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Looking for the most current news, updates, and articles relating to microbiology, go to The American Society for Microbiology educational website Microbe World. Tag words: antibiotic, antimicrobial, antibiotic resistance, penicillin, Fleming, methicillin, vancomycin, MRSA, VRE, ESBL, horizontal gene transfer, HGT, antibiotic sensitivity, zone of inhibition.
To get the best possible experience using our website, we recommend that you upgrade to latest version of this browser or install another web browser. The introduction of penicillin in the 1940s, which began the era of antibiotics, has been recognized as one of the greatest advances in therapeutic medicine.
Antibiotics are compounds produced by bacteria and fungi which are capable of killing, or inhibiting, competing microbial species.
Returning from holiday on September 3, 1928, Fleming began to sort through petri dishes containing colonies of Staphylococcus, bacteria that cause boils, sore throats and abscesses. It was Howard Florey, Ernst Chain and their colleagues at the Sir William Dunn School of Pathology at Oxford University who turned penicillin from a laboratory curiosity into a life-saving drug. Meanwhile, biochemist Norman Heatley extracted penicillin from huge volumes of filtrate coming off the production line by extracting it into amyl acetate and then back into water, using a countercurrent system.
In 1940, Florey carried out vital experiments, showing that penicillin could protect mice against infection from deadly Streptococci.
Substantial amounts of penicillin would be needed for the extensive clinical trials required to confirm the promise of the early results and to provide adequate supplies of the drug for therapeutic use if it did live up to its potential. Yale physiologist John Fulton helped to put his British colleagues in touch with individuals who might be able to assist them in their goal.
Orville May, Director of the NRRL, agreed to have the Laboratory undertake a vigorous program to increase penicillin yields under the direction of Robert Coghill, Chief of the Fermentation Division.
It was recognized that the Oxford group's method of growing the mold on the surface of a nutrient medium was inefficient, and that growth in submerged culture would be a superior process.
Soon a global search was underway for better penicillin producing strains, with soil samples being sent to the NRRL from around the world.
While Norman Heatley remained in Peoria helping the NRRL staff to get the penicillin work started, Howard Florey visited various pharmaceutical companies to try to interest them in the drug. Florey next visited his old friend Alfred Newton Richards, then vice president for medical affairs at the University of Pennsylvania.
Although there was some concern that investments in fermentation processes might be wasted if a commercially-viable synthesis of penicillin were developed, other companies also began to show an interest in the drug. Pharmaceutical and chemical companies played an especially important role in solving the problems inherent in scaling up submerged fermentation from a pilot plant to a manufacturing scale. Because penicillin needs air to grow, aerating the fermentation mixture in deep tanks presented a problem. Lilly was particularly successful in making the mold synthesize new types of penicillin by feeding precursors of different structure. The steps of fermentation, recovery and purification and packaging quickly yielded to the cooperative efforts of the chemical scientists and engineers working on pilot production of penicillin. Meanwhile, clinical studies in the military and civilian sectors were confirming the therapeutic promise of penicillin. The increasingly obvious value of penicillin in the war effort led the War Production Board (WPB) in 1943 to take responsibility for increased production of the drug. One of the major goals was to have an adequate supply of the drug on hand for the proposed D-Day invasion of Europe. By 1949, the annual production of penicillin in the United States was 133,229 billion units, and the price had dropped from twenty dollars per 100,000 units in 1943 to less than ten cents. In Britain, Chain and Abraham continued to work on the structure of the penicillin molecule, aided by the X-ray crystallographic work of Dorothy Hodgkin, also at Oxford.
The co-operative efforts of American chemists, chemical engineers, microbiologists, mycologists, government agencies, and chemical and pharmaceutical manufacturers were equal to the challenge posed by Howard Florey and Norman Heatley in 1941. The American Chemical Society and Royal Society of Chemistry designated the Discovery and Development of Penicillin an International Historic Chemical Landmark on November 19, 1999, at the Alexander Fleming Laboratory Museum in London, UK.
Building on its experience with fermentation techniques first implemented twenty years earlier to manufacture citric acid, Pfizer succeeded in producing large quantities of penicillin using deep-tank fermentation.
Learn more about the Development of Deep-tank Fermentation National Historic Chemical Landmark.
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The discovery of penicillin and the initial recognition of its therapeutic potential occurred in the United Kingdom, but, due to World War II, the United States played the major role in developing large-scale production of the drug, thus making a life-saving substance in limited supply into a widely available medicine. Before its introduction there was no effective treatment for infections such as pneumonia, gonorrhea or rheumatic fever. This phenomenon has long been known; it may explain why the ancient Egyptians had the practice of applying a poultice of moldy bread to infected wounds. He then set his assistants, Stuart Craddock and Frederick Ridley, the difficult task of isolating pure penicillin from the mold juice. Their work on the purification and chemistry of penicillin began in earnest in 1939, just when wartime conditions were beginning to make research especially difficult. Edward Abraham, another biochemist who was employed to help step up production, then used the newly discovered technique of alumina column chromatography to remove impurities from the penicillin prior to clinical trials. Then, on February 12, 1941, a 43-year old policeman, Albert Alexander, became the first recipient of the Oxford penicillin. A number of British companies, including Glaxo (now GlaxoSmithKline) and Kemball Bishop, a London firm later bought by Pfizer, took up the challenge. Florey recognized that large-scale production of penicillin was probably out of the question in Britain, where the chemical industry was fully absorbed in the war effort.

