 to 47.

In 1998, another surge in the number of cases occurred, with the number almost doubling that reported in 1997. In 2004, a total of 56 countries officially reported cholera activity to WHO. A total of 101,338 cases and 2345 deaths were reported. Africa and Asia continue to report the highest number of cases.

Mortality/Morbidity

• In 1950, during the sixth pandemic, case fatality rates were very high, and as many as 50-70% of patients died. With the replacement of classic cholera with El Tor, a less virulent strain, case fatality rates reduced dramatically during the 1960s.
• Fatality rates have declined further because of better treatment and, in particular, increasingly available oral rehydration therapy, which was introduced during the early 1970s but became widely available in many parts of the world in the 1980s.
• For most patients, treatment with oral rehydration is sufficient; however, when safe water or oral rehydration salts are not available, case fatality rates can be very high.
• A case fatality rate of 25-50% was estimated among untreated patients in refugee camps in Goma. Where good treatment is readily accessible, the case fatality rate is less than 1%. In Africa, a marked decline in case fatality rates has occurred since 1970; however, Africa continues to have the highest reported case fatality rates (approximately 5% in 1998 and 4% in 1999) compared to the rest of the world.
• Average case fatality rates for Europe and the Americas continue to hover around 1%. Because the fatality rates vary in different parts of the world, the global case fatality rates only partly reflect the trends in each region because the global rates also are affected by the global distribution of cases.

Age

In nonendemic areas, incidence of infection is similar in all age groups, although adults are less likely to become asymptomatic than children. The exception is breastfed children, who are protected against severe disease because of less exposure and because of the antibodies to cholera they obtain in breast milk.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Diarrhea
• • Profuse watery diarrhea is a hallmark of cholera. Cholera should be suspected when a patient older than 5 years develops severe dehydration from acute, severe, watery diarrhea (usually without vomiting) or in any patient older than 2 years who has acute watery diarrhea in an area where an outbreak of cholera has occurred.
  • Stool volume during cholera is more than that of any other infectious diarrhea. Patients with severe disease may have a stool volume of more than 250 mL/kg body weight in a 24-hour period.
  • The stool may contain fecal material early in the course of clinical illness. The characteristic cholera stool is an opaque white liquid that is not malodorous and often is described as having a rice water appearance (ie, in color and consistency, it resembles water that has been used to wash or cook rice).
  • V cholerae does not elicit an inflammatory response, and cholera stool contains few leukocytes and no erythrocytes.
  • Because of the large volume of diarrhea, patients with cholera have frequent and often uncontrolled bowel movements.
  • Patients experience abdominal cramps, probably caused by distention of loops of small bowel as a result of the large volume of intestinal secretions.
• Vomiting
• • Vomiting is a prominent manifestation of illness. It occurs early in the course of the disease when the vomiting is caused by decreased gastric and intestinal motility and later in the course of the disease when academia is more likely.
  • If untreated, the diarrhea and vomiting lead to isotonic dehydration and, in patients with severe disease, vascular collapse, shock, and death.
  • Dehydration can develop with remarkable rapidity, within hours after the onset of symptoms. This contrasts with disease produced by infection from any other enteropathogen.
  • Because the dehydration is isotonic, water loss is proportional between 3 body compartments, intracellular, intravascular, and interstitial.

Physical

• Dehydration
• • Dehydration has been classified into the following 3 categories to facilitate patient treatment: severe, some (previously termed moderate in the WHO criteria for the classification of dehydration), and none (previously termed mild by the WHO). Table 1 shows the clinical findings associated with the classification. 

    Table 1. Assessment of the Patient With Diarrhea for Dehydration

    Condition	Eyes	Tears	Mouth and Tongue	Thirst	Skin Pinch	Decision
    Well, alert	Normal	Present	Moist	Drinks normally, not thirsty	Goes back quickly	Patient has no signs of dehydration.
    *Restless, irritable	Sunken	Absent	Dry	*Thirsty, drinks eagerly	*Goes back slowly	If the patient has 2 or more signs, including at least 1 * sign, some dehydration is present.
    *Lethargic or unconscious, floppy	Very sunken and dry	Absent	Very dry	*Goes back very slowly	*Goes back very slowly	If the patient has 2 or more signs, including at least 1 * sign, severe dehydration is present.

