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Sulphapyridine in typhoid fever
157 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. X X X V I I . No. 2. S e p t e m b e r , 1943.
SULPHAPYRIDINE IN
T Y P H O I D FEVER
BY
M. RACHMILEWITZ, M.D., AND
K. BRAUN, M.D. (From the Medical Department, Division B, of the Rothschild-Hadassah- University Hospital, fferusalem).
Reports in literature on the effect of the drugs of the sulphonamide group in typhoid fever are few. LoNG (1940) reported that the treatment of typhoid fever with sulphanilamide and other drugs of this group was not effective. The same statement was made by CAREY (1940). On the other hand, HAaaIs, SWYER and THOMPSON (1939) described seven patients who were treated with sulphanilamide and were favourably influenced. Some experiments were made on mice which had been inoculated with Bacillus typhosus. They were treated with sulph~nilamide and the results were very satisfactory. (BUTTLE et al., 1937; KOLMER and RULE, 1939.) Typhoid fever in Palestine has had for some time a relatively mild course not requiring any special therapeutic measures. During last year, however, it has appeared in a more severe form, with a higher mortality than previously. Finding the need for more active treatment in the more severe cases, we began
158
SULPHAPYRIDINE IN TYPHOID
to use the drugs of the sulphonamide group. In all, there were 64 cases of typhoid fever u n d e r our care during this period. Of these 46 were not given any special medication either because the disease was mild or because the patients did not tolerate the sulphonamide drugs. F o u r deaths occurred in the untreated group. Eighteen specially selected severe cases were treated with sulphapyridine (dagenan, M. & B. 693) : nine showed both rigors and toxaemia as prominent features of the clinical picture and nine severe toxaemia only. Fifteen of these cases had a positive blood culture. T h e treatment was begun at the time when the patients showed signs of severe toxaemia. In all these patients, with the exception of two, there was a definite effect of the drug on the toxaemia and on the rigors when present. In two patients the signs of t o x a e m i a ' w e r e unaffected in spite of sufficient treatment with sulphapyridine, and severe toxaemia was the cause of death. T h e r e were two additional instances of death in the group treated with sulphapyridine but "in these two the general toxic manifestations were definitely and favourably influenced by the drug and the deaths were due to complications." uraemia in the one and intestinal perforation with peritonitis in the other case. In the patients who recovered the effect of the drug was most convincing when treatment was instituted at the height of the septic state. T h i s is illustrated in the cases reported below. Case 1.
J. F., 30 years old, admitted to the hospital on the 1.1th day of his illness. Fever, 37 ° to 39 ° C. In spite of this comparatively low temperature, he was very toxic. The blood culture was positive. Fourteen days after admission to the hospital his condition became worse, his temperature rose to 39"6° C., and on the following days he had daily rigors. There were no complications to account for these rigors. The blood culture continued to be positive. After five rigors we gave sulphapyridine treatment ; 24 hours after having been given I "5 gramme his temperature fell to 35"8° C. (Chart 1).
CHART 1.
There were no signs of collapse. On the contrary, in spite of the sttdden drop of the temperature, the patient was feeling quite well. The treatment with sulphapyridine was continued for 7 days, the patient having received during this period the total amount of
M. R A C H M I L E W I T Z
AND K. BRAUN
159
19.5 grammes of the drug. No rigors occurred during this period and the temperature was kept on a lower level. T h e patient's general condition improved. At that stage sulphapyridine was discontinued. Three days later the patient's temperature again rose, with rigors and sweats, sulphapyridine was again administered a n d the results were the same as before. T h e patient made a rapid recovery except for the complication of thrombophlebitis of the saphenous vein which was not accompanied by fever. Case 2. W. H., 37 years old, was admitted to the hospital at the beginning of the 2nd week of his illness. He appeared severely ill and ran a temperature ranging between 38 ° C. and 41 ° C: He suffered from severe headaches. Blood culture was negative. His condition grew worse and he was highly toxic and delirious. Thirteen days after his admission the patient had a rigor for the first time. On the following day there were two rigors, and his temperature rose to 41 ° C. Sulphapyridine was given and in response there were no further rigors. (Chart 2.)
CHART 2.
