Alexander Fleming and Penicillin:

The Accidental Discovery?

By Joanna Martin

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

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 onetwentieth what they were in 1900

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

The DoctorbySirLukeFildes

Physicians could only watch and wait hoping a patients

immune system could topple an infection

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

Our story begins . . .

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

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

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

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

Water Polo?
WaterpolowascreatedinEnglandduring
the1860'sbecauseswimmingwas
becomingapopularsport

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

St Marys Hospital

St Marys Hospital Lab

Fleming was working for
Sir Almroth Wright who
had discovered an antityphoid 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

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

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

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

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)

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

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

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

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

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

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

Making the Connections

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

Disorganization Leads to Genius

Fleming had a
notoriously
disorganized lab

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

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

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

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

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

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

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

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)

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

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

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

Florey and Chain

The Players Assemble, continued

Chain accidentally bumped into CambellRenton 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

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

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

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

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

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

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

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.

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

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

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!

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%

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

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 drugresistant bacterial infections

Modern Day Treatments

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