When was penicillin discovered?
Alvin Ingram
During World War II, Bushnell Hospital treated approximately 13,000 military patients with various illnesses and injuries, and in 1944, it housed 3,286 GI–patients. The U.S. Army designated Bushnell Hospital as the military’s first center for the study of penicillin’s possible use. On April 1, 1943, the first shipment of penicillin arrived at Bushnell, and during the War, it administered penicillin more than any other institution in the United States. In addition to administering some of the first doses of penicillin, Ingram promoted its use to the surrounding Brigham community. In speech by then-Captain Alvin Ingram to the Rotary Club of Brigham City, he explained how penicillin was discovered in 1928 by Alexander Fleming, and extolled recent successes of administering the drug at nearby Bushnell Hospital. According to historian Richard Polenberg, “[w]artime advances in medicine, particularly in the production of penicillin (which first became generally available for civilian use in the spring of 1944) saved countless [military and civilian] lives.
Norman Heatley
On returning home, he realised that in haste and darkness, he had put his underpants on back to front, and noted this in his diary too, adding "It really looks as if penicillin may be of practical importance." In order to conduct tests on human patients, even more of the drug had to be produced, and again it was Heatley who realised that the most effective vessel for this purpose was something like the porcelain bedpans in use at the Radcliffe Infirmary. These were in short supply because the ongoing World War II, so Heatley designed a modified version which was manufactured in the Potteries. With the help of these, the Oxford laboratory became the first penicillin factory, and subsequent tests on humans proved the efficacy of the new treatment. Even so, it was very difficult to produce enough for sustained treatment.
Howard Florey
Howard Walter Florey, Baron Florey, (24 September 189821 February 1968) was an Australian pharmacologist and pathologist who shared the Nobel Prize in Physiology or Medicine in 1945 with Sir Ernst Chain and Sir Alexander Fleming for his role in the development of penicillin.
Brefeldin A
The compound gets its name from a species of anamorph fungus of the "Penicillium" genus known as "Eupenicillium brefeldianum", though it is found in a variety of species that span several genera. It was first isolated from "Penicillium decumbens" in 1958 by V.L. Singleton who initially called it Decumbin. It was later identified as a metabolite by H.P. Siggs who then went on to identify the chemical structure of the compound in 1971. Since then several successful total synthesis methods have been described. Interest in researching brefeldin A was initially lacking due to poor antiviral activity. However, upon discovery of its mechanism involving disruption of protein transport by Takatsuki and Tamura in 1985 and the cytotoxic effects observed in certain cancer cell lines, research efforts were revitalized. It is currently used solely in research mainly as an assay tool for studying membrane traffic and vesicle transport dynamics between the endoplasmic reticulum and Golgi apparatus.
Medical microbiology
In 1929 Alexander Fleming developed the most commonly used antibiotic substance both at the time and now: penicillin.
Penicillium chrysogenum
Penicillin was discovered in 1928 when Alexander Fleming's lab assistant accidentally left a window open overnight and mold spores covered his "Staphylococcus" bacterial specimens in a Petri dish. At first, Fleming was very irritated at the contamination, but as he was about to throw the specimens away, he noticed something interesting. He looked under the microscope at the bacteria surrounding the blue-green mould and noticed that many were dead or dying. This later turned out to have been due to the mould's prevention of the bacteria from making new cell walls and reproducing. He identified the mold as "Penicillium notatum", which releases the antibiotic penicillin G into the medium (his identification has been subsequently shown to be incorrect: the fungal species was actually the related " P. rubens"). After this, he did some testing on humans and animals and discovered that not only did it kill bacteria, but it was also suitable for use as a medication in humans and animals. However, the discovery did not attract much attention until the 1940s, when Howard Florey, Norman Heatley, and Ernst Chain developed methods for mass production and application in humans, incited by the urgent war-time need for antibacterial agents. The work of Andrew J. Moyer was important in these early developments.
Charles Thom
In 1929, a year after discovering penicillin, Alexander Fleming published a well-known paper in which he identified the mold "Penicillium rubrum" as the one responsible for creating the drug. Harold Raistrick succeeded in growing the organism on a simple culture medium, but could not isolate the penicillin produced by the mold when grown this way. With Thom's assistance, they correctly identified the organism as "Penicillium notatum" and, in 1941, developed a method to scale up production at the Department of Agriculture's Northern Regional Research Laboratory in Peoria, Illinois, which ultimately resulted in an inexpensive supply of the drug.
Thom held his job with the Bureau of Chemistry until 1927, when the position was abolished. He was then appointed Principal Mycologist of the Division of Soil Microbiology for the newly created Bureau of Chemistry and Soils. In a few years, Thom became known as an authority on soil microbiology, and was often invited to present papers at national and international meetings. In one of Thom's important contributions to the field, he led the research group responsible for advances that enabled the control of cotton root rot, which at the time was a major problem in the southwestern United States. In collaboration with his protégé Kenneth Raper, they published the "Manual of Penicillin" in 1940. Thom formally retired in 1942, although he remained active as a consultant and guest speaker until shortly before his death.
Mycotoxicology
Patulin: Patulin, 4-hydroxy-4H-furo[3,2c]pyran-2(6H)-one, is produced by many different molds but was first isolated as an antimicrobial active principle during the 1940s from Penicillium patulum (later called Penicillium urticae, now Penicillium griseofulvum). The same metabolite was also isolated from other species and given the names clavacin, claviformin, expansin, mycoin c, and penicidin. A number of early studies were directed towards harnessing its antibiotic activity. For example, it was tested as both a nose and throat spray for treating the common cold and as an ointment for treating fungal skin infections However, during the 1950s and 1960s, it became apparent that, in addition to its antibacterial, antiviral, and antiprotozoal activity, patulin was toxic to both plants and animals, precluding its clinical use as an antibiotic. During the 1960s, patulin was reclassified as a mycotoxin.
Gladys Lounsbury Hobby
Hobby is recognized for her work in creating a form of penicillin that was effective on human hosts. In 1940, Hobby and her colleagues, Dr. Karl Meyer and Dr. Martin Henry Dawson, wrote to Howard Florey and Ernst Chain to procure a sample of penicillin. They naively decided to make some penicillin and soon became experts in the fermentation process, and began refining it into a drug. Hobby, Meyer, and Dawson performed the first tests of penicillin on humans in 1940 and 1941, before presenting at the American Society for Clinical Investigation. They discovered that penicillin was a powerful germ-killer that reduced the severity of infectious diseases and made procedures such as organ transplantation and open-heart surgery possible. Their findings received media coverage, which helped attract funding from the United States Government to mass-produce penicillin during World War II, saving the lives of many soldiers.
