1. Alexander Fleming and Penicillin: The Accidental Discovery?
By Joanna Martin

2. A Clinical Case
A 48 year old policeman presents to Urgent Care with a small cut on his face after shaving
The cut is slightly red and draining a small amount of pus
Before the 1940s this small, infected cut could lead to a swift death

3. The Discovery of Penicillin: One of the Most Important Events in Medical History
For the first time, doctors had a way to treat infections and miraculously save lives
Prior to the discovery of penicillin patients often died from trivial injuries or infections
Today in the United States, deaths by infectious bacterial diseases are one-twentieth what they were in 1900
Reference from

4. Prior to Penicillin
Physicians had little ability to help patients suffering from infection

5. A brief history of antibiotics
1495, mercury to treat syphilis.
1630, quinine (chinchona tree) for malarial fever by South American Indians.
1910, Paul Ehrlich developed arsenical compound (Salvarsan) for syphilis, term: the chemical knife.
1929, Alexander Fleming found penicillin.
1940, Ernst Chain and Howard Flory demonstrated the effect of penicillin.
, search for new antibiotics
Recent years: modifying old drugs, finding new discipline in combating antibiotics resistance 5
For lecture only
BC Yang

6. Historical Perspective
100 years ago- 1 in 3 children died of infectious disease before age 5
Germ theory of disease
Koch’s postulates
Robert Ehrlich- microbe specific dyes
Sir Alexander Fleming-discovered penicillin (1929) 6

7. The Doctor by Sir Luke Fildes
Physicians could only watch and wait hoping a patient’s immune system could topple an infection

8. Fleming and Penicillin8

9. Plate of Staphylococcus aureus inhibited by Penicillium notatum9

10. Fungus as Treatment
Folk remedies using fungi have been used for thousands of years
3000 years ago, the Chinese were using moldy soybean curd on boils and other skin infections

11. Our story begins . . .
Alexander Fleming was born in Lochfield Scotland in 1881, the son of a pig farmer

12. Fleming’s Childhood
The seventh of eight children, Fleming received a very good education and was able to attend the University of London on scholarship

13. The Boer War
In 1900 the Boer War started between the UK and the colonies in Southern Africa
Fleming and his two brothers joined a Scottish regiment
They never saw a battlefield and instead spent lot of time swimming, shooting and playing water polo

14. Fleming gets an MD
Fleming was left money after his uncle died and his older brother (already an MD) recommended he go to medical school
Fleming got very high scores on his entrance exams and was able to choose from three medical schools
He chose St Mary’s in London because he had once played water polo against them

15. Water Polo?
Water polo was created in England during the 1860's because swimming was becoming a popular sport

16. Career Choices
Fleming graduated from medical school in 1906 at the age of 25
He was offered a job as research assistant at the inoculation department at St Mary’s Hospital in London not just for his medical background but also because he was a very good shot – his shooting skills would strengthen the hospital’s rifle team

17. St Mary’s Hospital

18. St Mary’s Hospital Lab
Fleming was working for Sir Almroth Wright who had discovered an anti-typhoid vaccine in 1896
Both Fleming and Wright went to France during WWI to treat wounded soldiers and saw firsthand there was no effective treatment for most infections

19. Fleming’s Personality
Unlike Wright who had an arrogant, forceful personality, Fleming was a shy man
Fleming also was a lackluster lecturer who was described by one student as “a shocking lecturer, the worst you could possibly imagine”
Nevertheless, Fleming inspired many by his future work
Quote from Cecil Paine MD

20. Treating Syphilis
Incidentally, St Mary’s was one of the first places Salvarsan was used to treat syphilis
Fleming had published on this topic and was considered an expert at administrating salvarsan
If fact, Fleming made quite a bit of extra income treating members of the London Arts community for syphilis
Often, artists would give him paintings as payment for his services
Fleming’s background in administering salvarsan exposed him to the ill-effects of substances that interfere with natural host defense processes

