Effect of doxycycline on transmission of Vibrio cholerae infection among family contacts of cholera patients in Calcutta*

Bulletin of the World Health Organization, 56 (2): 323-326 (1978 Effect of doxycycline on transmission of Vibrio cholerae infection among family contacts of cholera patients in Calcutta* P. G. SEN GUPTA,1 B. K. SIRCAR,2 S. MoNDAL,3 S. P. DE,4 D. SEN,1 S. N. SIKDER,5 B. C. DEB,6 & S. C. PAL 7 Doxycycline was used among the family contacts of hospitalized cholera patients in Calcutta to determine its effectiveness in controlling transmission of V. cholerae infection. A total of 137 such contacts were given a single oral dose of doxycycline in graded doses according to age. A similar group of139 contacts received a single dose ofmultivitamins as placebo. All 276 contacts were examined bacteriologically dailyfor 10 daysfor thepresence ofV. cholerae in their stools. The results showed that doxycycline was effective in signifi- cantly reducing the load of V. cholerae infection for up to S days following treatment. The seventh cholera pandemic due to the eltor biotype of V. cholerae, involving a large number of countries in three continents, brought to light the possible role of cholera carriers in the spread of this disease. The inability of the cholera vaccines currently in use to afford significant protection against cholera for a long period as well as to control carriers has led various workers to consider chemoprophylaxis for the control of transmission of cholera infection. De et al. (1) recently used doxycycline in the treatment of cholera patients. Of three dosage schedules used by these workers, a 300-mg single oral dose of doxycycline was found to be almost as effective as a 6-hourly, 2-day schedule of tetra- cycline. The objective of the present study was to determine whether a single dose of doxycycline would also be effective in reducing the load of V. cholerae infection * From the Cholera Research Centre, 3 Kyd Street, Calcutta-700016, India. These studies were carried out under the joint auspices of the Indian Council of Medical Research, the Health Department of the Government of West Bengal, and the World Health Organization. I Research Officer. 2 Senior Research Officer. ' Research Fellow. 'Assistant Director. Assistant Statistician. Deputy Director. 7Director. among contacts of cholera patients and, if so, the duration of its effectiveness. MATERIALS AND METHODS Between April and August 1976, stool samples or rectal swabs of 276 family contacts of 59 cholera index cases (bacteriologically established) were collected daily for 10 consecutive days and processed as described earlier (2). After the samples had been collected on the first day, the family contacts of index cases were given either doxycycline or multi- vitamins (placebo). A graded dosage schedule was used for doxycycline: adults over 15 years of age received a single oral dose of 300 mg; those under 15 years of age were given 6 mg of doxy- cycline per kg of body weight. Age-specific weights were calculated on the basis of an Indian Council of Medical Research report (3). Biscuits were given before administration of the medicines to prevent possible gastric irritation. Infants under 3 months of age were excluded from the study. The age and sex distribution of the 276 contacts are shown in Table 1, and it can be seen that there was a fair degree of similarity between the two treatment groups. Of the expected total of 2760 samples from 276 contacts, 2672 (96.8 %) were collected. RESULTS The results of sampling the 276 contacts in the two groups on all 10 days are shown in Table 2. It 3695 -323- P. G. SEN GUPTA ET AL. Table 1. Distribution of the study population by age and sex No. of persons Age ~~~~~~~~~~~~~~~~~~~~~~~~~~~~TotalAge group Doxycycline Placebo (years)__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Male Female Total % Male Female Total % No. % 64 9 8 17 12.4 6 12 18 12.9 35 12.7 5-9 6 15 21 15.3 1 1 9 20 14.4 41 14.9 10-14 17 8 25 18.2 12 11 23 16.5 48 17.4 >15 38 36 74 54.0 40 38 78 56.1 152 55.1 All ages 70 67 137 100.0 69 70 139 100.0 276 100.0 Table 2. Sampling of 276 contacts in two groups on different days of follow-up and isolation of V. cholerae from them Treatment groups Days of Doxycycline Placebo Sampling follow-up coverage Number Number Number Number sampled positive sampled positive 1 137 5 135 4 98.6 2 135 2a 136 10 98.2 3 134 nil a 135 6 97.5 4 136 nil a 135 6 98.2 5 132 1 b 133 7 96.0 6 131 4 136 6 96.7 7 131 4 136 4 96.7 8 131 2 136 3 96.7 9 132 2 132 2 95.7 10 128 3 131 4 93.8 a Significantly different from placebo group (P < 0.5). b Difference near significance. is seen that doxycycline was effective immediately after administration in reducing the load of infection among family contacts, compared with the control group. This effectiveness was maintained until the fifth day, after which no difference was observed between the two groups. Although the difference between the results on the fifth day was not statisti- cally significant, it was very close to significance. The distribution of 12 carriers who excreted V. cholerae more than once is shown in Table 3. None of the carriers in the doxycycline group excreted V. cholerae more than twice, whereas in the placebo group two carriers excreted V. cholerae 5 