Medicinal fungi
Alexander Fleming led the way to the beta-lactam antibiotics with the "Penicillium" mold and penicillin. Subsequent discoveries included alamethicin, aphidicolin, brefeldin A, Cephalosporin, cerulenin, citromycin, eupenifeldin, fumagillin, fusafungine, fusidic acid, itaconic acid, MT81, nigrosporin B, usnic acid, verrucarin A, vermiculine and many others.
Radcliffe Infirmary
A number of pioneering moments in medical history occurred at the hospital. Penicillin was first tested on patients on 27 January 1941 and the Nuffield Laboratory of Ophthalmology was founded on the site in 1942.
Paracetamol
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886. But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives. Harmon Northrop Morse had already synthesized paracetamol at Johns Hopkins University via the reduction of "p"-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company. Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes a barbiturate.
Meningeal syphilis
The most popular treatment forms for any type of syphilis uses penicillin, which has been an effective treatment used since the 1940s. 
Other forms also include Benzathine penicillin, which is usually used for primary and secondary syphilis (it has no resistance to penicillin however). Benzathine penicillin is used for long acting form, and if conditions worsen, penicillin G is used for late syphilis.
History of penicillin
In 17th-century Poland, wet bread was mixed with spider webs (which often contained fungal spores) to treat wounds. The technique was mentioned by Henryk Sienkiewicz in his 1884 book "With Fire and Sword". In England in 1640, the idea of using mold as a form of medical treatment was recorded by apothecaries such as John Parkinson, King's Herbarian, who advocated the use of mold in his book on pharmacology.
Nobel Prize controversies
The 1945 prize was awarded to Ernst Boris Chain, Howard Florey and Alexander Fleming "for the discovery of penicillin and its curative effect in various infectious diseases". Fleming accidentally stumbled upon the then-unidentified fungal mold. However, some critics pointed out that Fleming did not in fact discover penicillin, that it was technically a rediscovery; decades before Fleming, Sir John Scott Burdon-Sanderson, William Roberts (physician), John Tyndall and Ernest Duchesne had already done studies and research on its useful properties and medicinal characteristics. Moreover, according to Fleming himself, the first known reference to penicillin was from Psalm 51: "Purge me with hyssop and I shall be clean". Meanwhile, he had learned from mycologist Charles Thom (the same who helped Fleming establish the identity of the mysterious fungal mold) that "Penicillium notatum" was first recognized by Per Richard Westling, a Swedish pharmacist, from a specimen of decayed hyssop. In this award, as it had been pointed out, several deserving contemporaneous contributors had been left out of the Prize altogether.
Alexander Fleming
Fleming's discovery of penicillin changed the world of modern medicine by introducing the age of useful antibiotics; penicillin has saved, and is still saving, millions of people around the world.
Meningitis
The first report of bacterial infection underlying meningitis was by the Austrian bacteriologist Anton Weichselbaum, who in 1887 described the "meningococcus". Mortality from meningitis was very high (over 90%) in early reports. In 1906, antiserum was produced in horses; this was developed further by the American scientist Simon Flexner and markedly decreased mortality from meningococcal disease. In 1944, penicillin was first reported to be effective in meningitis. The introduction in the late 20th century of "Haemophilus" vaccines led to a marked fall in cases of meningitis associated with this pathogen, and in 2002, evidence emerged that treatment with steroids could improve the prognosis of bacterial meningitis. World Meningitis Day is celebrated on 24 April each year.
Penicillin (counter-artillery system)
The Penicillin or 1B75 Penicillin is an acoustic-thermal artillery reconnaissance system developed by the Ruselectronics for the Russian Armed Forces. The system is to detect and locate enemy's artillery, mortars, MLRS, anti-aircraft or tactical missiles firing positions via seismic and acoustic sensors, without emitting any radio waves. It detects enemy fire within 5 seconds, in 25 km wide area. It began state trials in 2017 and is expected to enter combat duty in 2020.
John C. Sheehan
For three decades after the discovery of natural penicillin by Sir Alexander Fleming, the source of the antibiotic hardly changed. Scientists made the drug by natural fermentation of Penicillium mold. However, during World War II, the United States government undertook a massive effort to determine the chemical structure of penicillin and to chemically synthesize it in large quantities. The scale of this project was compared to the development of the atomic bomb. This stemmed from the dire need for the antibiotic to treat soldiers on the battlefield. More than a thousand chemists working at thirty-nine laboratories were involved in the project. Despite the huge investment by the government, none proved to be successful in solving this elusive problem.
History of penicillin
Dorothy Hodgkin determined the correct chemical structure of penicillin using X-ray crystallography at Oxford in 1945. In Kundl, Tyrol, Austria, in 1952, Hans Margreiter and Ernst Brandl of Biochemie (now Sandoz) developed the first acid-stable penicillin for oral administration, Penicillin V. American chemist John C. Sheehan of the Massachusetts Institute of Technology (MIT) subsequently completed the first chemical synthesis of penicillin in 1957. The second-generation semi-synthetic β-lactam antibiotic methicillin, designed to counter first-generation-resistant penicillinases, was introduced in the United Kingdom in 1959. Methicillin-resistant forms of "Staphylococcus aureus" likely already existed at the time.
Penicillin
Once Fleming made his discovery he grew a pure culture and discovered it was a "Penicillium" mould, now known as "Penicillium chrysogenum". Fleming coined the term "penicillin" to describe the filtrate of a broth culture of the "Penicillium" mould. Fleming asked C. J. La Touche to help identify the mould, which he incorrectly identified as "Penicillium rubrum" (later corrected by Charles Thom). He expressed initial optimism that penicillin would be a useful disinfectant, because of its high potency and minimal toxicity in comparison to antiseptics of the day, and noted its laboratory value in the isolation of "Bacillus influenzae" (now called "Haemophilus influenzae").
Clodomiro Picado Twight
Clodomiro Picado Twight (April 17, 1887 - May 16, 1944), also known as "Clorito Picado", was a Costa Rican scientist, born in Nicaragua, who was recognized for his research and discoveries. He was a pioneer in the researching of snakes and serpent venoms; his internationally recognized achievement is the development of various antivenins. His work on molds was a precursor to the formal discovery of penicillin. His work resulted in compounds which he used to treat patients at least one year before the re-discovery of penicillin by Alexander Fleming. He wrote over 115 works, mainly books and monographs.
Citrinin
Citrinin was one of the many mycotoxins which were discovered by H. Raistrick and A.C. Hetherington in the 1930s. In 1941 H. Raistrick and G. Smith identified citrinin to have a broad antibacterial activity. After this discovery the interest in citrinin rose. However, in 1946 A.M. Ambrose and F. DeEds demonstrated that citrinin was toxic in mammalians. Because of the toxicity, the interest in citrinin decreased, but there still was a lot of research. In 1948 the chemical structure was solved by W.B. Whalley and coworkers. Citrinin is a natural compound and it was first isolated from "Penicillium citrinum", but it is also produced by other "Penicillium" species, the "Monascus" species and the "Aspergillus" species, which are all fungi. During the 1950s W.B. Whalley and A.J. Birch and others identified citrinin as a polyketide and investigated its biosynthesis using radioisotopes. During the 1980s and 1990s J. Staunton, U. Sankawa and others also investigated its biosynthesis using stable isotopes and NMR. During the mid-2000s the gene cluster for citrinin was discovered by T. Nihira and coworkers.
