Ciprofloxacin Multiple Dose for Adult Cholera
Ciprofloxacin Multiple Dose for Adult Cholera
Cholera is an important diarrhoeal disease and an important cause of death, particularly
 during epidemic outbreaks, in Bangladesh and many other developing countries. Used as an
 adjunct to management of dehydration, antimicrobial therapy using an appropriate agent
 reduces diarrhoea duration and stool volume in severe cholera by about half.

 The usefulness of antimicrobials has, however, been greatly eroded by the increasing
 prevalence of resistant strains of V. cholerae O1. From October 2004 at the Matlab Hospital
 and from December 2004 at the Dhaka Hospital of ICDDR, B, V. cholerae strains became
 increasingly resistant to tetracycline and erythromycin- two drugs used in the treatment of
 severe cholera in adults and children respectively. Because of this high prevalence of
 resistance we resorted in early 2005 to using ciprofloxacin for treatment against multi drug
 resistant V. cholerae. Although all isolates were susceptible to ciprofloxacin when standard
 thresholds for disc-diffusion or E-test were used, but majority of the strains demonstrated a
 MIC value of 0.250 µg/ml, over hundred-folds greater than the V. cholerae strains tested in
 earlier years, which generally had a MIC of <0.003 µg/ml.

 In this randomized, double blind, controlled trial we will assess clinical and
 bacteriological response to 12 hourly oral dose of ciprofloxacin for 3 days in which the
 first two doses will be 1 g each and the later 4 doses will be 500 mg each, and compare them
 with a single 1 g oral dose of azithromycin. We are using azithromycin as the comparator drug
 because current circulating V. cholerae isolates are susceptible (MIC ≤ 0.125 µg/ml) to this
 azithromycin, and single-dose azithromycin has been evaluated earlier to be effective in the
 treatment of cholera.
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

 Resistance of V. cholerae to commonly used drugs such as tetracycline, doxycycline,
 furazolidone and trimethoprim-sulfamethoxazole have also been reported from Asia, Africa and
 Latin America,17-20 In the early 1990's increasing prevalence of V. cholerae resistant to
 antimicrobials commonly used in the treatment of cholera (tetracycline, ampicillin,
 co-trimoxazole) prompted our group and others to conduct series of trials to identify newer
 affective agents for treatment of cholera. We evaluated ciprofloxacin in both adult and
 children infected with V. cholerae O1 and O139, and observed very good rates of both clinical
 and bacteriological response when used in multiple doses or in a single dose administered
 only once.11, 21, 22

 Ciprofloxacin, is a member of the class of drugs called fluoroquinolones, which act by
 blocking the action of bacterial DNA gyrase.23 This enzyme, which is not present in human
 cells, is responsible for supercoiling of bacterial DNA, an essential element for DNA
 functions.24 Without the three-dimensional DNA structure the cell is unable to replicate, and
 thus bacterial growth is rapidly halted. Ciprofloxacin is the most active of the fluorinated
 4-quinolones (ciprofloxacin, norfloxacin, ofloxacin) against bacterial diarrhoea pathogens
 in-vitro as assessed by MIC. It has a relatively long serum half-life.25 Due to its multiple
 mechanisms of excretion toxic levels of quinolones do not usually accumulate in the body.
 Experience suggests that resistance against ciprofloxacin develops much more slowly than
 against the older quinolone agent such as nalidixic acid, as the rate of spontaneous mutation
 is much lower and multiple mutations are required to confer frank resistance.26, 27 Increases
 in the MIC, however, can occur with single mutation, and this is the likely sequence that has
 occurred among currently circulating V. cholerae isolates in Bangladesh.

 Because of resistance to other agents and susceptibility of the isolates to ciprofloxacin
 in-vitro, disc diffusion tests, Dhaka and Matlab Hospitals of ICDDR, B changed their
 treatment policy (early 2005) to single-dose ciprofloxacin therapy for treatment of cholera
 irrespective of patients' age, except for cholera in pregnant women. However, experienced
 physicians at the Dhaka Hospital quickly noted sub-optimal clinical response to ciprofloxacin
 therapy- higher stool output and longer hospitalisation. A quick review of the clinical study
 that we recently published in the New England Journal of Medicine confirmed these findings.28
 In that study only 26 (27%) of 98 patients who were infected with V. cholerae O1 experienced
 an optimal clinical response to single-dose ciprofloxacin, while only 10 (10%) of the 98
 patients had a bacteriologic cure, as defined in the protocol. Eventual determination of MICs
 of the V. cholerae strains from that study revealed that the inferior clinical and
 bacteriological response to ciprofloxacin was associated with an increase in MIC values.29
 Table 1 below shows the increase in ciprofloxacin MIC values that were observed during
 1993-1994 when we first conducted clinical trials with ciprofloxacin to subsequent years
 including in 2005 when ciprofloxacin was first introduced for routine use in the treatment of
 cholera at the Dhaka Hospital. We can see, the median MICs has increased approximately one
 hundred folds between 1993 and 2006.
Inclusion Criteria:

 -  Age: 18 - 60 years.

 -  Gender: Male

 -  Duration of diarrhoea: Not exceeding 24 hours

 -  Written informed consent for participation.

 -  Dehydration status: Severe dehydration.

 -  Positive stool dark-field microscopic examination for V. cholerae & culture positive
 for V cholerae

 -  For patients assigned to receive ciprofloxacin, an MIC of the V. cholerae isolates to
 ciprofloxacin of > 0.190 µg/ml and to azithromycin of ≤ 0.125 µg/ml.

 Exclusion Criteria:

 -  History of receiving an antimicrobial agent known to be effective in cholera in
 adults.

 -  Concomitant infection requiring antimicrobial therapy other than the study drugs.

 -  Chronic illness.