Single Dose Azithromycin in the Treatment of Adult Cholera
Single Dose Azithromycin in the Treatment of Adult Cholera
Cholera remains an important cause of diarrhoeal illness and death in Asia, Africa and Latin
 America. Antimicrobial therapy is an important adjunct to fluid therapy in the management of
 patients with cholera, and should be given to all patients with clinically moderate-to-severe
 disease since they can reduce the diarrhoea duration and stool volume by half. Current
 therapy for cholera is limited by increasing prevalence of multiply-resistant strains of
 Vibrio cholerae O1 or O139. Tetracycline and doxycycline had been the drugs of choice for
 treating cholera, but multiply-resistant strains are now present in all areas where cholera
 is endemic or epidemic. There is thus a need to identify alternative drugs that are effect in
 treating this disease.

 Azithromycin, a newer macrolide agent, is active in-vitro against V. cholerae, attains high
 concentrations in the gut lumen, has a long half-life, and is better tolerated than
 erythromycin, and older macrolide. In this study we will compare efficacy of a single, 1.0 g
 oral doses of azithromycin and ciprofloxacin in male patients, aged 18-60 years, with cholera
 due to V. cholerae O1 or O139. Patients with typical "Rice watery" stools of cholera, signs
 of severe dehydration and characteristic cholera vibrios in a dark-field stool microscopy.
 Patients who have coexisting illness which may confound assessment of the efficacy or safety
 will not be eligible. Only those patients who have V. cholerae O1 or O139 isolated from their
 pre-therapy stool and/or rectal swab culture and remains in the hospital for the entire
 duration of the study will be eligible for efficacy evaluation. A written informed consent
 will be obtained from each patients for their enrollment in the study.

 Patients will be hospitalized for full 5 days, and asked to return for a follow up evaluation
 7 days after discharge. After initial rehydration, patients will be observed for 4 hours, and
 only those with ³ 20 ml/kg of watery stools during this period will be enrolled for study.
 Treatment will be random, and blinded to study staff and patients. Clinical success of
 therapy will be defined as resolution of watery stool within 48 hours of administration of
 the study drug, and bacteriologic success will be defined as the inability to isolate V.
 cholerae O1 or O139 from fecal/rectal swab cultures of patients after 48 hours of therapy,
 i.e. on day 3 and on all subsequent days of the study. Patients in whom therapy clinically
 fails will be treated for 3 days with an effective alternate drug without opening the study
 code. Ninety one evaluable patients will be required in each group to show with a power of
 80% and a type I error of 5% that the two treatment regimens are equivalent (i.e. the 95%
 confidence interval for the difference in efficacy between the two groups is not greater than
 10%).

 If single-dose azithromycin therapy is found effective it will provide an important option
 for the treatment V. cholerae infections, especially those caused by multiply-resistant
 strains.
A total of 182 evaluable patients (those with a positive stool culture for V. cholerae O1 or
 V. cholerae O139 and remain in the study for full 5 days) will be required for this study.

 Patients who meet the initial entry criteria will be admitted into the study ward of the
 ICDDR,B, weighed (Dehydration Weight), assessed for hydration status and rehydrated using an
 intravenous polyelectrolyte solution ("Dhaka Solution" containing 133 mmol/l of sodium, 13
 mmol/l of potassium, 98 mmol/l of chloride and 48 mmol/l of bicarbonate) over a 3-hour period
 in accordance with the WHO guidelines [53], and re-weighed (Rehydration Weight). Rice-based
 oral rehydration salts (ORS) solution (sodium 90 mmol/l, potassium 20 mmol/l, chloride 80
 mmol/l, bicarbonate 30 mmol/l, and rice powder 50 gram per litre) will be used as the primary
 maintenance fluid once initial rehydration is accomplished, however, intravenous
 polyelectrolyte solution will be used as the maintenance fluid for patients with excessive
 vomiting (usually > 4 episodes per hour) or with rapid stool losses (usually >10 ml/kg.hour),
 or those who are unable to drink enough ORS solution for maintenance of their hydration.
 Patients will be allowed to drink plain water ad libitum after the initial rehydration. All
 fluid intake and output during rehydration (and throughout the study) will be recorded. A
 stool specimen will be collected from the patients for dark-field microscopic examination to
 document the presence of V. cholerae.

 Following rehydration, stool output will be measured for a 4-hour period in the maintenance
 phase, to be called "Observation Period", and those with a stool output of ³ 20 ml/kg during
 this period and those who also have V. cholerae demonstrated in their stool dark-field
 examination will be considered eligible for enrollment into the study if they provide
 voluntary informed consent. This observation period will help establish that patients
 enrolled in the study have moderate to severe disease, so that the potential impact of
 therapy can be evaluated (as any therapy is likely to appear effective in mild disease).

 On final enrollment into the study, a more complete history and physical examination will be
 performed, and all findings will be recorded on pre-designed data collection forms.

