The Antibiotic Age: Alexander
Fleming and the Discovery of the
Wonder Drug
Miranda Rasmussen
Senior Division
Historical Paper
2,490 Words
“I have been trying to point out that in our lives chance may have an astonishing influence and,
if I may offer advice to the young laboratory worker, it would be this--never neglect an
extraordinary appearance or happening.”
- Alexander Fleming
A Fortuitous Encounter
Returning from vacation on September 3, 1928, Professor of Bacteriology at Saint
Mary’s Hospital in London, England, Alexander Fleming discovered something highly unusual.
While sorting through petri dishes containing staphylococcus, a bacteria that commonly causes
boils and sore throats, Fleming noticed one petri dish seemed to have a ring of mold growing
inside. The mold itself was nothing out of the ordinary, but on closer inspection he found that the
area around where the mold was appeared to be completely free of any visible bacteria. This
made Fleming question: was the mold somehow stopping the bacterial growth? Curious, Fleming
continued to investigate. He discovered that a liquid could be separated from the mold.
Fleming’s aptly named “mold juice” turned out to be actually quite potent--later identified as a
rare strand of penicillium notatum, the mystery liquid was found to have the ability to kill a
broad range of harmful bacteria, such as meningococcus, streptococcus, streptococcal,
staphylococcal, gonococcal infections, and diphtheria bacillus. Alexander Fleming and his
discovery of the first true antibiotic, almost unknowingly and certainly accidentally,
heralded a new era in American science and history, the Antibiotic Age, and led to
advancements in health care, pharmacy, and the manufacturing and research of lifesaving
medicines that impacted the lives and futures of people around the world.
From the late 1880’s to the mid 1920’s hospitals across the world were crowded with ill
and sickly people seeking medical attention. Industrialization, along with an influx of immigrants
moving into the United States, led to, as stated in an article located on the CDC’s website,
entitled Achievements in Public Health, 1900-1999: Control of Infectious Diseases,
“overcrowding in poor housing served by inadequate or nonexistent public water supplies and
waste-disposal systems.” These unhealthy conditions contributed to the rampant spread of
influenza, pneumonia, yellow fever, typhoid fever, rheumatic fever, tuberculosis, blood
poisoning, gonorrhea, malaria, dysentery, syphilis, and cholera. In fact, it was in the early 20th
century that one of the worst epidemics in world history, the influenza pandemic of 1918,
occurred, lasting less than one year, and took the lives of roughly 500,000 people in the United
States alone and about 20 million people worldwide. Because there were no antibiotics available
at this time doctors could do little more for patients than wait and hope.
Exploration, Investigation, and Development
Antibiotics, defined by the Merriam-Webster dictionary as drugs “used to kill harmful
bacteria and to cure infections” or more scientifically as “substance[s] produced by… a
microorganism… [that are] able... to inhibit or kill another microorganism” were not officially
put in use until 1941 when the first human subject, 43-year old Albert Alexander, was injected
with the first true antibiotic, penicillin, in an attempt to save his life. Despite showing promising
signs of recovery, Albert Alexander died several days later due to the lack of availability of the
newly procured drug. The realization of, according to Alexander Fleming in the British Journal
of Experimental Pathology, published in June of 1929, “the potential therapeutic” benefits that
penicillin could offer led to an increase in demand for production on a much larger scale.
Alexander Fleming and two assistants, Frederick Ridley and Stuart Craddock, began tests
to try and isolate pure penicillin. They were able to obtain only a crude solution, and were
therefore mostly unsuccessful, but they were not alone in their task. Competition arose from
Harold Raistrick, Professor of Biochemistry at the London School of Hygiene and Tropical
Medicine, who also tried, but failed, to perfect purified penicillin. Finally in 1939, at the Sir
William Dunn School of Pathology at Oxford University, Ernst Chain and Howard Florey
succeeded in transforming penicillin from a questionable mold filtrate to a viable drug with
lifesaving medicinal value.
