Vol. 34, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1990, p. 939-940 0066-4804/90/050939-02$02.00/0 Copyright © 1990, American Society for Microbiology
Double-Blind, Randomized, Controlled Clinical Trial of Norfloxacin for Cholera S. K. BHATTACHARYA,l* M. K. BHATTACHARYA,l P. DUTTA,1 D. DUTTA,1 S. P. DE,' S. N. SIKDAR,1 A. MAITRA,2 A. DUTTA,2 AND S. C. PAL' National Institute of Cholera and Enteric Diseases (ICMR), P-33, C.I. T. Road, Scheme X M, Beliaghata, Calcutta 7 00 010,1 and Infectious Diseases Hospital, Calcutta,2 India Received 17 October 1989/Accepted 1 February 1990
In a double-blind, randomized clinical trial with 78 adults with acute watery diarrhea and severe dehydration, 37 subjects were positive for Vibrio cholerae. In conjunction with rehydration therapy, 13 patients received norfloxacin, 12 received trimethoprim-sulfamethoxazole (TMP-SMX), and 12 received a placebo. Norfloxacin was superior to TMP-SMX and to the placebo in reducing stool output, duration of diarrhea, fluid requirements, and vibrio excretion. TMP-SMX was no better than the placebo.
mg) twice daily, and group C (n = 27) received the placebo twice daily. The two drugs and the placebo were in the form of tablets which were identical in size, shape, and appearance and were coded. The code was opened only after completion of the study and analysis of the results. Treatment with drugs or placebo was continued for 5 days. Statistical analysis was done using Student's t test. Of 78 patients included in the study, 37 were positive for V. cholerae. Therefore, only these 37 cases were considered in the final analysis to compare drug efficacies. There were 13 patients who received norfloxacin, 12 patients who received TMP-SMX, and 12 patients who received placebo. All of the patients in the three groups could be rehydrated with fluids (intravenous and oral), and there was no mortality in the present series. Patients in the two treatment groups and the control group had comparable characteristics before allocation to therapy (Table 1). Table 2 shows the stool output, duration of diarrhea, and fluid requirements of the patients in the three groups. The group of patients receiving norfloxacin had statistically significant (P < 0.05) less stool output, shortened duration of diarrhea, and lower fluid requirements compared with the groups of patients receiving either TMP-SMX or the placebo. The group of patients receiving TMP-SMX had stool output, duration of diarrhea, and fluid requirements similar to those of the group of patients receiving the placebo. Patients stopped excreting V. cholerae within 24 to 48 h after initiation of treatment with norfloxacin, whereas patients receiving the placebo or TMP-SMX excreted V. cholerae in their stools for up to 4 or 5 days. In vitro drug susceptibility tests showed that all of the V. cholerae isolates
Acute watery diarrhea caused by Vibrio cholerae is an important cause of hospitalization in Calcutta (6). Several drugs, namely tetracycline (2, 8), furazolidone (5), and trimethoprim-sulfamethoxazole (TMP-SMX) (3), have been found to be effective in reducing stool volume, duration of diarrhea, and vibrio excretion in patients with cholera. Recently, a wide range of bacterial enteropathogens including V. cholerae have been found to be highly susceptible to norfloxacin (4, 7), a 4-quinolone which is similar to nalidixic acid. In this report, we present the findings of a comparative evaluation of the use of norfloxacin, TMP-SMX, or placebo in the treatment of cholera accompanied by severe dehydration. Subjects included in the study were adult male (for ease of collection of stool and urine separately) patients, of more than 18 years of age, who had been admitted to the diarrhea ward of the Infectious Diseases Hospital, Calcutta, with acute watery diarrhea and severe dehydration (11) of less than 24-h duration. Those patients who had received any drug or intravenous fluid before admission or who had any systemic illness were excluded from the study. After enrollment, all patients were placed on cholera cots and were rehydrated with intravenous Ringer lactate and oral rehydration solution as recommended by the World Health Organization (11). A thorough history was taken, a physical examination was performed, and findings were recorded on a prepared form. The amounts of intravenous and oral fluid administered, volume of stool output, and duration of diarrhea were recorded. On admission, a fresh stool sample was collected by using a sterile rectal catheter and was immediately sent to the laboratory for screening of bacterial enteropathogens according to standard techniques (10). Thereafter, rectal swabs collected from all patients for 5 consecutive days were examined for isolation of V. cholerae. All of the V. cholerae isolates were tested for their susceptibility to drugs such as tetracycline, chloramphenicol, ampicillin, TMP-SMX, nalidixic acid, and norfloxacin by the KirbyBauer disk diffusion technique (1). Informed consent was obtained from all patients. Patients included in the study were randomly assigned to one of three treatment groups by using a random number table: group A (n = 26) received norfloxacin (400 mg) twice daily, group B (n = 25) received TMP (160 mg)-SMX (800 *
TABLE 1. Characteristicsa of the three subject groups upon hospital admission Drug treatment group
Age
(Ar) Y
Duration of diarrhea
(h)
Norfloxacin 37.7 ± 14.8 11.8 ± 4.0 (n = 13) TMP-SMX 39.4 ± 13.8 11.9 ± 3.6 (n = 12) Placebo 38.4 ± 13.2 11.6 ± 3.1 (n = 12)
Corresponding author.