  • In adults and children older than 5 years, other signs for severe dehydration include absent radial pulse and low blood pressure.
  • The skin pinch may be less useful in patients with marasmus (severe wasting), kwashiorkor (severe malnutrition with edema), or obesity.
  • Tears are relevant signs only for infants and young children.
  • Patients with severe dehydration have a characteristic clinical appearance that is attributable to the loss of approximately 15% of total body water (approximately 10% of total body weight).
  • Intracellular and intravascular dehydration is manifested in decreases skin turgor, sunken eyes, and wrinkled ("washer woman") hands.
  • Decreased intravascular volume is manifested by tachycardia, absent or barely palpable peripheral pulses, and hypotension.
  • Tachypnea and hypercapnia also are part of the clinical picture and are attributable to the metabolic acidosis that invariably is present in patients with cholera who are dehydrated.
  • Children with some (moderate) dehydration have lost approximately 7-10% of body water (approximately 5% of body weight). In these patients, cardiac output and vascular resistance are normal, and changes in interstitial and intracellular volume are the primary manifestations of illness. Children have decreased skin turgor, as manifested by prolonged skin tenting in response to a skin pinch (the most reliable sign of isotonic dehydration), and a normal pulse.
  • Children without clinically significant dehydration (<5% loss of body weight) may have increased thirst without other signs of dehydration.
• Metabolic and systemic manifestations
• • After dehydration, hypoglycemia is the most common lethal complication of cholera in children. Hypoglycemia is a result of diminished food intake during the acute illness, exhaustion of glycogen stores, and defective gluconeogenesis secondary to insufficient stores of gluconeogenic substrates in fat and muscle.
  • Acidosis in cholera is a result of bicarbonate loss in stools, accumulation of lactate because of diminished perfusion of peripheral tissues, and hyperphosphatemia.
  • Acidemia occurs when respiratory compensation is unable to sustain a normal blood pH.
  • Hypokalemia results from potassium loss in the stool, with a mean potassium concentration of approximately 30 mmol/L. Because of the existing acidosis, however, children often have normal serum potassium concentrations when first observed, despite severe total body potassium depletion. Hypokalemia develops only after the acidosis is corrected and intracellular hydrogen ion is exchanged for extracellular potassium. Hypokalemia is most severe in children with preexisting malnutrition who have diminished body stores of potassium and may be manifested as paralytic ileus.
  • Rehydration therapy with bicarbonate-containing fluids also can produce hypocalcemia by decreasing the proportion of serum calcium that is ionized.
  • Chvostek and Trousseau signs often are present, and spontaneous titanic contractions can occur.

Causes

Cholera can be an endemic, epidemic, or a pandemic disease. Initiation and maintenance of epidemic and pandemic disease by V cholerae require human infection and poor sanitation with assistance from human migration and seasonal warming of coastal waters. Certain environmental and host factors appear to play a role in the spread of V cholerae.