Ernst Chain
Sir Ernst Boris Chain, FRS (19 June 1906 – 12 August 1979) was a German-born British biochemist, and a 1945 co-recipient of the Nobel Prize for Physiology or Medicine for his work on penicillin.
Ampicillin
Ampicillin has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci. Ampicillin (originally branded as "Penbritin") also demonstrated activity against Gram-negative organisms such as "H. influenzae", coliforms, and "Proteus" spp.
Sir Alexander Fleming College
Fleming is named after Sir Alexander Fleming, the man who discovered penicillin.
Infection
Alexander Fleming discovered the world's first antibiotic, Penicillin, which Florey and Chain then developed.
Ethel Léontine Gabain
Gabain's WAAC commissions allowed her to explore her interest in the innovative medical techniques which were being developed during the war. In 1944, as well as depicting Sir Alexander Fleming working in the laboratory where he had discovered penicillin, Gabain also recorded, in "A Child Bomb-Victim Receiving Penicillin Treatment", a young girl being treated with the drug. She recorded pioneering treatments of burns victims, including the introduction of a new continuous irrigation method.
Antibiotic misuse
Antibiotics have been around since 1928 when penicillin was discovered by Alexander Fleming. In the 1980s, antibiotics that were determined medically important for treatment of animals could be approved under veterinary oversight. In 1996, the National Antimicrobial Resistance Monitoring System (NARMS) was established. Starting in 2010, publications regarding antimicrobial drugs in food become an annual report. Starting in 2012, there was publicly solicited input on how data is to be collected and reported for matters relating to the use of antimicrobials for food-producing animals. Resulting from this, the FDA revised its sampling structure within NARMS with the goal of obtaining more representative livestock data for the key organisms under surveillance. “NARMS partners at CDC and USDA have published over 150 peer-reviewed research articles examining the nature and magnitude of antimicrobial resistance hazards associated with antibiotic use in food-producing animals.” In 2014, the FDA began working with the United States Department of Agriculture (USDA) and the Centers of Disease Control and Prevention (CDC) to explore additional mechanisms to obtain data that is representative of antibiotic use in food-producing animals. In 2015, the FDA issues the Veterinary Feed Directive (VFD) final rule. Under this rule veterinarians must authorize the use of antimicrobials within feed for the animals they serve.
Tuskegee syphilis experiment
Medical ethics considerations were limited from the start and rapidly deteriorated. The PHS asked black Tuskegee Institute physicians to participate in the study by offering funds, employment, and interns to encourage the ongoing participation of the patients. Additionally, the study intentionally employed Eunice Rivers, a black nurse from Macon County, to be primary source of contact and build personal, trusting relationships with patients to promote their participation. To ensure that the men would show up for the possibly dangerous, painful, diagnostic, and non-therapeutic spinal taps, the doctors sent the 400 patients a misleading letter titled "Last Chance for Special Free Treatment". The study also required all participants to undergo an autopsy after death in order to receive funeral benefits. After penicillin was discovered as a cure, researchers continued to deny such treatment to many study participants. Many patients were lied to and given placebo treatments so that researchers could observe the full, long-term progression of the fatal disease.
The Tuskegee Study published its first clinical data in 1934 and issued its first major report in 1936. This was prior to the discovery of penicillin as a safe and effective treatment for syphilis. The study was not secret since reports and data sets were published to the medical community throughout its duration.
Penicillium chrysogenum
The discovery of penicillin ushered in a new age of antibiotics derived from microorganisms. Penicillin is an antibiotic isolated from growing "Penicillium" mold in a fermenter. The mold is grown in a liquid culture containing sugar and other nutrients including a source of nitrogen. As the mold grows, it uses up the sugar and starts to make penicillin only after using up most of the nutrients for growth.
Phenoxymethylpenicillin
Phenoxymethylpenicillin, also known as penicillin V and penicillin VK, is an antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for the treatment of strep throat, otitis media, and cellulitis. It is also used to prevent rheumatic fever and to prevent infections following removal of the spleen. It is given by mouth.
Side effects include diarrhea, nausea, and allergic reactions including anaphylaxis. It is not recommended in those with a history of penicillin allergy. It is relatively safe for use during pregnancy. It is in the penicillin and beta lactam family of medications. It usually results in bacterial death.
Phenoxymethylpenicillin was first made in 1948. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$0.05–0.96 per day. In the United States a course of treatment costs less than $25.
Gladys Lounsbury Hobby
Gladys Lounsbury Hobby (November 19, 1910 – July 4, 1993), born in New York City, was an American microbiologist whose research played a key role in the development and understanding of antibiotics. Her work took penicillin from a laboratory experiment to a mass-produced drug during World War II.
History of penicillin
In Belgium in 1920, Andre Gratia and Sara Dath observed a fungal contamination in one of their "Staphylococcus aureus" cultures that was inhibiting the growth of the bacterium. They identified the fungus as a species of "Penicillium" and presented their observations as a paper, but it received little attention. An Institut Pasteur scientist, Costa Rican Clodomiro Picado Twight, similarly recorded the antibiotic effect of "Penicillium" in 1923.
Discovery and development of statins
In the 1970s the Japanese microbiologist Akira Endo first discovered natural products with a powerful inhibitory effect on HMGR in a fermentation broth of "Penicillium citrinum", during his search for antimicrobial agents. The first product was named compactin (ML236B or mevastatin). Animal trials showed very good inhibitory effect as in clinical trials, however in a long term toxicity study in dogs it resulted in toxic effects at higher doses and as a result was believed to be too toxic to be given to humans. In 1978, Alfred Alberts and colleagues at Merck Research Laboratories discovered a new natural product in a fermentation broth of "Aspergillus terreus", their product showed good HMGR inhibition and they named the product mevinolin, which later became known as lovastatin.
History of syphilis
One of the most infamous United States cases of questionable medical ethics in the 20th century was the Tuskegee syphilis study. The study took place in Tuskegee, Alabama, and was supported by the U.S. Public Health Service (PHS) in partnership with the Tuskegee Institute. The study began in 1932, when syphilis was a widespread problem and there was no safe and effective treatment. The study was designed to measure the progression of untreated syphilis. By 1947, penicillin had been shown to be an effective cure for early syphilis and was becoming widely used to treat the disease. Its use in later syphilis, however, was still unclear. Study directors continued the study and did not offer the participants treatment with penicillin. This is debated, and some have found that penicillin was given to many of the subjects.
