Effect of tetracycline on cholera carriers in households of cholera patients*

Bull. Org. mlond. Sante 1971, 45, 451-455 Bull. Wld Hlth Org. Effect of Tetracycline on Cholera Carriers in Households of Cholera Patients* JOINT ICMR-GWB-WHO CHOLERA STUDY GROUP,' CALCUTTA, INDIA A controlledfield study ofthe treatment ofcholera carriers is described. The households of cholera patients were assigned to two groups: one group received 2 doses of tetracycline daily for 3 days and the other received a placebo of multivitamins. From the second to the fifth day offollow-up, there was a significant decrease in the number of vibrio excretors in the treated group as compared with the placebo group. Soon after withdrawal of the drug, the number ofexcretors rose in the treatedgroup and ultimately it was the same in both groups. In an endemic area, a number of persons may ex- crete Vibrio cholerae without suffering from any appreciable ill-effects. Such symptomless carriers have been detected in households when cholera cases were present (Sinha et al., 1967; Joint ICMR-GWB- WHO Cholera Study Group, Calcutta, India, 1970; Dizon et al., 1970) and during inter-epidemic periods when cases were absent (Sinha et al., 1967). They transmit infection in the community and are obviously a great public health danger. Antibiotics, when used for treatment in combination with fluid and electro- lyte replacement, have proved to be highly effective in reducing the number of vibrios in stools and the duration of excretion of vibrios by cholera patients (Greenough et al., 1964; Carpenter et al., 1964), * Requests for reprints should be addressed to Dr Z. Bencic, " Andrija Stampar " School of Public Health, Rocke- fellerova 4, Zagreb-1, Yugoslavia. 1 This is a joint project under the auspices of the Indian Council of Medical Research (represented by the Cholera Research Centre), the Health Department of the West Bengal Government, and the World Health Organization. The fol- lowing workers participated in the present study: World Health Organization: Z. Bencic, Epidemiologist, WHO Consultant (present address: " Andrija Stampar " School of Public Health, Zagreb, Yugo- slavia); L. Prescott, Bacteriologist, Inter-regional Cholera Teams, Calcutta, India; R. Sakazaki, Bacteriologist, WHO Consultant (present address: National Institute of Health, Tokyo, Japan); K. Tamura, Bacteriologist, WHO Consultant (present address: National Institute of Health, Tokyo, Japan). Health Departmnent of West Bengal: Renuka Sinha, Medical Officer, Epidemiologist (present address: Cholera Research Centre. Calcutta, India). Indian Council of Medical Research, Cholera Research Centre: S. P. De, Jr, Research Officer, Bacteriologist; B. C. Deb, Research Officer, Epidemiologist; S. Mukerjee, Director; D. L. Shrivastava, Emeritus Scientist. but their efficacy as a public health measure for the control of cholera infection has not yet been properly established. METHODS The study population consisted of households in Calcutta that had hospitalized cholera cases during the epidemic period of 1969. Only typical cholera cases were selected. Even if a cholera case was not bacteriologically proved, the household involved was included in the study. Within 24-48 hours of onset of the disease, epidemiologists and field staff visited the patient's household. Stool samples were col- lected from each member of the household on the first day and all household contacts were included in the study. All these contacts received either tetracycline or a placebo (multivitamins), adminis- tered orally in syrup or capsules, depending on their age (Table 1), every 10-12 hours for 3 consecutive days. The treated household contacts (drug group) were matched with the non-treated household con- tacts (placebo group). Convalescent cholera patients were also included in the study if they were dis- charged during the study period, and were assigned to the same group as their household. The treatment was always administered by one of the investigators (Z.B., R.S., or B.C.D.) and on no occasion were capsules or syrup left in the home. In order to avoid bias, the study was designed as a doubled-blind trial. All the household contacts and discharged cholera patients were sampled every day for 10 days. An epidemiologist was always present during the samp- 2740 - 451 - JOINT ICMR-GWB-WHO CHOLERA STUDY GROUP Table 1. Dosage of tetracycline Age-group mg per dose Total mg (years) per day 0-3 4-5 6-12 13 + 125 250 250 500 250 500 500 1 000 Form of administration syrup syrup capsule capsule ling. Generally stool samples were taken, but rectal swabs were collected from children under 5 years of age and from adults if stool samples were not avail- able. The samples were put in McCartney bottles con- taining 10 ml of alkaline