During 5 days he got the totalamount of 12 grammes of sulphapyridine. Three days after we discontinued its administration his temperature rose again to 42 ° C. We repeated the treatment and obtained the same result as previously. The sulphapyridine not only stopped the rigors but it seemed that the temperature was being kept at a lower level--between 37.5 ° C. and 38.5 ° C. There was a marked improvement in the patient's general condition after this treatment. His headaches subsided and his mental condition became normal, though the fever, remittent in character, continued for several weeks more. During this period he had a haemorrhage of the intestines and later a cholecystiris with jaundice. All these complications cleared up. T h e patient left the hospital 117 days after admission. In this case the treatment with sulphapyridine affected favourably the septic features of typhoid, stopping the rigors immediately, but did not seem to shorten the duration of the illness and did not prevent comolications. I n s e v e n o t h e r p a t i e n t s , t h e septic m a n i f e s t a t i o n s a n d t h e rigors w h i c h o c c u r r e d d u r i n g t h e course of t h e disease were s i m i l a r l y affected b y s u l p h a -
160
SULPHAPYRIDINE IN TYPHOID
pyridine treatment. The duration of the disease did not seem to be shortened, however, in this group. Nine other cases had no rigors, but the disease was accompanied by signs of severe toxaemia, high temperature, dulling of sensorium, meteorism, etc. Two of these cases had severe diarrhoea and incontinence of urine and faeces. One of them was a young man 19 years old. He was admitted to the hospital at the beginning of the 2nd week of illness. His condition was serious. He had a diffuse roseolar eruptioia and severe diarrhoea. His temperature rose to 41 ° C. Blood culture was positive for B. typhosus. In spite of large doses of opium and hypertonic solution of sodium chloride intravenously, as well as a continuous intravenous infusion of normal saline, no improvement was obtained. On the contrary, his condition was getting worse, and the signs of toxaemia increased. The patient had 20 to 30 stools a day, with complete incontinence. At this stagesulphapyridine was administered. (This was 10 days after his admission to the hospital.) He was given S grammes in the first 24 hours. After this his temperature dropped from 38"8 ° C. to 35"8° C. (Chart 3.)
CHART 3.
The signs of toxaemia markedly subsided and his diarrhoea stopped completely. During the following 7 days the patient was given 3 grammes of sulphapyridine daily. His general condition improved, his fever also was kept at a lower level. Sulphapyridine was discontinued and the patient was recovering. On the 43rd day he had a relapse which lasted 18 days. In this case, as in the preceding cases, it is obvious that the sulphapyridine did not shorten the period of pyrexia nor was the relapse prevented, but it had an immediate and definite effect on the toxic manifestations of the disease.
M. R A C H M I L E W I T Z
AND K. BRAUN
161
Another case to illustrate the immediate effect of sulphapyridine on the toxaemia in typhoid fever was a boy 13 years old, who was admitted to the hospital on the 14th day of his illness. On admission the patient was highly toxic; restlessness, dulling of the sensorium, headache and nausea were the prominent features of the toxaemia. The blood culture was negative. The temperature ranged between 38"8 ° and 40"4 ° C. After 2 days of sulphapyridine treatment (the total amount given was 6"5 grammes), the temperature dropped to 37"4 ° C. (Chart 4). Together with the drop in his temperature all the toxic
CHART4. manifestations of the disease disappeared. The treatment was continued for 7 days more (the total amount given being 32"5 grammes). During this period the temperature gradually became normal and the patient made a speedy recovery. The impression was gained in this particular case that not only were the toxic manifestations favourably affected but also that the duration of the disease was shortened by the sulphapyridine. The blood picture of all our patients prior to the administration of sulphapyridine showed leucopenia (4,000 to 8,000 leucocytes). Under the influence of the drug we did not see a further marked decrease in the number of leucocytes or granulocytopenia. FRIEDBERG (1941) and other authors made the same observation on patients suffering from pneumonia with leucopenia who were treated, nevertheless, successfully with sulphapyridine. It follows, therefore, that leucopenia is no contra-indication to sulphapyridine therapy. The drop in leucocytes occasionally observed following its administration depends less on the original white cell count than on the individual response of the haematopoietic system to the drug.
162
SULPHAPYRIDINE IN TYPHOID
SUMMARY. Our observations on eighteen cases suffering from typhoid fever treated with sulphapyridine lead to the conclusion that the septic and toxic features of the disease may be favourably affected by this drug. The rigors, if present, stop, and the toxic manifestations of the disease usually disappear although the duration of the disease does not seem to be shortened. Sulphapyridine may therefore be considered a valuable aid in combating certain phases in typhoid fever. REFERENCES. BUTTLE, G. A. H., PARISH,H. I., McLEOD, M. & STEPHENSON,DOaA. (1937). Lancet, 1, 681. CAREY,BENJAMINW. (1940). J. Amer. med. Ass., 115, 925. 'FmEDBERG, C. K. (1941). Ibid., 116, 270. HARRIS, E. H. R., SWYER, R., & THOMPSON, N. (193~). Lancet, 1, 1321. KOLMER, I. A. & Rt~LE, A . M . (1939). Proc. Soc. exp. Biol., N . Y . , 40, 615. LONG, P. (1940). Bull. N . Y . Acad. Med., 16.