Beecham Group
In 1959, Brockham Park became famous when Beecham scientists there discovered the penicillin nucleus, 6-APA (6-aminopenicillanic acid); This discovery allowed Beecham, working in tandem with Bristol-Myers, to synthesize of a number of new semisynthetic penicillins. Beecham marketed Broxil (phenethicillin), followed shortly by the more potent Celbenin (methicillin), which was active against "Staphylococcus aureus". The group continued to focus on pharmaceutical development, producing further semi-synthetic penicillins. However, when Penbritin (ampicillin) came on the market in 1961, Beecham's facilities were soon inadequate for the worldwide demand the drug generated. A complex at Worthing came on line in the early 1960s to produce phenethicillin, followed by the ability to produce 6-APA, the base for semisynthetic penicillins.
Multidrug tolerance
Recognition of antibiotic tolerance dates back to 1944 when Joseph Bigger, an Irish physician working in England, was experimenting with the recently discovered penicillin. Bigger used penicillin to lyse a suspension of bacteria and then inoculated culture medium with the penicillin-treated liquid. Colonies of bacteria were able to grow after antibiotic killing. The important observation that Bigger made was that this new population could again be killed by penicillin except for a small residual population. Hence the residual organisms were not antibiotic resistant mutants but rather a subpopulation of what he called ‘persisters’. The formation of persisters is now known to be a common phenomenon that can occur by the formation of persister cells prior to the antibiotic treatment or in response to a variety of antibiotics.
Biotechnology
Biotechnology has also led to the development of antibiotics. In 1928, Alexander Fleming discovered the mold "Penicillium". His work led to the purification of the antibiotic compound formed by the mold by Howard Florey, Ernst Boris Chain and Norman Heatley – to form what we today know as penicillin. In 1940, penicillin became available for medicinal use to treat bacterial infections in humans.
History of penicillin
The history of penicillin follows a number of observations and discoveries of apparent evidence of antibiotic activity in molds before the modern isolation of the chemical penicillin in 1928. There are anecdotes about ancient societies using molds to treat infections, and in the following centuries many people observed the inhibition of bacterial growth by various molds. However, it is unknown if the species involved were "Penicillium" species or if the antimicrobial substances produced were penicillin.
Antibiotic
In 1928, Sir Alexander Fleming postulated the existence of penicillin, a molecule produced by certain molds that kills or stops the growth of certain kinds of bacteria. Fleming was working on a culture of disease-causing bacteria when he noticed the spores of a green mold, "Penicillium chrysogenum", in one of his culture plates. He observed that the presence of the mold killed or prevented the growth of the bacteria. Fleming postulated that the mold must secrete an antibacterial substance, which he named penicillin in 1928. Fleming believed that its antibacterial properties could be exploited for chemotherapy. He initially characterized some of its biological properties, and attempted to use a crude preparation to treat some infections, but he was unable to pursue its further development without the aid of trained chemists.
Phage therapy
While knowledge was being accumulated regarding the biology of phages and how to use phage cocktails correctly, early uses of phage therapy were often unreliable. Since the early 20th century, research into the development of viable therapeutic antibiotics had also been underway, and by 1942 the antibiotic penicillin G had been successfully purified and saw use during the Second World War. The drug proved to be extraordinarily effective in the treatment of injured Allied soldiers whose wounds had become infected. By 1944, large-scale production of Penicillin had been made possible, and in 1945 it became publicly available in pharmacies. Due to the drug's success, it was marketed widely in the U.S. and Europe, leading Western scientists to mostly lose interest in further use and study of phage therapy for some time.
Nancy Atkinson
Atkinson's early work at the IMVS involved the development, production and administration of the BCG vaccine in Australia to combat tuberculosis, as encouraged by Darcy Cowan. Atkinson and her team at the institute were responsible for manufacturing the first batch of penicillin in Australia, after eighteen months of work produced enough of the antibiotic to cover a threepenny piece in 1943. She also regularly put out calls for samples of Australian flora such as the Geraldton wax and native fungi, which were then analysed to determine if they could be used to develop new anti-bacterial substances. In 1943, Atkinson developed penicidin, an antibiotic which was proposed to be used as an alterative to penicillin, however the drug was reclassified in the 1960s as a mycotoxin.
History of penicillin
Between 1941 and 1943, Moyer, Coghill and Raper at the USDA Northern Regional Research Laboratory (NRRL) in Peoria, Illinois, United States, developed methods for industrialized penicillin production and isolated higher-yielding strains of the "Penicillium" fungus. In December 1942, survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin. Simultaneous research by Jasper H. Kane and other Pfizer scientists in Brooklyn developed the practical, deep-tank fermentation method for production of large quantities of pharmaceutical-grade penicillin.
Vincenzo Tiberio
Vincenzo Tiberio (May 1, 1869 – January 7, 1915) was an Italian researcher and medical officer of the Medical Corps of the Italian Navy and physician at the University of Naples. During his medical studies at the Faculty of Medicine in Naples he noticed that when the walls of a well which supplied drinking water was cleaned off, the people who drank the well’s water complained of intestinal disorders. After further research he published a paper in 1895 on the antibacterial power of some extracts of mold, making him one of several researchers whose work on a mold/antibiotic connection anticipated the discovery of the drug penicillin by Alexander Fleming thirty-five years later (see: Penicillin - Discovery). At the time, his work was disregarded as coincidence and received no further study.
Penicillium
The genus was first described in the scientific literature by Johann Heinrich Friedrich Link in his 1809 work "Observationes in ordines plantarum naturales", writing "Penicillium. Thallus e floccis caespitosis septatis simplicibus aut ramosis fertilibus erectis apice penicillatis", where penicillatis referred to "pencil-like" (referring to a Camel's hair pencil brush. Link included three species—"P. candidum", "P. expansum", and "P. glaucum"—all of which produced a brush-like conidiophore (asexual fruiting structure). The common apple rot fungus "P. expansum" was selected as the type species.
Robert W. Holley
Holley was born in Urbana, Illinois, and graduated from Urbana High School in 1938. He went on to study chemistry at the University of Illinois at Urbana-Champaign, graduating in 1942 and commencing his PhD studies in organic chemistry at Cornell University. During World War II Holley spent two years working under Professor Vincent du Vigneaud at Cornell University Medical College, where he was involved in the first chemical synthesis of penicillin. Holley completed his PhD studies in 1947.
DSM (company)
During World War II researchers worked on penicillin. The code name Bacinol was used to keep the research secret from the Germans. The research was done at the company Nederlandsche Gist- en Spiritusfabriek, Dutch Yeast and Spirits Factory, later becoming DSM Sinochem Pharmaceuticals, in Delft.