peptone water and sent to the laboratory within 2-3 hours of collection. The inoculated peptone water was incubated at 30-37 C for 6 or 8 hours (including the time required for transport from the field to the laboratory). After incubation, one or two loopfuls of the peptone water culture were inoculated on to plating medium. The peptone water culture was also inoculated into a further quantity of alkaline peptone water and plated on agar plates after 6 or 8 hours' incubation at 37 C. Each isolation plate was incubated overnight at 37 C. One plate each of TCBS agar and bile salt agar was used for each sample. The suspicious colonies on the plates were tested with the vibrio 0-1 antiserum of Gardner & Venka- traman, the slide agglutination technique being used for preliminary identification. Positive cultures were purified by reinoculation on to a nutrient agar plate and were then tested in several differential media and with typing sera for complete identification. RESULTS There were 344 subjects in the placebo group and 341 in the treated group (Table 2) (the index cases were excluded). In each group 15 healthy persons ex- creted V. cholerae during the first day of study before the treatment started. The baseline data are thus comparable. There was no statistically significant difference between the placebo group and the treated group or among the subgroups divided according to whether V. cholerae was or was not isolated from the index case. During the course of treatment with tetracycline (second to fourth follow-up days) there was a re- markable reduction in the number of excretors of V. chlolerae in the treated group (Table 3) as compared with the placebo group (Table 4). On the second day Table 2. Baseline data for placebo and treated groups Placebo group No. of No. of % of phersonpersons °/° °fV. cholerae persons persons cI sampled sampled pstv carriers) No. of persons in house- holds Treated group No.of %of persons persons sampled sampled isolated 192 187 within _. __ 24 hours not isolated 76 76 isolated 14 14 between 24 and 48 hours not isolated isolated total not isolated grand total 62 97.4 10 196 192 97.9 8 100.0 3 71 71 100.0 100.0 62 100.0 206 201 97.6 10 138 138 100.0 344 339 98.5 4 22 22 100.0 0 52 51 98.1 3 218 214 98.2 8 5 123 122 99.2 7 15 341 336 98.5 15 First visit after onset of disease in index case Isolation of V. cholerae from index case No. of persons in house- holds No. of persons V. cholerae positive (healthy carriers) 452 453TETRACYCLINE FOR TREATMENT OF CHOLERA CARRIERS Table 3. Excretion of V. cholerae in treated group First Within 24 hours Index case not Day of V. cholerae positive not follow- up zm cza n h01 0 0 0 0 0- 0 0 Zo.c Zooi Zo,) Zoc 2nd 196 194 2 69 3rd 195 193 3 68 4th 201 201 0 69 total 592 588 5 206 visit after onset of disease in index case Between 24 and 48 cholerae Index caseisolated from V chnlerae positive no ndex case 0 c00 0° __ _-q 22 i22 q &5 169 0 22 22 00 52 68Q 0 222)0 5 _) _ a 0 0c _ . _ 68 0 23 23 0 52 205 0 67 63 0 156 nours cn cn 0V. cholerae c co t isolated from e index case C. a Q X 0- 0 ' 0Q 65 6-c01Cc. 00 c: _ 0nOmD C° 6 Q E -2L__ _ _ L ,L 52 0 339 52 1 I 337 51 0 345 155 1 1021 337 2 335 4 343 0 1 015 6 of follow-up, there were 2 V. choleicae excretors in the treated group and 11 in the placebo group- a difference statistically significant at the 5% level. On the third day, there were 4 excretors in the treated group and 19 in the placebo group (a difference significant at the 1% level), and on the fourth day there were no excretors in the treated group as com- pared with 18 in the placebo group (a similarly sig- nificant difference). The differences between the treat- ed and placebo groups with regard to excretion of V. cholerae were statistically significant on each day during the treatment. After cessation of treatment (Table 5), on the fifth day of follow-up, there is still a statistical difference, but only at the 5 Co level, between the treated and placebo groups. From the sixth to the tenth follow- up day there are no differences between the two groups. Table 4. Excretion of V. cholerae in placebo group First visit after onset of disease in index case Within 24 hours Between 24 and 48 hours 0 V. cholerae V. cho/erae r_ c 0Indexcsse ~~not isolated from ine aenot isolated from 1-V. cholerae positive ine eV. cho/erae positive ineIas 0 0 c 00 c0 ~~~~~~ c~~~~ 00Q C) Q) 6 - 6. O 5~~~ 010 o,o t2t~~~~C3 C0o, -0 Ct c.c 00 c Ch ~~~~~ ~ ~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~cn0n0(n- 0 -oo3 O O8 0001 OQ oooOO o0 .00COO O 00 0 0 0~ 6n : 65 6tP- E 0 01 C565T0 61. H-c Ho Z0.c Z~~~~~~~~~~~A1 Z Zo.0oo, Zo~~~~~~~~~~~~~~~~~~~~~~~~Zoc ZooZo~~~~~~~~~~~~~~~~ Zo.0Zo0,Z ~~~~~~Z cX1) Z( 192 189 9 75 75 2 1 5 1 5 0 63 63- 0 345 342 1 1 _ 75 75 1 74 