SULPHAPYRIDINE IN
T Y P H O I D FEVER
BY
M. RACHMILEWITZ, M.D., AND
K. BRAUN, M.D. (From the Medical Department, Division B, of the Rothschild-Hadassah- University Hospital, fferusalem).
Reports in literature on the effect of the drugs of the sulphonamide group in typhoid fever are few. LoNG (1940) reported that the treatment of typhoid fever with sulphanilamide and other drugs of this group was not effective. The same statement was made by CAREY (1940). On the other hand, HAaaIs, SWYER and THOMPSON (1939) described seven patients who were treated with sulphanilamide and were favourably influenced. Some experiments were made on mice which had been inoculated with Bacillus typhosus. They were treated with sulph~nilamide and the results were very satisfactory. (BUTTLE et al., 1937; KOLMER and RULE, 1939.) Typhoid fever in Palestine has had for some time a relatively mild course not requiring any special therapeutic measures. During last year, however, it has appeared in a more severe form, with a higher mortality than previously. Finding the need for more active treatment in the more severe cases, we began
158
SULPHAPYRIDINE IN TYPHOID
to use the drugs of the sulphonamide group. In all, there were 64 cases of typhoid fever u n d e r our care during this period. Of these 46 were not given any special medication either because the disease was mild or because the patients did not tolerate the sulphonamide drugs. F o u r deaths occurred in the untreated group. Eighteen specially selected severe cases were treated with sulphapyridine (dagenan, M. & B. 693) : nine showed both rigors and toxaemia as prominent features of the clinical picture and nine severe toxaemia only. Fifteen of these cases had a positive blood culture. T h e treatment was begun at the time when the patients showed signs of severe toxaemia. In all these patients, with the exception of two, there was a definite effect of the drug on the toxaemia and on the rigors when present. In two patients the signs of t o x a e m i a ' w e r e unaffected in spite of sufficient treatment with sulphapyridine, and severe toxaemia was the cause of death. T h e r e were two additional instances of death in the group treated with sulphapyridine but "in these two the general toxic manifestations were definitely and favourably influenced by the drug and the deaths were due to complications." uraemia in the one and intestinal perforation with peritonitis in the other case. In the patients who recovered the effect of the drug was most convincing when treatment was instituted at the height of the septic state. T h i s is illustrated in the cases reported below. Case 1.
J. F., 30 years old, admitted to the hospital on the 1.1th day of his illness. Fever, 37 ° to 39 ° C. In spite of this comparatively low temperature, he was very toxic. The blood culture was positive. Fourteen days after admission to the hospital his condition became worse, his temperature rose to 39"6° C., and on the following days he had daily rigors. There were no complications to account for these rigors. The blood culture continued to be positive. After five rigors we gave sulphapyridine treatment ; 24 hours after having been given I "5 gramme his temperature fell to 35"8° C. (Chart 1).
CHART 1.
There were no signs of collapse. On the contrary, in spite of the sttdden drop of the temperature, the patient was feeling quite well. The treatment with sulphapyridine was continued for 7 days, the patient having received during this period the total amount of
M. R A C H M I L E W I T Z
AND K. BRAUN
159
19.5 grammes of the drug. No rigors occurred during this period and the temperature was kept on a lower level. T h e patient's general condition improved. At that stage sulphapyridine was discontinued. Three days later the patient's temperature again rose, with rigors and sweats, sulphapyridine was again administered a n d the results were the same as before. T h e patient made a rapid recovery except for the complication of thrombophlebitis of the saphenous vein which was not accompanied by fever. Case 2. W. H., 37 years old, was admitted to the hospital at the beginning of the 2nd week of his illness. He appeared severely ill and ran a temperature ranging between 38 ° C. and 41 ° C: He suffered from severe headaches. Blood culture was negative. His condition grew worse and he was highly toxic and delirious. Thirteen days after his admission the patient had a rigor for the first time. On the following day there were two rigors, and his temperature rose to 41 ° C. Sulphapyridine was given and in response there were no further rigors. (Chart 2.)
CHART 2.