21. Chemical Antiseptics Lister (1827-1912)
The idea of using chemical antiseptics to kill germs was a revolutionary idea of the late 19th century popularized by Joseph Lister
Lister was a Scottish surgeon, influenced by Pasteur, who believed that germs caused infection
Lister ( )

22. Lister continued . . .
In 1874 he developed the method of using carbolic acid to kill germs and prevent wound infections after surgery
Lister’s theories revolutionized surgery
Lister argued that antiseptics could also be used on wounds to kill bacteria

23. Fleming Disagrees
Based on Lister’s theory, physicians of the time generally believed that if antiseptics killed germs they were therefore useful in treating wound infections
Fleming strongly disagreed with this idea
Fleming and his mentor, Wright, argued that the best way to treat wound infections was to enhance the body’s natural immune response

24. A Revolutionary Approach to Wound Care
Fleming and Wright noted that, although antiseptics kill bacteria, they also kill leukocytes of the immune system more rapidly than they kill invading bacteria
They recommended using saline solution to cleanse wounds instead of antiseptic solutions

25. Lysozyme Research
Few accepted Wright and Fleming’s recommendation for wound care
This rejection fueled Fleming’s search for antibacterial agents
Fleming believed that the best way to treat wound infections was to enhance the body’s natural immune response

26. Research into Antibodies
In Fleming found that a culture of his own nasal mucous inhibited the growth of staph cultured from that same mucous

27. Making the Connections

28. Disorganization Leads to Genius
Fleming had a notoriously disorganized lab

29. Discovery . . .
In 1928 after returning to his lab following a two week vacation Fleming encountered the place in its usual disarray
Fleming had a inoculated a number of petri dishes with staphylococci prior to leaving on vacation
He hadn’t placed them in an incubator because he knew that the staph would sufficiently multiply over the long vacation
Little did he know that penicillium mold grows well at room temperature

30. Fleming’s observation
Fleming returned to his lab to find many of his culture plates contaminated with fungus
He immediately started preparing to clean all his plates but it happened that a former member of his lab was visiting that day
Fleming took some of the contaminated cultures to show his visitor and that’s when he noticed the inhibition zone around the fungus

31. Fleming’s Observation cont.
Fleming was not very knowledgeable about fungi but knew that the mold in his dish was a species of penicillin
Eventually determined to be Penicillium notatum

32. Accidental?
Fleming’s observation was made under some accidental circumstances but clearly made sense in light of Fleming’s research background
Fleming had the sophistication to realize that anti-bacterial agents existed – this view was really fueled by his background in lysozyme research

33. The Power of Penicillin
It was obvious to Fleming that penicillin was much more powerful because his crude extracts could be diluted 1000 times and still be effective in killing bacteria

34. 1929 Paper In 1929 Fleming published a paper detailing his discovery
This was also a crucial moment because his ideas reached a large audience
But it wasn’t until ten years later that other scientists began trying to use penicillin to treat clinical disease

35.
Fleming continued to work on and off with penicillin during this time but was never able to produce it in quantities necessary for practical testing or applications
Fleming found that many of his cultures were unstable and stopped producing mold after eight days
Interestingly, Fleming initially conceived of penicillin as a topical agent and did not think of using it as an injectable or ingestible medication

36. Fleming’s Research
Fleming did inject one rabbit and one mouse with penicillin to make sure there were no ill effects (there were none) but never injected these animals with a simultaneous bacterial strain
Ironically, even though Fleming was an expert at administering intravenous salvarsan to syphilis patients, he only thought of penicillin as an external germicide
Fleming, in his 1929 article, compares penicillin’s effects to carbolic acid (anti-septic favored by Lister and his followers for treating wound infections)

37. Fleming Moves On
Fleming, when asked why he abandoned his initial research, noted that his preparations quickly lost their antibacterial effects
He lacked the help of a biochemist to assist him with penicillin extraction
Wright wouldn’t allow the presence of a biochemist is the lab because he thought chemists lacked humanism

