- Email: [email protected]
Treatment of epidemic typhus with chloromycetin
163 TRANSACTIONSOF THE ROYAL SOCIETYOF TROPICAL MEDICINE AND HYGIENE. Vol. 42. No. 2. September, 1948.
T R E A T M E N T OF EPIDEMIC TYPHUS W I T H CHLOROMYCETIN.* BY
EUGENE H. PAYNE, A.M., ~a.D., Dept. of Clinical Investigation, Parke, Davis and Company, Detroit, Michigan, E. A. SHARP, M.D., Director, Dept. of Clinical Investigation, Parke, Davis and Company, Detroit, Michigan, AND
JOSE A. KNAUDT, M.D., Professor of Bacteriology, University of La Paz, La Paz, Bolivia.
This paper is a report of results obtained following the treatment of 22 cases of epidemic typhus with chloromycetin. Chloromycetin, a new antibiotic isolated by EHRLICI-I (1947), and associates from Streptomyces sp. was found in soil originating near Caracas, Venezuela. It is a neutral c o m p o u n d stable in aqueous solution for over 24 hours at a p H range from 2 to 9. i n distilled water it is unaffected by boiling for 5 hours. F r o m the laboratory studies of EHRLICH (1947) and associates, and SMADEL and JACKSON (1947), it seemed probable that chloromycetin would be effective in treatment of the rickettsial diseases, t Opportunity for clinical trial was * Material used was supplied by Parke, Davis and Company, Detroit, Michigan. The Bolivian Office of the Institute of Inter-American Affairs rendered invaluable assistance in connection with this study. ]-Toxicity and safety tests were performed by the Research Department, Parke, Davis and Company, Detroit, Michigan.
t64
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
afforded by an epidemic of typhus which occurred in the province of Camacho, Department of La Paz, Bolivia, during late 1947. The province of Camacho, with a population of approximately 120,000, 90 per cent. of whom are pure Aymara, lies 203 km. north of the capital, La Paz, on the eastern shore of Lake Titicaca and borders Peru on the north. Puerto Acosta (population 1,200) is the seat of the provincial government. The climate is rigorous, the altitude being approximately 14,000 feet above sea level, and surrounding snow-capped mountains cause the temperature to remain quite low.
-II Plan Of the t o w n of Puerto Aeosta.
g
Area invaded by t y p h u s epidemic is shaded.
Originating across the border in Peru during October, 1947, the epidemic spread south and east into Bolivia, reaching Puerto Acosta in mid-November. It persisted in Puerto Acosta until about the 15th December, when the activities of Servico Corporativo Inter-Americano de Sulde Pubtica checked its progress by means of immunizations and a vigorous D D T campaign. During the two months of the epidemic, deaths from typhus amounted to at least 60, the majority occurring in the bordering villages of the canton of Conima in Peru. Later the epidemic spread to other provinces, where this study was continued. A preliminary report by PAYNE and KNAUDT (1948) of the first cases treated has already appeared.
EUGENE H. PAYNE, E., A .
165
SHARP AND JOSE A. KNAUDT
TABLE.
Dose (gramme). Case.
1 2 3 4 5 6 7 8 9 10 -11 12 13 14 15 16 17 18 19 20 21 22
Age and sex.
15 F. 16 F. 12 F. I4 M. 32 F~ 18 M . 17 M . 38 F. 18 M . 45 M . 48 F. 38 F. 30 M . 25 M . 29 F. 52 M . 22 M . 48 M . 17 F. 43 M . 54 M . 42 F.
WeftFelix.
Temp. ° C.
Pulse.
Daily.
-
Return to normal. - - - -
Symptoms relieved.
Total.
1 : 1,200 1 : 1,200 1 : ],400 1 : 1,200 1 : 1,200 1 : 1,400 1 : 1,200 1 : 1,200 1 : 400 1 : 600 1 : 1,200 1 : 600 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 600 1 : 1,200 1 : 600 1 : 400
40.9 39.7 40-0 41.0 39.0 39.5 40-0 40.2 38.9 Sub-normal 40.8 39-7 39.4 40.3 40.1 39.6 39-7 40.2" 39.7 39.5 39-7 40.6
i40 130 140 140 120 130 140 140 120 130 140 120 120 140 140 120 140 140 120 120 I40 140
-I O r a l
I.V.
1-0 1-0
-. -0.4 0.5 --0.8 0.8 -1.0 1.0 0-8 ---1-2 0-6 -----0.3
-2.0 1.5 -1-0 2.0 1.0 1.5 2.0 3.0 3.5 1.5 2.0 1-5 1.5 1.5 1.5 1.5 3.0
.
