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Report of a case of influenzal meningitis treatedwith Polymyxin B (aerosporin)
REPORT
OF A CASE OF I N F L U E N Z A L M E N I N G I T I S T R E A T E D WITH POLYMYXIN B (AEROSPORIN) ELIZABETH BRA~ELEu M.D. MONTCLAIR, N. J.
recently, influenzal meningitis carried with it an almost U N100T I Lpercomparatively cent fatality rate. With the introduction of sulfanilamide, the mortality rate decreased slightly and was reduced still f u r t h e r with sulfadiazine. T h e use of specific rabbit antiserum for Hemophilus influenzae, type B, introduced by Alexander in ]939, brought about a f u r t h e r improvement. B u t with the advent of streptomycin there was a much more marked drop in the mortality rate. ~ Now there is a nearly 100 per cent recovery with the use of streptomycin alone" or in combination with sulfadiazine and specific rabbit antiserum. But in severe cases, Alexander ~ states, there may be failures with the use of streptomycin due to the existence of resistance of some of the strains of the organisms. In a later report, Alexander 3 states, "In mild or moderately severe cases, either streptomycin alone or sulfadiazine in conjunction with specific rabbit antiserum, can be expected to cure I00 per ,cent of them .... Those patients with severe, chronic or uncontrolled meningitis should receive sulfadiazine, streptomycin, and spe'cific rabbit antiserum simultaneously, as these three agents exert their destructive influence through three different mechanisms. This is especially important in young i n f a n t s . " In a recent article by Kagan, 4 he reports the successful treatment of a 13month-old infant with a new antibiotic, Polymyxin B (aerosporin). This b/fant had been treated with streptomycin and sulfadiazine for several weeks without improvement and had not been given specific rabbit antiserum until late in the course of the disease. Because the child was desperately ill, a new antibiotic, Polymyxin B, was begun and the patient recovered. Polymyxin A was first reported in E n g l a n d in 1947 by Ainsworth, Brown, and Brownlee. ~ It was isolated from soil and called aerosporin, as the organism from which it is derived is Bacillus aerosporus, which may be Bacillus polymyx~a. They state that it is selective in its action egainst gram-negative organisms~ It is bactericidal in action and cultural methods have failed to produce resistant strains. It is relatively stable, readily produced, and is of high in~ trinsi~ potency. Weight for weight, it has the same order o~ chemotherapeutica] activity against gram-negative organisms as has penicillin against gram-positive. About the same time Stansly, Shepherd, and White, ~ working independently in this country, reported t h a t an organism had been isolated from soil which prod u c e d on agar plates a wide zone of inhibition of the gram-negative pathogen, Salmonella schottmfdleri. The antibiotic-producing organism was identified as B. polymy,xa. They state that polymyxin is specific for gram-negative bacteria. It is itherapeutically active in experimental infections in mice and is relatively nonto2ic. F r o m a variety of sensitive species, strains resistant to polymyxin were not obtained u n d e r conditions which readily yield strains completely resistant to streptomycin. 42
BRAKELEY:
I N F L U E N Z A L I~IENINGITIS AND P O L Y M Y X I N B
43
I n 1948, Brownlee and B u s h b y 7 report f u r t h e r on P o l y m y x i n A, the fornl of the antibiotic produced in England. They say, " T h e high activity of aerosporin in the test tube against strains of H. influenzae and its equal efficiency with streptomycin in the t r e a t m e n t of intracerebral infections of mice, indicates t h a t aerosporin m a y be at least as effective as streptomycin in H. influenzae meningitis in man. I t is well tolerated intratheeally in rabbits and a therapeutic concentration in the eerebrospinal fluid m a y be maintained f o r twenty-four hours after a single dose . . . . I t s action is restricted to several gram-negative pathogens against which it is f r o m ten to m a n y hundreds times more active than streptomycin. I t is not absorbed f r o m the gut. W h e n given p a r e n t e r a l l y it disappears f r o m the blood stream quickly, hence four-hourly maintenance doses are necessary. I t is more acutely toxie t h a n streptomycin, but in terms of intrinsic antibacterial efficiency their therapeutic indices are of the same order. I t is nonhemolytic. Aerosporin concentrates are more or less contaminated with an anti diuretic p r i n c i p l e and a substance which damages the renal tubules. Purified material is free f r o m the second factor and the first has not been shown to act in
mail.