• Environmental factors
• • V cholerae is a saltwater organism, and its primary habitat is the marine ecosystem where it lives in association with plankton.
  • Cholera has 2 main reservoirs, man and water. V cholerae rarely is isolated from animals, and animals do not play a role in transmission of disease.
  • Primary infection in humans is acquired incidentally. Risk of primary infection is facilitated by seasonal increases in the number of organisms, possibly associated with changes in water temperature and algal blooms.
  • Secondary transmission occurs through fecal-oral spread of the organism through person-to-person contact or through contaminated water and food. Such secondary spread commonly occurs in households but also can occur in clinics or hospitals where patients with cholera are treated.
  • Infection rates predictably are highest in communities in which water is not potable and personal and community hygiene standards are low.
• Host susceptibility factors that may affect the course of infection with V cholerae O1
• • Malnutrition
  • Hydrochlorhydria or achlorhydria of any cause (including Helicobacter pylori infection, gastric surgery, vagotomy, use of H2 blockers for ulcer disease): The reason it is easily discernible is that gastric acid can quickly render an inoculum of V cholerae noninfectious before it reaches the site of colonization in the small bowel.
  • O blood group: The role played by O blood group is less certain. The cause is unknown, but incidence of infection appears to be twice as high in this population.
  • Previous exposure and acquired immunity: Infection rates of household contacts of cholera patients range from 20-50%. Rates are lower in areas where infection is endemic and if there are preexisting vibriocidal antibodies from previous encounters with the organism, especially in adults. For the same reason, adults are symptomatic less frequently than children, and second infections rarely occur or are mild.
  • Asymptomatic carriers: This may have a role in transfer of disease in areas where the disease is not endemic. Although carriage usually is short-lived, a few individuals may excrete the organisms for a prolonged period.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Direct microscopic examination: V cholerae is a gram-negative curved bacillus that is motile by means of a single flagellum. Laboratory diagnosis is required not only for identification but also for epidemiological purposes.
• • Gram stain: Although observed as a gram-negative organism, the characteristic motility of Vibrio species cannot be identified on a Gram stain.
  • Dark field organism: The characteristic motility can be examined easily by direct dark field examination of the stool. Moreover, it can be confirmed by adding Vibrio antisera, which results in cessation of motility of only the homologous organism; however, this examination may not be attempted in countries where cholera is not endemic, and the antisera may be unavailable. This is an excellent quick method of identification, even in small labs in endemic regions.
• Culture: V cholerae is not fastidious in nutritional requirements for growth. However, it does need an adequate buffering system if fermentable carbohydrate is present because viability is severely compromised if the pH is less than 6, often resulting in auto sterilization of the culture. Many of the selective media used to differentiate enteric pathogens do not support the growth of V cholerae.
• • Routine differential media: Colonies are lactose-negative, like all other intestinal pathogens, but sucrose-positive. When plated onto triple sugar iron agar to screen for Salmonella and Shigella species, the organism gives the nonpathogenic pattern of an acid (yellow) slant and acid butt because of fermentation of the sucrose contained in triple sugar iron agar. Unlike other Enterobacteriaceae, V cholerae is oxidase-positive; hence, in countries where selective media are not available and cholera is not endemic, V cholerae should be suspected if any motile, oxidase-positive, gram-negative rod isolated on routine differential media from the stool of a patient with diarrhea produces an acid reaction on triple sugar iron agar.
  • Alkaline enrichment media: As Vibrio species has the ability to grow at a high pH or in bile salts, which inhibit many other Enterobacteriaceae, peptone water (pH 8.5-9) or selective media containing bile salts (eg, thiosulfate-citrate-bile-sucrose-agar [pH 8.6]), are recommended to facilitate isolation and lab diagnosis. On thiosulfate-citrate-bile-sucrose-agar, the sucrose-fermenting V cholerae grow as large, smooth, round yellow colonies that stand out against the blue-green agar.
• Serotyping and biotyping
• • Specific antisera can be used in immobilization tests. A positive immobilization test result is produced only if the antiserum is specific for the Vibrio type present; the second antiserum serves as a negative control.
  • In addition, classic and El Tor biotypes also can be identified using the same method, which is useful for epidemiological studies.
• Hematological tests
• • The major laboratory derangements in patients with cholera derive from the alterations in intravascular volume and electrolyte concentrations.
  • Hematocrit, serum-specific gravity, and serum protein are elevated in dehydrated patients because of resulting hemoconcentration. When patients are first observed, they generally have a leucocytosis without a left shift.
• Serum electrolytes
• • Serum sodium usually is 130-135 mmol/L, reflecting the substantial loss of sodium in the stool that has accompanied the water.
  • Serum potassium usually is normal in the acute phase of the illness, reflecting the exchange of intracellular potassium for extracellular hydrogen ion in an effort to correct the acidosis.
  • Bicarbonate concentration usually is less than 15 mmol/L in severely dehydrated patients and often is nondetectable.
• Renal profile: Blood urea nitrogen and serum creatinine are elevated, reflecting the decrease in glomerular filtration. The extent of their elevation is dependent on the degree and duration of dehydration.
• Other biochemical tests: Blood glucose measurement and blood gases and bicarbonate concentration are important parameters to monitor and treat as required.
• Definitive diagnosis, however, is not a prerequisite for the treatment of patients with cholera. The management of any watery diarrhea is basically the same, replacing the lost fluid and electrolytes and providing an antimicrobial agent when indicated.

Other Tests

• Several other methods, such as latex agglutination, enzyme immunoassay, and deoxyribonucleic acid (DNA)-based methods (eg, polymerase chain reaction [PCR], oligoprobes), have been tried to identify V cholerae but without success.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The WHO's guidelines for the management of cholera are the most practical, easily understood, and applied in clinical practice. These guidelines can be used for the treatment of any patient with diarrhea and dehydration. Diagnosis of cholera is not mandatory before therapy.

