Alexander Fleming and Penicillin: The Accidental Discovery?

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Alexander Fleming and Penicillin The Accidental
Discovery?
By Joanna Martin
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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

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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

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Prior to Penicillin

• Physicians had little ability to help patients
  suffering from infection

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Physicians could only watch and wait hoping a
patients immune system could topple an
infection

• The Doctor by Sir Luke Fildes

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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

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Our story begins . . .

• Alexander Fleming was born in Lochfield Scotland
  in 1881, the son of a pig farmer

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Flemings Childhood

• The seventh of eight children, Fleming received a
  very good education and was able to attend the
  University of London on scholarship

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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 Marys in London because he had once
  played water polo against them

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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 Marys Hospital in
  London not just for his medical background but
  also because he was a very good shot his
  shooting skills would strengthen the hospitals
  rifle team

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St Marys Hospital
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St Marys 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

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Flemings 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

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Treating Syphilis

• Incidentally, St Marys 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
• Flemings background in administering salvarsan
  exposed him to the ill-effects of substances that
  interfere with natural host defense processes

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The Discovery of Lysozyme

• In 1922 Fleming described lysozyme
• Lysozymes are enzymes present in diverse
  materials such as tears, mucous, egg whites etc
  that cause bacteria to lyse
• His lysozyme research grew out of his interest in
  showing the ineffectiveness of chemical
  antiseptics to treat infection

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Chemical Antiseptics

• 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 (1827-1912)
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Lister continued . . .

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

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Fleming Disagrees

• Based on Listers 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 bodys natural immune response

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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

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Lysozyme Research

• Few accepted Wright and Flemings recommendation
  for wound care
• This rejection fueled Flemings search for
  antibacterial agents and particularly his
  interest in lysozyme
• Like leukocytes, lysozyme was an endogenous way
  to treat infections
• Fleming believed that the best way to treat wound
  infections was to enhance the bodys natural
  immune response

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Lysozyme continued

• In 1922 Fleming described lysozyme when he noted
  that lysozyme-containing material would interfere
  with the growth of bacterial cultures
• Fleming found that a culture of his own nasal
  mucous inhibited the growth of staph cultured
  from that same mucous

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Lysozymes continued

• Fleming was fortunate in that the strain of
  bacteria he was culturing was particularly
  sensitive to lysozyme
• However, Fleming was disappointed in that the
  bacteria most susceptible to lysozyme were those
  that arent as infectious in humans

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Making the Connections

• Flemings background with lysozyme research
  prepared him for his next major discovery

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Disorganization Leads to Genius

• Fleming had a notoriously disorganized lab

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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 hadnt 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

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Flemings 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 thats when he noticed the
  inhibition zone around the fungus

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Flemings 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

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Accidental?

• Flemings observation was made under some
  accidental circumstances but clearly made sense
  in light of Flemings research background
• Fleming had the sophistication to realize that
  anti-bacterial agents existed this view was
  really fueled by his background in lysozyme
  research

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The Power of Penicillin

• It was obvious to Fleming that penicillin was
  much more powerful than lysozymes because his
  crude extracts could be diluted 1000 times and
  still be effective in killing bacteria

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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 wasnt until ten years later that other
  scientists began trying to use penicillin to
  treat clinical disease

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1929-1931

• 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

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Flemings 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
  penicillins effects to carbolic acid
  (anti-septic favored by Lister and his followers
  for treating wound infections)

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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 wouldnt allow the presence of a
  biochemist is the lab because he thought chemists
  lacked humanism

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Dr. Cecil Paine and Mold Juice

• Paine - student of Fleming who was first to
  demonstrate the value of penicillin in medicine
• After reading Flemings article, Paine obtained
  from Fleming a sample of the PCN mold, made
  cultures and used it to treat the lacerated eye
  of a local miner. The miner still had a piece of
  the stone in his eye with a severe pneumococcal
  infection
• Paine irrigated the eye with crude PCN extract
  mold juice and the patients eye was saved
• Paine also irrigated the eyes of a baby born to a
  mother with gonorrhea and saved the childs eyes

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The Players Assemble

• Paine never published his results but did share
  them with 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 Flemings 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

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Florey and Chain
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The Players Assemble, continued

• Chain accidentally bumped into Cambell-Renton in
  the hall one day while she was carrying a flask
  of Flemings 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

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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

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Florey, Chain continued

• Another important observation was that the
  penicillin powder turned the mices 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

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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

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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

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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 patients urine to give back to him
  but the patient didnt survive

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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

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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.

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Production in North America

• Floreys 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

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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

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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!

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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

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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

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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

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Modern Day Treatments

• A 48 year old policeman presents to Urgent Care
  with a small cut on his face after shaving
• Today prescribe antibiotics

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