Theodor Morell
After the 20 July 1944 assassination attempt against Hitler, Morell treated him with topical penicillin, which had only recently been introduced into testing by the U.S. Army. Where he acquired it is unknown, and Morell claimed complete ignorance of penicillin when he was interrogated by American intelligence officers after the war. When members of Hitler's inner circle were interviewed for the book "The Bunker," some claimed Morell owned a significant share in a company fraudulently marketing a product as penicillin.
Albert Alexander (police officer)
The ability of penicillin to slow or counteract bacterial infection had first been noticed by Sir Alexander Fleming in 1928. Florey, Ernst Boris Chain and Norman Heatley, at the Sir William Dunn School of Pathology, University of Oxford were working on the medical applications of penicillin, as produced by the mould "Penicillium notatum", and attempting to isolate quantities of penicillin from the mould large enough for a human trial.
Clan Fleming
According to the "Collins Scottish Clan and Family Encyclopedia", Alexander Fleming who discovered Penicillin is the most distinguished bearer of the name in recent times.
Penicillin
The term "penicillin" is often used generically to refer to benzylpenicillin (penicillin G, the original penicillin found in 1928), procaine benzylpenicillin (procaine penicillin), benzathine benzylpenicillin (benzathine penicillin), and phenoxymethylpenicillin (penicillin V). Procaine penicillin and benzathine penicillin have the same antibacterial activity as benzylpenicillin but act for a longer period of time. Phenoxymethylpenicillin is less active against gram-negative bacteria than benzylpenicillin. Benzylpenicillin, procaine penicillin and benzathine penicillin can only be given by intravenous or intramuscular injections, but phenoxymethylpenicillin can be given by mouth because of its acidic stability.
Lysozyme
The antibacterial property of hen egg white, due to the lysozyme it contains, was first observed by Laschtschenko in 1909, although it was not until 1922 that the name 'lysozyme' was coined, by Alexander Fleming, the second scientist to discover penicillin. But according to one publication, it was Fleming "who first clearly showed that an enzymic substance present in a wide variety of secretions is capable of rapidly lysing (ie.., dissolving) certain bacteria, particularly a yellow "coccus" that he studied". Fleming first observed the antibacterial action of lysozyme when he treated bacterial cultures with nasal mucus from a patient suffering from a head cold.
Penicillic acid
Penicillic acid is a mycotoxin that is produced by "Aspergillus flavus" and "Penicillium roqueforti" mold. It is also the major product of acid degradation of penicillin. Its first practical synthesis was reported in 1947 by Ralph Raphael, who had worked on penicillin during World War II.
Antimicrobial resistance
In 1952 it was shown that penicillin-resistant bacteria existed before penicillin treatment; and also preexistent bacterial resistance to streptomycin. In 1962, the presence of penicillinase was detected in dormant endospores of "Bacillus licheniformis", revived from dried soil on the roots of plants, preserved since 1689 in the British Museum. Six strains of "Clostridium", found in the bowels of William Braine and John Hartnell (members of the Franklin Expedition) showed resistance to cefoxitin and clindamycin.
History of penicillin
The modern history of penicillin research begins in earnest in the 1870s, in the United Kingdom. Sir John Scott Burdon-Sanderson, who started out at St. Mary's Hospital (1852–1858) and later worked there as a lecturer (1854–1862), observed that culture fluid covered with mold would produce no bacterial growth. Burdon-Sanderson's discovery prompted Joseph Lister, an English surgeon and the father of modern antisepsis, to discover in 1871 that urine samples contaminated with mold also did not permit the growth of bacteria. Lister also described the antibacterial action on human tissue of a species of mold he called "Penicillium glaucum". A nurse at King's College Hospital whose wounds did not respond to any traditional antiseptic was then given another substance that cured her, and Lister's registrar informed her that it was called Penicillium. In 1874, the Welsh physician William Roberts, who later coined the term "enzyme", observed that bacterial contamination is generally absent in laboratory cultures of "Penicillium glaucum". John Tyndall followed up on Burdon-Sanderson's work and demonstrated to the Royal Society in 1875 the antibacterial action of the "Penicillium" fungus. By this time, "Bacillus anthracis" had been shown to cause anthrax, the first demonstration that a specific bacterium caused a specific disease.
History of penicillin
Many later scientists were involved in the stabilization and mass production of penicillin and in the search for more productive strains of "Penicillium". Important contributors include Ernst Chain, Howard Florey, Norman Heatley, and Edward Abraham. Shortly after the discovery of penicillin, scientists found that some disease-causing pathogens display antibiotic resistance to penicillin. Research that aims to develop more effective strains and to study the causes and mechanisms of antibiotic resistance continues today.
Jenapharm
During the occupation of Germany at the end of World War II, all pharmaceutical companies from Nazi Germany were located in the Western-occupied areas. Jena, which fell in the Soviet-controlled area, had an Institute for Microbiology — the Schott-Zeiss Institute — that had the prerequisites for small scale pharmaceutical production. Although the institute had been founded in 1944 with just 9 employees, Hans Knöll produced there the first batch of penicillin made in Germany, right before the end of the war. In 1948 the institute was producing 10 billion IUs of penicillin per month.
Amoxicillin
Amoxicillin was one of several semisynthetic derivatives of 6-aminopenicillanic acid (6-APA) developed at Beecham, England in the 1960s. It became available in 1972 and was the second aminopenicillin to reach the market (after ampicillin in 1961). Co-amoxiclav became available in 1981.
History of penicillin
At Oxford, Howard Walter Florey organized a large and very skilled biochemical research team, notable among them Ernst Boris Chain and Norman Heatley, to undertake clinical trials and produce a stable penicillin in quantity. In 1940, Chain and Edward Abraham reported the first indication of antibiotic resistance to penicillin, an "E. coli" strain that produced the penicillinase enzyme, which was capable of breaking down penicillin and completely negating its antibacterial effect.
General paresis of the insane
GPI was originally considered to be a type of madness due to a dissolute character, when first identified in the 18th century. Then the cause-effect connection with syphilis was discovered in the late 1880s. Subsequently, the discovery of penicillin and its use in the treatment of syphilis rendered paresis curable and avoidable. Prior to these events, paresis was inevitably fatal unless another terminating illness intervened, and it accounted for as much as 25% of the primary diagnoses for residents in public psychiatric hospitals.
Penicillium sanguifluum
Penicillium sanguifluum is a species of fungus in the genus "Penicillium". It was first described scientifically in 1912 by Norwegian mycologist Olav Johan Sopp, who called it "Citromyces sanguifluus". Philibert Biourge transferred it to the genus "Penicillium" in 1923. "P. sanguifluum" is classified in the section "Citrina" of "Penicillium".