2.5 2.5 1.2 1.25 4.0 3.0 2.8 4-2 3.5 5'8 4.0 3"9 3'8 3'9 4.0 4.0 3-0 3-6 3.0 3 0 3"0 8.8
Temp.
Pulse.
Hours. 48 48 54 48 48 42 24 32 24 48 38 24 24 24 24 24 24 36 26 24 28 44
Hours. 54 48 48 36 48 46 24 36 30 30 38 30 24 24 24 24 24 42 30 24 36 48
Hours. 60 60 72 54 48 36 42 48 48 72 52 60 48 48 48 48 36 54 42 48 48 72
The Table presents the 22 cases of epidemic typhus treated with chloromycetin. The results in tabulated form show the rapid recovery of the patients following treatment. In this list Cases No. 8, 11, 14 and 19 presented signs and symptoms of probable death. Cases No. 10, 15, 16, 18 and 22 gave evidence of certain death. CONTROLS.
For controls we studied 50 untreated cases of typhus occurring in the same epidemic, with the following results : Well-Felix 37 cases.) Number
at dilutions of I : 600 to I : 1,400 ; average I : 1,200.
of deaths
(Readings
done on
14, o r 2 8 p e r c e n t .
Deaths occurred on the time was not exact.)
llth
to 20th
day of disease;
average
14 d a y s .
(In
six cases
166
TREATMENT OF EPIDEMIC TYPHUS W I T H CHLOROMYCETIN
Patients recovering without treatment with chloromycetin entered conv a l e s c e n c e o n 12th t o 2 6 t h d a y of disease ; average, 18 days. S p a c e does n o t p e r m i t t h e p u b l i c a t i o n of t h e e x t e n s i v e r e c o r d s of e a c h c a s e r e p o r t e d , a n d since t h e s y m p t o m s a n d p r o g r e s s are q u i t e similar, o n l y t h r e e b r i e f case r e c o r d s are h e r e w i t h p r e s e n t e d . CASE No. 8. Basilia de Zalles. General Hospital, La PaT. Female. Age 38 years~ Colour, white. Weil-Felix reaction positive in a dilution of 1 : 1,200. 17th December, 1947. This patient exhibited all the signs and symptoms of a grave infection of epidemic typhus. Onset 6 days ago was violent with chills, vomiting, intense headache and backache. T h e patient had insomnia and was stuporous. On examination a clear, generalized exanthema was found accompanied by conjunctivitis, partial paralysis of tongue, coughing and dyspnoea. R.B.C., 4,200,000; W.B.C., 4,110; Hb., 39 per cent. U r i n e : albumin, trace ;: casts, negative. T h e temperature, 40.2 ° C. Pulse, 140. Prognosis, grave. 18th December, 1947. In consultation the medical staff agreed that the patient had lost ground during the night. T h e symptoms and physical findings were more pronounced. There was profound stupor, interspersed with delirium. Treatment with chloromycetin was begun at once. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse, 11.20 a.n,. 0-2 intravenously 40"8 ° C. 140 2.30 p.n,. 0-2 intravenously 39"5 ° C. 120 5.25 p.m. 0.2 intravenously 36"6 ° C. 90 0.5 orally 9.30 p.m. 0.2 intravenously 38"0 ° C. 120 0.5 orally At the time of the 9.30 p.m. dose there was noted obvious improvement in the patient's condition, and she was found asleep soon afterwards. 19th December, 1947. Morning : T h e cephalgia, rachialgia and polydipsia were less intense than on the previous day. Improvement was noted in the general appearance of the patient. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 10.30 a.m. 0.2 intravenously 37"8 ° C. 100 0-5 orally 9.30 p.m. 0-2 intravenously 36"6 ° C. 80 0.5 orally During the afternoon the improvement became more pronounced. All headache and. backache disappeared. T h e patient sat up to eat her evening meal, and enjoyed a good night's sleep. R.B.C., 4,080,000; W.B.C., 4,000; Hb., 37 per cent. U r i n e : albumin, trace ; casts, negative. 20th December, 1947. T h e patient felt well, all symptoms had subsided and the petechiae were almost gone. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 10.30 a.m. 0.5 orally 36"6 ° C. 80 5.30 p.m. 0.5 orally 36"6 ° C. 80
EUGENE H. PAYNE, E. A. SHARP AND JOSE A. KNAUDT
167