a
939
All values are expressed as means
+
Systolic blood
Body wt
pressure (mm Hg)
(kg)
29.6 ± 9.0
43.2 ± 4.2
30.8 ± 7.9
43.4 ± 4.0
30.4 ± 8.4
42.4 ± 3.6
standard deviations.
940
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 2. Stool output, duration of diarrhea, and fluid intake in the three subject groupsa
Drug treatment group
Norfloxacin (n = 13) TMP-SMX (n = 12) Placebo (n = 12)
Fluidb
Stool output (ml)
Duration of diarrhea (h)
required (ml)
1,929.0 ± 1,017.0
19.2 ± 4.4
4,195.0 ± 1,666.6
1,425.0
27.5 ± 4.0
6,660.0 ± 1,945.0
3,507.0 ± 1,621.0
29.3 ± 4.5
7,290.0 ± 2,777.0
3,458.0
±
a All values are expressed as means ± standard deviations. Differences in the means between the norfloxacin and TMP-SMX groups and between the norfloxacin and placebo groups are statistically significant (P < 0.05). The difference in the means between the TMP-SMX and placebo groups is not (P > 0.05). b Administered both orally and intravenously.
were highly susceptible to norfloxacin, tetracycline, chloramphenicol, and nalidixic acid and resistant to TMP-SMX and ampicillin. No adverse side effects were observed with norfloxacin. Drugs are used as an adjunct to intravenous replacement of fluids and electrolytes for the treatment of severe cholera. Drug therapy reduces the stool volume and shortens the duration of diarrhea and excretion of V. cholerae in stool. The present study clearly demonstrates that norfloxacin fulfilled all of the criteria of drug therapy in severe cholera. Norfloxacin was not only better than the placebo but also superior to TMP-SMX in the treatment of cholera with severe dehydration. Moreover, in view of the reported emergence of tetracycline-resistant (9) strains of V. cholerae in some areas, norfloxacin may be used as an alternative drug in the treatment of cholera in adults in conjunction with fluid therapy. We thank B. S. Anand, professor of gastroenterology, G. B. Pant Hospital, New Delhi, for valuable guidance in designing the study, and the superintendent of the Infectious Diseases Hospital, Calcutta, for allowing us to carry out this study. We also thank Ranbaxy Laboratories Ltd. for kindly supplying norfloxacin, TMP-SMX, and placebo in coded form. Secretarial help from Shyamal K. Das is also acknowledged.