• Steps in the treatment of a patient with suspected cholera
  • Step 1: Assess for dehydration. As described earlier, Table 1 can be used to assess the degree of dehydration and categorize it into severe dehydration, some dehydration, or no signs of dehydration
  • Step 2: Rehydrate the patient and monitor frequently. Then reassess hydration status. The primary objectives of the treatment of patients with cholera are to correct dehydration, if present, and then maintain hydration.
  • Step 3: Maintain hydration. Replace ongoing fluid losses until diarrhea stops.
  • Step 4: Administer an oral antibiotic to the patient with severe dehydration.
  • Step 5: Feed the patient.

  Severe dehydration

  • Administer IV fluid immediately to replace fluid deficit. Use lactated Ringer solution or, if not available, isotonic sodium chloride solution. Start IV fluid immediately. If the patient can drink, begin giving oral rehydration salt (ORS) solution by mouth while the drip is being set up. For patients older than 1 year, give 100 mL/kg IV in 3 hours—30 mL/kg as rapidly as possible (within 30 min) then 70 mL/kg in the next 2 hours. For patients younger than 1 year, administer 100 mL/kg IV in 6 hours—30 mL/kg in the first hour then 70 mL/kg in the next 5 hours.
  • Monitor the patient very frequently. After the initial 30 mL/kg have been administered, the radial pulse should be strong and blood pressure should be normal. If the pulse is not yet strong, continue to give IV fluid rapidly. Administer ORS solution (about 5 mL/kg/h) as soon as the patient can drink, in addition to IV fluid.
  • Reassess the patient after 3 hours (infants after 6 h), using Table 1. If signs of severe dehydration (rare) still exist, repeat the IV therapy already given. If signs of some dehydration are present, continue as indicated below for some dehydration. If no signs of dehydration exist, maintain hydration by replacing ongoing fluid losses.

    Table 2. Electrolyte Concentration of Cholera Stools and Common Solution Used for Its Treatment

    	Electrolyte and Glucose Concentration (mmol/L)
    	Na+	Cl-	K+	HCO3-	Glucose
    Cholera Stool
    Adults	130	100	20	44
    Children	100	90	33	30
    Intravenous Solutions
    Lactated Ringer solution	130	109	4	28	0
    Dhaka	133	98	13	48	0
    Isotonic sodium chloride solution	154	154	0	0	0
    Peru polyelectrolyte	90	80	20	30	111
    WHO ORS	90	80	20	30	111

• Some dehydration
• • Administer ORS solution according to the amount recommended in Table 3.

    Table 3. Approximate Amount of ORS Solution to Administer in the First 4 Hours
    

    Age1	<4 mo	4-11 mo	12-23 mo	2-4 y	5-14 y	³15 y
    Weight	<5 kg	5-7.9 kg	8-10.9 kg	11-15.9 kg	16-29.9 kg	³30 kg
    ORS solution in mL	200-400	400-600	600-800	800-1200	1200-2200	2200-4000

    
    
    

    ¹ Use the patient's age only when weight is unknown. The approximate amount of ORS required (in mL) also can be calculated by multiplying the patient's weight (in kg) times 75.

  • If the patient passes watery stools or wants more ORS solution than shown, give more. Monitor the patient frequently to ensure that ORS solution is taken satisfactorily and to identify patients with profuse ongoing diarrhea who require closer monitoring.
  • Reassess the patient after 4 hours, using Table 1. If signs of severe dehydration have appeared (rare), rehydrate for severe dehydration, as above. If some dehydration still is present, repeat the procedures for some dehydration and start to offer food and other fluids. If no signs of dehydration are present, maintain hydration by replacing ongoing fluid losses.
• No signs of dehydration
• • Patients who are first observed with no signs of dehydration can be treated at home. Give these patients ORS packets to take home, enough for 2 days. Demonstrate how to prepare and give the solution. The caretaker should give the patient the amount of ORS solution shown in Table 4.