Recovery was so far advanced that treatment was suspended, and the patient allowed up. Observation during the succeeding 10 days failed t o show any relapse of fever or symptoms. Forty-eight hours after treatment : R.B.C., 4,000,000 ; W.B.C., 4,200 ; I-Ib., 35 per cent. Urine : albumin, trace ; casts, negative. Seventy-two hours after treatment: R.B.C., 4,070,000; W.B.C., 4,500; Hb., 35 per cent. Urine : albumin, trace ; casts, negative. Six days after treatment : R.B.C., 5,700,000 ; W.B.C., 6,100 ; Hb., 49 per cent. Total chloromycetin given : 4.2 gramme. CASE N o . 10. Gregorio Zalles. General Hospital, La Paz. Age 45 years, Race, Aymara. Early Weil-Felix reaction was positive in dilution of 1 : 600. The length of time this patient had been ill is not certain, but somewhere between 12 days and 3 weeks. During the previous 5 days that the patient had been in the hospital he had received three daily doses of tartar emetic, 3 c.c. each. Also intravenous glucose solution, cardiac tonics, and general symptomatic therapy. His condition grew steadily worse from the first violent onset of the disease. Blood specimen lost. Urine : albumin, + -}- ; casts, present, granular. 18th December, 1947. The patient was presented to the authors for treatment with chloromycetin. On examination a middle-aged male was found in a coma, who had not spoken or taken food or water for three days. He was emaciated, his eyes sunken and lustreless. The mouth was foul with sordes and the mucous membrane contained many lesions. The temperature had fallen to sub-normal. The heart was weak and irregular, the pulse, faint and thready, averaging about 120 to 140. Respiration was of Cheyne-Stokes type. The rJatient appeared to be in extremis, and this impression was verified when it was found that the death certificate had been completed, except for date, and the burial arranged. Treatment with chloromycetin was begun with little hope of success, due to the advanced state of the disease.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 11.40 a.m. 0.2 intravenously 35"0 ° C. 120 :h 2.30 p.m. 0.2 intravenously 35"2 ° C. 110-46.45 p.m. 0"2 intravenously 35-1 o C. 110 ± 10.10 p.m. 0.2 intravenously 35-0 ° C. 100 Forty minutes after the first dose the patient aroused and spoke for the first time in 3 days. He asked for and drank a glass of water. He remained in a stuporous condition throughout the night, the only improvement noticed was the strengthening of the pulse. Blood specimen lost. 19th December, 1947. In general the patient seemed to be about the same except pulse had returned to normal, it was regular and of fair volume and strength.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 9.10 a.m. 0.2 intravenously 35"1 ° C. 80 1.30 p.m. 0.2 intravenously 35 "0° C. 80 4.10 p.m. 0.2 intravenously 35"7 ° C. 80 7.30 p.m. 0.2 intravenously 35"2 ° C. 80 10.20 p.m. 0.2 intravenously 35"0 ° C. 80 1.0 orally As night approached the patient began talking. He moved his tongue freely, and called repeatedly for food and water which was furnished. The prognosis has changed rapidly for the better. 20th December, 1947. Cardiac tones and pulse were good this morning. The patient is fairly alert, and drinks water frequently, no doubt due to the extreme dehydration.
168
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
Treatment. Chloromycetin. Temperature. Pulse. Gramme. Hour. 36"8 ° C. 90 0.2 intravenously 9.20 a.m. 0.5 orally 36"6 ° C. 80 0.2 intravenously 6.30 p.m. 0-2 intravenously 36"6 ° C. 80 11.45 p . m . 0.5 orally R.B.C., 2,700,000 ; W.B.C., 3,100 ; Hb., 29 per cent. U r i n e : albumin, + + ; casts, present, granular. 21th December, 1947. T h e patient passed a good night and awoke free of symptoms excepf for a slight glossitis.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 9.10 a.m. 0.2 intravenously 38"2 ° C. 100 0.5 orally 11.30 p.m. 0-2 intravenously 36"6 ° C. 80 22ndDecember, 1947. Beginning on this day the patient was allowed to sit up and feed himself. He appeared to b e convalescing rapidly. Chloromyeetin, 0"5 gramme, was given orally in the forenoon as the last specific medication. Liver extract and polyvitamins were prescribed to combat the anaemia and malnutrition, caused by the disease. Th e patient was kept in the hospital for treatment of severe decubitus. His return to normal health was steady and uneventful. Total ehloromycetin taken, 5.80 gramme. T e n days after treatment was started: R.B.C., 3,900,000; W.B.C., 4,700; Hb., 35 per cent. Urine : Album!n, trace ; casts, negative. CASE No. 17. Daniel Aneiva. Student of medicine. Age 22 years. Race, white. Weil-Felix reaction in dilution, 1 : 1,200. 21stFebruary, 1948. T h e present illness began 8 days ago with a sudden onset of fever, intense headache and backache and nausea with mucus vomiting with intense thirst. O n examination there were petechiae over the chest, abdomen, and extremities, a marked glossitis, and conjunctivitis, and a light cough with severe dyspnoea. T h e patient was suffering from periods of delirium and stupor.