''
Schoenbaeh, Bryer, and Bliss 8 report the use of polymyxin in total daily doses of up to 5 rag. per kilogram of body weight, given in a special buffer solu-
tion (pll 7.4) at intervals of three hours. They say, "Its acute toxicity ill experimental animals is considerably greater than that of penicillin or streptomycin. After intramuscular injection it promptly enters the blood stream but does not pass the blood-brain barrier. It is excreted slowly in the urine. In certain experimental infections produced by the inoculation of gram-negative organisms in mice, p o l y m y x i n appears to be definitely Inore effective than streptomycin. ' ' Because of the favorable report by K a g a n on the use of P o l y m y x i n B in a ease Of severe influenzal meningitis in an infant, it was decided to t r y it in a ease of influenzal meningitis in a 3-year-old child recently admitted to Mountainside Hospital, Montelair, N . J. This was a p p a r e n t l y also a severe case with a septic type of t e m p e r a t u r e curve reaching as high as 104.6 ~ F. and the spinal fluid sugar at zero. There was a heavy growth of H. i~fluenzae, type B in the spinal fluid and m a n y organisms were seen in the direct smear. I n the thirty-six hours which elapsed before the P o l y m y x i n B *~could be obtained, penicillin, sulfadiazine, and streptomyein were all used. B u t when the P o l y m y x i n B was begun, all other t r e a t m e n t was discontinued except t h a t 100 nag. of specific rabbit antiserum was given. P o l y m y x i n B was used for eleven days with four doses given intratheeally. The t e m p e r a t u r e gradually r e t u r n e d to normal and the child recovered. CASE REPORT
P. T., a Negro female child 3~/2 years old, was admitted to the hospital in the middle of the night, sent in by her family doctor with a diagnosis of pneumonia. She gave a history of having been ill at home f o r f o u r days with an u p p e r - r e s p i r a t o r y infection and a cough. W h e n she failed to improve, she was referred to the hospital. A t the time of admission her t e m p e r a t u r e was 102 ~ F. *The P o l y m y x i n B w a s supplied b y B u r r o u g h s W e l l e o m e & Co. (U.S.A.), Inc.
44
THE JOURNAL OF PEDIATRICS
and she was lethargic, t i e r pupils reacted sluggishly but were equal. H e r ears were normal and her throat was injected. H e r neck was almost rigid; the abdominal reflexes were absent; the knee jerks were diminished; the Kernig's and Brudzinski's signs were both present. The lungs showed sig~s of consolidation in the right base posteriorly and there were scattered moist r~les throughout. A lumbar puncture, done the next morning, showed colorless, eloudy (ground glass) fluid u n d e r slightly increased pressure. The cell eount ~vas 500 white blood cells per cubie millimeter, 35 per cent polymorphonuelears, 65 per cent lymphoeytes ; glucose was 3 rag. per 100 e.e. and protein 98 rag. per 100 e.e. The smear showed short gram-negative bacilli. The culture yielded a heavy growth of H. influenzae, type B. At the time of the spinal puncture, she was given 25 mg. of streptomycin intrathecally. The other laboratory findings on admission were as follows : hemoglobin 9.5 Gin. per 100 c.e., red blood count 3.4 million per cubic millimeter, white blood count 15.8 thousand per eubie millimeter with 77 per cent polymorphonuelear eells, 22 per eent lymphoeytes, 1 per cent monoeytes; sedimentation rate 117. A chest x-ray showed hazy densities scattered throughout both lung fields and moderate eardiae enlargement. The tubereulin patch test was negative. Two blood cultures taken the seeond and third days after admission were sterile. She was started on penicillin 30,000 units every three hours, streptomyein 125 rag. intramuscularly every four hours, and sulfadiazine 1.0 Gin. the first dose, then 0.5 Gin. every four hours. Another spinal puncture was done the next day. The pressure was 220 ram. of water. The fluid was still slightly cloudy. The cell count was 736 white blood cells per cubic millimeter with 66 per cent lymphocytes. The glucose was zero. She was given 50 rag. of streptomycin intratheeally. The spinal fluid eulture was still positive for H. influenzae, type B. The ehild's condition remained about the same with the temperature going up to 104.6 ~ F. She was lethargic and had a eompletely rigid neck. The chest