    Table 4. Estimate of ORS Solution Packets to be Administered at Home

    Age	Amount of Solution After Each Loose Stool	ORS Packets Needed
    <24 mo	50-100 mL	Enough for 500 mL/d
    2-9 y	100-200 mL	Enough for 1000 mL/d
    >10 years	As much as is wanted	Enough for 200 mL/d

  • Instruct the patient or the caretaker to return if any of the following signs develop:
  • • Increased number of watery stools
    • Eating or drinking poorly
    • Marked thirst
    • Repeated vomiting
    • Any signs indicating other problems (eg, fever, blood in stool)
• Routes for parenteral rehydration
• • Accessing a peripheral vein is relatively easy, despite the severe dehydration. If a peripheral vein is not readily accessible, scalp veins have been used for initial rehydration. As the vascular volume is reestablished, a larger needle or catheter can be introduced in a peripheral vein.
  • Intraosseous routes have been used successfully in young children when veins cannot be accessed.
  • The intraperitoneal route, although tried, is not recommended.
  • ORS solution can be administered via nasogastric tube if the patient has some signs of dehydration and cannot drink or if the patient has severe dehydration and IV therapy is not possible at the treatment facility.
  • A risk of overhydration exists with intravenous fluids; it usually is first manifested by puffiness around the eyes. Continued excessive administration of intravenous fluids can lead to pulmonary edema and has been observed even in children with normal cardiovascular reserve. It is important to monitor patients who are receiving intravenous rehydration hourly. Serum-specific gravity is an additional measure of the adequacy of rehydration.
  • Most patients absorb enough ORS solution to achieve rehydration, even when they are vomiting. Vomiting usually subsides within 2-3 hours, as rehydration is achieved.
  • Urine output decreases as dehydration develops and may cease. It usually resumes within 6-8 hours after starting rehydration. Regular urinary output (ie, every 3-4 h) is a good sign that enough fluid is being given.
• Maintenance of hydration
• • Maintain hydration of patients presenting with severe or some dehydration. Replace ongoing fluid losses until diarrhea stops.
  • When a patient who has been rehydrated with IV fluid or ORS solution is reassessed and has no signs of dehydration, continue to administer ORS solution to maintain normal hydration. The aim is to replace stool losses as they occur with an equivalent amount of ORS solution.

    Table 5. Guide for Amount of ORS to be Administered for Maintenance

    Age	Amount of Solution After Each Loose Stool
    <24 mo	100 mL
    2-9 y	200 mL
    ³10 y	As much as is wanted

  • The amount of ORS solution actually required to maintain hydration varies greatly among patients, depending on the volume of stool passed. The amount required is highest in the first 24 hours of treatment and is especially large in patients who present with severe dehydration. In the first 24 hours, the average requirement of ORS solution in such patients is 200 mL/kg, but some patients may need as much as 350 mL/kg.
  • Continue to reassess the patient for signs of dehydration at least every 4 hours to ensure that enough ORS solution is being taken. Patients with profuse ongoing diarrhea require more frequent monitoring. If signs of some dehydration are detected, the patient should be rehydrated as described earlier, before continuing with treatment to maintain hydration. A few patients, whose ongoing stool output is very large, may have difficulty in drinking the volume of ORS needed to maintain hydration. If these patients become tired, vomit frequently, or develop abdominal distension, ORS solution should be stopped and hydration should be maintained intravenously with lactated Ringer solution or isotonic sodium chloride solution, administering 50 mL/kg in 3 hours. After this is done, resuming treatment with ORS solution is usually possible.
  • Keep the patient under observation, if possible, until diarrhea stops or is infrequent and of small volume. This is especially important for any patient presenting with severe dehydration. If a patient must be discharged from the hospital before diarrhea has stopped, show the caretaker how to prepare and give ORS solution, and instruct the caretaker to continue to give ORS solution, as above. Also instruct the caretaker to return the patient to the hospital if any signs of danger appear.
• Use of oral antibiotics in patients with severe dehydration
• • An effective antibiotic can reduce the volume of diarrhea in patients with severe cholera and shorten the period during which V cholerae O1 is excreted. In addition, it usually stops the diarrhea within 48 hours, thus shortening the period of hospitalization.
  • If the patient is severely dehydrated and older than 2 years, administer an antibiotic. Begin antibiotic therapy after the patient has been rehydrated (usually in 4-6 h) and vomiting has stopped. No advantage exists to using injectable antibiotics, which are expensive. No other drugs should be used in the treatment of cholera.
• Feeding of patients (See Diet.)
• Cholera cots
• • In areas where cholera is endemic, cholera-cots have been used to assess the volume of ongoing stool losses. A cholera cot is a cot covered by a plastic sheet with a hole in the center to allow the stool to collect in a calibrated bucket underneath.
  • Use of such a cot allows minimally trained health workers to calculate fluid losses and replacement needs. The volume of stool is measured every 2-4 hours, and the volume of fluid administered is adjusted accordingly.
  • In the initial phase of therapy, urine losses account for only a small proportion of fluid losses, and the amount of fluid in the bucket is an adequate reflection of stool losses. With rehydration, urine should be collected separately, so that a vicious circle of increasing urine output and overhydration can be avoided.

