Elsevier

The Lancet

Volume 348, Issue 9023, 3 August 1996, Pages 296-300
The Lancet

Articles
Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139

https://doi.org/10.1016/S0140-6736(96)01180-4Get rights and content

Summary

Background

Effective antimicrobial therapy can reduce the duration and volume of cholera diarrhoea by half. However, such treatment is currently limited by Vibrio cholerae resistance to the drugs commonly prescribed for cholera, and by the difficulties involved in the administration of multi-drug doses under field conditions. Because of its favourable pharmacokinetics we thought it likely that single-dose ciprofloxacin would be effective in the treatment of cholera.

Methods

In this double-blind study treatment was either a single 1 g oral dose of ciprofloxacin plus doxycycline placebo, or a single 300 mg oral dose of doxycycline plus ciprofloxacine placebo. 130 moderately or severely dehydrated men infected with V cholerae O1 and 130 infected with V cholerae O139 were randomly assigned treatment. Patients stayed in hospital for 5 days. We measured fluid intake and stool volume every 6 h, and a sample of stool for culture was obtained daily. The primary outcome measures were clinical success-the cessation of watery stool within 48 h; and bacteriological success-absence of V cholerae from cultures of stool after study day 2.

Findings

Among patients infected with V cholerae O1, treatment was clinically successful in 62 (94%) of 66 patients who received ciprofloxacin and in 47 (73%) of 64 who receive doxycycline (difference 21% [95% CI 8–33]); the corresponding proportions with bacteriological success were 63 (95%) and 44 (69%) (27% [14–39]). Among patients infected with V cholerae O139, treatment was clinically successful in 54 (92%) of 59 patients who received ciprofloxacin and in 65 (92%) of 71 who received doxycycline (<1% [−9 to 9]), and bacteriologically successful in 58 (98%) and 56 (79%), respectively (19% [9–30]). Total volume of watery stool did not differ significantly between ciprofloxacin-group and doxycycline-group patients infected with either V cholerae O1 or O139. All but one of the V cholerae O1 and all of the O139 isolates were susceptible in vitro to doxycycline, whereas 48 (37%) of the V cholerae O1 isolates and none of the O139 isolates were resistant to tetracycline. Treatment clinically failed in 14 (52%) of 27 doxycycline-treated patients infected with a tetracycline-resistant V cholerae O1 strain, compared with three (8%) of 37 patients infected with a tetracycline-susceptible strain (44% [23–65]).

Interpretation

Single-dose ciprofloxacin is effective in the treatment of cholera caused by V cholerae O1 or O139 and is better than single-dose doxycycline in the eradication of V cholerae from stool. Single-dose ciprofloxacin may also be the preferred treatment in areas where tetracycline-resistant V cholerae are common. In V cholerae, in-vitro doxycycline susceptibilities are not a useful indicator of the in-vivo efficacy of the drug.

Introduction

Cholera continues to be a major, worldwide public-health problem; more countries reported cases of Vibrio cholerae infection to WHO in 1994 than in any previous year.1 Antimicrobial treatment of V cholerae O1 infections can reduce the duration and volume of diarrhoea by half2, 3 and, thus, is an important adjunct to fluid replacement in the treatment of cholera.2, 3, 4 However, the efficacy of available antimicrobial agents has been reduced by the emergence of multiresistant strains of V cholerae O1 in Africa, Asia, and Latin America.5, 6 A cholera outbreak among Rwandan refugees in 1994 caused by such a strain resulted in more than 20 000 deaths.7

Fluroquinolone agents are commonly used in the treatment of enteric infections, because of their good in-vitro activity, the high serum and stool concentrations achieved after ingestion, and their safety.8 There have, however, been few studies of the efficacy of quinolones in cholera,9, 10, 11 and with one exception,10 the studies that have been done have been small and lacked power to detect differences in the comparison treatment. In addition, the efficacy of single-dose quinolones has not been assessed. Similarly, the efficacy of antimicrobial agents in the treatment of cholera caused by the newly identified Vcholerae O139, has not been systematically investigated.

Because of its in-vitro activity against multiresistant strains of V cholerae O1 and O139, its high concentration in the interstinal lumen, and long half-life, ciprofloxacin was a logical candidate to evaluate for single-dose therapy of cholera. In this study we compared single-dose ciprofloxacin with single-dose doxycycline treatment of patients with cholera caused by Vcholerae O1 or O139.

Section snippets

Methods

We recruited patients between April, 1993, and February, 1995, at two diarrhoea treatment centres maintained by the International Centre for Diarrhoeal Disease Research, Bangladesh-one in the capital, Dhaka, and the other in the rural district of Matlab. Eligible patients were men, aged 18–60 years, who had had watery diarrhoea for 24 h or less, and who were moderately or severely dehydrated.6 Patients who had a concomitant illness or had received antimicrobial treatment for this illness were

Results

We enrolled 272 patients. 12 patients (six ciprofloxacin, six doxycycline) were excluded from analysis: ten withdrew before completion of treatment, and two were transferred to other hospitals. 130 patients infected with V cholerae O1 (66 ciprofloxacin, 64 doxycycline), and 130 patients infected with V cholerae O139 (59 ciprofloxacin, 71 doxycycline) were included in the analysis.

The treatment groups were well matched in terms of pretreatment characteristics (table 1).

Among patients infected

Discussion

We found a higher rate of bacteriological cure with ciprofloxacin than with doxycycline among patients infected with V cholerae O1 or O139, but a higher rate of clinical cure only among O1-infected patients. The higher rate of bacteriological success in ciprofloxacin-treated patients is probably attributable to the high stool concentrations of ciprofloxacin relative to the concentration of drug required to inhibit growth of the infecting strain of V cholerae. V cholerae was cleared from the

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