signs were the same as on admission. On the evening of the second day the P o l y m y x i n B ' w a s received and all other treatment was diseontinued. P o l y m y x i n B in normat saline 10 rag. (100,000 units) was given intramuscularly every four hours. A third lumbar puncture was done and 1 mg. (10,000 units) was given intrathecally. The following day 35 rag. (35,000 units) of Polymyxin B were given intratheeally. As this lumbar puncture was slightly bloody, it was of no value for determining cell count or protein, but the culture was sterile. On this same day she was given 100 mg. of speeific rabbit antiserum. The following day the patient's serum showed eapsular swelling with H. influenzae isolated from the spinal fluid. The following day, the third from the beginning of this new therapy, 35 mg. (35,000 units) of Polymyxin B were again given intratheeally. The spinal fluid was very slightly cloudy, the cell count was 300 white blood count with 84 per ,cent lymphoeytes, and the glucose was 51 rag. per 100 e.e. ; the protein was 98 mg. per 100 c.e. ; the chlorides 677. There was no growth on eulture. The child's condition remained much the same with a high septic type of temperature and a very stiff neck. As her hemoglobin had dropped to 8 Gin., she was given two transfusions of whole blood, 250 e.c. each, twenty-four hours apart. Following this she became more alert and began to eat better. The f o u r t h day from the beginning of therapy. 35 rag. (35,000 units) of P o l y m y x i n B were given intrathecally for the third and last time. This lumbar puncture was again slightly bloody and so unfit for cell count. The patient was showing" gradual improvement. H e r temperature range was. less, she was turning over in bed, was eating better, and was more alert. H e r blood eount had improved. Two days after the transfusions, the hemoglobin was 12 Gin. per 100 e.e. ; red blood eount 4.1 million per cubic millimeter; white blood count 18.9 thousand per eubie millimeter with 83 per cent polymorphonuelears. Daily urine
BRAKELEY : INFLUENZAL MENINGITIS AND FOLYMYXIN B
45
analyses had shown no albumin but an occasional hyalin cast. W h e t h e r this was due to the t r e a t m e n t or to the infection, it is not possible to say. F o u r days a f t e r the last i n t r a t h e c a l t r e a t m e n t with P o l y m y x i n B, the lumbar p u n c t u r e showed clear fluid, white blood count 154, mostly lymphocytes; protein 96 rag. per 100 c.c. ; sugar 56 rag. p e r 100 c.e. ; chlorides 677 rag. per 100 e.e. Three days a f t e r this l u m b a r puncture, another one was done which showed white blood count 72 with 92 per cent lymphocytes; sugar 48 mg. per 100 c.c. ; protein 48 mg. per 100 c.c. At this point the intramuscular t r e a t m e n t with Polymyxin B was discontinued; 10 mg. (10,000 units) had been given continuously every f o u r hours for ten days. The high spiking t e m p e r a t u r e began to come down a f t e r eight days. A final l u m b a r puncture, done ten days after t r e a t m e n t had been stopped, showed white blood count down to 45 and sugar 68 rag. per 100 c.c. Because she continued to run a low-grade fever, between 100 ~ and 100.6 ~ F. she was given d i h y d r o s t r e p t o m y c i n 100 rag. i n t r a m u s c u l a r l y every six hours for f o u r days. A later communication f r o m Burroughs We]lcome & Co. has suggested t h a t this low-grade fever m a y be a f o r m of toxicity f r o m the Po]ymyxin B. No other toxic manifestations were noted. The child had improved g r e a t l y ; her neck was no longer stiff; she was talking and p l a y f u l and was eating well. H e r lung signs had nearly cleared. A few days before she was allowed out of bed, a coarse t r e m o r of the hands was noted, but this soon cleared. W h e n she was allowed to get up and begin walking, a definite unsteadiness of gait was observed with a positive Romberg sign. This unsteadiness decreased b u t was still present on her discharge f r o m the hospital. E x c e p t for this she seemed to be a normal child when she ]eft the hospital twentyeight days a f t e r admission. She had gained 4 pounds in weight and was eating well. A week a f t e r her discharge she was seen in the clinic. She was still slightly u n s t e a d y but not as much as at the time she left the hospital. W h e t h e r this was due to her intrathecal t r e a t m e n t with P o l y m y x i n B or streptomycin or to her illness, no one can tell. Seven weeks a f t e r discharge f r o m the hospital this un~ steadiness seemed to have disappeared completely. She could walk and r u n like a n y child her age and her mother said she seemed to be in as good condition as before her illness. SU~[:MARY
