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Fulton, penicillin and chance

Yale Medicine Magazine, 1999 - Fall / 2000 - Winter


On May 27 of this year, in a nursing home in Connecticut’s Northwest Corner, Anne Sheafe Miller died at the age of 90. She owed the last 57 years of her life to a coincidence that placed her, in 1942, in a hospital room down the hall from John F. Fulton, M.D.

Medicine had failed Miller. During four weeks of treatment her temperature soared above 106 degrees, and no medications, not even sulfa drugs, had broken the fever. She was dying of streptococcal septicemia, a common infection resulting from miscarriage.

Her physician, John Bumstead, M.D., also was treating Fulton, who occupied a bed in a nearby room, for an infection. What followed would make medical history and usher in the modern use of antibiotics.

Fulton was already a clinician and researcher of renown who had done extensive research into the relationship between the brain and disease. During the war, however, Fulton had abandoned his specialty to study the effects of altitude on pilots. He also put his reputation and contacts to work to help a friend from his days at Oxford, where he had studied in the 1920s. His friend was Howard Florey, an Australian researcher who expanded on Alexander Fleming’s 1928 discovery of penicillin by isolating its active ingredient and demonstrating its therapeutic properties.

When German planes bombarded London in World War II, Florey sent his children to New Haven to live with the Fultons. Florey followed two years later and Fulton helped him secure support for the production of penicillin, impossible in wartime England.

Anne Miller’s physician, Bumstead, went to Fulton with a plea. Aware of Fulton’s friendship with Florey, Bumstead asked Fulton if he could obtain a sample of penicillin. “Fulton got on the telephone on Thursday,” recalled Lycurgus M. Davey, M.D. ’43, HS ’52, “and by Saturday they had a small quantity of penicillin to give to Mrs. Miller.” It took several phone calls to track down officers of Merck and Co., which had produced a small amount of the antibiotic. A sample was flown to New Haven from Washington and delivered to the hospital by a state trooper.

The quantity was 5.5 grams. “At that time they did not know how much to give or how to give it because they were in the very early stages,” recalled Rocko Fasanella, M.D. ’43, HS ’50, then a medical student. At the time, it had saved four of six patients who had taken it in England, but it had never been tried in the United States.

Miller began receiving her first dose via intravenous drip at 3:30 p.m. on a Saturday. The next morning her temperature, which had hovered between 103 and 106.5 degrees, dropped to normal for the first time in four weeks. By Monday her appetite had returned and she had eaten four full meals. Her bacteria count dropped.

As a student volunteer, it fell to Fasanella to administer the medicine at midnight and 4 a.m. When he picked up the patient’s chart, now on display at the Smithsonian Institution, he realized she was the wife of Yale athletic director Ogden Miller, who years earlier, as a recruiter, had encouraged him to attend Yale College. Fasanella injected the yellowish liquid into the IV tube twice that night while Miller slept. “I would slip in quietly and give it and make off again,” said Fasanella, who would later became chief of the ophthalmology section in the Department of Surgery and established Yale’s first residency program in ophthalmology.

Herbert Tabor, M.D., HS ’43, the intern with primary responsibility for injecting the drug, had another task. He saved Miller’s urine and sent it back to Merck, where up to 70 percent of the scarce and costly drug could be recovered and reused.

In his diary, Fulton noted the results. “The case of Mrs. Ogden Miller, who for four weeks had been going downhill with what appeared, on the basis of all previous experience, to be a fatal hemolytic streptococcus septicemia. She had had a temperature ranging from 103 to 106.5 degrees steadily for four weeks despite liberal administration of the sulfa drugs. It is still too soon to say she is cured, but the response has been most dramatic.” Miller went on to live a full and productive life.

Although clinical trials were under way, Tabor, who went on to a career at the National Institutes of Health, believes Miller’s recovery convinced the pharmaceutical industry that the antibiotic was viable and worthy of mass production. “That was really the importance of this case,” said Tabor. “It showed people that they could go ahead.”