The Evolution of Antibiotics During World War II

Infections During War• War in the beginning years of

American history resulted in more soldiers dying from disease than combat.

• Disease was rampant, as evidenced by the typhoid fever outbreak during the Spanish-American War and in the influenza epidemic in World War I.

• Death rates were fueled by crowded, unsanitary camps, improper disposal of human and animal waste, poor personal hygiene, lack of bathing facilities and recycling the clothing of soldiers dead from disease.

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Infections During War

•The widespread implementation of vaccinations and the adoption of medical treatment with antibiotics put an end from the high mortality rate from infection, with combat deaths outnumbering deaths by disease in every war since World War II. •Dying of disease is so rare for today’s soldiers that even deaths by suicide outnumber the deaths by disease in the present war.

Infections During War

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•Death tolls underestimate the full impact of disease on warfare. •The health of a unit is crucial for its ability to be prepared and ready for its mission. •According to military hygienist Alfred A. Woodhull, “the sick are for the time as ineffective as the dead”.

Vaccinations • Entering World War II, our

soldiers were immunized against smallpox, typhoid fever, cholera, plague, tetanus, yellow fever, and typhus.

• This was definitely not the case worldwide and gave us an advantage.

• Tetanus was responsible for innumerous deaths during World War I, but during the second war there were only 11 cases and four deaths attributed to it. http://www.vaccines.mil/default.aspx?cnt=resource/viewImage&imgID=29

Therapies• Medicine at that time was

targeted toward symptomatic relief, but not a cure.

• Included painkillers like morphine, mercury, arsenic, antimony for schistosomiasis, and quinine.

• The major manufacturing companies made and distributed products such as aspirin, chloroform, cocaine, emetine, hydroquinone, lanolin, and phenacetin.

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Biological Debridement• First written reports of the beneficial effects of

maggots dates back to 1557, but introduced in the United States in 1931.

• The first scientific studies of maggots medicinal uses were conducted by Dr. W.S. Baer during World War II.

• He was inspired after encountering soldiers in the first World War. Although they had laid unattended for 7 days, their compound fractures and abdominal wounds contained healthy granulation tissue.

• In 1920s and 1930s he successfully treated osteomyelitis and chronic leg ulcers in over ninety patients.

Antiseptic agents

• Carbolic acid, an antiseptic agent, is being sprayed by the apparatus to the right.

• It showers the mist over the patient to kill any infectious agents.

• This makes this procedure a “clean” surgery.

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Proflavine

• Introduced to medical society in 1934. • Orange to red colored dye with bacteriostatic and

bacteriocidal properties when used topically. • During World War II, extensively used as wound

antiseptic.

Atabrine• Cinchona bark, which contains

quinine and cinchona, was used to treat malaria.

• Once the essential elements were able to be isolated, they were given instead of the actual bark.

• The 1930s yielded synthetic antimalarials, one of which was atabrine.

• It was highly effective, but could cause yellowed skin, headaches, nausea, vomiting, and a temporary psychosis.

Syphilis • Salvarsan, an

arsenobenzene compound, used for syphilis.

• The drug was 32% arsenic and could cause severe tissue necrosis and death if not injected into the vein.

• IV infusion was alternated with intramuscular mercury and bismuth.

• Average duration of treatment >18 months.

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Sulphonamides• Gerhard Domagk, German biochemist, was involved in researching

therapeutic potential of metal based compounds, such as gold, tin, antimony, and arsenic.

• After changing jobs to a chemical company that manufactured products for coloring textiles, he began to test azo dyes.

• In 1932, he discovered a bright red dye named Prontosil, that could cure infections caused by streptococcal bacteria in mice.

• His used his severely ill daughter as his test subject and the drug eradicated her infection.

• Prontosil was metabolized into two parts, one of which is sulphanilamide. It is this entity that carries the bacteriostatic ability.

Sulphonamides • Prontosil was effective against

streptococci, but not against pneumococcal infections.

• Pharmaceutical firm Mary and Baker developed M & B 693, which was sulfadiazine, which had an extended spectrum of treatment.

• Sulfadiazine was hailed for treating puerperal fever, erysipelas, mastoiditis, meningitis, and gonorrhea .

• This became a major breakthrough because it is the first class capable of treating bacteremia.

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Sulphonamides• Side effects could be limiting, including drug fevers, blood

dyscrasias, renal complications, and disruption of coordination.

• They were not uniformly successful, even against disease in which their effectiveness had been demonstrated.

• By 1941, 1700 tons had been administered to ten million Americans and strains of sulpha resistant streptococci had surfaced.

• Controls over pharmaceuticals then were minimal; there were reports of a series of deaths caused by a sulfanilimide elixir containing diethylene glycol.

• They were the only available effect drug until penicillin.