In order for penicillin to be put into public use as an antibiotic, the drug would need to be
tested and the speed and efficiency of production would need to be increased. Because of this,
Oxford University became a temporary penicillin factory. The production of around 500 liters,
which is equal to approximately 133 gallons, of penicillin was necessary each week in order to
move forward with animal experimentation and human clinical tests. Because of the substantial
amount of the drug needed, Chain, Florey, and their colleagues, desperate to continue
production, fermented the drug in bedpans, food tins, milk churns, and even bath tubs. In
addition, Oxford employed several women nicknamed “penicillin girls” who monitored the
fermentation process and growth of the Oxford penicillin. Despite these efforts, Chain and
Florey realized that, as WWII began to absorb the attention of British chemical manufacturers,
mass production of penicillin would not be feasible in Britain.
Oxford Penicillin Journeys to the United States
In the summer of 1941, Florey and Norman Heatley, who had become Florey’s research
associate in 1940, aided by the Rockefeller Foundation, made the decision to travel to the United
States with the hopes of interesting American pharmaceutical companies in the large-scale
development of penicillin. The two were put in contact with the U.S. Department of
Agriculture’s Robert Thorn, an expert mycologist, and the Department’s Northern Regional
Research Laboratory, known as the NRRL, located in Peoria, Illinois. The NRRL had experts in
their Fermentation Division, such as Orville May and Robert Coghill, who were unequivocally
valuable to the eventual success of penicillin.
NRRL Increases Yield and Efficiency of Production
Andrew Moyer of the NRRL made two key discoveries that allowed penicillin to be
produced more effectively. First, Moyer found that replacing sucrose with lactose in the
fermentation process increased yield significantly. Second, he discovered that adding corn-steep
liquor, a waste byproduct of the corn milling process, exponentially increased yield. In addition,
the Peoria lab was able to increase yield yet again by adding an organic compound called
phenylacetic acid to the fermenting penicillium culture.
As production grew, the need for a proper fermentation vesicle became more and more
obvious. The scientists of the NRRL learned that penicillin did not grow best when submerged
and thus developed a method of fermenting penicillin in a large tank, still in a submerged style,
that could be constantly aerated and agitated. With these changes in the fermentation process
came changes to the actual penicillin compound.
Florey’s original penicillium culture was replaced by a different strain, discovered by the
NRRL’s Kenneth Raper, that produced a greater yield of penicillin when growing in a
submerged fashion. A mutant of Raper’s new strain, ironically discovered on a moldy cantaloupe
from a Peoria fruit market, was capable of again yielding more penicillin than the prior strain.
According to the American Chemical Society’s article entitled Alexander Fleming Discovery and
Development of Penicillin, an even “more productive mutant was produced by the use of x-rays
at the Carnegie Institute. When this strain was exposed to ultraviolet radiation at the University
of Wisconsin, its productivity was increased still further.”
ORSD and Pharmaceutical Companies Take Interest
As penicillin became more readily available and the purification process was nearly
perfected, Florey reached out to several American pharmaceutical companies, hoping to incite
them to take up the cause. His encounters with these companies were disappointing at best and
only four major companies--Merck, Squibb, Lilly, and Pfizer--showed any real interest.
Thankfully for Florey, Alfred Newton Richards, the VP of Medical Affairs at the University of
Pennsylvania and Chair of the Committee on Medical Research, or CMR, of the Office of
Scientific Research and Development, or OSRD--which was created in 1941 to make sure that
due attention was given to important scientific research that related to national defense--was
willing to help. Richards approached the pharmaceutical companies who had seemed interested
in producing penicillin and informed them that there was a good chance that, if they pursued
mass production of the drug, the federal government would help support them as penicillin had
certainly become a national, if not international, interest.
WWII Renews Urgency in Production
Exactly ten days after Pearl Harbor, and the United States official entry into WWII,
Richards again approached the pharmaceutical companies at a CMR conference in New York.
Representatives from Merck, Squibb, Pfizer, and Lederle were all present and Robert Coghill’s
report on the production process was highly encouraging and optimistic. Coghill quoted George
W. Merck, who had voiced his opposition to penicillin before, as having, “... immediately spoke
up, saying that if these results could be confirmed... it was possible to produce the kilo of
material [needed] for Florey, and [the] industry would do it!” The four companies agreed to
continue their research on penicillin separately. However, they also agreed to inform the CMR of
new developments, therefore allowing the CMR, with permission from the company involved, to
spread shared information to the public if the public could benefit from the knowledge.