times, two 4 times and two 3 times during the 10-day period of follow-up. Moreover, no excretion of V. cholerae was detected in the doxycycline group during the first 5 days after treatment, whereas in the placebo group excretion was detected in eight carriers. Ten out of 137 contacts (7.3%), although they were given biscuits immediately before the admin- istration of doxycycline, complained of nausea. Similarly, four (2.9%) of the same group suffered from mild vomiting. However, these minor reactions 324 DOXYCYCLINE TREATMENT OF CHOLERA Table 3. Distribution of 12 carriers,a with dates of excretion of V. cholerae, in the two groups Treatment No Days of follow-up on which group V. cholerae excreted doxycycline I Ist,b 7th 2 6th, 7th 3 6th, 9th placebo I 1 st,b 2nd 2 1st,b 2nd, 3rd 3 lst,b 3rd, 4th 4 2nd, 3rd, 5th, 6th 5 2nd, 3rd, 5th, 6th 6 2nd, 6th 7 4th, 5th, 6th, 8th, 10th 8 4th, 10th 9 6th, 7th, 8th, 9th, 10th a These carriers (23.1 % of the total) excreted V. cholerae on more than one occasion. b Treatment was given after collection of stool samples on the first day. did not result in any lack of cooperation by the families during the subsequent 9 days of follow-up. DISCUSSION Previous chemoprophylaxis trials, although effec- tive in various degrees in reducing the number of contact cholera carriers, revealed the limitations of the different drugs used. None could be recom- mended for single oral dose therapy in cholera chemoprophylaxis. Tetracycline, although effective, requires repeated administration for 3-5 days and is consequently not ideal for routine purposes. As a result, sulfadoxine was tested in Calcutta (4). This drug, when given as a single oral dose, was effective for the same length of time as tetracycline but was sluggish in its action during the initial period. This time-lag was considered vital since some of the carriers, though treated with sulfa- doxine, might pass on the infection during the first 24 hours. The present trial, on the other hand, showed that doxycycline given as a single oral dose could effectively reduce the number of cholera carriers almost immediately. Furthermore, it has been observed (2) that the number of carriers among those treated with tetracycline remained significantly low for only 2 days after the last dose had been administered on the third day, whereas in the present trial, the effect of doxycycline was still evident for 4 days following treatment. The minor reactions observed with a single dose of doxycycline might have been further reduced if the drug had been administered after a large meal. Doxycycline, therefore, appears to be a safe, long acting, and effective prophylactic when given in a single oral dose. Moreover, these trials were conducted in a hyperendemic area where the chance of reinfection is greater; in a nonendemic area doxycycline might be even more effective. ACKNOWLEDGEMENTS The authors are thankful to Dr D. Barua, World Health Organization, Geneva for his helpful cooperation and comments on the results of this study. The Vibramycin brand of doxycycline used in the present trial was supplied by the Pfizer Chemical Co. The authors also thank the authorities of the Health Department of the Government of West Bengal for their continued cooperation. Finally, the excellent assistance provided by the field and laboratory workers of the Cholera Research Centre is gratefully acknowledged. RtSUMmt EFFET DE LA DOXYCYCLINE SUR LA TRANSMISSION DE L INFEC1ION A VIBRIO CHOLERAE PARMI LES CONTACTS FAMILLAUX DES PERSONNES ATTEINTES DE CHOLtRA A CALCUTTA La doxycycline, antibiotique A effet r6manent, a ete employee A Calcutta chez un certain nombre de contacts familiaux de malades souffrant de cholera pour deter- miner si elle permettait d'empecher la transmission de l'infection chol6rique. Une seule dose orale de doxy- cycline, plus ou moins forte selon l'Age des interesses, 325 326 P. G. SEN GUPTA ET AL. a ete administree a un total de 137 contacts. Un autre groupe de contacts, au nombre de 139, a requ une dose unique de placebo sous forme de multivitamines. L'en- semble de ces 276 contacts ont ete soumis A un examen bact6riologique quotidien pendant 10 jours en vue de deceler la pr6sence de V. cholerae dans leurs selles. Les r6sultats ont montre que la doxycycline permettait de reduire de maniere significative 1'excretion de V. cholerae pendant une p6riode de 5 jours au maximum apres le traitement. La doxycycline a donc ete jugee constituer un instrument prophylactique de choix dans une region non endemique oih risque de se produire une nouvelle poussee de cholera. REFERENCES 1. DE, S. ET AL. Bulletin of the World Health Organiz- ation, 54: 177-179 (1976). 2. JomIr ICMR-GWB-WHO CHOLERA STUDY GROUP, CALcuTrA. Bulletin of the World Health Organiz- ation, 45: 451-455 (1971). 3. INDIAN COUNCIL OF MEDICAL RESEARCH, STATISTICS DIVISION. Studies on growth and physical development of Indian infants and children. Part IA-all India. New Delhi, ICMR, vol. 2, 1968. 4. DEB, B. C. ET AL. Bulletin of the World Health Organization, 54: 171-175 (1976). ERRATA Vol. 55, No. 1 Evaluation simplifiee sur le terrain de 1'etat nutritionnel des jeunes enfants: suggestions pratiques pour les pays en developpement Re'sume Page 85, 2e colonne, 13e ligne: au lieu de i poids pour l'age> lire #poids pour la taille))