A 3-year-old Negro child With severe influenzal meningitis was treated with a new antibiotic, P o l y m y x i n B (aerosporin), which was given four times intrathecally and for eleven days i n t r a m u s c u l a r l y with a p p a r e n t complete recovery. Previous to this treatment, for thirty-six hours she had been given streptomycin, penicillin, and sulfadiazine. No toxic effects were noted except a moderate unsteadiness in gait and this disappeared completely in a few weeks. REFERENCES 1. Alexander, H a t t i e E.: Type B AntLInfluenzM R a b b i t Serum for Therapeutic Put'poses, Prec. Soc. Exper. Biol. & lVs 40: 313, 1939. 2. Alexander, H a t t i e E.: S t r e p t o m y c i n in Pediatrics, J. PEDIAT. 29: :192, ]947. 3. Alexander, H a t t i e E., a n d Leidy, Grace: P r e s e n t Status of T r e a t m e n t of Influenzal Meningitis, Am. 3". :~ed. 2: 457, 1947. 4. Xagan, B. IV[.: Influenzal M e n i n g i t i s ; Recovery of a Case of Four W e e k s ' Duration W i t h the Use of a New Drug, P o l y m y x i n B (aerosporin), P e d i a t r i c s 4: 323, 1949. 5. Ainsworth, G. C., Brown, A. ~V[., a n d Brownlee, G.: Aerosporin~ Antibiotic Produced by Bacillus Aerosporus Greer, :Nature 160: 263, 1947. 6. Stansly, P. G., Shepherd, R. G., and White, It. J.: Polymyxin" New Chemotherapeutic Agent, Bull. J o h n s Hopkins Hosp. 81: 43, ]947. 7. Brownlee, G., and Bushby, S. R . M . : Chemotherapy and Pharmacology of Aerosporin, L a n c e t 1: 127, 1948. 8. Schoenbach, E. B., Bryer, IV[. S., Bliss, E. A., and Long, P. tI.: Polymyxin, J. A. M. A. 136: 1096, 1948.
OF A CASE OF I N F L U E N Z A L M E N I N G I T I S T R E A T E D WITH POLYMYXIN B (AEROSPORIN) ELIZABETH BRA~ELEu M.D. MONTCLAIR, N. J.
recently, influenzal meningitis carried with it an almost U N100T I Lpercomparatively cent fatality rate. With the introduction of sulfanilamide, the mortality rate decreased slightly and was reduced still f u r t h e r with sulfadiazine. T h e use of specific rabbit antiserum for Hemophilus influenzae, type B, introduced by Alexander in ]939, brought about a f u r t h e r improvement. B u t with the advent of streptomycin there was a much more marked drop in the mortality rate. ~ Now there is a nearly 100 per cent recovery with the use of streptomycin alone" or in combination with sulfadiazine and specific rabbit antiserum. But in severe cases, Alexander ~ states, there may be failures with the use of streptomycin due to the existence of resistance of some of the strains of the organisms. In a later report, Alexander 3 states, "In mild or moderately severe cases, either streptomycin alone or sulfadiazine in conjunction with specific rabbit antiserum, can be expected to cure I00 per ,cent of them .... Those patients with severe, chronic or uncontrolled meningitis should receive sulfadiazine, streptomycin, and spe'cific rabbit antiserum simultaneously, as these three agents exert their destructive influence through three different mechanisms. This is especially important in young i n f a n t s . " In a recent article by Kagan, 4 he reports the successful treatment of a 13month-old infant with a new antibiotic, Polymyxin B (aerosporin). This b/fant had been treated with streptomycin and sulfadiazine for several weeks without improvement and had not been given specific rabbit antiserum until late in the course of the disease. Because the child was desperately ill, a new antibiotic, Polymyxin B, was begun and the patient recovered. Polymyxin A was first reported in E n g l a n d in 1947 by Ainsworth, Brown, and Brownlee. ~ It was isolated from soil and called aerosporin, as the organism from which it is derived is Bacillus aerosporus, which may be Bacillus polymyx~a. They state that it is selective in its action egainst gram-negative organisms~ It is bactericidal in action and cultural methods have failed to produce resistant strains. It is relatively stable, readily produced, and is of high in~ trinsi~ potency. Weight for weight, it has the same order o~ chemotherapeutica] activity