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Reflections on the First Use of Penicillin in the United States

By Charles Grossman, M.D.

The first dose of penicillin was given in the United States at Yale-New Haven Hospital on March 14, 1942 to a patient dying of septicemia. As a young intern I found myself involved in what few of us then realized was a very profound sequence of events. It was my ninth month of service and I was Acting Assistant Resident.

On the private floor of our separate Isolation Hospital a very ill patient suffered beta-hemolytic streptococcal sepsis. She had run a steady fever of 103-106 F degrees for four weeks. Her private physician, Dr. John Bumstead, persuaded another patient of his, Dr. John F. Fulton, Sterling Professor of Physiology, and ill with a severe pulmonary infection later diagnosed as coccidiomycosis, to try to obtain a new drug, penicillin, which was not available in this country.

Dr. Fulton, a member of the National Research Council (NRC) Committee on Aviation Medicine, and Dr. Francis G. Blake, Sterling Professor of Medicine and a member of the National Academy of Science Chemotherapy Committee, used their considerable influence to complete the tortuous route required to release the small amount of penicillin available to Dr. John Bumstead. Dr. Norman Heatley, a colleague of Dr. H. W. Florey in Oxford, brought the vial to New Haven from Merck in Rahway, New Jersey. The Oxford team had successfully treated some patients in England in 1941 (1). They came to the U.S. to try to help increase the production of penicillin, since England was so busy with the war.

Dr. Bumstead and I took the vial to Dr. Morris Tager, Associate Professor of Bacteriology and Immunology. We discussed what to do with the pungent, brown-red powder. “We decided to dissolve it in saline and pass it through an E. K. Seitz (asbestos) filter pad to sterilize it,” wrote Dr. Tager in 1976 (2). Dr. Bumstead and I returned to the patient and I injected 5000 units into the rubber tubing of her continuous intravenous infusion. That was at about 4 pm on March 14. According to a letter to Yale Medicine, the midnight dose and 4 am dose of 5,000 units were administered by Rocko Fasanella, a medical student (3). Sunday’s doses were delivered every 4 hours into the rubber tubing of her intravenous infusion. By Monday morning she was eating hearty meals, the infusion was stopped, and the patient subsequently received 5,000 units every 4 hours intravenously. My fellow intern, Dr. Herbert Tabor, was involved in saving all of the patient’s urine, which Dr. Heatley took back to Rahway. More penicillin was recovered from the urine than the cultures produced at that time. The patient survived until age 90 when she died of other causes (3).

Dr. Howard Florey and his associate, Dr. Norman Heatley, had come to the United States to see if they could persuade American Drug manufacturers to look into the possibility of increasing penicillin production, since England was so busy at war with Germany. (Dr. Florey was a close friend of Dr. Fulton from earlier days at Oxford, and Florey’s children were living with the Fultons in New Haven to escape the London bombings). The two British visitors went to Peoria, Illinois to visit the Northern Regional Research Laboratory of the U.S. Department of Agriculture when there was considerable interest and experience with fermentation. Florey left for home in a few days while Heatley stayed on. An amusing part of the history occurred in the fall of 1941. While walking through a street market in Peoria, Heatley saw and bought “an overripe, moldy cantaloupe.” The penicillin cultivated produced 20 times more penicillin than prior cultures (5).

 
Penicillin Production
In the first 5 months of 1943, 400 million units of penicillin were produced. In the next 7 months, 20.5 billion units were produced, an increase of over 500 times. By August 1945, 650 billion units were distributed each month. The sub-surface liquid culture medium produced so well that when the structures of penicillin F & G were established it was decided that the cost of producing penicillin by culture would be far lower than any chemical synthetic method (5).

Drug Company Cooperation
The government and some of its agencies and the American drug industry undertook a collaborative program of penicillin research and development. Merck and Co. and ER Squibb and Sons in 1942, with government approval, agreed to participate and invited other drug companies to join. Lederle and Charles Pfizer and Co. soon joined, as did other drug companies. There was to be joint ownership of inventions. The agreement lasted until 1945. It led to the rapid increase in production as noted to meet the needs of the Armed Forces and the civilian population. The American and British efforts included 5 American and 4 British universities, 5 British and 10 American commercial firms, 1 British and 4 American government organizations, and 2 British and 2 American research foundations. Actually 21 drug companies were given financial assistance by the War Production Board. Production costs changed so that the cost of an ampoule of 100,000 units was “scarcely more than the cost of material and labor to put it into an ampoule” (5).

It was of interest to me to find the name of Lt. Col Frank B. Queen MD and a pathologist at the Bushnell Hospital in Utah as the person who had suggested to Dr. Chester Keefer (NRC) in April 1943 the potential for vigorous testing of penicillin in soldiers returning from the Pacific theater with war wounds. I met Dr. Queen in 1950. He was an Associate Professor of Pathology at the University of Oregon Medical School. I, a Clinical Instructor in Medicine, was involved in some biochemical research. We became warm friends, and he helped often with suggestions. Neither of us knew that our names would be later documented in the history of penicillin, nor were either of us aware of the other’s involvement. Dr. Queen died in 1964.

Of far greater importance was the joint effort to increase production. The drug companies had agreed to share all information regarding penicillin production without concern for patient and profit. Their unprecedented cooperation ended in 1945 (5). Today, patent and profit remain the driving forces of the lucrative drug industry.

If any one person is to be credited with the development of penicillin in this country, it should be Dr. John F. Fulton. The literature does indeed tell about his significant role (2,3,67). The telephone calling from his hospital bed demonstrated his persistence, perspicacity, patience (when needed), propriety, and personal influence. He recognized a need, a possible fulfillment of this need, and effectively pushed the sequence of events that transpired. Fleming, Florey, and Chain received the Nobel Prize in Medicine for their contributions. Fulton deserved credit together with Dr. Francis G. Blake for making it possible to prove the enormous value of penicillin and effecting the birth of the antibiotic era.

References:

1) Abraham, E.P., Gardner, A.D., Chain E et al. Further Observations of Penicillin. Lancet 1941, August 16; pp 6155-66.

2) Tager, M Fulton, Coccidiomycosis and Penicillin. Yale J Biology and Medicine, 1976, 49: pp 391-8.

3) Fulton, Curtis J. Penicillin and Chance. Yale Medicine. Fall 1999/Winter 2000.

4) Dr. J. Heatley, personal communication.

5) Richards, AN. Production of Penicillin in the United States (1941-1946). Nature 1964;201: pp 441-5.

6) Dohrmann, GH. Fulton and Penicillin. Surg. Neurol. 1975. 3: pp 277-80.

7) Fulton, John F. Diary, Vol. 18, pp9-15, pp 16-22, March 1942.