Clodomiro Picado Twight
In March 2000, doctors from the San Juan de Dios Hospital in San José, the capital of Costa Rica, published his manuscripts, in which he explains his experiences between 1915 and 1927 with the inhibiting action of fungi of the "Penicillium" genus in the growth of "Staphylococci" and "Streptococci" (bacteria that cause a series of infections). In 1927, he demonstrated the inhibitory action of the bacillus genus "Penicillium" on the proliferation of the bacteria "Staphylococcus" and "Streptococcus". Although, the discovery of penicillin has been attributed to Alexander Fleming, Picados' old laboratory notebooks from 1923 show records of the antibiosis of "Penicillium sp".
Alexander Fleming
Fleming published his discovery in 1929, in the British "Journal of Experimental Pathology," but little attention was paid to his article. Fleming continued his investigations, but found that cultivating "Penicillium" was quite difficult, and that after having grown the mould, 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, but Fleming largely abandoned penicillin work, leaving Howard Florey and Ernst Boris Chain at the Radcliffe Infirmary in Oxford to take up research to mass-produce it, with funds from the U.S. and British governments. They started mass production after the bombing of Pearl Harbor. By D-Day in 1944, enough penicillin had been produced to treat all the wounded in the Allied forces.
Health in Norway
In the 1900s many vaccines were developed and the first antibiotic, penicillin, came about in the 1940s. These introductions were very powerful tools in preventing and treatment of childhood diseases.
A. D. Gardner
Arthur Duncan Gardner, FRCP, FRCS (28 March 1884 – 28 January 1977) was a member of the team of Oxford University scientists who developed penicillin and was Regius Professor of Medicine at Oxford from 1948 to 1954.
Penicillamine
John Walshe first described the use of penicillamine in Wilson's disease in 1956. He had discovered the compound in the urine of patients (including himself) who had taken penicillin, and experimentally confirmed that it increased urinary copper excretion by chelation. He had initial difficulty convincing several world experts of the time (Denny Brown and Cumings) of its efficacy, as they held that Wilson's disease was not primarily a problem of copper homeostasis but of amino acid metabolism, and that dimercaprol should be used as a chelator. Later studies confirmed both the copper-centered theory and the efficacy of -penicillamine. Walshe also pioneered other chelators in Wilson's such as triethylene tetramine dihydrochloride and tetrathiomolybdate.
Mold
Howard Florey, Ernst Chain, Norman Heatley, Edward Abraham, also all at Oxford, continued the work. They enhanced and developed the concentration technique by using organic solutions rather than water, and created the "Oxford Unit" to measure penicillin concentration within a solution. They managed to purify the solution, increasing its concentration by 45–50 times, but found that a higher concentration was possible. Experiments were conducted and the results published in 1941, though the quantities of Penicillin produced were not always high enough for the treatments required. As this was during the Second World War, Florey sought USA Government involvement. With research teams in the UK and some in the US, industrial-scale production of crystallized penicillin was developed during 1941–1944 by the USDA and by Pfizer.
Tuskegee University
From 1932 to 1972, Tuskegee Institute collaborated with the United States government in the Tuskegee syphilis experiment by which the effects of deliberately untreated syphilis were studied. These experiments have become infamous for misleading study participants by telling them that they were being treated for syphilis when in fact researchers were only monitoring the progression of the disease. Syphilis is a debilitating disease that can leave its victims with permanent neurological damage and horrifying scars (see granulomatous gummas). Penicillin was discovered in 1927 and it was being used to treat human disease by the early 1940s. In 1947 it had become the gold standard in treating syphilis and often only required one intramuscular dose to completely eliminate the disease. The researchers were well aware of this information and in order to continue their experiments, they chose to withhold the life-saving treatment. The researchers proceeded to actively deter study participants from obtaining penicillin from other physicians. The patients were told that they had "bad blood." This experiment was conducted by the U.S. Public Health Service in collaboration with the Tuskegee Institute. This was a direct violation of the Hippocratic Oath, however, not a single researcher, nor the Tuskegee University was legally punished.
Antimicrobial resistance
The discovery of penicillin in 1928 and other antibiotics in the 20th century proved to be a significant medical achievement, saving millions of lives and significantly reducing the burden of infectious diseases. The 1950s to 1970s represented the golden age of antibiotic discovery, where countless new classes of antibiotics were discovered to treat previously incurable diseases such as tuberculosis and syphilis. However, since that time the discovery of new classes of antibiotics has been almost nonexistent, and represents a situation that is especially problematic considering the resiliency of bacteria shown over time and the continued misuse and overuse of antibiotics in treatment.
Ernest Duchesne
Ernest Duchesne (30 May 1874 – 12 April 1912) was a French physician who noted that certain molds kill bacteria. He made this discovery 32 years before Alexander Fleming discovered the antibiotic properties of penicillin, a substance derived from those molds, but his research went unnoticed.
Peter Doyle (chemist)
Along with Ralph Batchelor, George Rolinson and John Nayler, he was part of the team at Betchworth that discovered and synthesised new penicillins. A Royal Society of Chemistry blue plaque now marks this discovery. Doyle retired in 1983.
History of biotechnology
The belief that the needs of an industrial society could be met by fermenting agricultural waste was an important ingredient of the "chemurgic movement." Fermentation-based processes generated products of ever-growing utility. In the 1940s, penicillin was the most dramatic. While it was discovered in England, it was produced industrially in the U.S. using a deep fermentation process originally developed in Peoria, Illinois. The enormous profits and the public expectations penicillin engendered caused a radical shift in the standing of the pharmaceutical industry. Doctors used the phrase "miracle drug", and the historian of its wartime use, David Adams, has suggested that to the public penicillin represented the perfect health that went together with the car and the dream house of wartime American advertising. Beginning in the 1950s, fermentation technology also became advanced enough to produce steroids on industrially significant scales. Of particular importance was the improved semisynthesis of cortisone which simplified the old 31 step synthesis to 11 steps. This advance was estimated to reduce the cost of the drug by 70%, making the medicine inexpensive and available. Today biotechnology still plays a central role in the production of these compounds and likely will for years to come.
Clevedon
The first large-scale production of penicillin took place in the town. In 1938 Howard Florey was working at Lincoln College, Oxford University with Ernst Boris Chain and Norman Heatley, when he read Alexander Fleming's paper discussing the antibacterial effects of "Penicillium notatum" mould. He made arrangements for this to be grown in deep culture tanks at the Medical Research Council's Antibiotic Research Station in Clevedon, enabling mass production of this mould for the injections of the forthcoming soldiers of World War II who suffered from infections.
Penicillin
Chemist John C. Sheehan at the Massachusetts Institute of Technology (MIT) completed the first chemical synthesis of penicillin in 1957. Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of peptides, as well as new protecting groups—groups that mask the reactivity of certain functional groups. Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehan's synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin. Attaching different groups to the 6-APA 'nucleus' of penicillin allowed the creation of new forms of penicillin.
