Transcript Antibiotics

The Evolution of Antibiotics
During World War II
Infections During War
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War in the beginning years of
American history resulted in more
soldiers dying from disease than
combat.
Disease was rampant, as evidenced
by the typhoid fever outbreak during
the Spanish-American War and in the
influenza epidemic in World War I.
Death rates were fueled by crowded,
unsanitary camps, improper disposal
of human and animal waste, poor
personal hygiene, lack of bathing
facilities and recycling the clothing of
soldiers dead from disease.
http://home.att.net/~steinert/wwii.htm
Infections During War
•The widespread implementation of vaccinations and the adoption
of medical treatment with antibiotics put an end from the high
mortality rate from infection, with combat deaths outnumbering
deaths by disease in every war since World War II.
•Dying of disease is so rare for today’s soldiers that even deaths by
suicide outnumber the deaths by disease in the present war.
Infections During War
•Death tolls underestimate the
full impact of disease on warfare.
•The health of a unit is crucial for
its ability to be prepared and
ready for its mission.
•According to military hygienist
Alfred A. Woodhull, “the sick are
for the time as ineffective as the
dead”.
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Vaccinations
• Entering World War II, our
soldiers were immunized
against smallpox, typhoid
fever, cholera, plague, tetanus,
yellow fever, and typhus.
• This was definitely not the
case worldwide and gave us an
advantage.
• Tetanus was responsible for
innumerous deaths during
World War I, but during the
second war there were only 11
cases and four deaths
attributed to it.
http://www.vaccines.mil/default.aspx?cnt=resource/viewImage&imgID=29
Therapies
• Medicine at that time was
targeted toward symptomatic
relief, but not a cure.
• Included painkillers like
morphine, mercury, arsenic,
antimony for schistosomiasis,
and quinine.
• The major manufacturing
companies made and
distributed products such as
aspirin, chloroform, cocaine,
emetine, hydroquinone,
lanolin, and phenacetin.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1279970&tool=pmcent
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Biological Debridement
• First written reports of the beneficial effects of
maggots dates back to 1557, but introduced in the
United States in 1931.
• The first scientific studies of maggots medicinal uses
were conducted by Dr. W.S. Baer during World War II.
• He was inspired after encountering soldiers in the first
World War. Although they had laid unattended for 7
days, their compound fractures and abdominal wounds
contained healthy granulation tissue.
• In 1920s and 1930s he successfully treated
osteomyelitis and chronic leg ulcers in over ninety
patients.
Antiseptic agents
• Carbolic acid, an
antiseptic agent, is
being sprayed by the
apparatus to the right.
• It showers the mist over
the patient to kill any
infectious agents.
• This makes this
procedure a “clean”
surgery.
http://www.vaccines.mil/default.aspx?cnt=resource/viewImage&imgID=29
Proflavine
• Introduced to medical society in 1934.
• Orange to red colored dye with bacteriostatic and
bacteriocidal properties when used topically.
• During World War II, extensively used as wound
antiseptic.
Atabrine
• Cinchona bark, which contains
quinine and cinchona, was
used to treat malaria.
• Once the essential elements
were able to be isolated, they
were given instead of the
actual bark.
• The 1930s yielded synthetic
antimalarials, one of which
was atabrine.
• It was highly effective, but
could cause yellowed skin,
headaches, nausea, vomiting,
and a temporary psychosis.
Syphilis
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• Salvarsan, an
arsenobenzene compound,
used for syphilis.
• The drug was 32% arsenic
and could cause severe
tissue necrosis and death if
not injected into the vein.
• IV infusion was alternated
with intramuscular mercury
and bismuth.
• Average duration of
treatment >18 months.
Sulphonamides
• Gerhard Domagk, German biochemist, was involved in researching
therapeutic potential of metal based compounds, such as gold, tin,
antimony, and arsenic.
• After changing jobs to a chemical company that manufactured
products for coloring textiles, he began to test azo dyes.
• In 1932, he discovered a bright red dye named Prontosil, that
could cure infections caused by streptococcal bacteria in mice.
• His used his severely ill daughter as his test subject and the drug
eradicated her infection.
