Winter 2008/2009 - University of Utah - School of Medicine

mind and subsequently led to a miracle
drug and a Nobel Prize. The mold was
determined to be from the Penicillium
genus. Thus started the work that
characterized penicillin and the effects
on medicine that followed.
Fleming’s work was published
in 1929. It attracted little attention
for about a decade. He continued his
laboratory studies, but never considered
the antibiotic effect of the mold as an
opportunity for drug development. The
small amount produced by the mold,
problems of its recovery and purification
appeared to him, quite correctly in
his station, to limit its potential use in
therapeutics of human infections.
FROM SCIENTIFIC
CURIOSITY TO APPLICATION
DURING WARTIME
Following a hiatus of nearly a decade,
two other scientists, Ernst Chain
and Howard Florey, working entirely
independently in another London
institution, became interested in further
scientific study of penicillin. Chain, a
chemist, developed methods to isolate
and concentrate penicillin and with
Florey, a physician with pharmacologic
interests, began observations of
the pharmacology of penicillin. With
the background of World War II they
carried on the work with the engagement
of microbiologists in the US
Department of Agriculture who sorted
out and developed high penicillin producing
strains of Penicillium. Following
the bombing of Pearl Harbor, December
7, 1941, the US and UK governments
collaborated in developing systems for
mass production of penicillin. At the
end of World War II enough penicillin
was made in medicinal form to treat
wounded soldiers of all allied forces.
As with Fleming the fame that
came to Chain and Florey was not the
result of a determined goal to develop
the laboratory curiosity into a practical
drug, but the opportunity to extend
scientific investigation of an interesting
biologic phenomenon. The end result
of the interest and endeavors of these
astute, but ordinary biologic scientists
following their academic curiosity, gifted
the world the miracle drug of the 20th
Century to the benefit of all mankind.
INTRODUCTION OF
PENICILLIN INTO CLINICAL USE
In 1945 I received my M.D. from the
University of Utah and an appointment
for internship on the Harvard Services
of the Boston City Hospital. The supply
of penicillin had reached the level
to satisfy the military need and was being
released for clinical trials in civilian
practice. Chester Keefer, a professor
of Medicine at Boston University School
of Medicine, known for his interest
and knowledge of infectious diseases,
was appointed as “penicillin czar”.
All petitions for its clinical use and
the protocol for doing so were cleared
through Dr. Keefer.
At the Boston City Hospital,
Maxwell Finland, my mentor, was
a recognized leader in infectious
diseases and an expert in research
on pneumococcal pneumonia. My
work with him and the early treatment
of civilian cases led to my first
scientific publication and shaped
the destiny of my career path.
The sterile vial of penicillin
was not the soft white
crystalline powder any recent
physician would see, but a
solid hard brown rock. Its solution in
saline or glucose solution was not rapid,
but possible. When later knowledge
became available it was learned that the
early preparations were composed of a
group of isomers and racemic penicillin
molecules, one of which was penicillin
G, the form that became the standard
penicillin. Intramuscular injection
of 10,000 units (one unit being the
amount to inhibit growth of a sensitive
strain of Staphylococcus aureus) was the
usual regimen. Patients with pneumococcal
pneumonia, Osler’s, “Captain
of the Men of Death”, often with the
complication of bacteremia were among
the early patients to receive treatment.
The history of untreated pneumococcal
pneumonia was if the patient survived
for about a week, the time required
for production of natural antibodies
to appear, the patient would undergo
a “crisis” with defervescence, but often
with sequellae of empyema, meningitis
or metastatic abscess formation. Movies
of the time often played out this medical
drama. Penicillin was indeed a miracle
drug for the patients and their physicians,
as those treated with it usually
recovered clinically in 24-48 hours and
had a remarkable reduction in complicating
sequellae.
Frequent daily doses were necessary
because penicillin was cleared from the
blood stream with each single passage
through the kidneys. Thus the half-life
of the drug (the time for elimination of
50% of the dose) was only a couple of
hours. In the very early days with the
scarcity of the precious drug, urine
of treated patients was sometime
saved in order to
recrystallize
penicillin
from
Benzylpenicillin
model
the urine, which was as rich a source as
the liquor from the Penicillium growth.
Designation of penicillin as a
miracle drug was applied and justified
again in its mechanism of antibacterial
action In the chemotherapy of bacterial
infections drugs were sought that had
a favorable differential ratio of toxicity
for bacteria and host cells.The penicillin
binding protein was not present in any
host cells. This mechanism of action
endowed the drug with its miraculous
toxicity ratio of all against the bacteria
and none for host cells.
RESULTS AND EXPECTATIONS
In the early part of the 20th Century,
the fatality rate from pneumococcal
pneumonia was estimated to be about
40%. Specific antiserum and sulfonamides
reduced it substantially, but it
remained a principal cause of death.
