The Sheffield penicillin story

28

THE SHEFFIELD PENICILLIN STORY M WAINWRIGHT AND H T SWAN Departments of Microbiology and Haematology, University of Sheffield, SlO 2TN Recently discovered clinical records show that the first cures using unpurified penicillin which have been documented were achieved by C G Paine and his associates at Sheffield's Royal Infirmary as early as 1930. In January 1929 a young, recently qualified doctor, Cecil George Paine (Fig. 1), left London for Sheffield, where he took up his first appointment in the city in which he was to devote his working life to med ical research and teaching. Within a year or so he began to work with penicillin. Clinical records relating to Paine's penicillin work have been recently discovered and they show that with the help of his associates, A R Hallam and A B Nutt (Fig. 2), he achieved cures with crude penicillin as early as 1930 (Wainright & Swan, 1986), predating Fleming's first clear cut suc cess with penicillin by some two years.

Fig 1. C G Paine in the mid-1930s. Paine was born in London in 1905 ana after attending Christs Hospital School, he enrolled at St. Mary's in 1924, where four years later Fleming discovered penicillin. He saw Fleming's original culture plate on which a contaminant of Penicillium notatum could be seen inhibiting Staphylococcus aureus, describ-

ing it as 'a great treat, but one which didn 't leave much of an impression at the time' - a view which reflects the initial lack of interest shown in Fleming's discovery. Although Paine spent his last six months at St Mary's working in the laboratory he never saw Fleming's attempt to use the crude filtrates on patients. Paine did his penicillin work at Sheffield's Royal Infirmary (and not as has often been stated at the Jessop Hospital). He obtained a culture of P notatum from Fleming and grew it on meat broth, essentially as Fleming did, and then tested the potency of the filtrates against Staphylococcus albus. Paine's init ial attempts at penicillin therapy were assisted by the Hospital dermatologist Rupert Hallam, whose patients were often referred to Paine to enable organisms responsible for their infections to be cultured and identified. Many of these patients were suffering from the skin disease sychosis barbae, an unsightly infection of the beard caused by Staphylococcus aureus. Unfortunately, their attempts to cure sychosis barbae with crude penicillin were completely unsuccessful. The penicillin solutions were probably too weak to be effective or else they failed to reach the site of infection. Undeterred by these failures, Paine instead turned his attention to us-

Fig 2. A R Hallam (front row third from right) and A B Nutt (back row second from left) in a group of Sheffield doctors in 1922·23.

29 unearthed case notes showing that Paine achieved cures with crude penicillin as early as 1930. The first of the case notes describes (Fig. 3) how penicillin was used to cure a three week old baby called Peter who is recorded as suffering from bilateral ophthalmia neonatorum of gonococcal origin with copious discharge from the eyes since some time after birth. The baby had initially received the conventional treatment at another Sheffield Hospital (Nether Edge) without success. He was admitted to the Royal Infirmary on 25 November 1930 and treated with crude penicillin. On 2 December 1930 both eyes were reported as 'clean' and the boy was allowed home on 11 December. In the second clinical note which describes a similar case, crude penicillin was again used to cure an eye infection, this time of a three year old girl. Sheila. In this case the infective organism was described as being diphtheroid. Treatment of this case began on 4 December 1930 and after hourly irrigation with crude penicillin the infection was cleared by 22 December and once again the patient was allowed home in time for Christmas. Although Fleming tried to use crude penicillin topically on infections from soon after this discovery in 1928 no

ing crude penicillin on eye infections. It was this work. done with the help of A. B Nutt, which led to some .promising cures. the most dramatic of which concerned a local miner whose eye had been injured by a stone and was infected with Pneumococcus. The surgeons considered that it was far too risky to operate with the infection present, and for a time the prognosis looked critical. However, following irrigation with crude penicillin the eye infection was defeated and a successful operation led to the miner's eyesight being fully restored. In the second series of experiments, Paine and Nutt used crude penicillin on the eye infection. ophthalmia neonatorum, a condition which at that time was responsible for a large proportion of total blindness from childhood. It was described as a purulent conjunctivitis occurring in newborn babies. The disease was usually of gonococcal origin and was contracted during birth. Once again these treatments led to cures, some details of which were related to David Masters for inclusion in his excellent early book on the penicillin story, 'Miracle Drug'. Our knowledge of this work to date has largely depended upon Dr Paine's memory and has not previously been corroborated by written case notes. However, we have recently

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30 clinical records have appeared to confirm the work. It appears that Fleming collaborated with the eminent London surgeon Arthur Dickson Wright in some of this work. Dickson Wright was a friend of Fleming's and a noted authority on indolent ulcers of the leg. Fleming describes one apparently successful, but uncollaborated, treatment of such an infection using crude penicillin in the following way: 'One patient treated during the last ten days is interesting. A woman had indolent ulcers in various parts of her body. These ulcers had existed for over two months and showed little signs of healing ... The filtrate was applied in compresses every four hours ... Healing commenced and is progressing rapidly.' With the exception of comments such as these, nothing has yet been found to suggest that Fleming used penicillin as a curative agent prior to 1932. Surprisingly, considering their successes, neither Paine nor his associates continued to work with the penicillin. In addition they never published details of their work, nor did they present their work at scientific meetings. Paine apparently thought that there were insufficient successful cases to merit publication. Unfortunately, the Penicillium culture which he was using also began to lose its ability to produce penicillin, thereby frustrating further attempts to use the filtrates on patients. Undoubtedly, the most important reason which made Paine discontinue his penicillin work was that just when he was successful he was offered a better post at the Firth Auxiliary of Sheffield's Jessop Hospital - an isolation hospital situated on the outskirts of the city. Here Paine could work on his particular interest puerperal fever, the distressing disease of child-birth. Ironically puerperal fever was later to respond miraculously to purified penicillin. Paine's involvement in the penicillin story did not end in 1930. In 1932 a new professor was appointed to the Joseph Hunter Chair of Pathology at Sheffield University. Paine told the new Professor, Howard Florey, about his penicillin

work, but at that time Florey showed no obvious interest. Florey of course was later to head the Oxford team which purified penicillin and demonstrated its amazing therapeutic powers. It seems that Chain was initially interested in studying gramicidin other than penicillin, but Florey suggested that he should concentrate on trying to purify Fleming's 'mould-juice'. It is tempting to wonder if Florey thought back to 1932 to his discussion with Paine when he made this suggestion. One of the main reasons for both Paine and Fleming failing to continue their work on the therapeutic potential of crude penicillin was a belief that it would have to be purified before it could be used on patients. However, extensive work done in the 1940s showed that remarkable cures could be achieved with crude penicillin (Wainwright, 1987). Most notably crude filtrates were given by injection by Duhig and Gray in 1945 to cure an Australian woman who was dying of septicaemia. Had either Fleming or Paine built up a dossier of similar cures using crude mould filtrate it is inconceivable that the purification of penicillin would have had to wait until 1939.Such a view of course is made with the knowledge of hindsight. It seems that the time was not right for the development of antibiotics in the early nineteen thirties. Fortunately, the pioneering efforts of Fleming and Paine were eventually brought to fruition by the drive and brilliance of Florey, Chain and the other members of the Oxford team. Postscript. Dr Paine made major contributions to the study of the aetiology of puerperal fever and continued with his research and teaching career in Sheffield until his retirement. He is now an active octogenarian and lives in Devon. REFERENCES M ~ SWAN, H T (1986). C G Paine and the earliest surviving clinical records of penicillin therapy. Medical History 30, 42-56. WAINWRIGHT, M (1987). The history of the therapeutic use of crude penicillin. Medical History (In Press). WAINWRIGHT,