• Prontosil was metabolized into two parts, one of which is
sulphanilamide. It is this entity that carries the bacteriostatic ability.
Sulphonamides
• Prontosil was effective against
streptococci, but not against
pneumococcal infections.
• Pharmaceutical firm Mary and
Baker developed M & B 693,
which was sulfadiazine, which
had an extended spectrum of
treatment.
• Sulfadiazine was hailed for
treating puerperal fever,
erysipelas, mastoiditis,
meningitis, and gonorrhea .
• This became a major
breakthrough because it is the
first class capable of treating
bacteremia.
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Sulphonamides
• Side effects could be limiting, including drug fevers, blood
dyscrasias, renal complications, and disruption of
coordination.
• They were not uniformly successful, even against disease in
which their effectiveness had been demonstrated.
• By 1941, 1700 tons had been administered to ten million
Americans and strains of sulpha resistant streptococci had
surfaced.
• Controls over pharmaceuticals then were minimal; there
were reports of a series of deaths caused by a sulfanilimide
elixir containing diethylene glycol.
• They were the only available effect drug until penicillin.
Sulphonamides
•Soldiers were distributed
first aid bags that were to be
carried on the belt.
•These bags contained the
sulfa powder and a bandage
to wrap the wound.
•They were instructed to
sprinkle the drug on any
open wound.
Penicillin
• Alexander Fleming, a Scottish bacteriologist, worked at St.
Mary’s Hospital in London as a member of the inoculation
department.
• His work was centered primarily on lysozymes, which he
discovered and began researching in 1921.
• In 1928 he discovered a mold growth in the petri dishes
that was inhibiting growth of his staphylococcal colonies.
• He isolated and identified the mold as Penicillin.
• Fleming found his product inactive on Gram negative
bacteria. In addition, it’s chemical composition was
unstable and difficult to isolate the active ingredient; his
discovery soon fell by the wayside.
www.scran.ac.uk/.../image/0044/00442445.jpg
Sir Alexander Fleming, 1952
www.scran.ac.uk/.../image/0044/00442445.jpg
A Scanning Electron Micrograph of Penicillium Mold Producing Chains of
Spores.
Penicillin
• Ten years later, in 1939, Sir Howard Florey, the head of the
Pathology Department at Oxford, and his colleague,
biochemist Ernest Chain continued experimenting with
penicillin where Alexander Fleming left off.
• Knowing the challenges Fleming suffered, they engaged an
additional biochemist , Norman Heatley to assist with
improving production techniques.
• They were able to purify the drug and begin animal testing
on mice. They inoculated eight mice with fatal streptococci
doses and then gave four of them penicillin.
• The mice treated with penicillin survived, the others did
not.
Penicillin
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Early penicillin culture facility at the Sir William Dunn School of Pathology, Oxford, England.
© Museum of the History of Science, Oxford
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The dosage of penicillin was defined in
Oxford units. This is the amount that
would produce a clear zone free of
bacteria of 25 millimeters on petri dish
culture.
Despite their efforts, they were unable to
isolate more than two units per cubic
centimeter from their flasks.
They developed a concentration protocol
which produced a dry stable penicillin salt
with a potency of about 50,000 units per
gram.
The extraction process lost nearly two
thirds of the penicillin originally in the
culture medium.
97% of this dry extraction was impurities
and it was only sufficient to treat one
person for half a day.
Penicillin
• The team produced enough penicillin to try on a patient. 48 year
old London Constable Albert Alexander developed staphylococcal
septicemia following a scratch while pruning his roses and had
developed septicemia and numerous facial abscess and carbuncles.
• Upon admission to the treatment facility, he had been administered
a sulfa drug with no effect.
• When physicians believed he had only hours left to live, Florey
asked for permission to treat the patient with penicillin.
• The patient defervesced and improved a great deal.
• The small penicillin supply began to run out, even though his urine
was collected to recycle as much of the drug as possible.
• The Constable relapsed and died on the fifth day, after the drug
supply had been depleted after four days of treatment.
Penicillin
• In search of a larger
production of the drug and
funding, Florey came to the
United States and resumed his
work at the Northern Regional
Research Laboratory in Peoria,
Illinois .
