Treatment of Cholera in Adults with Single-Dose Azithromycin

Abstract & Commentary

By Mary-Louise Scully, MD

Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA

Dr. Scully reports no financial relationships relevant to this field of study.

Synopsis: Single-dose azithromycin is now the preferred antibiotic treatment for cholera in adults and children. Unfortunately, azithromycin-resistant cholera strains are already emerging, reinforcing the need for improved sanitation and clean water to ultimately eliminate outbreaks of cholera.

Source: Saha D, et al. Single-Dose Azithromycin for the Treatment of Cholera in Adults. N Engl J Med. 2006;354:2452-2462.

A double-blind, randomized, partially manufacturer-supported trial was performed in Dhaka, Bangladesh, to compare a single 1g dose of azithromycin against ciprofloxacin therapy, also 1g dose, for the treatment of severe cholera. One hundred ninety-five men between the ages of 18 and 60 years were enrolled between December 11, 2002 and May 2, 2004. Entry criteria for the study were watery diarrhea of ≤ 24 hours duration, severe dehydration, stool volume of at least 20 mL/kilogram for the first 4 hours after rehydration, and Vibrio cholerae 01 or 0139 isolated from a stool culture or rectal swab. Clinical success of therapy was defined as the cessation of watery stools within 48 hours after the dosage of the study drug, and bacteriologic success was defined as negative cultures for V. cholerae 01 or 0139 from stool within 48 hours after the dosage of study drug.

Clinical success was noted in 71 of 97 (73%) patients in the azithromycin group compared to 26 of 98 (27%) patients in the ciprofloxacin group (P ‹ 0.001). Bacteriologic success was noted in 76 of 97 (78%) patients treated with azithromycin compared to 10 of 98 (10%) patients randomized to receive ciprofloxacin (P ‹ 0.001). Secondary outcomes determined that azithromycin treated patients had a significantly shorter duration and volume of diarrhea, less vomiting, and decreased requirements for intravenous and oral fluids. One patient in the azithromycin group and 3 in the ciprofloxacin group reported abdominal pain, but there were no other serious adverse events noted.

Antimicrobial susceptibility testing on the V. cholerae isolates demonstrated both azithromycin and ciprofloxacin susceptibility by disk diffusion and eTEST® methods for the determination of minimum inhibitory concentrations. However, actual MICs of ciprofloxacin for V. cholerae 01 isolates were 11 times as high as for V. cholerae 0139, and 11- to 83-fold higher than in previous studies evaluating ciprofloxacin in the treatment of cholera. The decreased susceptibility of V. cholerae 01 isolates is the likely reason for the observed lack of efficacy of ciprofloxacin in the study.

Commentary

V. cholerae is conventionally classified by O group and by biotype (classical and El Tor) and serotype (Ogawa, Inaba, and rarely Hikojima). The V. cholerae strains belonging to the serogroup 01 were believed to be the only etiologic agents of epidemic cholera until 1992, when V. cholerae serogroup 0139 emerged in the Indian subcontinent and neighboring countries.1 Seven cholera pandemics have occurred since 1817, the last caused by V. cholerae strains in O group 1, biotype El Tor.2 In 2004, 101,383 cholera cases and 2345 deaths were reported to the World health Organization from 56 countries.3 This likely represents severe underreporting. Since 2001, the majority of outbreaks have occurred in southern and western Africa. Already, as of June 19th of this year, 46,758 cases and 1893 deaths have been reported from Angola.4

Cholera is characterized by severe watery diarrhea, which can lead rapidly to severe dehydration and death if left untreated. The incubation period can range from 12 hours to 5 days. The majority of infected patients actually have mild or inapparent disease but, in severe cases (cholera gravis), rates of diarrhea can peak to as high as 1 liter per hour and, without adequate rehydration, circulatory collapse and death can occur within a matter of hours. A study of cholera cases in Peru found that persons with blood type O are more likely to develop severe cholera.5 Cholera stools have a pale gray "rice water" appearance. The mainstay of treatment is rehydration with either oral rehydration therapy (ORT) or by use of intravenous rehydration. Antibiotics can decrease the volume of diarrhea and shorten the excretion time of the organisms, but rehydration remains the critical factor for survival.

Many cholera strains are now resistant to what were once effective cholera medications, such as trimethoprim-sulfamethoxazole, furazolidone, and tetracycline antibiotics. In this present study, ciprofloxacin failed 73% of the time clinically and 90% of the time microbiologically. Now, even azithromycin-resistant cholera strains have emerged and, as elegantly stated by Richard Guerrant in an editorial, efforts to eradicate cholera should focus on improved sanitation and the availability of clean water; an approach that was successful in eliminating cholera from North America and Europe.6

There are currently no cholera vaccines available in the United States. An older, injectable, whole-cell vaccine was abandoned by the WHO years ago due to its short duration of protection and low efficacy. An oral, inactivated, whole cell, recombinant cholera vaccine (Dukoral) is licensed for protection against cholera and diarrhea caused by enterotoxigenic Escherichia coli, and is widely available outside the United States. Two doses are given (3 doses for children ages 2-6 years), and protection is obtained 7 days after the last dose is given.7 However, there is no current vaccine effective against the 0139 Bengal strain of cholera.

References

  1. Nair GB, et al. Spread of Vibrio cholerae 0139 Bengal in India. J Infect Dis. 1994;169:1029-1034.
  2. Morris JG Jr. Cholera and Other Types of Vibriosis: A Story of Human Pandemics and Oysters on the Half Shell. Clin Infect Dis. 2003;37:272-280.
  3. World Health Organization. Cholera, 2004. Wkly Epidemiol Rec. 2005;80:261-268.
  4. World Health Organization. Cholera in Angola-Update 5 at www.who.int/csr/don/2006_06_21/en/ Accessed 6-30-2006.
  5. Swerdlow DL, et al. Severe Life-Threatening Cholera Associated with Blood Group O in Peru: Implications for the Latin American Epidemic. J Infect Dis. 1994;170:468-472.
  6. Guerrant RL. Cholera—Still Teaching Hard Lessons. N Engl J Med. 2006;354:2500-2502.
  7. Travax EnCompass at www.travax.com Accessed 6-30-2006.