Single-Dose Azithromycin for the Treatment of Cholera in Adults

Background: Cholera is a gastrointestinal bacterial infection whose infecting organism, V. Cholerae, is developing resistance to antimicrobials that have been previously effective in the treatment of the disease.

 

Objective: This study compared the efficacy of single-dose azithromycin to single-dose ciprofloxacin in the treatment of cholera in adults.

 

Methods: The study was prospective, randomized and double-blinded. Patients were enrolled between December 11,2002 and May 2, 2004 at the Dhaka Diarrhoea Treatment Centre in Bangladesh. Subjects were eligible if they were male, between the ages of 18 and 60, and had diarrhea for no greater than 24 hours, were severely dehydrated according to the World Health Organization criteria, had a stool volume greater than or equal to 20 mL per kilogram of the subject’s body weight, and V. Cholerae present in their stool or from a rectal swab culture. Subjects were excluded if they were female, had a simultaneous illness, or had already received an antimicrobial to treat cholera. Eligible patients were rehydrated and observed for four hours. Those subjects who met the criteria and gave consent were randomized into two groups. For a power of 80%, 91 patients were needed in each group to set the confidence intervals for the difference of the primary outcomes less than 10%. One hundred and ninety eight patients were randomized to receive either 1 gram of azithromycin and ciprofloxacin placebo (99 patients) or 1 gram of ciprofloxacin and azithromycin placebo (99 patients). All subjects were admitted to the treatment center for five days. Vital signs and presence of diarrhea were determined every 6 hours. Volumes of stool and urine and volumes of oral and intravenous fluids administered were measured and recorded. Primary outcomes were clinical and bacteriological success of therapy. Secondary outcomes included relapse rates, duration of diarrhea, volume of watery stools, and duration of V. cholerae excretion. Intent to treat analysis was used to evaluate the data the primary outcomes.

 

Results: Overall, 92% of the subjects completed the study (95% of the ciprofloxacin group and 89% of the azithromycin group). Seventy-one of 97 patients in the azithromycin group (73%) and 26 of 98 patients in the ciprofloxacin group (26%) showed clinical success (p<0.001, difference 47, 95% CI 33 to 58).  Seventy-six of 97 patients in the azithromycin group (78%) and 10 of 98 patients in the ciprofloxacin group (10%) showed bacteriologic success (p < 0.001, difference 68, 95% CI 56 to 77). No difference between clinical and bacteriologic relapse occurred between the groups (p=1.00, difference –1, 95% CI     -7 to 5, and p=0.17, difference –6, 95% CI –14 to 1, respectively). Subjects treated with azithromycin did have a shorter duration of diarrhea than the ciprofloxacin group (30 vs. 78 hrs, p<0.001) and shorter duration of V. Cholerae excretion (p<0.001). Patients in the azithromycin group had less volume of vomitus (0 vs. 28 mL/kg, p<0.001) and less volume of diarrhea (114 vs. 322 mL/kg, p<0.001) than the ciprofloxacin group. A smaller volume of oral fluids and intravenous fluids were given to the azithromycin subjects than the ciprofloxacin subjects (802 vs. 1369 mL/kg, p<0.001 and 0 vs. 292 mL/kg, p<0.001, respectively).

 

Strengths: This study was properly designed using randomization, double-blinding and parallel study groups. Outcome measures were objective leading to less bias in the study’s results. In-house observation of the subjects allowed for fewer differences in data collecting.

 

Weaknesses: Patients were excluded from the study if they were female. This exclusion may hinder extrapolation of the study’s results to the population. Ciprofloxacin may have not been the most comparable active control due to increasing resistance. Also, Pfizer, the manufacturer of azithromycin supported the study, which may have led to biased results. For those reasons, azithromycin may have had an advantage over ciprofloxacin. Also, the study took place at one treatment center in Bangladesh, which makes it difficult to apply the results to other areas in Asia and Africa.

 

Conclusion: This study indicates that azithromycin is more effective in eradicating V. cholerae than ciprofloxacin in Bangladesh. However, as mentioned above, the various patterns of resistance of V. cholerae may prevent extrapolation of these results to other areas where cholera is a common disease. Therefore, studies in other areas of Africa and Asia are necessary to determine which antibiotics are most effective for cholera in those specific regions. 

 

Saha D, Karim MM, Khan WA, Ahmed S, Salam MA, Bennish, ML. Single-dose azithromycin for the treatment of cholera in adults. N Engl J Med 2006;354:2452-2462.

 

Sarah Workman, Pharm.D. Candidate

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