Download Alexander Fleming and the discovery of Penicillin

The miraculous mold…
Fleming’s
Life Saving
Discovery
A
By Jay Hardy, CLS, SM (NRCM)
Jay Hardy is the founder and
president of Hardy Diagnostics.
He began his career in
microbiology as a Medical
Technologist in Santa Barbara,
California.
In 1980, he began manufacturing
culture media for the local
hospitals. Today, Hardy
Diagnostics is the third largest
culture media manufacturer in the
United States.
To ensure rapid and reliable turn
around time, Hardy Diagnostics
maintains seven distribution
centers, and produces over 3,500
products used in clinical and
industrial microbiology
laboratories throughout the world.
lexander Fleming is
credited with the
discovery of penicillin; perhaps
the greatest achievement in
medicine in the 20th Century.
Having grown up in Scotland,
Fleming moved to London
where he attended medical
school. After serving his
country as a medic in World
War I, he returned to London
where he began his career as a
bacteriologist. There he began
his search for more effective
antimicrobial agents. Having
witnessed the death of many
wounded soldiers in the war, he
noticed that in many cases the
use of harsh antiseptics did
more harm than good.
By 1928, Fleming was
investigating the properties of
staphylococci. He was already
well-known from his earlier
work, and had developed a
reputation as a brilliant
researcher, but his laboratory in
the basement of St. Mary’s
Hospital in London was often
untidy.
His famous discovery happened
on the day that Fleming
returned to his laboratory
having spent August on holiday
with his family. Before leaving,
he had stacked all his cultures
of staphylococci on a bench in a
corner of his laboratory. On
returning, Fleming noticed that
one culture was contaminated
with a fungus, and that the
colonies of staphylococci that
had immediately surrounded it
had been destroyed, whereas
other colonies farther away
were normal.
Figure 1: Alexander Fleming in his
London laboratory.
"When I woke up just after
dawn on September 28, 1928, I
certainly didn't plan to
revolutionize all medicine by
discovering the world's first
antibiotic, or bacteria killer,"
Fleming would later say, "But I
suppose that was exactly what I
did.”
Fleming grew the mold in a
pure culture and found that it
produced a substance that killed
a number of pathogenic
bacteria. He identified the mold
as being from Penicillium
notanum, and after some
months of calling it "mold
juice" named the substance it
released penicillin in March of
1929.
“…I certainly didn't plan to
revolutionize all medicine by
discovering the world's first
antibiotic…”
He investigated its positive antibacterial effect on many
organisms, and noticed that it
affected bacteria such as
staphylococci and many other
Gram positive pathogens that
cause scarlet fever, pneumonia,
meningitis and diphtheria, but
not typhoid fever or paratyphoid
fever, which are caused by
Gram-negative bacteria, for
which he was seeking a cure at
the time. It also effectively
killed Neisseria gonorrhoeae,
although this bacterium is Gram
negative.
Fleming published his
discovery in 1929 in the British
Journal of Experimental
Pathology, but little attention
was paid to his article.
Fleming finally abandoned
penicillin. Not long after he
did, Howard Florey and Ernst
Chain at the Radcliffe Infirmary
in Oxford took up researching
and mass-producing it with
funds from the U.S. and British
governments. They started mass
production after the bombing of
Pearl Harbor. When D-Day
arrived, they had made enough
penicillin to treat all the
wounded Allied forces.
Figure 2: Fleming’s photo of the
fungus, Penicillium notatum,
inhibiting Staphylocccus.
It was Ernst Chain and Edward
Abraham who finally developed
the method to isolate and
concentrate penicillin. Shortly
after the team published its first
results in 1940, Fleming
telephoned Howard Florey,
Chain's head of department, to
say that he would be visiting
within the next few days. When
Chain heard that he was
coming, he remarked, "Good
God! I thought he was dead."
Fleming continued his
investigations, but found that
cultivating penicillium was
quite difficult. After having
grown the mold, it was even
more difficult to isolate the
antibiotic agent.
Fleming's impression was that
because of the problem of
producing it in quantity, and
because its action appeared to
be rather slow, penicillin would
not be important in treating
infection. Fleming also became
convinced that penicillin would
not last long enough in the
human body (in vivo) to kill
bacteria effectively. Many
clinical tests were inconclusive,
probably because it had been
used as a surface antiseptic. In
the 1930s, Fleming’s trials
occasionally showed more
promise, and he continued until
1940 to try to interest a chemist
skilled enough to further refine
usable penicillin.
