If You Use Penicillin, Use Enough

Every schoolchild is told the story. Alexander Fleming went on holiday, left a culture dish on his bench, came back to find mould growing on it, and discovered penicillin. The day usually given is 28 September 1928.

The story is true as far as it goes. What it leaves out is everything that came next, which took twelve years, other people, and a war, and very nearly didn't happen.

The plate

Fleming was a bacteriologist at St Mary's Hospital in London, and he was not looking for an antibiotic. In his Nobel lecture in 1945 he was frank about it. Penicillin, he said, "arose simply from a fortunate occurrence which happened when I was working on a purely academic bacteriological problem which had nothing to do with antagonism, or moulds, or antiseptics, or antibiotics."

He had, though, been primed to notice. In 1922 he had described lysozyme, a substance in tears and egg white that dissolved some bacteria, unfortunately mostly ones that don't infect people. So when a plate of staphylococci came back contaminated, he saw what another man might have scraped into the bin. "It was noticed that for some distance around the mould colony the staphylococcal colonies had become translucent and evidently lysis was going on," he said. The bacteria near the mould were being destroyed.

He grew the mould on its own, a species of Penicillium, and found that the broth it grew in killed some common germs and left others alone, and seemed harmless to animals. He published in 1929 and called the substance penicillin.

"My only merit," he said later, "is that I did not neglect the observation and that I pursued the subject as a bacteriologist."

Why nothing happened for ten years

What he couldn't do was make enough of it, or make it pure. The active substance was unstable and present in tiny amounts. Fleming did little further research on it, and for most of the 1930s penicillin stayed a laboratory curiosity.

The work was picked up at the Sir William Dunn School of Pathology in Oxford, by a team led by the Australian pathologist Howard Florey with the biochemist Ernst Chain. The man who made it physically possible was Norman Heatley, whom the Science Museum calls the forgotten man of penicillin. With wartime shortages of everything, he built a purification system out of a bookcase, and the team grew mould in whatever improvised vessels they could get.

On 25 May 1940 they ran the experiment that mattered. Mice were infected with bacteria, and some were given penicillin. The treated mice survived longer than the untreated ones. It worked in a living animal.

The policeman

The first person treated was Albert Alexander, a police constable, at the Radcliffe Infirmary in Oxford, on 12 February 1941. He was gravely ill with a septic wound. Oxford's history of the case says the infection came from lacerations he had suffered in an air raid.

He began to recover quickly. Then the penicillin ran short. The doctors were so desperate that one of them, Dr Fletcher, would take the patient's urine and cycle with it to the Dunn School, so that the penicillin he had excreted could be recovered and injected again. It wasn't enough. Alexander relapsed, and he died in March 1941.

He is usually remembered as a failure, and he was the proof. Six patients were selected for that first trial, and four made a complete recovery. The drug worked. The problem was quantity.

A melon in Peoria

With Britain under bombing, in 1941 two Oxford scientists took the mould to the United States, to the Department of Agriculture's Northern Regional Research Laboratory in Peoria, Illinois.

The laboratory there worked out how to grow the mould submerged in deep tanks, fed on a brew of corn-steep liquor, a by-product of milling maize. It also went looking for a better mould. The best strain anyone found came, in the agriculture department's own account, from a cantaloupe bought at a Peoria market. Who found it is still disputed. A laboratory worker named Mary Hunt claimed it, and was nicknamed Moldy Mary. Another account credited an unnamed Peoria woman who handed the melon in at the gate. The strain, or its descendants, became the ancestor of the penicillin still made today.

By the end of the war, according to PBS, American companies were making 650 billion units a month of a drug that had once been recycled from one policeman's urine.

The warning

Fleming shared the 1945 Nobel prize in medicine with Florey and Chain. His lecture, given in Stockholm on 11 December 1945, included something nobody much wanted to hear.

It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.

He gave an example. A man with a sore throat buys some penicillin and takes not enough to kill the bacteria "but enough to educate them to resist penicillin". He infects his wife. She gets pneumonia, the penicillin fails, and she dies. "Moral: If you use penicillin, use enough."

The science has moved on in its details, and doctors now worry as much about antibiotics taken when they aren't needed at all as about courses taken too short. But Fleming's central point, that every dose that fails to kill teaches the survivors, is the principle on which the whole modern fight against resistance rests.

Eighty years later

The bill has arrived. A study published in the Lancet in 2022, the largest of its kind, estimated that in 2019 bacterial infections resistant to antibiotics directly killed 1.27 million people, and played a part in 4.95 million deaths. A follow-up in 2024, led from Oxford among others, found that resistance had claimed at least a million lives a year every year since 1990, and forecast some 39 million more deaths from it by 2050.

Fleming's imagined shop, where anyone could buy the drug, describes much of the world today. Heatley's bookcase, and Dr Fletcher on his bicycle with a bottle of urine, describe how precious the stuff was when there was almost none of it.

Sources

• Alexander Fleming, "Penicillin", Nobel Lecture, 11 December 1945 (the chance observation and the "purely academic" problem; lysozyme in 1922; the contaminated plate and the lysis around the mould; Penicillium notatum; the 1929 publication; "my only merit"; the warning about underdosing, Mr and Mrs X and "if you use penicillin, use enough").
• PBS NewsHour, "The real story behind the world's first antibiotic" (Fleming's return from holiday in September 1928; the discovery usually dated to 28 September; his limited further research; the roles of Florey, Chain and Heatley; US production of 650 billion units a month by the end of the war).
• Science Museum, "Oxford and the forgotten man of penicillin" (Heatley's purification system made from a bookcase amid wartime shortages; Albert Alexander dying because there was not enough penicillin for a full course).
• University of Oxford, "Penicillin" (the mouse experiment of 25 May 1940; Albert Alexander's admission in January 1941 with an infection from lacerations sustained in an air raid, and the start of treatment on 12 February).
• Oxfordshire Blue Plaques Board, "Penicillin" (Alexander as an Abingdon police constable treated on 12 February; his rapid recovery and relapse; Dr Fletcher cycling his urine to the Dunn School; his death in March; four complete recoveries among the first six patients).
• US Department of Agriculture, Agricultural Research Service, "The Enduring Mystery of 'Moldy Mary'" (the mould brought to Peoria by two Oxford scientists in 1941; submerged deep-tank fermentation with corn-steep liquor; the cantaloupe from a Peoria market; the dispute over who found it; the strain as ancestor of penicillin still in use).
• University of Oxford, "Antibiotic resistance has claimed at least one million lives each year since 1990", September 2024 (deaths from resistance every year since 1990 and the forecast of 39 million deaths to 2050).
• STAT, "New global data showing 1.27 million deaths a year reveal the urgent need to address antimicrobial resistance", January 2022 (the Lancet study's estimate of 1.27 million deaths directly attributable to resistance in 2019 and 4.95 million associated).