LITERATURE CITED 1. Bauer, A. W., W. M. M. Kirby, J. C. Sherris, and M. Tarck. 1966. Antibiotic susceptibility testing by a standarized single disc method. Am. J. Chin. Pathol. 45:493-496. 2. Carpenter, C. C. J., D. Barua, R. B. Sack, C. K. Wallace, P. P. Mitra, S. R. Kanra, T. S. Werner, T. E. Duffy, and A. Oleinick. 1966. Clinical studies in Asiatic cholera. IV. Antibiotic therapy in cholera. Bull. Johns Hopkins Hosp. 118:230-242. 3. Francis, T., I. E. A. Lewis, A. B. 0. 0. Oyediran, 0. A. Okubadio, D. Montefiore, I. I. Onyewote, I. Mohammed, E. A. Ayoola, and R. Vincent. 1971. Effect of chemotherapy on the duration of diarrhoea and on vibrio excretion by cholera patients. J. Trop. Med. Hyg. 74:172-176. 4. Morris, J. G., J. H. Tenney, and G. L. Drusano. 1985. In vitro susceptibility of pathogenic Vibrio species to norfloxacin and six other antimicrobial agents. Antimicrob. Agents Chemother. 28:442-445. 5. Pierce, N. F., J. G. Banwell, R. C. Mitra, G. J. Caranasos, R. I. Keimowitz, J. Thomas, and A. Mondal. 1968. Controlled comparison of tetracycline and furazolidone in cholera. Br. Med. J. 3:277-280. 6. Sen, D., M. R. Saha, S. K. Niyogi, G. B. Nair, S. P. De, P. Dutta, D. Dutta, S. C. Pal, R. Bose, and J. Roychoudhury. 1985. Aetiological studies on hospital in-patients with acute diarrhoea. Trans. R. Soc. Trop. Med. Hyg. 77:212-214. 7. Shungu, D. L., E. Weinberg, and H. H. Gadebusch. 1983. In vitro antibacterial activity of norfloxacin (MK-0366, AM-715) and other agents against gastrointestinal tract pathogens. Antimicrob. Agents Chemother. 23:86-90. 8. Wallace, C. K., P. N. Anderson, T. C. Brown, S. R. Khanra, G. W. Lewis, N. F. Pierce, S. N. Sanyal, G. V. Segre, and R. H. Waldman. 1968. Optimal antibiotic therapy in cholera. Bull. W.H.O. 39:239-245. 9. World Health Organization. 1980. Cholera and other Vibrioassociated diarrhoeas. Publication WHO/CDD/EPE/80.3. Diarrhoeal Diseases Control Programme, World Health Organization, Geneva. 10. World Health Organization. 1983. Manual for laboratory investigation of acute enteric infection. Publication CDD/83.3. Programme for Control of Diarrhoeal Diseases, World Health Organization, Geneva. 11. World Health Organization. 1983. A manual for the treatment of acute diarrhoea. Publication WHO/CDD/SER/80.2. Programme for Control of Diarrhoeal Diseases, World Health Organization, Geneva.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1990, p. 939-940 0066-4804/90/050939-02$02.00/0 Copyright © 1990, American Society for Microbiology
Double-Blind, Randomized, Controlled Clinical Trial of Norfloxacin for Cholera S. K. BHATTACHARYA,l* M. K. BHATTACHARYA,l P. DUTTA,1 D. DUTTA,1 S. P. DE,' S. N. SIKDAR,1 A. MAITRA,2 A. DUTTA,2 AND S. C. PAL' National Institute of Cholera and Enteric Diseases (ICMR), P-33, C.I. T. Road, Scheme X M, Beliaghata, Calcutta 7 00 010,1 and Infectious Diseases Hospital, Calcutta,2 India Received 17 October 1989/Accepted 1 February 1990
In a double-blind, randomized clinical trial with 78 adults with acute watery diarrhea and severe dehydration, 37 subjects were positive for Vibrio cholerae. In conjunction with rehydration therapy, 13 patients received norfloxacin, 12 received trimethoprim-sulfamethoxazole (TMP-SMX), and 12 received a placebo. Norfloxacin was superior to TMP-SMX and to the placebo in reducing stool output, duration of diarrhea, fluid requirements, and vibrio excretion. TMP-SMX was no better than the placebo.