They were referred to Robert Thom of the Department of Agriculture, a foremost mycologist and authority on the Penicillium mold, and eventually to the Department's Northern Regional Research Laboratory (NRRL) in Peoria, Illinois, because of the expertise of its Fermentation Division.
It was agreed that Heatley would remain in Peoria to share his expertise with his American colleagues.
In submerged culture fermentation, the mold is grown in large tanks in a constantly agitated and aerated mixture, rather than just on the surface of the medium. Ironically, the most productive strain came from a moldy cantaloupe from a Peoria fruit market. Although Florey was disappointed in the immediate results of his trip, three of the companies (Merck, Squibb and Lilly) had actually conducted some penicillin research before Florey's arrival and Pfizer seemed on the verge of investigating the drug as well.
More importantly, Richards was chair of the Committee on Medical Research (CMR) of the Office of Scientific Research and Development (OSRD).
As the scale of production increased, the scientists at Merck, Pfizer, Squibb and other companies faced new engineering challenges. When corn steep liquor was used as the culture medium, bubbling sterile air through the mixture caused severe foaming. Once the fermentation was complete, recovery was also difficult; as much as two-thirds of the penicillin present could be lost during purification because of its instability and heat sensitivity. On March 1, 1944, Pfizer opened the first commercial plant for large-scale production of penicillin by submerged culture in Brooklyn, New York. The drug was shown to be effective in the treatment of a wide variety of infections, including streptococcal, staphylococcal and gonococcal infections.
The WPB investigated more than 175 companies before selecting 21 to participate in a penicillin program under the direction of Albert Elder; in addition to Lederle, Merck, Pfizer and Squibb, Abbott Laboratories (which had also been among the major producers of clinical supplies of penicillin to mid-1943) was one of the first companies to begin large-scale production. Feelings of wartime patriotism greatly stimulated work on penicillin in the United Kingdom and the United States. Chester Keefer of Boston, Chairman of the National Research Council's Committee on Chemotherapy, had the unenviable task of rationing supplies of the drug for civilian use. Production of the drug in the United States jumped from 21 billion units in 1943, to 1,663 billion units in 1944, to more than 6.8 trillion units in 1945, and manufacturing techniques had changed in scale and sophistication from one-liter flasks with less than 1% yield to 10,000-gallon tanks at 80-90% yield. Most British companies moved over to the deep tank fermentation production of penicillin, pioneered in the United States, after the end of the war to meet civilian needs.
The unique feature of the structure, which was finally established in 1945, is the four-membered highly labile beta-lactam ring, fused to a thiazolidine ring.
As Florey observed in 1949, "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. Hospitals were full of people with blood poisoning contracted from a cut or a scratch, and doctors could do little for them but wait and hope. But it was not until 1928 that penicillin, the first true antibiotic, was discovered by Alexander Fleming, Professor of Bacteriology at St. It proved to be very unstable, and they were only able to prepare solutions of crude material to work with.
To carry out a program of animal experiments and clinical trials the team needed to process up to 500 liters a week of mold filtrate. He had scratched the side of his mouth while pruning roses, and had developed a life-threatening infection with huge abscesses affecting his eyes, face, and lungs. With the support of the Rockefeller Foundation, Florey and his colleague Norman Heatley traveled to the United States in the summer of 1941 to see if they could interest the American pharmaceutical industry in the effort to produce penicillin on a large scale. This contact proved to be crucial to the success of the project, as the NRRL was a key contributor of innovations that made large-scale production of penicillin possible.
Within a few weeks, Andrew Moyer found that he could significantly increase the yield of penicillin by substituting lactose for the sucrose used by the Oxford team in their culture medium. Florey's Penicillium culture, however, produced only traces of penicillin when grown in submerged culture.
A more productive mutant of the so-called cantaloupe strain was produced with the use of X-rays at the Carnegie Institution. At this time, however, the promise of penicillin was still based on only limited clinical trials.
The OSRD had been created in June, 1941, to assure that adequate attention was given to research on scientific and medical problems relating to national defense.