Within a decade, the results of treatment
with penicillin erased fear of the
disease, permitted treatment without
hospitalization and eliminated it as a
significant cause of death. A decline in
empyema, chronic bronchiectasis, lung
abscess, purulent sinusitis and other sites
of local respiratory infection followed.
Other infections caused by organisms
of somewhat less susceptibility to
penicillin were treated successfully
as doses of millions of units replaced
the initial use of a few thousand.
Decreased frequency, severity and
fatality across the spectrum of the most
common severe bacterial infections
became an accepted expectation. .
When penicillin was introduced
in 1945, fatalities from rheumatic
fever in the United States
exceeded 2,000
per year. Within 25 years, with a much
larger population, there were fewer than
100 recorded fatalities; today the fatality
rate is less than 1 per 300,000 population.
The reduction in the prevalence of
acute rheumatic fever since the introduction
of penicillin is estimated at
99.9% with an equally dramatic decline
in rheumatic heart disease and
other sequellae.
Treponema pallidum, the cause
of syphilis is among the most sensitive of
microorganism to penicillin. Treatment
of acute, congenital and neurosyphilis
with penicillin yielded impressive cures
in each of these syndromes. Latency,
failed case detection and social behavior
regarding sexually transmitted diseases,
including gonorrhea, have combined to
restrict the efficacy of effective treatment
to eradicate or more completely diminish
their prevalence. A side effect of this
success is a cavalier loss of fear of acquiring
infection which has permitted cyclic
increases in infection rates to continue.
Unfortunately human behavior is the
first trump people have exercised
in defeating the potential benefits
of the miracle means of treatment
and prevention of infections with
susceptible bacteria.
IRRATIONAL EUPHORIA
With recognition of all its miraculous
properties and the emergent capability
of fermentation chemists began to
produce large amounts of pure penicillin
cheaply, and the expansion in world
wide use of penicillin proceeded
at a whirlwind rate. Indications
for its use were broadened to
include any whimper of
justification for treatment
or prophylaxis
of suspected bacterial
infection.
Within a quarter
century after the introduction
of penicillin, more
than 90% of people in the
developed countries ofthe
world had received one or
more courses of penicillin;
it was found in sewer
samples from urban
areas and in up to
10% of dairy milk
samples, illustrating
the spread of its use in veterinary
medicine. Confidence in the drug was
so high that even the placebo effect led
some to the belief that in unknown
ways penicillin was “just good for you”.
The trend was an unquenchable social
phenomenon with ineffectual academic
restraints; some academic leaders even
declared victory over infectious diseases,
disbanding the academic specialty from
their faculties. “Why take time in a
crowded program and claim space in a
building …for a field of medicine presently
regarded as having only historical
interest?” This quotation from Rene
Dubos in 1954 captured the irrationality
of the euphoria that had penetrated
academia and was prevalent in all of the
society during the last half of the twentieth
century.
The fictional term, “antibiotic last
rites”, captured the universality of confidence
in miraculous results of antibiotic
treatment. The interaction of medical
practice and human desire for perpetual
health and longevity has shown it has
consequences and lessons to be learned
for application to the advances of the
21st Century.
The short sighted detriment of
the social attitudes of the period was
effective in diminishing vigilance in
the epidemiology of infectious diseases,
and slowing acquisition of academic
knowledge of primary host pathophysiology
in susceptibility and immunity
to infections of various types. With the
high expectations that chemotherapy
was sufficient to control infectious
diseases the well developed state public
health departments which informed
and served the public in control of
community epidemics were dismantled
and fiscally starved to a shadow of their
earlier prominence. Fear and need for
preparations for continuing epidemics
and pandemics is once again being realized
and expressed.
Perhaps the most severe ultimate
cost of the irrational euphoria ignited
by penicillin and its antibiotic sequitors,
was prophylaxis and trial and error
therapy, and a utopian aim to have
broad antibiotic regimens that would
prevent and/or cure the entire spectrum
of human infections. It set the stage for
the emergence of penicillin resistance
and sequentially more extensive and
complete resistance to other antibiotics
that followed. That is the yield being
harvested in the present era.
A NEW PERSPECTIVE
The antibiotic story of the 21st Century
will not have the aura nor realize the
fullness of the benefits, at least not with
the same drugs, that were so miraculously
effective during the golden last half of
the 20th Century. It is likely that new
and perhaps equally miraculous chemotherapeutic
agents can be developed
using the advanced knowledge gained
about the sophisticated molecular biology
of bacteria, viruses and fungi and
new capabilities in microbial genetics
and combinatorial chemistry. The
expectations and accepted patterns of
their use will need to be more specifically
directed and general use against a
broad spectrum of targets limited, if the
medical profession and public learned
the lessons from use of the miracle
drug that heralded the 20th Century
era--penicillin.
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