Treatment. Chloromycetin. Gramme. 1-5 orally
Hour. Temperature. Paise. 11.20 a.m. 39"7 ° C. 140 2.00 p,m. 39-1 ° C. 120 5.10 p.m. 38"6 ° C. 120 9.30 p.m. 37"9 ° C. 110 11.15 p.m. 37"6 ° C. 110 Treatment was begun with a single daily oral dose of 1.5 gramme chloromycetin. 22ndFebruary, 1948. T h e stupor had diminished along with the headache and backache. Delirium was no longer present.
Treatment. Hour. 9.30 a.m. 12.10 p.m. 3.20 p.m. 6.30 p.m. 9.10 p.m. 11.15 p.m.
Chloromycefin. Gramme. 1-5 orally
Temperature. 37"4 ° C. 36"7 ° C. 36-4 ° C. 36-6 ° C. 36-8 ° C. 36"4 ° C.
Pulse. 100 90 82 80 80 80
Case 10.
To face page
Typhus patient with grave prognosis.
168.
One week after completion of" treatment.
EUGENE H. PAYNE,
E. A. SHARP
AND
JOSE
A. KNAUDT
169
23rd February, 1948. The temperature and pulse were normal and remained so during the following days of observation. Symptoms Of the previous days had disappeared and the patient was feeling well. He left the hospital 25th February, and resumed his assignments the next day. Blood Studies.
Complete blood counts were done on all patients and five normal controls before, during and after treatment with chloromycetin. No consistent change was observed in either white or red cells, and the changes which did occur either fell within the possibility of error or could be explained by improvement of the circulatory blood following the termination of fever. DISCUSSION.
Chloromycetin was supplied in two forms. For intravenous use, 0.1 gramme per c.c. was dissolved in propylene glycol and finished in rubbercapped vials containing ,10 c.c. Tablets for oral medication each contained 0,1 gramme of chloromycetin. The results following slow intravenous injection were rapid. Three hours after the first injection, the headache and backache showed improvement and vision was often normal. The solvent must be considered as a possible complicating factor in these results, but, in the authors' opinion, it is of minor importance. Oral dosage was equally effective but required 8 to 12 hours longer for results to appear. Later, it was found that many of the tablets were excessively compressed and required several hours to disintegrate. For convenience, the dosage regime adopted toward the end of the study was 1.5 gramme daily as a single oral dose for 2 or 3 days. This treatment gave uniformly satisfactory results. Patients treated during this study varied in age from 12 to 52 years. There were both Indians and white patients included in the group studied. No toxic reactions or signs of intoler~mce were observed in the dose range used. The blood count did not vary outside the limits of error for field estimation. Five normal controls who took the drug for 3 days helped to confirm this observation. The rapid beneficial effect on the heart actions suggests that chloromycetin has the additional virtue of being a myocardial tonic. CONCLUSION. 1. Chloromycetin has been a safe antibiotic for intravenous use in the dosage used. Indications are that the oral dose may be increased with safety over the intravenous amounts employed.
170
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
• 2. T h e favourable effects of treating typhus (epidemic) with chloromycetin appear rapidly and the patient usually enters convalescence within 3 days. 3. Chloromycetin is e~ective either parenterally or orally. REFERENCES. (1948). Isolation and characterization of chloromycetin. The Journal of Biological Chemistry, 172, 445. EHRLICH, J., BARTZ, Q. R., SMITH, R. M., JOSLYN, D. A. & BURKHOLDER,P . R . (1947). Chloromycetin, a new antibiotic from a soil actinomycete. Science, 106,417. PAYNE, E. H., KNAUDT, J. A. ~ PALACIOS, S. (!948). Treatment of epidemic typhus with chloromycetin. J. Trop. Med. Hyg., 51, 68. BARTZ, Q . R .
SMADEL, J. E. ¢%JACKSON, E. a . (1947). Chloromycetin, an antibiotic with chemotherapeutic activity in experimental rickettsial and viral infections. Science, 106, 418. SMITH, R. IV[., JOSLYN, D. A., GRUHZIT, O. M., McLEAN, I. W., JR., PENNER, M. A. &
EHRLICH, J. (1948). Chloromycetin : biological studies. J. Bact., 55, 425.
