Randomized, Double Blind, Controlled Clinical Trial to Evaluate the Efficacy of Multiple-dose Ciprofloxacin With Single Dose Azithromycin Therapy for Adults With Cholera Due to Multiply Resistant Strains of V. Cholerae O1 or O139

Cholera is caused by infection of the human intestine with Vibrio cholerae O1 or V. cholerae O139. It is a major health problem in many developing countries including Bangladesh.1 The importance of cholera as a worldwide public health problem is evident from the large number of countries affected by cholera epidemics.2 Data of the Diarrhoeal Disease Surveillance system of the Dhaka Hospital demonstrated that V. cholera O1 was the most frequently isolated pathogens (617/2,068 i.e. 30%) in patients attending the hospital with diarrhoeal illnesses in 2006. By extrapolating the number of patients enrolled in the surveillance system we estimate that over 30,000 out of the total 106,531 patients attending the hospital in 2006 had cholera- a huge number of patients indeed.

Like other diarrhoeal illnesses, prevention and management of dehydration using appropriate oral and/or intravenous fluids is the mainstay in the management of cholera, irrespective of severity. However, appropriate antimicrobial therapy is a very useful adjunct therapy that reduces the duration of diarrhoea, the volume of diarrhoeal stools (thus the amount of oral and intravenous fluids), and also the duration of faecal excretion of the pathogen, V. cholerae O1 and O139 by about 50%. 3-6 Based on these observations made in numerous clinical trials, routine use of an appropriate antimicrobial therapy is recommended in the management of severe cholera, both in adults and children. All three benefits, as described above, are very important in resources-constraint settings where cholera is endemic and also during epidemic outbreaks.

Nosocomial transmission of cholera has also been increasingly recognized as an important problem,7 and reducing the duration of excretion of Vibrio cholerae in the stool associated with appropriate antimicrobial therapy will presumably decrease the rate of nosocomial infection. Lastly, by shortening the course of illness, patients and their families' can more quickly return to their normal life, lessening their financial burden, which is of particular relevance to socio-economically disadvantaged population who disproportionately share the most of the disease burden from cholera.

From the time of the initial controlled trials of antimicrobial therapy for cholera, almost four decades ago,3 a number of antimicrobial agents have been evaluated to be useful in the treatment of cholera. Tetracycline, chloramphenicol, doxycycline, furazolidone and trimethoprim-sulfamethoxazole have all been found to be effective in the treatment of cholera when given in multiple doses for 3 days.8-14 Tetracycline and it's long-acting congener doxycycline are also effective when administered in a single 1 or 2 g and 200 or 300 mg oral doses respectively in adults.13, 14 Vomiting is a common problem in association with doxycycline therapy and the problem is greater when doxycycline is used in 300 mg dose (39%) compared to when 200 mg dose is used (30%); however, the therapeutic efficacy is better with the higher dose (mean duration of diarrhoea were 32h vs. 40h respectively.14

Antimicrobial resistance has now become an important problem in the clinical management of cholera. For example, in 2006 virtually all of the 683 clinical strains of V. cholerae O1 isolated from patients attending the Dhaka Hospital were multiply drug resistant with 100% resistance to ampicillin, furazolidone and co-trimoxazole, 83% to erythromycin and 85% to tetracycline.15 All V. cholerae strains remained susceptible to ciprofloxacin by disc-diffusion testing, but in E-test their MIC were noted to have increased from 0.002 µg/ml during 1993-2003 to 0.250-0.380 µg/ml in 2006