• A new fermentation method
using corn steep liquor in the
culture medium greatly
increased their yield.
• Now the Penicillin was grown
submerged in vats instead of
only on the surface in flasks,
contributing to the higher
quantities.
Penicillin
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At the beginning of the war, the
government put together a committee to
oversee the development of
chemotherapeutic agents and medical
research.
Once the efficacy of penicillin and its poor
available supply were reported, penicillin
became a government priority.
Other pharmaceutical companies were
called upon for production.
Military hospitals conducted clinical
studies for the drug.
By D-Day in 1944, there was enough
available to allow unlimited treatment of
allied servicemen.
The drug was only for use for the US and
British military until after the war.
Penicillin
• Proved highly effective against
most bacterial etiologies.
• Before penicillin, pneumonia
fatality rate was around 30%;
it dropped to around 6%
afterward.
• U.S. military deaths from
infection during World War II
were drastically reduced.
• Penicillin did not replace the
sulphonamides, rather it
added to the efficacy of
antibiotic therapy at the time.
Penicillin
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Compound fractures and penetrating
gunshot wounds received in the field
were often problematic.
Infection could be seeded from the
soil, wading in pungent water, or bits
of clothing driven into the wound by
the bullet.
Physicians of the time noted “under
the protection of penicillin, it was
possible to remove foreign bodies
and dead bone, to revise the soft
parts so that the bone was covered,
and to restore the normal contours of
the limb, applying grafts of bone,
muscle and skin wherever
necessary”.
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Penicillin
• Penicillin was not proven
efficacious for syphilis treatment
until 1943.
• Syphilis was one of the leading
cause of death in the United
States before World War II,
behind tuberculosis, pneumonia,
and cancer.
• The decline in syphilis rates can
be attributed in large to the
availability of penicillin.
• The use of the drug eventually led
to greater control of syphilis in
the United States, such that the
disease is no longer screened for
among new recruits.
Penicillin
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http://home.att.net/~steinert/wwii.htm
In World War I, the Army lost nearly 7
million person days and discharged
more than 10,000 men because of
STD’s.
In the early years of World War II, the
War Department launched a massive
educational and prophylactic
campaign.
Before penicillin, post-exposure
prophylaxis with sulfathiazole was
used.
Following reports of an unpublished
trial during the Korea War with
penicillin prophylaxis given to troops
before liberty period and a resultant
marked reduction in STD rates,
penicillin prophylaxis was authorized
for general use.
Streptomycin
• In 1940 Selman Waksman, a soil
microbiologist isolated an
antibiotic called actinomycin.
• Actinomycin was bacteriocidal,
but it was too toxic for a clinic
trial.
• In 1944 he discovered another
fungal species with bacteriocidal
properties, Streptomycin.
• Streptomycin proved to be active
against a variety of gram negative
and acid fast bacteria, as well as
gram positive organisms resistant
to penicillin.
• Most importantly, it was the first
antimicrobial used in treatment
of tuberculosis.
Nobel Peace Prize Winners
Gerhard Domagk
(1895-1964)
References
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Crillo, Vincent J. Perspectives in Biology and Medicine. Chicago: Winter 2008, Vol 51,
Iss 1:p121-133.
Henderson, John W. The Yellow Brick Road to Penicillin: A Story of Serendipity. History
of Medicine. Volume 72(7), July 1997, p.683-687.
Porter, Roy. The Greatest Benefit to Mankind. W.W.Norton & Company LTD, 1997, p.
428-461.
Prain, David. Penicillin in War Wounds. The Lancet, April 1, 1944.
Rasnake, Mark, Conger, Nicholas et al. History of U.S. Military Contributions to the
Study of Sexually Transmitted Diseases. Military Medicine. Volume 170, 4:61, 2005,
p. 61-65.
Tansey, E.M. Medicines and men: Burroughs, Wellcome & Co, and the British drug
industry before the Second World War. Journal of the Royal Society of Medicine.
Volume 95(8), August 2002, p. 411-416.
Waksman, Selman. Streptomycin: background, isolation, properties, and utilization.
Nobel lecture found at www.waksmaninstitute of microbiology.