Diet

• Resume feeding with a normal diet when vomiting has stopped.
• Continue breastfeeding infants and young children.
• Malnutrition after infection is not a major problem, as observed after infection with Shigella species or rotavirus diarrhea.
• The catabolic cost of the infection is relatively low, anorexia is neither profound nor persistent, and intestinal enzyme activity remains intact after infection; hence, intestinal absorption of nutrients is near normal.
• No reason to withhold food from cholera patients exists.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

An effective antibiotic can reduce the volume of diarrhea in patients with severe cholera and shorten the period during which V cholerae O1 is excreted. In addition, it usually stops the diarrhea within 48 hours, thus shortening the period of hospitalization.

If the patient is severely dehydrated and older than 2 years, administer an antibiotic. Initiate the antibiotic after the patient has been rehydrated (usually in 4-6 h) and vomiting has stopped. No advantage exists to using parenteral antibiotics, which are expensive. No other drugs should be used in the treatment of cholera.

Antimicrobial therapy for cholera is an adjunct to fluid therapy and is not an essential therapeutic component. However, it reduces diarrhea volume and duration by approximately 50%. The choice of antibiotics is determined by the susceptibility patterns of the local strains of V cholerae O1 or O139.

Antimicrobial agents typically are administered for 3-5 days; however, single-dose therapy with tetracycline, doxycycline, furazolidone, or ciprofloxacin has been shown effective in reducing the duration and volume of diarrhea.

If antimicrobial therapy is to be initiated, it should be given when the patient is first seen and cholera is suspected. Little reason exists to wait for culture and susceptibility reports.

Table 6. Antimicrobial Therapy Used in the Treatment of Cholera*

Antibiotic	Single Dose (PO)	Multiple Dose (PO)
Doxycycline†	7 mg/kg; not to exceed 300 mg/dose‡	2 mg/kg bid on day 1; then 2 mg/kg qd on days 2 and 3; not to exceed 100 mg/dose
Tetracycline†	25 mg/kg; not to exceed 1 g/dose‡	40 mg/kg/d divided qid for 3 d; not to exceed 2 g/d
Furazolidone	7 mg/kg; not to exceed 300 mg/dose	5 mg/kg/d divided qid for 3 d; not to exceed 400 mg/d
Trimethoprim and sulfamethoxazole	Not evaluated	<2 months: Contraindicated >2 months: 5-10 mg/kg/d (based on trimethoprim component) divided bid for 3 d; not to exceed 320 mg/d trimethoprim and 1.6 g/d of sulfamethoxazole
Ciprofloxacin§	30 mg/kg; not to exceed 1 g/dose‡	30 mg/kg/d divided q12h for 3 d; not to exceed 2 g/d
Ampicillin	Not evaluated	50 mg/kg/d divided qid for 3 d; not to exceed 2 g/d
Erythromycin	Not evaluated	40 mg/kg/d erythromycin base divided tid for 3 d; not to exceed 1 g/d

^*Antimicrobial therapy is an adjunct to fluid therapy of cholera and is not an essential component. However, it reduces diarrhea volume and duration by approximately 50%. The choice of antibiotics is determined by the susceptibility patterns of the local strains of V cholerae O1 or O139.

^†Tetracycline and doxycycline can discolor permanent teeth of children younger than 8 years. However, the risk is small when these drugs are used for short courses of therapy, especially if used in a single dose.

^‡Single-dose therapy of these drugs has not been evaluated systematically in children, and recommendations are extrapolated from experience in adults.

^§Fluoroquinolones (eg, ciprofloxacin) are not approved in the United States for use in persons younger than 18 years. When given in high doses to juvenile animals, they cause arthropathy. Clinical experience indicates that this risk is very small in children when used for short courses of therapy.