38. The Players Assemble
Dr. Howard Florey at Oxford who became actively interested in penicillin in the 1930s
Coincidentally, a researcher at Oxford Ms. Campbell-Renton had some of Fleming’s original mold passed down to her from an old boss who had used it for some unsuccessful research
Dr Ernst Chain, a talented biochemist who fled Nazi Germany, persuaded by Dr. Florey to join his Oxford team

39. Florey and Chain

40. The Players Assemble, continued
Chain accidentally bumped into Cambell-Renton in the hall one day while she was carrying a flask of Fleming’s mold
Chain went to Florey with the idea to research biochemical and biological properties of antibacterial substances produced by microorganisms
Funding was obtained and research began

41. Florey, Chain continued
Soon after beginning his research, Chain discovered that penicillin was not an enzyme but a molecule
He was intrigued by the fact that penicillin was a very unstable molecule
Chain was able to freeze- dry the penicillin and produce a stable brown powder
Tested on mice, a huge dose proved safe

42. Florey, Chain continued
Another important observation was that the penicillin powder turned the mice’s urine brown – it passed unaltered and without loss of effects into the urine
This meant that PCN could pass through the body and fight infections wherever they were
The Oxford team was ecstatic about their discovery and began work immediately to prove their findings were correct

43. Experimental Testing
Florey next experimented with mice and lethal doses of streptococci
Eight mice were injected with the bacteria and only four mice received penicillin prior to the bacterial injection: the four “PCN mice” survived and the others all died
The first landmark paper detailing the mice experiments were published in August 1940

44. Timing
England was very close to jeopardy at this point in WWII and members of this Oxford team all rubbed penicillin mold on the inside of their clothing fearing that if Germany should invade and occupy Britain one might be able to escape to North America with mold spores!
They know that PCN had the potential to save millions of lives

45. Human Testing
After the researchers were confident that PCN was safe in mice they began human testing
48 y/o policeman with bacterial sepsis after cutting himself while shaving improved dramatically after treatment with the PCN but he required such high doses that the supply was quickly gone
The researches even tried to recrystallize the PCN from this patient’s urine to give back to him but the patient didn’t survive

46. Human Testing Continued
The researchers continued but changed their patient focus to small children thinking they required less PCN for good outcomes
Almost all the children were miraculously cured of infection

47. Mass Production of Penicillin
Penicillin Production began in Britain on a small scale in 1941
The British government encouraged the development of a number of small production facilities at this time. Large scale companies could easily be bombed by German war planes.

48. Production in North America
Florey’s visited the US and Canada with a vial of the sample mold July 1941
It was recommended by an American professor that Florey meet with the head of the USDA research laboratory in Peoria, IL Dr. Robert Coghill
Coghill suggested deep fermentation would likely make the production of penicillin more efficient and convenient

49. Mass Production and Peoria
The search was on for even better sources for penicillin producing Penicillium
The best specimen was mold found on a cantaloupe purchased at a Peoria market
Penicillium chrysogenum

50. Production Accelerates
From January to May 1943 only 400 million units of penicillin had been made
By the time the war ended US companies were making 650 billion units a month!

51. Infections and World War
During WWI the death rate from pneumonia in the US Army totaled 18%
During WWII the death rate fell to less than 1%

52. Awards Fleming and Florey were knighted in 1944
Chain was later knighted in 1965
The Nobel Prize in Physiology or Medicine was awarded to Fleming, Florey and Chain in 1945

53. Drug resistance
Although the discovery of penicillin is arguably one the greatest discoveries of humankind, drug resistance poses an enormous problem
In 1994, 13,300 patients died of drug-resistant bacterial infections

54. Modern Day Treatments
A 48 year old policeman presents to Urgent Care with a small cut on his face after shaving
Today: prescribe antibiotics