Antibiotic
Ernst Chain, Howard Florey and Edward Abraham succeeded in purifying the first penicillin, penicillin G, in 1942, but it did not become widely available outside the Allied military before 1945. Later, Norman Heatley developed the back extraction technique for efficiently purifying penicillin in bulk. The chemical structure of penicillin was first proposed by Abraham in 1942 and then later confirmed by Dorothy Crowfoot Hodgkin in 1945. Purified penicillin displayed potent antibacterial activity against a wide range of bacteria and had low toxicity in humans. Furthermore, its activity was not inhibited by biological constituents such as pus, unlike the synthetic sulfonamides. (see below) The development of penicillin led to renewed interest in the search for antibiotic compounds with similar efficacy and safety. For their successful development of penicillin, which Fleming had accidentally discovered but could not develop himself, as a therapeutic drug, Chain and Florey shared the 1945 Nobel Prize in Medicine with Fleming.
Alexander Fleming
Sir Alexander Fleming (6 August 1881 – 11 March 1955) was a Scottish physician, microbiologist, and pharmacologist. His best-known discoveries are the enzyme lysozyme in 1923 and the world's first antibiotic substance benzylpenicillin (Penicillin G) from the mould "Penicillium notatum" in 1928, for which he shared the Nobel Prize in Physiology or Medicine in 1945 with Howard Florey and Ernst Boris Chain. He wrote many articles on bacteriology, immunology, and chemotherapy.
Peter D. Mitchell
He was appointed a research post in the Department of Biochemistry, Cambridge, in 1942, and was awarded a Ph.D. in early 1951 for work on the mode of action of penicillin.
Doxycycline
After penicillin revolutionized the treatment of bacterial infections in WWII, many chemical companies moved into the field of discovering antibiotics by bioprospecting. American Cyanamid was one of these, and in the late 1940s chemists there discovered chlortetracycline, the first member of the tetracycline class of antibiotics. Shortly thereafter, scientists at Pfizer discovered terramycin and it was brought to market. Both compounds, like penicillin, were natural products and it was commonly believed that nature had perfected them, and further chemical changes could only degrade their effectiveness. Scientists at Pfizer led by Lloyd Conover modified these compounds, which led to the invention of tetracycline itself, the first semi-synthetic antibiotic. Charlie Stephens' group at Pfizer worked on further analogs and created one with greatly improved stability and pharmacological efficacy: doxycycline. It was clinically developed in the early 1960s and approved by the FDA in 1967.
John C. Sheehan
After the efficient completion of RDX synthesis, John Sheehan had the experience of applying organic chemistry to real-life problems. Having struggled against pneumonia and mastoiditis in his earlier years, Sheehan was eager to start working on antibiotics. He wrote, "If my doctors had had a course of treatment as effective as that made possible by penicillin, I would probably not have lost that year." In 1941, he accepted a position at Merck & Co. in Rahway, New Jersey. He worked there until 1946 as a senior research chemist under the supervision of Dr. Max Tishler. Sheehan had good results for his work on many projects, including those on calcium pantothenate, streptomycin, and vitamin B6. However, he wanted to pursue the synthesis of penicillin, which was hard in an industrial setting driven by results given that many scientists of his time believed that it was impossible. John Sheehan's work attracted the attention of Arthur C. Cope, who was the head of the Department of Chemistry at the M.I.T. at the time. He decided to join the M.I.T. faculty as an assistant professor at a salary that was half of what he made at Merck. Within his first few years at M.I.T., John Sheehan was already recognized for his ingenuity in synthetic organic chemistry, especially for his new methods of synthesis of peptides, three new syntheses of β-lactams, first synthesis of the penicillin ring system, and his work on several other natural products.
Penicillin
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. This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillin's concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined. Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.
Norman Heatley
In December 1940, a 43-year-old police constable, Albert Alexander, was accidentally scratched by a rose thorn on his mouth, and was succumbing to septicaemia. Alexander was admitted to the Radcliffe Infirmary, where various conventional treatments all failed, and his case was brought to Florey and Heatley's attention. Having previously tried penicillin only on mice, Heatley was concerned about the side effects large doses of penicillin might have. A patient in a terminal condition with nothing to lose was needed as a human volunteer, and Constable Alexander met this requirement. On 12 February 1941, Alexander was given an intravenous infusion of 160 mg (200 units) of penicillin. Within 24 hours, Alexander's temperature had dropped, his appetite had returned and the infection had begun to subside. However, owing to the instability of penicillin and the wartime restrictions placed on Florey's laboratory, only a small quantity was available, and although Florey and colleagues extracted any remaining penicillin from Alexander's urine, they had run out by the fifth day and Alexander died a month later. Florey and his team thereafter decided to work only on sick children, who did not need such large doses of penicillin, until their methods of production improved.
Rachel Fuller Brown
Penicillin had been discovered in 1928, and in the years that followed, antibiotics were increasingly used to fight bacterial illness. However, one side effect was that these antibiotics allowed for a rapid growth of fungus, which could lead to sore mouths or upset stomachs. Other fungal diseases without cures including infections attacking the central nervous system, athlete’s foot, and ring worms were also a major problem during this time. However, fungal diseases were not well understood at this time, and there were no antifungal medications safe for human use. At this time, people knew of microorganisms called actinomycetes that lived in soil and were known to produce antibiotics, some of which killed fungus. However, these antibiotics also proved fatal in tests involving lab mice and thus could not be put into production.
Andrew J. Moyer
Andrew J. Moyer (November 30, 1899 – February 17, 1959) was an American microbiologist. He was a researcher at the USDA Northern Regional Research Laboratory in Peoria, Illinois. His group was responsible for the development of techniques for the mass production of penicillin. This led to the wide scale use of penicillin in World War II. Moyer was inducted into the National Inventors Hall of Fame in 1987. A scholarship fund was created in his name at the University of Maryland in 1977.
Mary Percy Jackson
The first time she used an antibiotic was after a colleague in Edmonton sent her a small vial containing crystals of penicillin for a Christmas gift. She wondered if this new drug was as good as everyone said it was, and whether it was safe. She decided she would give some of it to the next person who was so sick that she was sure that person would die, having no more she could do for that person. This proved to be a little native girl with pneumonia, whom Jackson believed would not live through the night. She mixed the penicillin and gave a small amount to the girl her every three hours until she was better. The child markedly improved with every hour after beginning the injections of penicillin, and went home completely well. Jackson, many years later, expressed her view with certainty that the child would have died that night without penicillin.
History of penicillin
In 1877, French biologists Louis Pasteur and Jules Francois Joubert observed that cultures of the anthrax bacilli, when contaminated with molds, could be successfully inhibited. Some references say that Pasteur identified the strain as "Penicillium notatum". However, Paul de Kruif's 1926 "Microbe Hunters" describes this incident as contamination by other bacteria rather than by mold. In 1887, Garré found similar results. In 1895, Vincenzo Tiberio, an Italian physician at the University of Naples, published research about a mold in a water well in Arzano that showed antibacterial action.