Pharmaceutical manufacturers and the chemical industry played a huge role in ramping
up production of penicillin. Pfizer’s John L. Smith described penicillin as being “as
temperamental as an opera singer, the yields are low, the isolation is difficult, the extraction is
murder, the purification invites disaster, and the assay is unsatisfactory.” Despite the hardships
associated with producing penicillin the companies persevered and production increased from 21
billion units to 1,663 billion units to over 6.8 trillion units from 1943 to 1945 alone.
Techniques also improved substantially so that production rose from liter tubs with a
measly 1% yield to 10,000-gallon tanks with 85% yield. Pharmaceutical scientists utilized
methods from freeze drying with vacuum technology to cooling, mixing, and anti-foaming
solutions to create effective, pure, stable, and useful penicillin.
Clinical studies and military trials confirmed what many experts had long believed:
penicillin was indeed nothing short of a wonder drug. By March 1942, penicillin was finally
ready to be put in action and 11 people were treated in a one month span with penicillin
produced by Merck. Shortly after, the U.S. Army had plans to utilize penicillin to treat infected
wounds. The WPB, also known as the War Production Board, took over the responsibility for the
production of penicillin in 1943. The WPB picked around 30 pharmaceutical companies to
participate in a production program headed by Albert Elder and provided these companies with
all supplies necessary to have an appropriate amount of penicillin ready for the D-Day invasion
of Normandy.
Patriotism was utilized to unify the competing pharmaceutical companies and increase
manufacture of the drug. Using WWII as a way to motivate companies, Elder urged them “to
impress upon every worker in your plant that penicillin produced today will be saving the life of
someone in a few days or curing the disease of someone already incapacitated.” He promoted the
idea of creating “enthusiasm for the job down to the lowest worker” of the penicillin factories.
Distribution to the American Public
As the American public became aware of the availability of penicillin, demand and
prices, skyrocketed. Dr. Chester Keefer of Boston, Chairman of the National Research Council’s
Committee on Chemotherapy was tasked with rationing civilian use of penicillin in the United
States. The process of rationing was excruciating, as described in an article from the New York
Herald Tribune, published on October 17, 1943, which stated that, “Many laymen--husbands,
wives, parents, brothers, sisters, friends--beg Dr. Keefer for penicillin. In every case the
petitioner is told to arrange that a full dossier on the patient’s condition be sent by the doctor in
charge. When this is received, the decision is made on a medical, not an emotional basis.”
Eventually, as WWII came to a close, the rationing stopped. Pfizer opened their very first
commercial plant dedicated to the production of penicillin in Brooklyn, New York, on March 1,
1944. About a year later, March 15, 1945, penicillin became available to the average consumer at
their local pharmacy. Prices declined from $20 to around 9¢. In the UK penicillin was finally
made available, although as a prescription only drug, on June 1, 1946.
Exchanging Information and Continued Discoveries
The mass production of penicillin would never have been possible without the joint
efforts of American and British chemists, mycologists, microbiologists, chemical engineers,
pharmaceutical manufacturers, and government agencies who helped with funding and
production of the wonder drug. The exchange of knowledge between Great Britain and America
contributed to discovery of other miraculous medicines able to cure a variety of ailments ranging
from viral illnesses to fungal infections and parasitic diseases.
Acknowledging the Scientists Behind Penicillin
In the year 1945, Alexander Fleming, Ernst Chain, and Howard Florey won the Nobel
Prize for physiology or medicine for their work with penicillin. Ernst Chain and Edward
Abraham continued studying penicillin, focusing on the structure of the penicillin molecule, and
using x-ray crystallographic technology developed by Dorothy Hodgkins at Oxford University;
the same place where penicillin was first purified. Norman Heatley, described as the pragmatic
and quiet hero behind the success of penicillin, was excluded from the Nobel Prize. Despite this,
Heatley received recognition for his work by being honored with the very first honorary
doctorate in Oxford University’s 800-year long history. The Royal Society of Chemistry, in
partnership with the American Chemical Society, deemed the “Discovery and Development of
Penicillin” an “International Historic Chemical Landmark” in the year 1999, 44 years after
Alexander Fleming’s death, and awarded the Alexander Fleming Laboratory Museum in London
with a plaque that reads: “In 1928, at Saint Mary’s Hospital, London, Alexander Fleming
discovered penicillin. This discovery led to the introduction of antibiotics that greatly reduced
the number of deaths from infection. Howard W. Florey, at the University of Oxford working
with Ernst B. Chain, Norman G. Heatley, and Edward P. Abraham, successfully took penicillin
from the laboratory to the clinic as a medical treatment in 1941. The large-scale development of
penicillin was undertaken in the United States of America during the 1939-1945 World War, led
by scientists and engineers at the Northern Regional Research Laboratory of the U.S.