T R E A T M E N T OF EPIDEMIC TYPHUS W I T H CHLOROMYCETIN.* BY
EUGENE H. PAYNE, A.M., ~a.D., Dept. of Clinical Investigation, Parke, Davis and Company, Detroit, Michigan, E. A. SHARP, M.D., Director, Dept. of Clinical Investigation, Parke, Davis and Company, Detroit, Michigan, AND
JOSE A. KNAUDT, M.D., Professor of Bacteriology, University of La Paz, La Paz, Bolivia.
This paper is a report of results obtained following the treatment of 22 cases of epidemic typhus with chloromycetin. Chloromycetin, a new antibiotic isolated by EHRLICI-I (1947), and associates from Streptomyces sp. was found in soil originating near Caracas, Venezuela. It is a neutral c o m p o u n d stable in aqueous solution for over 24 hours at a p H range from 2 to 9. i n distilled water it is unaffected by boiling for 5 hours. F r o m the laboratory studies of EHRLICH (1947) and associates, and SMADEL and JACKSON (1947), it seemed probable that chloromycetin would be effective in treatment of the rickettsial diseases, t Opportunity for clinical trial was * Material used was supplied by Parke, Davis and Company, Detroit, Michigan. The Bolivian Office of the Institute of Inter-American Affairs rendered invaluable assistance in connection with this study. ]-Toxicity and safety tests were performed by the Research Department, Parke, Davis and Company, Detroit, Michigan.
t64
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
afforded by an epidemic of typhus which occurred in the province of Camacho, Department of La Paz, Bolivia, during late 1947. The province of Camacho, with a population of approximately 120,000, 90 per cent. of whom are pure Aymara, lies 203 km. north of the capital, La Paz, on the eastern shore of Lake Titicaca and borders Peru on the north. Puerto Acosta (population 1,200) is the seat of the provincial government. The climate is rigorous, the altitude being approximately 14,000 feet above sea level, and surrounding snow-capped mountains cause the temperature to remain quite low.
-II Plan Of the t o w n of Puerto Aeosta.
g
Area invaded by t y p h u s epidemic is shaded.
Originating across the border in Peru during October, 1947, the epidemic spread south and east into Bolivia, reaching Puerto Acosta in mid-November. It persisted in Puerto Acosta until about the 15th December, when the activities of Servico Corporativo Inter-Americano de Sulde Pubtica checked its progress by means of immunizations and a vigorous D D T campaign. During the two months of the epidemic, deaths from typhus amounted to at least 60, the majority occurring in the bordering villages of the canton of Conima in Peru. Later the epidemic spread to other provinces, where this study was continued. A preliminary report by PAYNE and KNAUDT (1948) of the first cases treated has already appeared.
EUGENE H. PAYNE, E., A .
165
SHARP AND JOSE A. KNAUDT
TABLE.
Dose (gramme). Case.
1 2 3 4 5 6 7 8 9 10 -11 12 13 14 15 16 17 18 19 20 21 22
Age and sex.
15 F. 16 F. 12 F. I4 M. 32 F~ 18 M . 17 M . 38 F. 18 M . 45 M . 48 F. 38 F. 30 M . 25 M . 29 F. 52 M . 22 M . 48 M . 17 F. 43 M . 54 M . 42 F.
WeftFelix.
Temp. ° C.
Pulse.
Daily.
-
Return to normal. - - - -
Symptoms relieved.
Total.
1 : 1,200 1 : 1,200 1 : ],400 1 : 1,200 1 : 1,200 1 : 1,400 1 : 1,200 1 : 1,200 1 : 400 1 : 600 1 : 1,200 1 : 600 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 1,200 1 : 600 1 : 1,200 1 : 600 1 : 400
40.9 39.7 40-0 41.0 39.0 39.5 40-0 40.2 38.9 Sub-normal 40.8 39-7 39.4 40.3 40.1 39.6 39-7 40.2" 39.7 39.5 39-7 40.6
i40 130 140 140 120 130 140 140 120 130 140 120 120 140 140 120 140 140 120 120 I40 140
-I O r a l
I.V.
1-0 1-0
-. -0.4 0.5 --0.8 0.8 -1.0 1.0 0-8 ---1-2 0-6 -----0.3
-2.0 1.5 -1-0 2.0 1.0 1.5 2.0 3.0 3.5 1.5 2.0 1-5 1.5 1.5 1.5 1.5 3.0
.
2.5 2.5 1.2 1.25 4.0 3.0 2.8 4-2 3.5 5'8 4.0 3"9 3'8 3'9 4.0 4.0 3-0 3-6 3.0 3 0 3"0 8.8
Temp.
