Penicillin — how antibiotics changed the world

This is part one of a series on a drug that miraculously transformed medicine — and the grave dangers that lie in store for the future of mankind and society.

For a number of years now, usually in order to initiate a discussion, I ask people the following question: How old is medicine? After I have heard the first five thousand and three thousand year guesses, I make the question more precise: when did it become advantageous, statistically, to visit a doctor in case of illness or infirmity? When did it become better to do so, than not to? The guesses do not change much, and people are surprised by the answer I have in mind: since around 75 years. Before that doctors, in general, did more harm than good.

But what exactly changed 75 years ago? It was the mass production of penicillin and broad band antibiotics that brought about the change. It immediately gave doctors the ability to cure, or at least alleviate, tens of thousands of diseases that, until then, they had been completely helpless to treat. Previously, pathogenic bacteria had not reacted to bleeding, prayer, ritual sacrifice — people simply died, often of what we today consider innocuous diseases. Or more serious ones. You may be interested to read my article “How I survived bubonic plague (sort of)”. I thought I may have caught a disease that had killed more than 50 million people in the 14th century. The doctor on the phone (in California, where the disease is still endemic) basically said “Take an Aspirin and come see me in the morning.” No big deal, plague — a shot of antibiotics would cure it.

Things were really different a couple of centuries ago. In December 1799 former president George Washington went riding in the rain and contracted what was probably a throat infection (epiglottitis). He received the best medical treatment available at the time: repeated blood-letting, with a total blood loss of 40 percent; enema, vinegar, sage, molasses, butter, throat blistering and wheat poultices. All to no effect — actually it may have been the blood-letting that killed him. You can read a graphic description here.

In previous centuries even simple injuries or illnesses could kill you — I have seen first hand what that was like, in some places of the world, even today. On a trip to Asia I accompanied some young doctors to remote villages where they were providing medical assistance. It was an area where most males are engaged in cutting slabs of granite out of the hills. That makes them prone to lacerations and skin damage. One man in the village had a bandaged hand, and when they unwrapped it the doctors said: “It’s gangrenous and partially necrotic — we have to amputate and administer immunoglobulin, and heavy antibiotics.” But the man refused and said he was comfortable with the treatment of the local medicine man — an Ayurvedic practitioner. While saying this he applied a new layer of chunam (plaster made from shell-lime and sand) infused with powdered betel leaves and other herbs. Then he carefully placed two copper coins on the chunam before rebandaging the hand. The (real) doctors were appalled, but they were not allowed to administer the cure against the will of a patient.

A week later we were back in the village and I witnessed something that no doctor in Europe or America has, I believe, ever seen. It was a man dying of tetanus. This infection is caused by a bacterium called Clostridium tetani, and the effect is truly horrifying.

Tetanus causes painful muscle spasms and a cramping of the jaw — hence the common name “lockjaw” for the infection. The man in the village was unable to open his mouth, swallow or even breathe properly. The doctors called a taxi and took him to a hospital. But he was dead on arrival.

I should mention that the infection is not generally curable with antibiotics—but it is essential to also administer penicillin to prevent bacteria from multiplying. In first world countries, tetanus is prevented by childhood immunization and periodic vaccination every ten years.

But let us return to the subject of this article. It was 75 years ago that everything changed — that was when antibiotics became available on an industrial scale. Actually the monumental breakthrough in clinical medicine began on the morning of Friday 28 September 1928, when Scottish microbiologist and pharmacologist Alexander Fleming, returning from a holiday, and cleaning up his laboratory, noticed that one of the petri dishes he used to grow staphylococcus bacteria had been contaminated by a spore, which had killed all the bacteria surrounding it. Clearly the spore was producing a substance that was toxic to them. Fleming discovered that the agent was penicillin, named after the mold that produced it, Penicillium notatum (the strain on his petri dish). He discovered that it could also kill other bacteria, crucially without harming human blood cells.

On March 14, 1942, the first patient was successfully treated with the drug penicillin. Half of the total world supply of the antibiotic was used on her. In July 1943, with a devastating war raging in Europe, a move was made to produce the drug on a massive scale. The Northern Regional Research Laboratory at Peoria, Illinois, produced 2.3 million doses just before the invasion of Normandy in 1944. A better strain of mould for production of penicillin was found (in a mouldy cantaloupe in a Peoria market, as described on page 8 of this Commemorative Booklet) and, using deep-tank fermentation, a new method of production of large quantities of pharmaceutical-grade penicillin was started. By June 1945, over 646 billion units per year were being produced, in 1945 that number had grown to more than 6.8 trillion units.

The world changed. Until this time, apart from the classical infectious diseases, any injuries, like the one my stone-cutter had suffered, were life threatening. This was especially true on the battlefields of WWII. There soldiers would be wounded and fall onto soil, where tetanus (and other) microbes would be waiting. Before penicillin the only hope was to wash the wounds with antiseptic fluids — usually some form of alcohol — or cut off the body parts that were infected. This had to be done before the bacteria could enter the blood-stream and be transported to all parts of the body — which usually led to death. Administering penicillin stopped the process, and patients were able to survive — in WWII in their tens of thousands, and perhaps millions.