against gram-negative organisms as has penicillin against gram-positive. About the same time Stansly, Shepherd, and White, ~ working independently in this country, reported t h a t an organism had been isolated from soil which prod u c e d on agar plates a wide zone of inhibition of the gram-negative pathogen, Salmonella schottmfdleri. The antibiotic-producing organism was identified as B. polymy,xa. They state that polymyxin is specific for gram-negative bacteria. It is itherapeutically active in experimental infections in mice and is relatively nonto2ic. F r o m a variety of sensitive species, strains resistant to polymyxin were not obtained u n d e r conditions which readily yield strains completely resistant to streptomycin. 42
BRAKELEY:
I N F L U E N Z A L I~IENINGITIS AND P O L Y M Y X I N B
43
I n 1948, Brownlee and B u s h b y 7 report f u r t h e r on P o l y m y x i n A, the fornl of the antibiotic produced in England. They say, " T h e high activity of aerosporin in the test tube against strains of H. influenzae and its equal efficiency with streptomycin in the t r e a t m e n t of intracerebral infections of mice, indicates t h a t aerosporin m a y be at least as effective as streptomycin in H. influenzae meningitis in man. I t is well tolerated intratheeally in rabbits and a therapeutic concentration in the eerebrospinal fluid m a y be maintained f o r twenty-four hours after a single dose . . . . I t s action is restricted to several gram-negative pathogens against which it is f r o m ten to m a n y hundreds times more active than streptomycin. I t is not absorbed f r o m the gut. W h e n given p a r e n t e r a l l y it disappears f r o m the blood stream quickly, hence four-hourly maintenance doses are necessary. I t is more acutely toxie t h a n streptomycin, but in terms of intrinsic antibacterial efficiency their therapeutic indices are of the same order. I t is nonhemolytic. Aerosporin concentrates are more or less contaminated with an anti diuretic p r i n c i p l e and a substance which damages the renal tubules. Purified material is free f r o m the second factor and the first has not been shown to act in
mail.
''
Schoenbaeh, Bryer, and Bliss 8 report the use of polymyxin in total daily doses of up to 5 rag. per kilogram of body weight, given in a special buffer solu-
tion (pll 7.4) at intervals of three hours. They say, "Its acute toxicity ill experimental animals is considerably greater than that of penicillin or streptomycin. After intramuscular injection it promptly enters the blood stream but does not pass the blood-brain barrier. It is excreted slowly in the urine. In certain experimental infections produced by the inoculation of gram-negative organisms in mice, p o l y m y x i n appears to be definitely Inore effective than streptomycin. ' ' Because of the favorable report by K a g a n on the use of P o l y m y x i n B in a ease Of severe influenzal meningitis in an infant, it was decided to t r y it in a ease of influenzal meningitis in a 3-year-old child recently admitted to Mountainside Hospital, Montelair, N . J. This was a p p a r e n t l y also a severe case with a septic type of t e m p e r a t u r e curve reaching as high as 104.6 ~ F. and the spinal fluid sugar at zero. There was a heavy growth of H. i~fluenzae, type B in the spinal fluid and m a n y organisms were seen in the direct smear. I n the thirty-six hours which elapsed before the P o l y m y x i n B *~could be obtained, penicillin, sulfadiazine, and streptomyein were all used. B u t when the P o l y m y x i n B was begun, all other t r e a t m e n t was discontinued except t h a t 100 nag. of specific rabbit antiserum was given. P o l y m y x i n B was used for eleven days with four doses given intratheeally. The t e m p e r a t u r e gradually r e t u r n e d to normal and the child recovered. CASE REPORT
P. T., a Negro female child 3~/2 years old, was admitted to the hospital in the middle of the night, sent in by her family doctor with a diagnosis of pneumonia. She gave a history of having been ill at home f o r f o u r days with an u p p e r - r e s p i r a t o r y infection and a cough. W h e n she failed to improve, she was referred to the hospital. A t the time of admission her t e m p e r a t u r e was 102 ~ F. *The P o l y m y x i n B w a s supplied b y B u r r o u g h s W e l l e o m e & Co. (U.S.A.), Inc.