Pulse.
Hours. 48 48 54 48 48 42 24 32 24 48 38 24 24 24 24 24 24 36 26 24 28 44
Hours. 54 48 48 36 48 46 24 36 30 30 38 30 24 24 24 24 24 42 30 24 36 48
Hours. 60 60 72 54 48 36 42 48 48 72 52 60 48 48 48 48 36 54 42 48 48 72
The Table presents the 22 cases of epidemic typhus treated with chloromycetin. The results in tabulated form show the rapid recovery of the patients following treatment. In this list Cases No. 8, 11, 14 and 19 presented signs and symptoms of probable death. Cases No. 10, 15, 16, 18 and 22 gave evidence of certain death. CONTROLS.
For controls we studied 50 untreated cases of typhus occurring in the same epidemic, with the following results : Well-Felix 37 cases.) Number
at dilutions of I : 600 to I : 1,400 ; average I : 1,200.
of deaths
(Readings
done on
14, o r 2 8 p e r c e n t .
Deaths occurred on the time was not exact.)
llth
to 20th
day of disease;
average
14 d a y s .
(In
six cases
166
TREATMENT OF EPIDEMIC TYPHUS W I T H CHLOROMYCETIN
Patients recovering without treatment with chloromycetin entered conv a l e s c e n c e o n 12th t o 2 6 t h d a y of disease ; average, 18 days. S p a c e does n o t p e r m i t t h e p u b l i c a t i o n of t h e e x t e n s i v e r e c o r d s of e a c h c a s e r e p o r t e d , a n d since t h e s y m p t o m s a n d p r o g r e s s are q u i t e similar, o n l y t h r e e b r i e f case r e c o r d s are h e r e w i t h p r e s e n t e d . CASE No. 8. Basilia de Zalles. General Hospital, La PaT. Female. Age 38 years~ Colour, white. Weil-Felix reaction positive in a dilution of 1 : 1,200. 17th December, 1947. This patient exhibited all the signs and symptoms of a grave infection of epidemic typhus. Onset 6 days ago was violent with chills, vomiting, intense headache and backache. T h e patient had insomnia and was stuporous. On examination a clear, generalized exanthema was found accompanied by conjunctivitis, partial paralysis of tongue, coughing and dyspnoea. R.B.C., 4,200,000; W.B.C., 4,110; Hb., 39 per cent. U r i n e : albumin, trace ;: casts, negative. T h e temperature, 40.2 ° C. Pulse, 140. Prognosis, grave. 18th December, 1947. In consultation the medical staff agreed that the patient had lost ground during the night. T h e symptoms and physical findings were more pronounced. There was profound stupor, interspersed with delirium. Treatment with chloromycetin was begun at once. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse, 11.20 a.n,. 0-2 intravenously 40"8 ° C. 140 2.30 p.n,. 0-2 intravenously 39"5 ° C. 120 5.25 p.m. 0.2 intravenously 36"6 ° C. 90 0.5 orally 9.30 p.m. 0.2 intravenously 38"0 ° C. 120 0.5 orally At the time of the 9.30 p.m. dose there was noted obvious improvement in the patient's condition, and she was found asleep soon afterwards. 19th December, 1947. Morning : T h e cephalgia, rachialgia and polydipsia were less intense than on the previous day. Improvement was noted in the general appearance of the patient. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 10.30 a.m. 0.2 intravenously 37"8 ° C. 100 0-5 orally 9.30 p.m. 0-2 intravenously 36"6 ° C. 80 0.5 orally During the afternoon the improvement became more pronounced. All headache and. backache disappeared. T h e patient sat up to eat her evening meal, and enjoyed a good night's sleep. R.B.C., 4,080,000; W.B.C., 4,000; Hb., 37 per cent. U r i n e : albumin, trace ; casts, negative. 20th December, 1947. T h e patient felt well, all symptoms had subsided and the petechiae were almost gone. Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 10.30 a.m. 0.5 orally 36"6 ° C. 80 5.30 p.m. 0.5 orally 36"6 ° C. 80
EUGENE H. PAYNE, E. A. SHARP AND JOSE A. KNAUDT
167
Recovery was so far advanced that treatment was suspended, and the patient allowed up. Observation during the succeeding 10 days failed t o show any relapse of fever or symptoms. Forty-eight hours after treatment : R.B.C., 4,000,000 ; W.B.C., 4,200 ; I-Ib., 35 per cent. Urine : albumin, trace ; casts, negative. Seventy-two hours after treatment: R.B.C., 4,070,000; W.B.C., 4,500; Hb., 35 per cent. Urine : albumin, trace ; casts, negative. Six days after treatment : R.B.C., 5,700,000 ; W.B.C., 6,100 ; Hb., 49 per cent. Total chloromycetin given : 4.2 gramme. CASE N o . 