It was agreed that although the companies would pursue their research activities independently, they would keep the CMR informed of developments, and the Committee could make the information more widely available (with the permission of the company involved) if that were deemed in the public interest. Merck's pilot plant continued to produce several hundred liters of penicillin culture per week using both flasks and tray, and in December, Heatley joined the Merck research staff for several months, where he introduced the Oxford cup plate method of penicillin assay, which soon became a standard method industry-wide. Squibb solved this problem by introducing glyceryl monoricinolate as an anti-foaming agent. The United States Army established the value of penicillin in the treatment of surgical and wound infections. These firms received top priority on construction materials and other supplies necessary to meet the production goals. Keefer had to restrict the use of the drug to cases where other methods of treatment had failed.
The American government was eventually able to remove all restrictions on its availability, and as of March 15, 1945, penicillin was distributed through the usual channels and was available to the consumer in his or her corner pharmacy.
In the United Kingdom, penicillin first went on sale to the general public, as a prescription only drug, on June 1, 1946. In the same year Alexander Fleming, Howard Florey, and Ernst Chain were awarded the Nobel Prize for their penicillin research. This discovery led to the introduction of antibiotics that greatly reduced the number of deaths from infection. Ask your doctor about using a non-hormone method of birth control (such as a condom, diaphragm, spermicide) to prevent pregnancy while using procaine penicillin. The zone immediately around the mold—later identified as a rare strain of Penicillium notatum—was clear, as if the mold had secreted something that inhibited bacterial growth.

Fleming published his findings in the British Journal of Experimental Pathology in June 1929, with only a passing reference to penicillin's potential therapeutic benefits. They began growing it in a strange array of culture vessels such as baths, bedpans, milk churns and food tins. Shortly thereafter, Moyer made the even more important discovery that the addition of corn-steep liquor to the fermentation medium produced a ten-fold increase in yield. Under the direction of Kenneth Raper, staff at the NRRL screened various Penicillium strains and found one that produced acceptable yields of penicillin in submerged culture. When this strain was exposed to ultraviolet radiation at the University of Wisconsin, its productivity was increased still further.
Richards had great respect for Florey and trusted his judgment about the potential value of penicillin. By March 1942 enough penicillin had been produced under OSRD auspices to treat the first patient (Mrs.
Submerged fermentation also required the design of new cooling systems for the vats and new mixing technology to stir the penicillin mash efficiently.
Methods of freeze-drying under vacuum eventually gave the best results in purifying the penicillin to a stable, sterile, and usable final form.
Clinical studies also demonstrated its effectiveness against syphilis, and by 1944, it was the primary treatment for this disease in the armed forces of Britain and the United States. Part of his job was also to collect detailed clinical information about the use of the drug so that a fuller understanding of its potential and limitations could be developed. At this stage it looked as if its main application would be in isolating penicillin-insensitive bacteria from penicillin-sensitive bacteria in a mixed culture. Later, a customized fermentation vessel was designed for ease of removing and, to save space, renewing the broth beneath the surface of the mold. Corn-steep liquor was a by-product of the corn wetmilling process, and the NRRL, in an attempt to find a use for it, tried it in essentially all of its fermentation work. He approached the four drug firms that Florey indicated had shown some interest in the drug (Merck, Squibb, Lilly and Pfizer) and informed them that they would be serving the national interest if they undertook penicillin production and that there might be support from the federal government. This at least was of practical benefit to bacteriologists, and kept interest in penicillin going. Better results followed with other patients though and soon there were plans to make penicillin available for British troops on the battlefield.
Later, the Peoria laboratory increased the yield of penicillin still further by the addition of penicillin precursors, such as phenylacetic acid, to the fermentation medium.
Others, including Harold Raistrick, Professor of Biochemistry at the London School of Hygiene and Tropical Medicine, tried to purify penicillin but failed. The next CMR penicillin conference, held in New York in December, ten days after Pearl Harbor and U.S. 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.
Abraham, successfully took penicillin from the laboratory to the clinic as a medical treatment in 1941. At this meeting, which was attended by the heads of Merck, Squibb, Pfizer and Lederle, as well as the company research directors, Robert Coghill's report on the success at the NRRL with corn steep liquor was encouraging to the industry leaders present.
Hormonal forms of contraception (such as birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.
Do not use this medication without telling your doctor if you are breast-feeding a baby.How should I use procaine penicillin?Procaine penicillin is given as an injection into a muscle. The discovery and development of penicillin was a milestone in twentieth century pharmaceutical chemistry.
Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it).
Keep this container out of the reach of children and pets.This medication can cause you to have unusual results with certain lab tests, including tests to check for glucose (sugar) in the urine.
Do not use the mixed medication if it has changed colors or has any particles in it.What happens if I miss a dose?Use the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up the missed dose.What happens if I overdose?Seek emergency medical attention if you think you have used too much of this medicine.
Overdose symptoms may include mood changes, agitation, confusion, and seizure (convulsions).What should I avoid while using procaine penicillin?Antibiotic medicines can cause diarrhea, which may be a sign of a new infection.
If you have diarrhea that is watery or has blood in it, stop using this medication and call your doctor. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides.
The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.Copyright 1996-2006 Cerner Multum, Inc.

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