74 2 15 15 0 65 65 1 - - 64 1--- 14 1 4 1 64 4 1 348 347 346 1 9 346 1 8 44 44 1 192 Day of follow- up 2nd 3rd 4th I A J_ 224 5total 192 11 034 ,~48 JOINT ICMR-GWB-WHO CHOLERA STUDY GROUP Table 5. Excretion of V. cholerae in the two groups after cessation of treatment Treated group Day of No. of No. of follow- persons No. of excre- up in persons tors house- sampled of V. holds cholerae 5th 351 6th 351 7th 349 8th 351 9th 347 10th total 346 2 095 345 348 346 349 341 342 2 071 6 8 9 Placebo group No. of personsi No. of in persons house- sampled holds 354 354 353 352 344 344 346 7 344 7 345 38 2 086 346 344 345 2 085 No. of excre- tors of V. cholerae mack et al. (1968) found that tetracycline given daily for 5 days, either in divided doses or in a single daily dose, was effective. However, this procedure is inconvenient in the field because healthy contacts of cholera patients are reluctant to take the drug over a long period. We therefore decided to reduce the period of treatment to 3 days and to give 2 doses per day. 10 As can be seen from the results (Tables 3, 4, and 5), there was a considerable decrease in the number of 13 vibrio excretors in the treated group. Excretion of vibrios was markedly reduced from the second to the 4 fifth day of follow-up in the treated group as com- - pared with the placebo group. The results also indi- 8 cate, however, that soon after withdrawal of the drug there is a rise in the number of excretors in the treated 7 group and that ultimately the numbers of excretors 9 51 DISCUSSION AND CONCLUSION After cholera patients are isolated in hospital, many excretors of V. cholerae remain in their house- holds. As these excretors can infect other persons it is necessary to find a drug that will eliminate V. cholerae in carriers. In a trial in Dacca, McCor- are the same in the two groups. The present investigation indicates that tetra- cycline reduces the incidence of infection during treat- ment and for one day afterwards, but fails to elimi- nate infection entirely from the household. It would appear from the results of this study that in a highly endemic area such as Calcutta infection in households where cholera cases occur cannot be eliminated by the method used. Treatment of house- hold contacts for longer than 3 days would probably be impracticable, but increasing the dose of tetracy- cline (up to 2 g per day for adults) might produce the desired result in an endemic area. ACKNOWLEDGEMENTS The authors are grateful to Dr A. Mondal, Professor of Infectious Diseases, Infectious Diseases Hospital, Cal- cutta (now Director, Cholera Research Centre), and Dr P. Manji, Superintendent, Infectious Diseases Hospi- tal, Calcutta, for their co-operation in this study. They are also greatly indebted to the entire field staff, without whose devoted work it would not have been possible to complete the study. RESUME ACTION DE LA TETRACYCLINE CHEZ DES PORTEURS DE VIBRIO CHOLERAE APPARTENANT A DES FAMILLES DE CHOLERIQUES On a procede a une etude contr6lee du traitement des porteurs de Vibrio cholerae dans des familles de malades atteints de cholera clinique typique, bacteriologiquement confirmne ou non. Dans les 24-48 heures suivant la decou- verte d'un cas, les contacts familiaux ont e repartis en deux groupes: les uns ont requ 2 doses quotidiennes, variables selon l'age, de tetracycline pendant 3 jours, 'a intervalle de 10-12 heures; les autres (groupe temoin), un placebo polyvitamine. Ensuite des coprocultures ont et pratiquees chaque jour pendant 10 jours. Au total, 344 contacts traites et 341 contacts temoins ont et suivis. Le ler jour de l'etude, avant tout traitement, on comptait 15 porteurs sains de V. cholerae dans chaque groupe. Du 2e au 5e jour, on a note une reduction, statisti- quement significative, du nombre des porteurs dans le 454 TETRACYCLINE FOR TREATMENT OF CHOLERA CARRIERS 455 groupe traite par rapport au groupe temoin. Du 6e au 108 jour, le traitement etant acheve, la proportion des sujets excreteurs de vibrions est redevenue sensiblement la meme dans les deux groupes. 11 semble que la tetracycline, a la dose indiquee, n'ait qu'une action transitoire sur 1'etat de porteur de germes du cholera et soit incapable d'eliminer completement l'infection dans une collectivite familiale. Peut-etre pourrait-on obtenir le resultat desire en augmentant les doses (jusqu'A 2 g par jour chez l'adulte). REFERENCES Carpenter, C. C. J. et al., (1964) Bull. Calcutta Sch. trop. Med., 12, 30 Joint ICMR-GWB-WHO Cholera Study Group, Calcutta, India (1970) Bull. Wld Hlth Org., 43, 379, 389, 401 Dizon, J. J. et al. (1967) Bull. Wld Hlth Org., 37, 737 Greenough, W. B. et al. (1964) Lancet, 1, 355 McCormack, W. M. et al. (1968) Bull. Wld Hlth Org., 38, 787 Sinha, R. et al. (1967) Bull. Wld Hlth Org., 37, 89