 Patients entered into study will be randomly assigned to receive either a single, 1 gram oral
 dose of azithromycin or a single, 1 gram oral dose of ciprofloxacin. Patients entered into
 study will be assigned a consecutive study number which will have been previously randomly
 assigned to one of the two treatment regimens, and this randomization will be done using a
 computer generated random number list with a fixed block length of 4. Study drugs will be
 administered after completion of the four-hour observation period, and at least 2 hours after
 the last food intake. The time of administering study drug will be considered as the
 beginning (the "0" hour) of the study. For patients who vomit within 10 minutes of ingestion
 of study drug, the dose of the study drug will be repeated. For this purpose, all study drugs
 will be available in duplicate. Such events will be recorded, and data of these patients will
 be carefully evaluated. The study drugs will be prepared in identical form to allow for
 blinding of treatment. Randomization will be done by Pfizer, USA who will also provide coded
 study drugs.

 Patients will be hospitalized for 5 complete days to be counted from the time of
 administration of the study drug (Each consecutive, 24-period constituting a day). The
 following clinical and laboratory evaluations will be done for each of the study patients:

 -  Body Weight: On initial entry into the study, after initial rehydration, at "0" hour of
 the study (which will coincide with administration of the study drug), and at 24 hour
 intervals beginning from the time of administration of study drug.

 -  History and physical examination: On admission, after initial rehydration, at "0" hour
 of the study, and at least once daily during hospitalization. This will also include
 evaluation for potential adverse events.

 -  Vital signs: Oral temperature, pulse and respiratory rates, and blood pressures will be
 recorded on admission (dehydrated), after rehydration, at the end of the 4-hour
 observation period ("0" hour of the study), and every 6 hours after administration of
 the study drug.

 -  Measurement of stool volume: Will be done for the rehydration period, the four hour
 observation period, and for each 6-hour period after administration of study drug.

 -  Characterization of stool: Individual stool will be categorized as either watery or soft
 or formed; the worst stool character of each 6 hour study period will be used to
 categorize that time period.

 -  Stool culture for V. cholerae O1, O139 and non-Ol; and Shigella and Salmonella: Will be
 done on admission, on study day two and at follow up.

 -  Rectal swab culture for V. cholerae O1 and O139: Will be done on admission, and on each
 study day.

 -  Hematological studies: Serum electrolytes, creatinine and serum Sp. gr., and haematocrit
 will be determined before and after rehydration, and 24 hours after administration of
 the study drug (3.0 ml of blood will be required for these tests each time, i.e. a total
 of 9.0 ml of blood). Complete blood count, and platelet count will be done just before
 administration of the study drug, however, this may also be done subsequently only if
 clinically indicated.

 -  Pharmacokinetic studies: For the first 40 patients enrolled into the study, venous blood
 will be obtained for determination of the serum concentration of the study drugs at
 either of the following time intervals from administration of the study drug- 3, 12, 24
 or 48 hours. An indwelling catheter with two way stop cock will be introduced to avoid
 repeated venipuncture which will be taken off 3 hours after administration of the study
 drug; all subsequent blood samplings will be done by individual venipunctures. This will
 require only 1.0 ml of venous blood, and serum will be separated and stored at -70EC
 until assayed. For determination of stool concentration of the study drugs, aliquots of
 stool (About 5.0 ml each) will be obtained from stool collected over each 6 hour period
 during the first two days of the study, and like serum, will be stored and analyzed.

 -  Handling of Treatment Failures: If the study treatment is judged to have failed
 clinically patients will be treated for 3 days with an agent other than azithromycin or
 ciprofloxacin to which the isolate of V. cholerae will be found to be susceptible to.
 The treatment code will not be broken for these patients. Patients with microbiological
 failure will be treated with a suitable drug as determined by antimicrobial
 susceptibility of such isolates.
Inclusion Criteria:

 -  Age: 18 - 60 years

 -  Gender: Male (To facilitate accurate measurement of stool and urine, and also due to
 the difficulties in hospitalizing women for longer duration)

 -  Duration of illness: 24 hours or less

 -  Written informed consent for participation in the study

 -  Dehydration status: Signs of severe dehydration as determined by World Health
 Organization criteria.

 -  Positive stool dark-field microscopic examination for V. cholerae, and subsequent
 isolation of V. cholerae O1 or O139 from an admission culture of a stool or rectal
 swab sample.

 Exclusion Criteria:

 -  History of receiving even one dose of an antimicrobial agent effective in the
 treatment of cholera, and even a single fose of the drugs under evaluation.

 -  Concomitant infection requiring antimicrobial therapy other than the study drugs which
 may interfere with evaluation of either the efficacy or safety of the study drugs.

 -  A concomitant illness which may confound evaluation of outcome or is a
 contraindication for use of either of the study drugs (chronic heart, lung, of kidney
 disease, or instance), or conditions which may confound evaluation of adverse events
 of the study drugs.