After the team had developed a
method of purifying penicillin
to an effective first stable form
in 1940, several clinical trials
ensued. Their amazing success
inspired the team to develop
methods for mass production
and distribution in 1945, which
was just in time to be of use in
World War II.
Figure 3: The chemical structure of
penicillin showing the beta-lactam
ring.
Fleming was modest about his
part in the development of
penicillin, describing his fame
as the "Fleming Myth" and he
praised Florey and Chain for
transforming the laboratory
curiosity into a practical drug.
In fact, several others reported
the bacteriostatic effects of
Penicillium earlier than
Fleming. The use of bread with
a blue mold (it is presumed,
Penicillium) as a means of
treating infected wounds was a
staple of folk medicine in
Europe since the Middle Ages.
However, Fleming was the first
to discover the properties of the
active substance, giving him the
privilege of naming it penicillin.
He also kept, grew and
distributed the original mold for
twelve years, and continued
until 1940 to try to get help
from any chemist who had
enough skill to make penicillin.
The structure of the penicillin
molecule features the β-Lactam
ring, which inhibits the
formation of the peptidoglycan
cross-links in the bacterial cell
wall, but has no direct effect on
cell wall degradation. The
relatively small size of the
molecule allows it to deeply
penetrate the cell wall.
In the early days, before
resistance developed, penicillin
was widely used and effective
in treating Staph and Strep
infections, as well as syphilis
and gonorrhea. It is still highly
effective against Groups A and
B Strep infections.
Fleming was very aware of the
ensuing bacterial resistance to
his new drug, and he cautioned
about the over use of penicillin
in his many speeches around the
world. He warned not to use
penicillin unless there was a
properly diagnosed reason for it
to be used, and that if it were
used, never to use too little, or
for too short a period, since
these are the circumstances
under which bacterial resistance
to antibiotics develops.
Figure 4: The early days of
Penicillium culturing and penicillin
production at the Dunn School of
Pathology in Oxford, England.
The challenge of massproducing this drug was
daunting. In 1942, the first
patient was treated for
streptococcal septicemia with
U.S. made penicillin produced
by Merck & Co. Half of the
total supply produced at the
time was used on that one
patient. In July 1943, the War
Production Board drew up a
plan for the mass distribution of
penicillin stocks to Allied
troops fighting in Europe.
Penicillin is actively excreted,
and about 80% of a penicillin
dose is cleared from the body
within three to four hours of
administration. Indeed, during
the early penicillin era, the drug
was so scarce and so highly
valued that it became common
to collect the urine from
patients being treated, so that
the penicillin in the urine could
be isolated and reused.
Figure 5: Mass production of
penicillin at Merck & Co. in 1945.
A moldy cantaloupe in a Peoria,
Illinois, market in 1943 was
found to contain the best and
highest-quality penicillin after a
worldwide search. The
discovery of the cantaloupe, and
the results of fermentation
research on corn steep liquor at
the Northern Regional Research
Laboratory at Peoria, Illinois,
allowed the United States to
produce 2.3 million doses in
time for the invasion of
Normandy in the spring of
1944. By 1945, over 646 billion
units per year were being
produced.
In a 1946 to 1948 study in
Guatemala, U.S. researchers
used prostitutes to infect prison
inmates, insane asylum patients,
and Guatemalan soldiers with
syphilis and other sexually
transmitted diseases, in order to
test the effectiveness of
penicillin in treating sexually
transmitted diseases. They later
tried infecting people with
"direct inoculations made from
syphilis bacteria poured into the
men's penises and on forearms
and faces that were slightly
abraded . . . or in a few cases
through spinal punctures.”
Approximately 1,300 people
were infected as part of the
study (including orphan
children). This study, now
highly criticized for its
unethical treatment of its
subjects, was sponsored by the
Public Health Service, the
National Institutes of Health
and the Pan American Health
Sanitary Bureau (now the
World Health Organization's
Pan American Health
Organization) and the
Guatemalan government. The
director of this study, John
Cuter, was also involved in the
infamous Tuskegee syphilis
experiments.
Since this famous discovery in
1928, many more effective
antimicrobials have been
developed which retain the beta
lactam ring that is characteristic
of penicillin, such as
carbenicillin, methicillin,
imipenem, and the
cephalosporins.
For his important life saving
discovery, he shared the Nobel
Prize in Physiology or Medicine
in 1945 with Howard Florey
and Ernst Chain.
Jay Hardy, CLS, SM (NRCM)
Santa Maria, California
The information contained in this article is for
educational purposes only and is not intended
nor recommended as a substitute for medical
advice, diagnosis, or treatment.