Furazolidone has been the agent routinely used in the treatment of cholera in children; however, resistance has been reported, and ampicillin, erythromycin, and fluoroquinolones are potentially effective alternatives.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Tetracycline (Sumycin)
Description	Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s).
Adult Dose	250-500 mg PO q6h
Pediatric Dose	Single dose: 25 mg/kg PO; not to exceed 1 g/dose Multiple dose: 40 mg/kg/d PO divided qid for 3 d; not to exceed 2 g/d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; risk is small when these drugs are used for short courses of therapy, especially if used in single dose; single-dose therapy of these drugs has not been evaluated systematically in children, and recommendations are extrapolated from experience in adults; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Furazolidone (Furoxone)
Description	Has been the agent routinely used in the treatment of cholera in children; however, resistance has been reported, and ampicillin, erythromycin, and fluoroquinolones are potentially effective alternatives.
Adult Dose	100 mg PO qid
Pediatric Dose	Single dose: 7 mg/kg PO; not to exceed 300 mg/dose Multiple dose: 5 mg/kg/d divided qid for 3 d; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	Increases levodopa blood concentrations and, thus, potential for toxicity; causes disulfiram reactions when taken with alcohol; toxicity of meperidine, paroxetine, fluoxetine, sertraline, trazodone, MAOIs, sympathomimetic amines, and tricyclic antidepressants increase when taken with furazolidone
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in G-6-PD deficiency when administering prolonged treatments; medication inhibits enzyme monoamine oxidase

Drug Name	Trimethoprim and sulfamethoxazole (Bactrim, Septra, Cotrim)
Description	Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Adult Dose	160 mg (TMP component)/800 mg (SMZ component) PO q12h (ie, 1 double-strength tab q12h)
Pediatric Dose	<2 months: Contraindicated >2 months: 5-10 mg/kg/d (based on TMP component) PO divided bid for 3 d; not to exceed 320 mg/d TMP and 1.6 g/d of SMZ
Contraindications	Documented hypersensitivity; megaloblastic anemia caused by folate deficiency; age <2 mo
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly patients; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use during last trimester of pregnancy due to potential toxicity to newborn (eg, jaundice, hemolytic anemia, kernicterus); discontinue at first appearance of rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; caution in folate deficiency (eg, chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation; decrease dose with moderate CrCl reduction

Drug Name	Ciprofloxacin (Cipro)
Description	Inhibits bacterial DNA synthesis and, consequently, growth.
Adult Dose	250-500 mg PO bid
Pediatric Dose	Not approved in the United States for children <18 y Single dose: 30 mg/kg PO; not to exceed 1 g/dose Multiple dose: 30 mg/kg/d PO divided bid for 3 d; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations May increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Fluoroquinolones, such as ciprofloxacin, are not approved in the United States for use in children <18 y; when given in high doses to juvenile animals, they cause arthropathy; clinical experience indicates that this risk is very small in children when used for short courses of therapy; single-dose therapy of these drugs has not been evaluated systematically in children, and recommendations are extrapolated from experience in adults

Drug Name	Ampicillin (Marcillin, Omnipen, Polycillin)
Description	Bactericidal activity against susceptible organisms.
Adult Dose	250-500 mg PO q6h
Pediatric Dose	50 mg/kg/d PO divided qid for 3 d; not to exceed 2 g/d
Contraindications	Documented hypersensitivity
Interactions	Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction

Drug Name	Erythromycin (E.E.S., Erythrocin)
Description	Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) q6h PO 1 h ac
Pediatric Dose	40 mg/kg/d PO erythromycin base divided tid for 3 d; not to exceed 1 g/d
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin, increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (give doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• The current response to cholera outbreaks tends to be reactive, in the form of an emergency response. Although this approach prevents many deaths, it fails to prevent cases of cholera.
• The legendary story about John Snow and the prevention of cholera spread in 1854 London remains an outstanding example of the use of epidemiologic methods.
• Efforts in prevention of cholera should involve the following strategies:
• • Early identification and case management: Rapid identification of cases in children and adults and prompt treatment will limit further spread of the disease.
  • Surveillance systems: Sensitive surveillance and prompt reporting contribute to the rapid containment of cholera epidemics. In many endemic countries, cholera is a seasonal disease, occurring every year usually during the rainy season. Surveillance systems can provide an early alert to outbreaks, which should lead to a coordinated response and assist in the preparation of preparedness plans.
  • Multisectoral approach: A multisectoral and coordinated approach is paramount to efficiently control a cholera outbreak. Key sectors to be involved are health, water and sanitation, fishery and agriculture, and education.
  • Water supply and sanitation: Cholera is usually transmitted through fecally contaminated water or food. Outbreaks can occur sporadically in any part of the world where water supply, sanitation, food safety, and hygiene are inadequate. WHO recommends improvements in water supply and sanitation as the most sustainable approach for protecting against cholera and other waterborne epidemic diarrheal diseases. However, such an approach is unrealistic for the many impoverished populations most affected by cholera.
  • Personal hygiene, food preparation, and health education: Outbreaks can be mitigated and case-fatality rates can be reduced by means of several other measures, many of which are suitable for community participation. Human behaviors related to personal hygiene and food preparation contribute greatly to the occurrence and severity of outbreaks.
  • Vaccines: Parenteral vaccines have been discontinued because of their poor efficacy. WHO has identified 3 oral vaccines, which are available in some countries but are used mainly by travelers. Efforts are underway to identify further use of these vaccines in endemic and epidemic situations.
    • WC/rBS vaccine: One vaccine consists of killed whole-cell V cholerae O1 with purified recombinant B-subunit of cholera toxoid (WC/rBS). Clinical trials have been performed in Bangladesh, Peru, and Sweden. Efficacy trials have shown that this vaccine is safe and confers 85-90% protection during 6 months in all age groups after administration of 2 doses, 1 week apart. In Bangladesh, protection declined rapidly after 6 months in young children but was still about 60% in older children and adults after 2 years.
    • Variant WC/rBS vaccine: As a result of technology transfer, a variant of the WC/rBS vaccine containing no recombinant B-subunit has been produced and tested in Vietnam. It is administered in 2 doses, 1 week apart. A field trial conducted in 1992-1993 in Vietnam showed a protective efficacy of 66% at 8 months in all age groups. The vaccine is licensed only in Vietnam.
    • CVD 103-HgR vaccine: Another vaccine consists of an attenuated live oral genetically modified V cholerae O1 strain (CVD 103-HgR). Placebo-controlled trials in several countries have demonstrated the safety and immunogenicity of a single dose of CVD 103-HgR. The efficacy of this oral vaccine has been investigated in adult volunteers in the United States, where it has been found that a single dose confers high protection (95%) against V cholerae. Classical and 65% protection against V cholerae El Tor following a challenge given 3 months after administration.
  • At the present time, the manufacture and sale of the only licensed cholera vaccine in the United States (Wyeth-Ayerst) has been discontinued. It has not been recommended for travelers because of the brief and incomplete immunity if offers. No cholera vaccination requirements exist for entry or exit in any country.

Complications

• Complications of the disease
• • Dehydration, which may lead to renal failure and death, is the most important complication.
  • Another complication is electrolyte imbalance if appropriate solutions (eg, those recommended by the WHO) are not used for rehydration.
  • Hypoglycemia is an important complication that should be evaluated for and treated with glucose therapy. Use of glucose-containing solutions, such as lactated Ringer solution, and avoidance of isotonic sodium chloride solution for rehydration can prevent hypoglycemia.
• Complications of therapy: Overhydration with parenteral fluid therapy presents with the earliest sign of puffiness of eyelids. If not recognized at this stage, it may lead to pulmonary edema.

Prognosis

• Before the development of effective regimens for replacing fluids and electrolyte losses, the mortality rate in severe disease was more than 50%.
• With the development of effective intravenous and oral rehydration solutions, no patient who reaches a cholera treatment center alive should die of the disease.
• Mortality rates are lowest where intravenous therapy is available. At the Treatment Center of the International Center for Diarrheal Disease Research, Bangladesh, fewer than 1% of patients with severe dehydration die.
• Although mortality rates in Africa remain higher, low case-fatality rates also have been achieved in South America, presumably because of the availability of adequate treatment facilities and trained personnel.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Although other differential diagnosis of gastroenteritis may be considered, the clinical picture of cholera is unlikely to be confused with any other disease. This is especially true in adults in whom no other infectious disease causes such profound dehydration so quickly. Unfortunately, in the United States, this may not trigger a diagnosis of cholera because medical personnel are not accustomed to thinking of cholera as a possibility.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 1, 2006