mg) twice daily, and group C (n = 27) received the placebo twice daily. The two drugs and the placebo were in the form of tablets which were identical in size, shape, and appearance and were coded. The code was opened only after completion of the study and analysis of the results. Treatment with drugs or placebo was continued for 5 days. Statistical analysis was done using Student's t test. Of 78 patients included in the study, 37 were positive for V. cholerae. Therefore, only these 37 cases were considered in the final analysis to compare drug efficacies. There were 13 patients who received norfloxacin, 12 patients who received TMP-SMX, and 12 patients who received placebo. All of the patients in the three groups could be rehydrated with fluids (intravenous and oral), and there was no mortality in the present series. Patients in the two treatment groups and the control group had comparable characteristics before allocation to therapy (Table 1). Table 2 shows the stool output, duration of diarrhea, and fluid requirements of the patients in the three groups. The group of patients receiving norfloxacin had statistically significant (P < 0.05) less stool output, shortened duration of diarrhea, and lower fluid requirements compared with the groups of patients receiving either TMP-SMX or the placebo. The group of patients receiving TMP-SMX had stool output, duration of diarrhea, and fluid requirements similar to those of the group of patients receiving the placebo. Patients stopped excreting V. cholerae within 24 to 48 h after initiation of treatment with norfloxacin, whereas patients receiving the placebo or TMP-SMX excreted V. cholerae in their stools for up to 4 or 5 days. In vitro drug susceptibility tests showed that all of the V. cholerae isolates
Acute watery diarrhea caused by Vibrio cholerae is an important cause of hospitalization in Calcutta (6). Several drugs, namely tetracycline (2, 8), furazolidone (5), and trimethoprim-sulfamethoxazole (TMP-SMX) (3), have been found to be effective in reducing stool volume, duration of diarrhea, and vibrio excretion in patients with cholera. Recently, a wide range of bacterial enteropathogens including V. cholerae have been found to be highly susceptible to norfloxacin (4, 7), a 4-quinolone which is similar to nalidixic acid. In this report, we present the findings of a comparative evaluation of the use of norfloxacin, TMP-SMX, or placebo in the treatment of cholera accompanied by severe dehydration. Subjects included in the study were adult male (for ease of collection of stool and urine separately) patients, of more than 18 years of age, who had been admitted to the diarrhea ward of the Infectious Diseases Hospital, Calcutta, with acute watery diarrhea and severe dehydration (11) of less than 24-h duration. Those patients who had received any drug or intravenous fluid before admission or who had any systemic illness were excluded from the study. After enrollment, all patients were placed on cholera cots and were rehydrated with intravenous Ringer lactate and oral rehydration solution as recommended by the World Health Organization (11). A thorough history was taken, a physical examination was performed, and findings were recorded on a prepared form. The amounts of intravenous and oral fluid administered, volume of stool output, and duration of diarrhea were recorded. On admission, a fresh stool sample was collected by using a sterile rectal catheter and was immediately sent to the laboratory for screening of bacterial enteropathogens according to standard techniques (10). Thereafter, rectal swabs collected from all patients for 5 consecutive days were examined for isolation of V. cholerae. All of the V. cholerae isolates were tested for their susceptibility to drugs such as tetracycline, chloramphenicol, ampicillin, TMP-SMX, nalidixic acid, and norfloxacin by the KirbyBauer disk diffusion technique (1). Informed consent was obtained from all patients. Patients included in the study were randomly assigned to one of three treatment groups by using a random number table: group A (n = 26) received norfloxacin (400 mg) twice daily, group B (n = 25) received TMP (160 mg)-SMX (800 *
TABLE 1. Characteristicsa of the three subject groups upon hospital admission Drug treatment group
Age
(Ar) Y
Duration of diarrhea
(h)
Norfloxacin 37.7 ± 14.8 11.8 ± 4.0 (n = 13) TMP-SMX 39.4 ± 13.8 11.9 ± 3.6 (n = 12) Placebo 38.4 ± 13.2 11.6 ± 3.1 (n = 12)
Corresponding author.
a
939
All values are expressed as means
+
Systolic blood
Body wt
pressure (mm Hg)
(kg)
29.6 ± 9.0
43.2 ± 4.2
30.8 ± 7.9
43.4 ± 4.0
30.4 ± 8.4
42.4 ± 3.6
standard deviations.
940
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 2. Stool output, duration of diarrhea, and fluid intake in the three subject groupsa
Drug treatment group
Norfloxacin (n = 13) TMP-SMX (n = 12) Placebo (n = 12)
Fluidb
Stool output (ml)
Duration of diarrhea (h)
required (ml)
1,929.0 ± 1,017.0
19.2 ± 4.4
4,195.0 ± 1,666.6
1,425.0
27.5 ± 4.0
6,660.0 ± 1,945.0
3,507.0 ± 1,621.0
29.3 ± 4.5
7,290.0 ± 2,777.0
3,458.0
±
a All values are expressed as means ± standard deviations. Differences in the means between the norfloxacin and TMP-SMX groups and between the norfloxacin and placebo groups are statistically significant (P < 0.05). The difference in the means between the TMP-SMX and placebo groups is not (P > 0.05). b Administered both orally and intravenously.