10. Gregorio Zalles. General Hospital, La Paz. Age 45 years, Race, Aymara. Early Weil-Felix reaction was positive in dilution of 1 : 600. The length of time this patient had been ill is not certain, but somewhere between 12 days and 3 weeks. During the previous 5 days that the patient had been in the hospital he had received three daily doses of tartar emetic, 3 c.c. each. Also intravenous glucose solution, cardiac tonics, and general symptomatic therapy. His condition grew steadily worse from the first violent onset of the disease. Blood specimen lost. Urine : albumin, + -}- ; casts, present, granular. 18th December, 1947. The patient was presented to the authors for treatment with chloromycetin. On examination a middle-aged male was found in a coma, who had not spoken or taken food or water for three days. He was emaciated, his eyes sunken and lustreless. The mouth was foul with sordes and the mucous membrane contained many lesions. The temperature had fallen to sub-normal. The heart was weak and irregular, the pulse, faint and thready, averaging about 120 to 140. Respiration was of Cheyne-Stokes type. The rJatient appeared to be in extremis, and this impression was verified when it was found that the death certificate had been completed, except for date, and the burial arranged. Treatment with chloromycetin was begun with little hope of success, due to the advanced state of the disease.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 11.40 a.m. 0.2 intravenously 35"0 ° C. 120 :h 2.30 p.m. 0.2 intravenously 35"2 ° C. 110-46.45 p.m. 0"2 intravenously 35-1 o C. 110 ± 10.10 p.m. 0.2 intravenously 35-0 ° C. 100 Forty minutes after the first dose the patient aroused and spoke for the first time in 3 days. He asked for and drank a glass of water. He remained in a stuporous condition throughout the night, the only improvement noticed was the strengthening of the pulse. Blood specimen lost. 19th December, 1947. In general the patient seemed to be about the same except pulse had returned to normal, it was regular and of fair volume and strength.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 9.10 a.m. 0.2 intravenously 35"1 ° C. 80 1.30 p.m. 0.2 intravenously 35 "0° C. 80 4.10 p.m. 0.2 intravenously 35"7 ° C. 80 7.30 p.m. 0.2 intravenously 35"2 ° C. 80 10.20 p.m. 0.2 intravenously 35"0 ° C. 80 1.0 orally As night approached the patient began talking. He moved his tongue freely, and called repeatedly for food and water which was furnished. The prognosis has changed rapidly for the better. 20th December, 1947. Cardiac tones and pulse were good this morning. The patient is fairly alert, and drinks water frequently, no doubt due to the extreme dehydration.
168
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
Treatment. Chloromycetin. Temperature. Pulse. Gramme. Hour. 36"8 ° C. 90 0.2 intravenously 9.20 a.m. 0.5 orally 36"6 ° C. 80 0.2 intravenously 6.30 p.m. 0-2 intravenously 36"6 ° C. 80 11.45 p . m . 0.5 orally R.B.C., 2,700,000 ; W.B.C., 3,100 ; Hb., 29 per cent. U r i n e : albumin, + + ; casts, present, granular. 21th December, 1947. T h e patient passed a good night and awoke free of symptoms excepf for a slight glossitis.
Treatment. Chloromycetin. Hour. Gramme. Temperature. Pulse. 9.10 a.m. 0.2 intravenously 38"2 ° C. 100 0.5 orally 11.30 p.m. 0-2 intravenously 36"6 ° C. 80 22ndDecember, 1947. Beginning on this day the patient was allowed to sit up and feed himself. He appeared to b e convalescing rapidly. Chloromyeetin, 0"5 gramme, was given orally in the forenoon as the last specific medication. Liver extract and polyvitamins were prescribed to combat the anaemia and malnutrition, caused by the disease. Th e patient was kept in the hospital for treatment of severe decubitus. His return to normal health was steady and uneventful. Total ehloromycetin taken, 5.80 gramme. T e n days after treatment was started: R.B.C., 3,900,000; W.B.C., 4,700; Hb., 35 per cent. Urine : Album!n, trace ; casts, negative. CASE No. 17. Daniel Aneiva. Student of medicine. Age 22 years. Race, white. Weil-Felix reaction in dilution, 1 : 1,200. 21stFebruary, 1948. T h e present illness began 8 days ago with a sudden onset of fever, intense headache and backache and nausea with mucus vomiting with intense thirst. O n examination there were petechiae over the chest, abdomen, and extremities, a marked glossitis, and conjunctivitis, and a light cough with severe dyspnoea. T h e patient was suffering from periods of delirium and stupor.
