Penicillin is 65 years old!

The discovery of penicillin marked a turning point in history and dramatically changed the impact of medicine. It is hard to comprehend now the fear that arose from even a minor infection, as treatment often required the lancing of swollen glands and sometimes amputation, in an attempt to save the patient's life. Death from even minor infections was common. The advent of penicillin changed not only the course of medicine, but of society as well, as it permitted physicians to prescribe a medication that could save lives within a few days of its administration.

Although Sir Alexander Fleming is widely accepted as the person who discovered penicillin, it is only because of the foresight, determination and courage of two other persons that the leap between the discovery and application of penicillin occurred.

The original discovery of penicillin by Fleming in 1928 is well known. (1,2) He was a microbiologist working at St. Mary's Hospital in London, England. On his return from summer vacation, he noticed that the growth of some staphylococci colonies he had inexplicably, but fortuitously, left on his laboratory bench, were inhibited in areas surrounding spots contaminated with a fungus which he identified as 'penicillium notatum'. He extracted the active ingredient from the mold, called it penicillin and demonstrated that it could also inhibit the growth of other bacteria.

Although he documented his findings, (3) he did not pursue the matter further even though he used a penicillium mold extract to treat a colleague's conjunctivitis. (4) The failure to utilize this new drug was due, in part, to the fact that Fleming's original findings could not be replicated. The reasons for this were not established until much later (5); the maximal growth rate of staphylococci is at temperatures around 35[degrees]C, and that of penicillium is around 20[degrees]C. Therefore, just dropping some penicillium mold on a staphylococci growth is not effective. Serendipity, however, was apparently on Fleming's side, as meteorological records indicate that during Fleming's summer vacation there was an exceptionally cold spell that lasted 9 days.

Penicillin had essentially to be rediscovered. This time, not by pure chance as in 1928, but by meticulous, and systematic work. In the late 1930s, Howard Florey and Ernest Chain at Oxford University, England, were studying potential bactericidal compounds and first confirmed the inhibitory activity of penicillin on bacterial cultures. They ascertained that it was not toxic to mice, and finally determined that it could cure experimentally-induced streptococcal infections in mice. (6,7)

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Although Florey and Chain realized the potential clinical use of penicillin, they were not able to interest a pharmaceutical company to produce large quantities of it. Florey, who was Head of the Department of Pathology, essentially converted his department into a factory and committed all his modest resources to the production of penicillin. (8) By 1941, enough penicillin was produced to test on humans.

On February 12, 1941, Dr. Charles Fletcher administered penicillin intravenously every three hours to Albert Alexander, a 43-year old policeman who had septicemia following multiple facial abscesses that had necessitated the enucleation of his left eye. (9) In order to maximize the use of penicillin, the patient's urine was collected and the excreted penicillin was extracted and used again. The patient started to feel better the very first day of therapy. Four days later his condition improved remarkably. Unfortunately, by the fifth day the supply of penicillin was exhausted; the patient deteriorated and subsequently died. Four other patients were treated, however, when more penicillin supplies became available. The results were spectacular. Major drug companies took over the production of penicillin, and in 1945, Florey, Chain and Fleming shared the Nobel Prize for their work.

It is sobering to realize that penicillin had to be essentially discovered twice for its potential use to be appreciated. The first discovery was purely serendipitous; the second, however, was the result of systematic scientific work and heralded a new era.

References

1. Fleming A. Discovery of penicillin. Br Med Bull 1944;2:4-5.

2. Macfarlane G. In Alexander Fleming: The Man and the Myth. Chatto and Windus, 1984.

3. Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of b infuenzae. Br J Exp Pathol 1929;10:226-236.

4. Le Fanu J. The Rise and Fall of Modern Medicine. Abacus 1999, pp 5-16.

5. Chain E. Thirty years of penicillin therapy. Proc R Soc Lond B Biol Sci 1971;179:293-319.

6. Abraham EP, Chain E, Florey HW, et al. Further observations on penicillin. Lancet 1941:177-188.

7. Chain E, Florey HW, et al. Penicillin as a chemotherapeutic agent. Lancet 1940;226-228.

8. Macfarlane G. In Howard Florey: The Making of a Great Scientist. Oxford, Oxford University Press, 1979.

9. Fletcher C. First clinical use of penicillin. BMJ 1984;289:1721-1723.</p> <pre> The best scientist is open to experience and begins with romance--the idea that anything is possible. --Ray Bradbury </pre> <p>Ronald C. Hamdy, MD, FACP, FRCP 

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