During 5 days he got the totalamount of 12 grammes of sulphapyridine. Three days after we discontinued its administration his temperature rose again to 42 ° C. We repeated the treatment and obtained the same result as previously. The sulphapyridine not only stopped the rigors but it seemed that the temperature was being kept at a lower level--between 37.5 ° C. and 38.5 ° C. There was a marked improvement in the patient's general condition after this treatment. His headaches subsided and his mental condition became normal, though the fever, remittent in character, continued for several weeks more. During this period he had a haemorrhage of the intestines and later a cholecystiris with jaundice. All these complications cleared up. T h e patient left the hospital 117 days after admission. In this case the treatment with sulphapyridine affected favourably the septic features of typhoid, stopping the rigors immediately, but did not seem to shorten the duration of the illness and did not prevent comolications. I n s e v e n o t h e r p a t i e n t s , t h e septic m a n i f e s t a t i o n s a n d t h e rigors w h i c h o c c u r r e d d u r i n g t h e course of t h e disease were s i m i l a r l y affected b y s u l p h a -
160
SULPHAPYRIDINE IN TYPHOID
pyridine treatment. The duration of the disease did not seem to be shortened, however, in this group. Nine other cases had no rigors, but the disease was accompanied by signs of severe toxaemia, high temperature, dulling of sensorium, meteorism, etc. Two of these cases had severe diarrhoea and incontinence of urine and faeces. One of them was a young man 19 years old. He was admitted to the hospital at the beginning of the 2nd week of illness. His condition was serious. He had a diffuse roseolar eruptioia and severe diarrhoea. His temperature rose to 41 ° C. Blood culture was positive for B. typhosus. In spite of large doses of opium and hypertonic solution of sodium chloride intravenously, as well as a continuous intravenous infusion of normal saline, no improvement was obtained. On the contrary, his condition was getting worse, and the signs of toxaemia increased. The patient had 20 to 30 stools a day, with complete incontinence. At this stagesulphapyridine was administered. (This was 10 days after his admission to the hospital.) He was given S grammes in the first 24 hours. After this his temperature dropped from 38"8 ° C. to 35"8° C. (Chart 3.)
CHART 3.
The signs of toxaemia markedly subsided and his diarrhoea stopped completely. During the following 7 days the patient was given 3 grammes of sulphapyridine daily. His general condition improved, his fever also was kept at a lower level. Sulphapyridine was discontinued and the patient was recovering. On the 43rd day he had a relapse which lasted 18 days. In this case, as in the preceding cases, it is obvious that the sulphapyridine did not shorten the period of pyrexia nor was the relapse prevented, but it had an immediate and definite effect on the toxic manifestations of the disease.
M. R A C H M I L E W I T Z
AND K. BRAUN
161
Another case to illustrate the immediate effect of sulphapyridine on the toxaemia in typhoid fever was a boy 13 years old, who was admitted to the hospital on the 14th day of his illness. On admission the patient was highly toxic; restlessness, dulling of the sensorium, headache and nausea were the prominent features of the toxaemia. The blood culture was negative. The temperature ranged between 38"8 ° and 40"4 ° C. After 2 days of sulphapyridine treatment (the total amount given was 6"5 grammes), the temperature dropped to 37"4 ° C. (Chart 4). Together with the drop in his temperature all the toxic
CHART4. manifestations of the disease disappeared. The treatment was continued for 7 days more (the total amount given being 32"5 grammes). During this period the temperature gradually became normal and the patient made a speedy recovery. The impression was gained in this particular case that not only were the toxic manifestations favourably affected but also that the duration of the disease was shortened by the sulphapyridine. The blood picture of all our patients prior to the administration of sulphapyridine showed leucopenia (4,000 to 8,000 leucocytes). Under the influence of the drug we did not see a further marked decrease in the number of leucocytes or granulocytopenia. FRIEDBERG (1941) and other authors made the same observation on patients suffering from pneumonia with leucopenia who were treated, nevertheless, successfully with sulphapyridine. It follows, therefore, that leucopenia is no contra-indication to sulphapyridine therapy. The drop in leucocytes occasionally observed following its administration depends less on the original white cell count than on the individual response of the haematopoietic system to the drug.
162
SULPHAPYRIDINE IN TYPHOID
SUMMARY. Our observations on eighteen cases suffering from typhoid fever treated with sulphapyridine lead to the conclusion that the septic and toxic features of the disease may be favourably affected by this drug. The rigors, if present, stop, and the toxic manifestations of the disease usually disappear although the duration of the disease does not seem to be shortened. Sulphapyridine may therefore be considered a valuable aid in combating certain phases in typhoid fever. REFERENCES. BUTTLE, G. A. H., PARISH,H. I., McLEOD, M. & STEPHENSON,DOaA. (1937). Lancet, 1, 681. CAREY,BENJAMINW. (1940). J. Amer. med. Ass., 115, 925. 'FmEDBERG, C. K. (1941). Ibid., 116, 270. HARRIS, E. H. R., SWYER, R., & THOMPSON, N. (193~). Lancet, 1, 1321. KOLMER, I. A. & Rt~LE, A . M . (1939). Proc. Soc. exp. Biol., N . Y . , 40, 615. LONG, P. (1940). Bull. N . Y . Acad. Med., 16.