Department of Agriculture, Abbott Laboratories, Lederle Laboratories, Merck & Co., Inc., Chas.,
Pfizer & Co., Inc., and E.R. Squibb & Sons. The discovery and development of penicillin was a
milestone in twentieth century pharmaceutical chemistry.”
The discovery of penicillin, the first true antibiotic, by Alexander Fleming led to the
beginning of a new age in American science and history, the Antibiotic Age, which impacted
advances in health care, pharmacy, and the manufacturing and research of lifesaving medicines
that affected the lives and futures of people around the world. In the words of Howard Florey:
“Too high a tribute cannot be paid to the enterprise and energy with which the American
manufacturing firms tackled the large-scale production of the drug. Had it not been for their
efforts there would certainly not have been sufficient penicillin by D-Day in Normandy in 1944
to treat all severe casualties, both British and American.”
Annotated Bibliography
Primary Sources
1. "Vital Statistics For 1927." The Lancet 211.5447 (1928): 141. Web. 21 Dec. 2015.
The 1928 United States Census is a primary source. The Census was used to
provide accurate information on causes of death in the year 1928, along with
evidence of why, how, and where. The information obtained from this document
helps to explain the importance of penicillin and the effect the drug had.
2.
Department of Commerce and Labor, Bureau of the Census. Mortality Statistics, 1900 to
1904, Washington, D.C.: U.S. Department of Commerce and Labor, 1906.
The mortality statistics of 1900-1904 are a primary source that reported on death
rates in the United States. This was used during the research process to provide
background information in addition to numerical statistics and evidence.
3.
National Office of Vital Statistics. Vital statistics--special reports, death rates by age,
race, and sex, United States, 1900-1953: tuberculosis, all forms; vol 43, no. 2. Washington, DC:
US Department of Health, Education, and Welfare, 1956.
This information is primary evidence from the National Office of Vital Statistics.
The source displayed multiple statistics utilized towards the conclusion of the
research process.
4.
CDC. Status report on the Childhood Immunization Initiative: reported cases of selected
vaccine-preventable diseases--United States, 1996. MMWR 1997;46:665-71.
This CDC report is a primary source. The information was used to develop and
expand knowledge of antibiotics along with vaccines. This became useful about
half way through the research process.
5.
Hinman A. 1889 to 1989: a century of health and disease. Public Health Rep
1990;105:374-80.
This source provided primary information about public health regulations and
information in the mid to late 1900’s.
6.
CDC. Update: staphylococcus aureus with reduced susceptibility to vancomycin--United
States, 1997. MMWR 1997;46:813-5.
This is a primary source, released by the CDC, that included information about
various antibiotics. This was used in the final stages of research.
7.
Mattila KJ, Valtonen VV, Nieminen MS, Asikainen S. Role of infection as a risk factor
for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis 1998;26:719-34.
This document is a primary source. The information included was beneficial to
building background knowledge on the subject of penicillin and antibiotics. The
document also described public health risk factors at the time.
8.
Crosby AW Jr. Epidemic and Peace, 1918. Westport, Connecticut: Greenwood Press,
1976:311.
This document is a primary source. Epidemic and Peace detailed the relationship
between epidemics and the spread of disease, along with public health, during the
early 20th century. This information was not used until much later in the research
process.
9.
Merriam-Webster. Merriam-Webster, Web. 09 Sep. 2016.
The Merriam-Webster dictionary is a primary source that was used to define
several words, including the word “antibiotic” which is quoted to clarify the
definition for all readers.