For discovering penicillin Alexander Fleming was knighted in 1944. In 1999 he appeared on the front page of Time Magazine as one of the “100 Most Important People of the 20th Century.” In 2002 a BBC’s television poll chose Alexander Fleming as one of the “100 Greatest Britons”, and in 2009 in a Scottish TV channel he was voted “third greatest Scot” (behind Robert Burns and William Wallace). Fleming died on March 11, 1955, and was buried in St Paul’s Cathedral.

Now it is not my intention to besmirch the name of the man whose discovery, in 1928, has saved countless millions of lives. But it hurts to see that nobody knows about Flemming’s careless handling of his discovery, or the names of the other heroic figures that brought us this most important revolution in history of medicine. I want to rectify that here briefly.

I learned most of what I am about to say from two books: Gwyn Macfarlane’s Man and Myth, which called into question the public recognition and adulation given to Fleming. The sensitive and well-written book reappraises the role Fleming played in the discovery of penicillin.

Bad Medicine by David Wootton has played an important role in my thinking on the subject. It is a general history of medicine that asks: how much good has medicine done over the centuries, and how much damage has it done (and continues to do)? Wootton shows how, until the invention of antibiotics in the 1930s, doctors, in general, did their patients more harm than good. Do you recognise the quiz question presented in the first paragraph of this article? Now you know where I originally got it.

Here’s the story: Alexander Fleming’s discovery may have brought penicillin’s antibacterial properties to the attention of researchers and the general public, but its effect had actually been known for fifty years before the Scottish doctor saw it in action in his petri dish. In 1871 John Burdon Sanderson found that a mold had contaminated his effort to cultivate certain bacteria — and he identified it as one of a group called Penicillin. A year later Joseph Lister discovered that Penicillin glaucum was killing bacteria. He immediately saw the therapeutic possibilities, and in 1884 used it to cure a young nurse of an infected wound.

Why then did he not develop the world’s first antibiotic drug almost 60 years before Fleming’s chance rediscovery of its property? Well, Lister was working on an important medicinal principle: he was showing doctors and surgeons how they could save lives essentially by washing their hands (antiseptic surgery — Wootton has a full chapter on this). Also Lister’s strain of Penicillin was not particularly active and initial tests were discouraging.

In 1895 an Italian scientist, Vincenzo Tibero, first injected penicillin mold into infected animals, an experiment that was also conducted by the French army doctor Duchesne in 1897 — unfortunately Duchesne died before he could complete his research. Still, we can safely say that Lister, Tibero and Duchesne had independently discovered penicillin long before Fleming did. Fleming knew nothing about their research — at least he does not mention it in his writings. The strain, Penicillin notatum, which had drifted through his window, happened to be very powerful, and in this respect Fleming was simply very lucky. Macfarlane writes: “If Burdon Sanderson, Lister, Tiberio, Duchesne, and many others had been lucky enough to have been visited by the mold that alighted on Fleming’s plate in 1928, they too would have discovered penicillin and might possibly have taken it further that he did.”

Further than trillions of units being produced by 1945, saving millions of lives? Well, it turns out that it was not Fleming who was responsible for this, either. He had recognized the therapeutic potential of his mold, but was more interested in the development of a vaccine against acne! And, to be fair, vaccines against boils, influenza, gonorrhoea, rabies, and other diseases. Later it was found that all his cures had been ineffectual — they did not help patients more than not taking anything.

Fleming was not interested in producing a better version of penicillin. He left that to two of his students, Stuart Craddock and Frederick Ridley, who worked under appalling conditions, in the corridor of the lab, but managed to produce the first viable samples of the drug. Fleming did not show any interest in their work, misreporting their findings and claiming the production of stable penicillin was generally impossible.

So, who was responsible for making it possible to produce penicillin on an industrial scale? Again it was not Fleming but two other researchers, Howard Florey and Ernst Chain, and their colleagues at Oxford University. Without knowing of Craddock and Ridley’s procedures, in May 1940 they had independently produced enough of the new drug to perform an experiment: they infected eight rats with streptococci and administered penicillin to four of them. The result: these four survived, the other four died.

On February 12, 1941, Albert Alexander, a 43-year old policeman, who had developed a life-threatening infection affecting his eyes, face, and lungs, was the first to be cured by the new Oxford penicillin. After that, the biochemists Norman Heatley and Edward Abraham developed techniques for the mass production of penicillin, paving the way for the substantial amounts that became available during the war.

Above are the great heroes from the Team Penicillin: Edward Abraham, Norman Heatley, Howard Florey and Ernst Chain; below them Margaret Jennings (Florey’s first wife) and Ethel Florey (his second). In the middle are two of the six women recruited by Florey to ‘farm’ penicillin and were nicknamed the ‘penicillin girls’. I have not found any pictures of Stuart Craddock and Frederick Ridley. There were many others who worked decisively on the project. But it was Fleming who got most of the glory — and continues to do so to this day. I quote Wootton:

The key experiment [of Florey and Chain] could have been carried out by Fleming, who certainly had, particularly as a result of the unappreciated work of Ridley and Craddock, an adequate supply of penicillin to inject into mice. Had he done this experiment in 1929 literally millions of lives could have been saved, lives that were lost without an adequate broad-spectrum antibiotic. If Fleming deserves the credit for recognizing the action of penicillin on his contaminated dish, he also carries the responsibility for this delay. — David Wootton, Bad Medicine, 2006.

Part two: Superbugs — the biggest threat to mankind
Why mankind faced a new threat from infectious disease, and why we are unable to combat it effectively.