44
THE JOURNAL OF PEDIATRICS
and she was lethargic, t i e r pupils reacted sluggishly but were equal. H e r ears were normal and her throat was injected. H e r neck was almost rigid; the abdominal reflexes were absent; the knee jerks were diminished; the Kernig's and Brudzinski's signs were both present. The lungs showed sig~s of consolidation in the right base posteriorly and there were scattered moist r~les throughout. A lumbar puncture, done the next morning, showed colorless, eloudy (ground glass) fluid u n d e r slightly increased pressure. The cell eount ~vas 500 white blood cells per cubie millimeter, 35 per cent polymorphonuelears, 65 per cent lymphoeytes ; glucose was 3 rag. per 100 e.e. and protein 98 rag. per 100 e.e. The smear showed short gram-negative bacilli. The culture yielded a heavy growth of H. influenzae, type B. At the time of the spinal puncture, she was given 25 mg. of streptomycin intrathecally. The other laboratory findings on admission were as follows : hemoglobin 9.5 Gin. per 100 c.e., red blood count 3.4 million per cubic millimeter, white blood count 15.8 thousand per eubie millimeter with 77 per cent polymorphonuelear eells, 22 per eent lymphoeytes, 1 per cent monoeytes; sedimentation rate 117. A chest x-ray showed hazy densities scattered throughout both lung fields and moderate eardiae enlargement. The tubereulin patch test was negative. Two blood cultures taken the seeond and third days after admission were sterile. She was started on penicillin 30,000 units every three hours, streptomyein 125 rag. intramuscularly every four hours, and sulfadiazine 1.0 Gin. the first dose, then 0.5 Gin. every four hours. Another spinal puncture was done the next day. The pressure was 220 ram. of water. The fluid was still slightly cloudy. The cell count was 736 white blood cells per cubic millimeter with 66 per cent lymphocytes. The glucose was zero. She was given 50 rag. of streptomycin intratheeally. The spinal fluid eulture was still positive for H. influenzae, type B. The ehild's condition remained about the same with the temperature going up to 104.6 ~ F. She was lethargic and had a eompletely rigid neck. The chest signs were the same as on admission. On the evening of the second day the P o l y m y x i n B ' w a s received and all other treatment was diseontinued. P o l y m y x i n B in normat saline 10 rag. (100,000 units) was given intramuscularly every four hours. A third lumbar puncture was done and 1 mg. (10,000 units) was given intrathecally. The following day 35 rag. (35,000 units) of Polymyxin B were given intratheeally. As this lumbar puncture was slightly bloody, it was of no value for determining cell count or protein, but the culture was sterile. On this same day she was given 100 mg. of speeific rabbit antiserum. The following day the patient's serum showed eapsular swelling with H. influenzae isolated from the spinal fluid. The following day, the third from the beginning of this new therapy, 35 mg. (35,000 units) of Polymyxin B were again given intratheeally. The spinal fluid was very slightly cloudy, the cell count was 300 white blood count with 84 per ,cent lymphoeytes, and the glucose was 51 rag. per 100 e.e. ; the protein was 98 mg. per 100 c.e. ; the chlorides 677. There was no growth on eulture. The child's condition remained much the same with a high septic type of temperature and a very stiff neck. As her hemoglobin had dropped to 8 Gin., she was given two transfusions of whole blood, 250 e.c. each, twenty-four hours apart. Following this she became more alert and began to eat better. The f o u r t h day from the beginning of therapy. 35 rag. (35,000 units) of P o l y m y x i n B were given intrathecally for the third and last time. This lumbar puncture was again slightly bloody and so unfit for cell count. The patient was showing" gradual improvement. H e r temperature range was. less, she was turning over in bed, was eating better, and was more alert. H e r blood eount had improved. Two days after the transfusions, the hemoglobin was 12 Gin. per 100 e.e. ; red blood eount 4.1 million per cubic millimeter; white blood count 18.9 thousand per eubie millimeter with 83 per cent polymorphonuelears. Daily urine