10.
Ross-Flanigan, Nancy; Uretsky Samuel, Nancy Ross-Flanigan, "Penicillin." World of
Microbiology; Immunology. 2003, "Penicillin." Medical Discoveries. 1997, William G. Gutheil,
"penicillin." The Columbia Encyclopedia, 6th Ed.. 2015, John M. Last, "penicillin." A
Dictionary of Nursing. 2008, Michael Allaby, "penicillin." World Encyclopedia. 2005,
"penicillin." A Dictionary of Biology. 2004, "penicillin." The Oxford Pocket Dictionary of
Current English. 2009, David A, T., and "penicillin." Oxford Dictionary of Rhymes. 2007.
"Penicillins." Encyclopedia.com. HighBeam Research, 01 Jan. 2006. Web. 17 Jan. 2016.
This encyclopedia is technically a primary source. The information on penicillin
was useful in providing a more thorough definition of the drug and more general
information about the antibiotic itself.
11.
Hoyert DL, Kochanek KD, Murphy SL. Deaths: Final data for 1997, Hyattsville,
Maryland: U.S. Department of Health and Human Services, Public Health Service, CDC,
National Center for Health Statistics, 1999. (National vital statistics reports, vol 47, no. 19).
These statistics are primary evidence. The report on mortality in the United States
was used to analyze the time period after penicillin was developed.
12.
United Nations Program on HIV/AIDS and World Health Organization, AIDS epidemic
update: December 1998. Geneva, Switzerland: World Health Organization, 1999. Available at
http://www.unaids.org/highband/document/epidemic/wadr98e.pdf.
This source is a primary source that provided information on AIDS and antibiotics
in general. This was used as supplemental information.
13.
CDC. Preventing emerging infectious diseases: a strategy for the 21st century. Atlanta,
Georgia: US Department of Health and Human Services, Public Health Service, 1998.
This source is a primary document that details emerging bacterial threats and
prevention of diseases in the United States. This was used further into the research
process.
14.
Institute of Medicine. Emerging infections: microbial threats to health in the United
States. Washington, DC: National Academy Press, 1994:vi.
This source was a primary source that details emerging bacterial threats in the
United States. This was used further into the research process as supplemental
information.
Secondary Sources
1. “Alexander Fleming Discovery and Development of Penicillin - Landmark.”American
Chemical Society. Web. 03 Oct. 2016
The American Chemical Society’s website, which includes a detailed article
regarding the discovery of penicillin, is a valuable secondary source that was
utilized primarily in the beginning phases of research. The organization’s website
as a whole was helpful in providing a thorough overview of the mass production
process of penicillin.
2.
“Alexander Fleming Museum.” Alexander Fleming Laboratory Museum, St. Mary’s
Hospital, Praed Street, London, W2 1NY. Web. 12 Jan. 2016.
This website is a secondary source. The site provided a fairly detailed overview
and explanation of the discovery of penicillin. Information from this source was
utilized mostly in early stages of research.
3.
“Alexander Fleming and Penicillin.” AwesomeStories.com. Web. 17 Jan. 2016.
The article found on the Awesome Stories website is a secondary source that
offers the reader a summary of the findings of Alexander Fleming. This was
helpful in offering specific pieces of evidence and primary resources that were
used to further research and to support claims.
4.
"Achievements in Public Health, 1900-1999: Control of Infectious Diseases." Centers for
Disease Control and Prevention. Centers for Disease Control and Prevention, Web. 25 Dec.
2015.
The CDC’s website is a secondary source. The information found on the website,
specifically the information from 1900 until 1999, was helpful in comprehending
the living situations and public health efforts in the 20th century.
5.
"Penicillin (Oral Route, Injection Route, Intravenous Route, Intramuscular Route)."
Description and Brand Names. N.p., n.d. Web. 17 Jan. 2016.
This website, detailing the multiple methods with which to take penicillin, is a
secondary source. This source was helpful in understanding how penicillin works
and its medical applications today.
6.
"Almanac: The Discovery of Penicillin." CBSNews. CBS Interactive, n.d. Web. 15 Nov.
2015.