were highly susceptible to norfloxacin, tetracycline, chloramphenicol, and nalidixic acid and resistant to TMP-SMX and ampicillin. No adverse side effects were observed with norfloxacin. Drugs are used as an adjunct to intravenous replacement of fluids and electrolytes for the treatment of severe cholera. Drug therapy reduces the stool volume and shortens the duration of diarrhea and excretion of V. cholerae in stool. The present study clearly demonstrates that norfloxacin fulfilled all of the criteria of drug therapy in severe cholera. Norfloxacin was not only better than the placebo but also superior to TMP-SMX in the treatment of cholera with severe dehydration. Moreover, in view of the reported emergence of tetracycline-resistant (9) strains of V. cholerae in some areas, norfloxacin may be used as an alternative drug in the treatment of cholera in adults in conjunction with fluid therapy. We thank B. S. Anand, professor of gastroenterology, G. B. Pant Hospital, New Delhi, for valuable guidance in designing the study, and the superintendent of the Infectious Diseases Hospital, Calcutta, for allowing us to carry out this study. We also thank Ranbaxy Laboratories Ltd. for kindly supplying norfloxacin, TMP-SMX, and placebo in coded form. Secretarial help from Shyamal K. Das is also acknowledged.
LITERATURE CITED 1. Bauer, A. W., W. M. M. Kirby, J. C. Sherris, and M. Tarck. 1966. Antibiotic susceptibility testing by a standarized single disc method. Am. J. Chin. Pathol. 45:493-496. 2. Carpenter, C. C. J., D. Barua, R. B. Sack, C. K. Wallace, P. P. Mitra, S. R. Kanra, T. S. Werner, T. E. Duffy, and A. Oleinick. 1966. Clinical studies in Asiatic cholera. IV. Antibiotic therapy in cholera. Bull. Johns Hopkins Hosp. 118:230-242. 3. Francis, T., I. E. A. Lewis, A. B. 0. 0. Oyediran, 0. A. Okubadio, D. Montefiore, I. I. Onyewote, I. Mohammed, E. A. Ayoola, and R. Vincent. 1971. Effect of chemotherapy on the duration of diarrhoea and on vibrio excretion by cholera patients. J. Trop. Med. Hyg. 74:172-176. 4. Morris, J. G., J. H. Tenney, and G. L. Drusano. 1985. In vitro susceptibility of pathogenic Vibrio species to norfloxacin and six other antimicrobial agents. Antimicrob. Agents Chemother. 28:442-445. 5. Pierce, N. F., J. G. Banwell, R. C. Mitra, G. J. Caranasos, R. I. Keimowitz, J. Thomas, and A. Mondal. 1968. Controlled comparison of tetracycline and furazolidone in cholera. Br. Med. J. 3:277-280. 6. Sen, D., M. R. Saha, S. K. Niyogi, G. B. Nair, S. P. De, P. Dutta, D. Dutta, S. C. Pal, R. Bose, and J. Roychoudhury. 1985. Aetiological studies on hospital in-patients with acute diarrhoea. Trans. R. Soc. Trop. Med. Hyg. 77:212-214. 7. Shungu, D. L., E. Weinberg, and H. H. Gadebusch. 1983. In vitro antibacterial activity of norfloxacin (MK-0366, AM-715) and other agents against gastrointestinal tract pathogens. Antimicrob. Agents Chemother. 23:86-90. 8. Wallace, C. K., P. N. Anderson, T. C. Brown, S. R. Khanra, G. W. Lewis, N. F. Pierce, S. N. Sanyal, G. V. Segre, and R. H. Waldman. 1968. Optimal antibiotic therapy in cholera. Bull. W.H.O. 39:239-245. 9. World Health Organization. 1980. Cholera and other Vibrioassociated diarrhoeas. Publication WHO/CDD/EPE/80.3. Diarrhoeal Diseases Control Programme, World Health Organization, Geneva. 10. World Health Organization. 1983. Manual for laboratory investigation of acute enteric infection. Publication CDD/83.3. Programme for Control of Diarrhoeal Diseases, World Health Organization, Geneva. 11. World Health Organization. 1983. A manual for the treatment of acute diarrhoea. Publication WHO/CDD/SER/80.2. Programme for Control of Diarrhoeal Diseases, World Health Organization, Geneva.
