• Information
  1. Introduction
  2. Cholera Toxins
  3. Clinical Features
  4. Treatment
  5. Vaccination

A. Introduction

1. Diarrheal illness due to toxins produced by Vibrios cholerae
2. V. cholerae is a motile, curved, gram-negative bacillus
3. There are 139 serogroups
4. Two serogroups, O1 and O139 (more virulent), have produced epidemics
5. Epidemics can occur, usually with introduction of strains to non-endemic areas
6. Recent epidemics have occurred in Latin America, South America, and Bangladesh
7. Death rates can be as high as 15 per 1000 infected due to massive dehydration
8. Increasing numbers of cases in USA with increased international travel

B. Cholera Toxins [3]

1. V. cholerae Toxins produce and secrete
   1. Enterotoxic exotoxin is the major toxin responsible for the disease cholera
   2. Also produces a zona-occludens toxin (ZOT)
2. The Exotoxin is composed of two units
   1. The A chain is the toxin, which requires a targetting molecule for activity
   2. The B chain is the binding unit, targets GM1-ganglioside
   3. Once the B chain binds, the A chain enters the cytoplasm
3. Cytoplasmic A chain Effects [4]
   1. Cholera toxin A chain catalyzes the ADP ribosylation and inactivation of Gi protein
   2. This Gi protein normally inhibits the activity of adenylate cyclase (AdCyc)
   3. Thus, AdCyc activity increases, and this leads to production of increased cyclic AMP
   4. Cyclic AMP (cAMP) is a potent second messenger with multiple effects
4. Cyclic AMP and Intestinal Cells
   1. Major effect on intestinal cells is activation of protein kinase A (PK-A) by cAMP
   2. PK-A phosphorylates the intestinal chloride channel (CFTR)
   3. Phosphorylation of CFTR leads to increased chloride secretion into intestine
   4. Increased cAMP also leads to hypersecretion of potassium and bicarbonate
   5. Water and sodium are lost as well
   6. Result is marked watery diarrhea with electrolyte loss
   7. Intestinal mucosal cells are not damaged by the toxin
5. V. cholerae does not invade intestinal mucosa
   1. Exotoxin produces all major symptoms
   2. ZOT increases leakage of interstitial fluid through epithelium into intestine

C. Clinical Features

1. Incubation period is hours to about 5 days
2. Stomach acid is highly toxic to V. cholerae
   1. Food protects V. cholerae from stomach acid
   2. Persons with acholhydria are at increased risk for severe infection
3. Diarrhea is non-bloody, with high volumes (may be >500cc/hr)
4. Dehydration, hypotension, tachycardia and vascular collapse can occur
5. Urine flow is decreased or absent; urine specific gravity is often >1.030gm/mL
6. Patients should be catagorized by degree of dehydration
7. All persons with diarrhea and recent international travel should be tested for cholera

D. Treatment

1. Oral rehydration therapy (ORT) is mainstay for mild and moderate dehydration
   1. Oral rehydration solution (ORS) with reduced osmolarity is superior to standard solution in children with cholera diarrhea [5]
   2. No difference between reduced and normal osmolarity ORS in adults with cholera [6]
   3. Addition of an amylase-resistant starch to ORS reduces fecal loss, diarrhea duration [7]
2. Intravenous rehydration is often required for moderate and severe dehydration
   1. Normal saline may be used in moderate cases
   2. Lactated Ringer's solution is recommended for severe dehydration
   3. Pre-emptive establishment of oral rehydration programs is less expensive than reactive
3. Oral Antibiotic Therapy
   1. Reduces duration of illness and fluid losses by ~50%
   2. Doxycycline (100mg po bid) or tetracycline (500mg po qid) may be used in adults
   3. Quinolones may be used in areas of tetracycline resistance
   4. Increasing quinolone resistance in certain areas
   5. Azithromycin or cotrimoxizole is recommended for children and pregnant women
   6. Erythromycin dose is 12.5mg/kg (maximum 500mg) po qid x 3 days (12 doses)
   7. Single azithromycin 20mg/kg (maximum 1000mg) po x 1 is as effective as standard erythromycin with much less vomiting and shorter duration of diarrhea [9]
   8. Single dose ciprofloxacin (20mg/kg dose po) achieves clinical outcomes at least as good as 12-dose erythromycin in children, but less effective in V. cholera stool eradication [11]
   9. Oral single dose azithromycin (1gm) superior to single dose ciprofloxacin (1gm) in areas of quinolone resistance in adults [12]
4. Racecadotril (acetorphan, an enkephalinase inhibitor) synergistic with ORS [8]
5. Careful hand washing, good personal hygiene, and clean water are critical to prevent spread

E. Vaccination

1. Inactivated oral cholera vaccine
   1. Efficacy for reduction in clinical disease is ~50% over 2-3 years wth 2-3 doses
   2. Addition to pre-emptive oral rehydration strategy adds cost but is effective
2. Recombinant B-toxin subunit (rBS) oral vaccine has shown efficacy after 2 doses
3. rBS-killed whole cell (rBS-WC)) oral cholera vaccine had 78% protection in African study [10]
4. Live, attenuated oral vaccines may require only one dose (Orochol Berna®)
5. No cholera vaccines are currently licensed in the USA, but are being tested in USA

References

1. Sack DA, Sack RB, Nair GB, Siddique AK. 2004. Lancet. 363(9404):223
2. Sanchez JL and Taylor DN. 1997. Lancet. 349(9068):1825
3. Raufman JP. 1998. Am J Med. 104(4):386
4. Farfel Z, Bourne HR, Iiri T. 1999. NEJM. 340(13):1012
5. International Study Group on Reduced Osmolarity ORS Solutions. 1996. Lancet. 345:282
6. Alam NH, Majumder RN, Fuchs GJ. 1999. Lancet. 354(9175):296
7. Ramakrishna BS, Venkataraman S, Srinivasan P, et al. 2000. NEJM. 342(5):308
8. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. 2000. NEJM. 343(7):463
9. Khan SA, Saha D, Rahman A, et al. 2002. Lancet. 360(9347):1722
10. Lucas MES, Deen JL, von Seidlein L, et al. 2005. NEJM. 352(8):757
11. Saha D, Khan SA, Karim MM, et al. 2005. Lancet. 366(9491):1085
12. Saha D, Karim MM, Khan WA, et al. 2006. NEJM. 354(23):2452