Oxacillin
Oxacillin, a derivative of methicillin, was first synthesized in the early 1960s as part of a research initiative led by Peter Doyle and John Naylor of Beecham, in consort with Bristol-Myers. Members of the isoxazolyl penicillin family, which includes cloxacillin, dicloxacillin, and oxacillin, were synthesized to counter the increasing prevalence of infections caused by penicillin-resistant "Staphylococcus aureus". While methicillin could only be administered via injection, the isoxazolyl penicillins, including oxacillin, could be given orally or by injection. Following the synthesis of cloxacillin and oxacillin, Beecham retained the right to commercially develop cloxacillin in the United Kingdom while Bristol-Myers was given the marketing rights for oxacillin in the United States.The following information provides the time period that a given strength of an oxacillin sodium product was produced and marketed by the companies listed below.
Arnold Demain
In early 1954, Demain and his wife Jody moved to Danville, Pennsylvania, where he worked as a research microbiologist for Merck Sharp & Dohme, studying the synthesis of penicillin. His work helped identify the amino acids that form the nucleus of penicillin, established the mechanisms that enable primary metabolites and carbon sources to regulate secondary metabolite synthesis, and demonstrated that penicillin was the product of synthesis and inactivation during fermentation. (He would later resume his penicillin research at the Massachusetts Institute of Technology.) In late 1955, Demain moved on to Merck's penicillin research laboratories in Rahway, New Jersey, where he “worked on fermentation microbiology, â-lactam antibiotics, flavor nucleotides, and microbial nutrition.”
Beta-lactamase
Penicillinase was the first β-lactamase to be identified. It was first isolated by Abraham and Chain in 1940 from Gram-negative "E. coli" even before penicillin entered clinical use, but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely. Penicillinase-resistant beta-lactams such as methicillin were developed, but there is now widespread resistance to even these.
Antistaphylococcal penicillins
Penicillin resistance in "Staphylococcus aureus" appeared very soon after penicillin entered general clinical use in 1943, and the mechanism of resistance was the production of β-lactamase. Modification of the penicillin molecule so that it was resistant to being broken down by β-lactamase was able to temporarily overcome this problem. These compounds became known as antistaphylococcal penicillins. The first of these compounds was methicillin, which is no longer in general use. The range of these penicillins available in each country is very different, and the reasons for this are historical.
6-APA
In 1958, Beecham scientists in the UK discovered the penicillin nucleus, 6-APA. From that starting material, a large number of new semisynthetic penicillins could be designed, whose activity was directed against problem infections.
Diseases and epidemics of the 19th century
Antibiotic drugs did not appear until the middle of the 20th century. Sulfonamides did not appear until 1935, and penicillin, discovered in 1928, was not available as a treatment until 1950.
Ernest H. Volwiler
Volwiler helped Abbott Laboratories to achieve commercial success for its pharmaceutical products including the commercialization of sulfa drugs and penicillin during World War II. Abbott was one of five companies enlisted in 1941 by the U. S. government to develop penicillin.
Zinaida Yermolyeva
In 1925, Ermol'eva was appointed head of the Department of Microbial Biochemistry at the USSR Academy of Sciences. There, she began her research on bacteriophages and naturally-occurring antimicrobial agents—lysozyme in particular. During the Second World War, she isolated a penicillin-producing strain of "Penicillium crustosum". It was first used in Soviet hospitals in 1943.
Mecillinam
Mecillinam (INN) or amdinocillin (USAN) is an extended-spectrum penicillin antibiotic of the amidinopenicillin class that binds specifically to penicillin binding protein 2 (PBP2), and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever. Because mecillinam has very low oral bioavailability, an orally active prodrug was developed: pivmecillinam. Neither drug is available in the United States.
Kaitocephalin
Kaitocephalin was originally isolated in 1997 from "Eupenicillium shearii", a fungus in the same genus as those that produce penicillin. Its absolute configuration was determined in 2001. Due to the small amounts of kaitocephalin available, its absolute structure was not determined through chemical degradation. Instead, NMR spectroscopy was performed on derivatives of kaitocephalin. Other methods used to determine its absolute configuration included Mosher’s method and NOESY.
Robert E. W. Hancock
At an early age Hancock recognized that he wanted to produce something “useful” and decided he was going to become a scientist, his dream was further reinforced years later when he read an article on the discovery of penicillin and he was struck by the powers of observation that led to this discovery.
La Follette-Bulwinkle Act
After the discovery of Penicillium at London's St. Mary's Hospital in 1928, the United States Congress appealed for the antibacterial discovery seeking to diminish the peril of bacterial infection among sexually exploratory populaces.
Mold
Alexander Fleming's accidental discovery of the antibiotic penicillin involved a "Penicillium" mold called "Penicillium notatum" (although the species identity is disputed as possibly being "Penicillium chrysogenum" or "Penicillium rubens"). Fleming continued to investigate Penicillin, showing that it could inhibit various types of bacteria found in infections and other ailments, but he was unable to produce the compound in large enough amounts necessary for production of a medicine. His work was expanded by a team at Oxford University; Clutterbuck, Lovell, and Raistrick, who began to work on the problem in 1931. This team was also unable to produce the pure compound in any large amount, and found that the purification process diminished its effectiveness and negated the anti-bacterial properties it had.
John Friend Mahoney
Mahoney was made aware of the possibilities of penicillin treatment by a paper of Wallace Herrell and colleagues from the Mayo Clinic. Particular attention was on the treatment of gonorrhea patients where the pathogen was resistant to sulfonamides. Mahoney could confirm this and also began to test penicillin for syphilis, first in vitro without success, then in rabbits. Once this had been successful he began clinical trials. He presented at a meeting of the American Public Health Association in New York in October 1943 the first results in four patients in the early stages of the disease. "Time" reported the findings. With Mahoney's involvement, the Committee on Medical Research began an extensive clinical trial with over 1400 patients in different hospitals. Mahoney led the study at the Staten Island Marine Hospital. In June 1944 penicillin was introduced as a standard treatment for syphilis in the United States Army.
Antoni Esteve Subirana
After returning from exile, the laboratory was moved to Barcelona, starting a new chapter in the history of the company marked not only by progressive expansion, but also by the introduction of original drug preparations into the market. In 1944, the laboratory was the first in Spain to obtain penicillin, and Alexander Fleming, who won the Nobel prize for penicillin, visited Esteve Laboratories in 1948. In 1952, the manufacture of a new antihemorrhagic agent enabled the company to expand internationally, an exceptional accomplishment for a Catalan company during the early years of the dictatorship.