Treatment. Chloromycetin. Gramme. 1-5 orally
Hour. Temperature. Paise. 11.20 a.m. 39"7 ° C. 140 2.00 p,m. 39-1 ° C. 120 5.10 p.m. 38"6 ° C. 120 9.30 p.m. 37"9 ° C. 110 11.15 p.m. 37"6 ° C. 110 Treatment was begun with a single daily oral dose of 1.5 gramme chloromycetin. 22ndFebruary, 1948. T h e stupor had diminished along with the headache and backache. Delirium was no longer present.
Treatment. Hour. 9.30 a.m. 12.10 p.m. 3.20 p.m. 6.30 p.m. 9.10 p.m. 11.15 p.m.
Chloromycefin. Gramme. 1-5 orally
Temperature. 37"4 ° C. 36"7 ° C. 36-4 ° C. 36-6 ° C. 36-8 ° C. 36"4 ° C.
Pulse. 100 90 82 80 80 80
Case 10.
To face page
Typhus patient with grave prognosis.
168.
One week after completion of" treatment.
EUGENE H. PAYNE,
E. A. SHARP
AND
JOSE
A. KNAUDT
169
23rd February, 1948. The temperature and pulse were normal and remained so during the following days of observation. Symptoms Of the previous days had disappeared and the patient was feeling well. He left the hospital 25th February, and resumed his assignments the next day. Blood Studies.
Complete blood counts were done on all patients and five normal controls before, during and after treatment with chloromycetin. No consistent change was observed in either white or red cells, and the changes which did occur either fell within the possibility of error or could be explained by improvement of the circulatory blood following the termination of fever. DISCUSSION.
Chloromycetin was supplied in two forms. For intravenous use, 0.1 gramme per c.c. was dissolved in propylene glycol and finished in rubbercapped vials containing ,10 c.c. Tablets for oral medication each contained 0,1 gramme of chloromycetin. The results following slow intravenous injection were rapid. Three hours after the first injection, the headache and backache showed improvement and vision was often normal. The solvent must be considered as a possible complicating factor in these results, but, in the authors' opinion, it is of minor importance. Oral dosage was equally effective but required 8 to 12 hours longer for results to appear. Later, it was found that many of the tablets were excessively compressed and required several hours to disintegrate. For convenience, the dosage regime adopted toward the end of the study was 1.5 gramme daily as a single oral dose for 2 or 3 days. This treatment gave uniformly satisfactory results. Patients treated during this study varied in age from 12 to 52 years. There were both Indians and white patients included in the group studied. No toxic reactions or signs of intoler~mce were observed in the dose range used. The blood count did not vary outside the limits of error for field estimation. Five normal controls who took the drug for 3 days helped to confirm this observation. The rapid beneficial effect on the heart actions suggests that chloromycetin has the additional virtue of being a myocardial tonic. CONCLUSION. 1. Chloromycetin has been a safe antibiotic for intravenous use in the dosage used. Indications are that the oral dose may be increased with safety over the intravenous amounts employed.
170
TREATMENT OF EPIDEMIC TYPHUS WITH CHLOROMYCETIN
• 2. T h e favourable effects of treating typhus (epidemic) with chloromycetin appear rapidly and the patient usually enters convalescence within 3 days. 3. Chloromycetin is e~ective either parenterally or orally. REFERENCES. (1948). Isolation and characterization of chloromycetin. The Journal of Biological Chemistry, 172, 445. EHRLICH, J., BARTZ, Q. R., SMITH, R. M., JOSLYN, D. A. & BURKHOLDER,P . R . (1947). Chloromycetin, a new antibiotic from a soil actinomycete. Science, 106,417. PAYNE, E. H., KNAUDT, J. A. ~ PALACIOS, S. (!948). Treatment of epidemic typhus with chloromycetin. J. Trop. Med. Hyg., 51, 68. BARTZ, Q . R .
SMADEL, J. E. ¢%JACKSON, E. a . (1947). Chloromycetin, an antibiotic with chemotherapeutic activity in experimental rickettsial and viral infections. Science, 106, 418. SMITH, R. IV[., JOSLYN, D. A., GRUHZIT, O. M., McLEAN, I. W., JR., PENNER, M. A. &
EHRLICH, J. (1948). Chloromycetin : biological studies. J. Bact., 55, 425.