BRAKELEY : INFLUENZAL MENINGITIS AND FOLYMYXIN B
45
analyses had shown no albumin but an occasional hyalin cast. W h e t h e r this was due to the t r e a t m e n t or to the infection, it is not possible to say. F o u r days a f t e r the last i n t r a t h e c a l t r e a t m e n t with P o l y m y x i n B, the lumbar p u n c t u r e showed clear fluid, white blood count 154, mostly lymphocytes; protein 96 rag. per 100 c.c. ; sugar 56 rag. p e r 100 c.e. ; chlorides 677 rag. per 100 e.e. Three days a f t e r this l u m b a r puncture, another one was done which showed white blood count 72 with 92 per cent lymphocytes; sugar 48 mg. per 100 c.c. ; protein 48 mg. per 100 c.c. At this point the intramuscular t r e a t m e n t with Polymyxin B was discontinued; 10 mg. (10,000 units) had been given continuously every f o u r hours for ten days. The high spiking t e m p e r a t u r e began to come down a f t e r eight days. A final l u m b a r puncture, done ten days after t r e a t m e n t had been stopped, showed white blood count down to 45 and sugar 68 rag. per 100 c.c. Because she continued to run a low-grade fever, between 100 ~ and 100.6 ~ F. she was given d i h y d r o s t r e p t o m y c i n 100 rag. i n t r a m u s c u l a r l y every six hours for f o u r days. A later communication f r o m Burroughs We]lcome & Co. has suggested t h a t this low-grade fever m a y be a f o r m of toxicity f r o m the Po]ymyxin B. No other toxic manifestations were noted. The child had improved g r e a t l y ; her neck was no longer stiff; she was talking and p l a y f u l and was eating well. H e r lung signs had nearly cleared. A few days before she was allowed out of bed, a coarse t r e m o r of the hands was noted, but this soon cleared. W h e n she was allowed to get up and begin walking, a definite unsteadiness of gait was observed with a positive Romberg sign. This unsteadiness decreased b u t was still present on her discharge f r o m the hospital. E x c e p t for this she seemed to be a normal child when she ]eft the hospital twentyeight days a f t e r admission. She had gained 4 pounds in weight and was eating well. A week a f t e r her discharge she was seen in the clinic. She was still slightly u n s t e a d y but not as much as at the time she left the hospital. W h e t h e r this was due to her intrathecal t r e a t m e n t with P o l y m y x i n B or streptomycin or to her illness, no one can tell. Seven weeks a f t e r discharge f r o m the hospital this un~ steadiness seemed to have disappeared completely. She could walk and r u n like a n y child her age and her mother said she seemed to be in as good condition as before her illness. SU~[:MARY
A 3-year-old Negro child With severe influenzal meningitis was treated with a new antibiotic, P o l y m y x i n B (aerosporin), which was given four times intrathecally and for eleven days i n t r a m u s c u l a r l y with a p p a r e n t complete recovery. Previous to this treatment, for thirty-six hours she had been given streptomycin, penicillin, and sulfadiazine. No toxic effects were noted except a moderate unsteadiness in gait and this disappeared completely in a few weeks. REFERENCES 1. Alexander, H a t t i e E.: Type B AntLInfluenzM R a b b i t Serum for Therapeutic Put'poses, Prec. Soc. Exper. Biol. & lVs 40: 313, 1939. 2. Alexander, H a t t i e E.: S t r e p t o m y c i n in Pediatrics, J. PEDIAT. 29: :192, ]947. 3. Alexander, H a t t i e E., a n d Leidy, Grace: P r e s e n t Status of T r e a t m e n t of Influenzal Meningitis, Am. 3". :~ed. 2: 457, 1947. 4. Xagan, B. IV[.: Influenzal M e n i n g i t i s ; Recovery of a Case of Four W e e k s ' Duration W i t h the Use of a New Drug, P o l y m y x i n B (aerosporin), P e d i a t r i c s 4: 323, 1949. 5. Ainsworth, G. C., Brown, A. ~V[., a n d Brownlee, G.: Aerosporin~ Antibiotic Produced by Bacillus Aerosporus Greer, :Nature 160: 263, 1947. 6. Stansly, P. G., Shepherd, R. G., and White, It. J.: Polymyxin" New Chemotherapeutic Agent, Bull. J o h n s Hopkins Hosp. 81: 43, ]947. 7. Brownlee, G., and Bushby, S. R . M . : Chemotherapy and Pharmacology of Aerosporin, L a n c e t 1: 127, 1948. 8. Schoenbach, E. B., Bryer, IV[. S., Bliss, E. A., and Long, P. tI.: Polymyxin, J. A. M. A. 136: 1096, 1948.