Read what part Oxford's orthopaedics played in the history of the 'wonder drug'.
In vivo trials at the Sir William Dunn School of Pathology
When Fleming published his famously serendipitous discovery of the antibacterial action of Penicillium notatum1, its therapeutic potential was largely ignored. It was in the late 1930s that researchers at the Dunn School of Pathology not only confirmed his findings but also started purification of the highly unstable substance.
In March 1940, Ernst Boris Chain asked his friend John Morrison Barnes to perform a first preliminary toxicity test on a lab animal. Dr. Barnes, who held the required license from the Home Office, had been a Nuffield Research Fellow in Orthopaedic Surgery and House Surgeon at the Wingfield-Morris Orthopaedic Hospital before joining Florey's department. Here, he conducted research and collaborated with the newly arrived Josep Trueta on work related to war injuries2.
Trueta recalls the incident in his biography: [...] A few weeks later Chain brought to the laboratory where Barnes and I were working some samples of a yellow liquid containing varying concentrations of penicillin. Barnes took some mice and injected them all with staphylococci and some with the penicillin serum. Eventually those mice which had been injected only with staphylococci died, while those which had also been inoculated with the new drug survived3.
This would later be described by Chain as 'the crucial day in the whole development of penicillin and the day on which everything became possible to us'4.
Further tests proved penicillin being active in vivo and findings were published in The Lancet5.
Clinical trials and the Wingfield-Morris Orthopaedic Hospital
Professor Florey and his co-workers in the Department of Pathology have discovered that one variety of a certain mold called penicillin [...] produces a most powerful substance intensely lethal to any organism that produce serious infection conditions. [...] Professor Florey has placed at our disposal a small quantity of the substance [...] for use in cases of severe infection. The evidence at present available suggests that it is a most valuable drug and it may perhaps prove effective in combating certain infections that have so far baffled us completely. - WMOH Annual Report, 1941
Preparative work was then undertaken to accumulate enough stable penicillin to permit trials on patients with normally fatal bacterial infections. Earlier treatment of septic wounds under Lady Florey's supervision directly applying gauze soaked in penicillin solution had failed to provide a clear proof of the efficacy of penicillin and it seemed likely that intravenous therapy would give clearer results.
In January 1941, Charles Fletcher from the Radcliffe Infirmary started to try out various routes of administration with a first test penicillin injection to a volunteer patient with breast cancer. Other than developing a rigor and temporary temperature rise there were no ill effects. This set the start and systematic penicillin treatment began on 12th February on a 43-year old patient from the septic ward (Case 1). The patient improved but unfortunately supplies exhausted after five days and he succumbed to the infection on 15 March.
The second patient was offered from the Wingfield by Gathorne Girdlestone, a 15-year old boy with a theatre acquired infection of a pinned epiphysiolysis (Case 2). Unresponsive to sulfonamides and blood transfusions, intravenous penicillin treatment started on 22nd February under Dr. Fletcher (100mg, 2-hourly, for 8 hours, then smaller dosage for 5 days). Despite of the short course and the small quantity given (total administration: 3.4g), the boy's condition improved and four weeks later he was fit enough to undergo surgery to remove the pin that caused the infection6, 7.
From this he recovered completely and, together with the four surviving members of the Oxford team that gave the world the 'wonder drug', he attended the 50th Anniversary celebrations at the Radcliffe Infirmary in 1991.
Ulrike Bilgram is currently working on a project focussing on the history of academic orthopaedics in Oxford and its relationship with orthopaedic care and training.
For details about the project visit the NDORMS History Project.
1. FLEMING, A. (1929). On the antibacterial action of cultures of a penicillium: with special reference to their use in isolation of B. influenzæ. British Journal of Experimental Pathology. 10.
2. TRUETA, J., & BARNES, J. M. (n.d.). The Rationale of Complete Immobilization in Treatment of Infected Wounds. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2178853.
3. TRUETA, J. (1980). Trueta, surgeon in war and peace: the memoirs of Josep Trueta, M.D., F.R.C.S., D. Sc. London, V. Gollancz, p.149-150.
4. CLARK, R. W. (1985). The life of Ernst Chain: penicillin and beyond. New York, St. Martin's Press, p.47
5. CHAIN, E. B., & FLOREY, H. (1940). Penicillin as a chemotherapeutic agent. The Lancet. 238, 226-228.
6. ABRAHAM, E., CHAIN, E., FLETCHER, C., GARDNER, A., HEATLEY, N., JENNINGS, M., & FLOREY, H. (1941). Further observations on Penicillin. The Lancet. 238, 177-189. 7. LAWRIE, R. (1985). First clinical use of penicillin. BMJ. 290, 397-397.
7. LAWRIE, R. (1985). First clinical use of penicillin. BMJ. 290, 397-397.