This source is a secondary source. It was mostly important to the furthering of
understanding of the importance of the discovery of penicillin. In addition, this is
a reliable source because of the general reliability associated with CBS, a
trustworthy news source.
7.
"Alexander Fleming and the Discovery of Penicillin." Germ Theory (n.d.): 265-93. Web.
The article located on this web page is a secondary source. The source provided
an overview of the discovery of penicillin. This was most useful in the beginning
stages of research.
8.
Hobbys, Gladys L. Penicillin: Meeting the Challenge. New Haven: Yale UP, 1985. Print.
The book by Gladys Hobbys, entitled Penicillin: Meeting the Challenge, is a
secondary source. The knowledge in the book was helpful in clarifying the
process of producing penicillin. The book also contained several quotes and
phrases that supported multiple key points and main ideas.
9.
"What If Fleming Had Not Discovered Penicillin?" What If Fleming Had Not Discovered
Penicillin? Web. 17 Jan. 2016.
This source is a secondary source. The source offers the reader a summary of the
findings of Alexander Fleming. This was helpful in the beginning phases of
research.
10.
"Alexander Fleming's Discovery of Penicillin." YouTube. YouTube, n.d. Web. 29 Sep.
2016.
This resource is a secondary source. This source is unique, different from other
sources listed, because it is a video. This type of medium was very useful in the
beginning phases of research.
11.
"Alexander Fleming | Chemical Heritage Foundation." Alexander Fleming | Chemical
Heritage Foundation. Web. 16 Jan. 2016.
The Alexander Fleming information page, located on the Chemical Heritage
Foundation’s website, is a secondary source. This source provided more information on
the scientific process behind the development of penicillin.
12.
Morrow PA. Report of the committee of seven of the Medical Society of the Country of
New York on the prophylaxis of venereal disease in New York City. N York M J 1901;74:1146.
This is a secondary source that related to antibiotics and the relationship of the
drug with disease. This was used as supplemental information.
13.
Lederberg J, Shope RE, Oaks SC Jr, eds. Microbial threats to health in the United States,
Washington, D.C.: National Academy Press, 1992.
This is a secondary source that revealed the importance of microorganism threats
to health. This was used late in the research process.
14.
"How Was Penicillin Discovered?" About.com Education. Web. 03 Jan. 2016.
This article is a secondary source that provided a fairly detailed overview and
explanation of the discovery of penicillin. It was utilized mostly in early stages of
research.
15.
"We've Done Great Things in the Past. Today, We're Doing Great Things for the Future."
Merck.com. Web. 18 Jan. 2016.
16.
The information on penicillin found on Merck Pharmaceutical’s website is a
secondary source. This information was most relevant in later research. The information
explained Merck’s involvement in the manufacture of penicillin.
Plikaytis BB, Marden JL, Crawford JT, Woodley CL, Butler WR, Shinnick TM.
Multiplex PCR assay specific for the multidrug-resistant strain W of mycobacterium
tuberculosis. J Clin Microbiol 1994;32:1542-6.
This is a secondary source that provided supplemental information on
tuberculosis. This information can be applied and associated with information on
penicillin and the illnesses the drug cures.
17.
"The Discovery of Penicillin (1964)." YouTube. YouTube, n.d. Web. 17 Jan. 2016.
This resource is a secondary source. This source is unique, different from other
sources listed, because it is a video. This type of medium was very useful in the
beginning phases of research.
18.
"Penicillin: An Accidental Discovery Changed the Course of Medicine."Penicillin: An
Accidental Discovery Changed the Course of Medicine. N.p., n.d. Web. 12 Jan. 2016.
This article is a secondary source that provided a fairly detailed overview and
explanation of the discovery of penicillin. It was utilized mostly in early stages of
research.
19.
"The Discovery of Penicillin." Discovery Science The Discovery of Penicillin Comments.
Web. 17 Jan. 2016.
This online article is a secondary source that provided an overview of the tests
and trials of penicillin. It was utilized mostly in early and middle stages of research.
20.
Renneberg, Reinhard, and A.L. Demain, Biotechnology for Beginners. Amsterdam:
Boston, 2008. Print.
This book by Renneberg about the discovery of penicillin and the technology
involved with that is technically a secondary source. This was useful in better
understanding the process of production.