Sulphonamides

•Soldiers were distributed first aid bags that were to be carried on the belt. •These bags contained the sulfa powder and a bandage to wrap the wound. •They were instructed to sprinkle the drug on any open wound.

Penicillin• Alexander Fleming, a Scottish bacteriologist, worked at St.

Mary’s Hospital in London as a member of the inoculation department.

• His work was centered primarily on lysozymes, which he discovered and began researching in 1921.

• In 1928 he discovered a mold growth in the petri dishes that was inhibiting growth of his staphylococcal colonies.

• He isolated and identified the mold as Penicillin. • Fleming found his product inactive on Gram negative

bacteria. In addition, it’s chemical composition was unstable and difficult to isolate the active ingredient; his discovery soon fell by the wayside.

Sir Alexander Fleming, 1952

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A Scanning Electron Micrograph of Penicillium Mold Producing Chains of Spores.

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Penicillin• Ten years later, in 1939, Sir Howard Florey, the head of the

Pathology Department at Oxford, and his colleague, biochemist Ernest Chain continued experimenting with penicillin where Alexander Fleming left off.

• Knowing the challenges Fleming suffered, they engaged an additional biochemist , Norman Heatley to assist with improving production techniques.

• They were able to purify the drug and begin animal testing on mice. They inoculated eight mice with fatal streptococci doses and then gave four of them penicillin.

• The mice treated with penicillin survived, the others did not.

Penicillin

• The dosage of penicillin was defined in Oxford units. This is the amount that would produce a clear zone free of bacteria of 25 millimeters on petri dish culture.

• Despite their efforts, they were unable to isolate more than two units per cubic centimeter from their flasks.

• They developed a concentration protocol which produced a dry stable penicillin salt with a potency of about 50,000 units per gram.

• The extraction process lost nearly two thirds of the penicillin originally in the culture medium.

• 97% of this dry extraction was impurities and it was only sufficient to treat one person for half a day.

Early penicillin culture facility at the Sir William Dunn School of Pathology, Oxford, England. © Museum of the History of Science, Oxford

Penicillin• The team produced enough penicillin to try on a patient. 48 year

old London Constable Albert Alexander developed staphylococcal septicemia following a scratch while pruning his roses and had developed septicemia and numerous facial abscess and carbuncles.

• Upon admission to the treatment facility, he had been administered a sulfa drug with no effect.

• When physicians believed he had only hours left to live, Florey asked for permission to treat the patient with penicillin.

• The patient defervesced and improved a great deal. • The small penicillin supply began to run out, even though his urine

was collected to recycle as much of the drug as possible.• The Constable relapsed and died on the fifth day, after the drug

supply had been depleted after four days of treatment.

Penicillin • In search of a larger

production of the drug and funding, Florey came to the United States and resumed his work at the Northern Regional Research Laboratory in Peoria, Illinois .

• A new fermentation method using corn steep liquor in the culture medium greatly increased their yield.

• Now the Penicillin was grown submerged in vats instead of only on the surface in flasks, contributing to the higher quantities.

Penicillin• At the beginning of the war, the

government put together a committee to oversee the development of chemotherapeutic agents and medical research.

• Once the efficacy of penicillin and its poor available supply were reported, penicillin became a government priority.

• Other pharmaceutical companies were called upon for production.

• Military hospitals conducted clinical studies for the drug.

• By D-Day in 1944, there was enough available to allow unlimited treatment of allied servicemen.

• The drug was only for use for the US and British military until after the war.

Penicillin

• Proved highly effective against most bacterial etiologies.

• Before penicillin, pneumonia fatality rate was around 30%; it dropped to around 6% afterward.

• U.S. military deaths from infection during World War II were drastically reduced.

• Penicillin did not replace the sulphonamides, rather it added to the efficacy of antibiotic therapy at the time.

Penicillin

• Compound fractures and penetrating gunshot wounds received in the field were often problematic.

• Infection could be seeded from the soil, wading in pungent water, or bits of clothing driven into the wound by the bullet.

• Physicians of the time noted “under the protection of penicillin, it was possible to remove foreign bodies and dead bone, to revise the soft parts so that the bone was covered, and to restore the normal contours of the limb, applying grafts of bone, muscle and skin wherever necessary”.

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Penicillin • Penicillin was not proven

efficacious for syphilis treatment until 1943.

• Syphilis was one of the leading cause of death in the United States before World War II, behind tuberculosis, pneumonia, and cancer.

• The decline in syphilis rates can be attributed in large to the availability of penicillin.

• The use of the drug eventually led to greater control of syphilis in the United States, such that the disease is no longer screened for among new recruits.

Penicillin • In World War I, the Army lost nearly

7 million person days and discharged more than 10,000 men because of STD’s.

• In the early years of World War II, the War Department launched a massive educational and prophylactic campaign.

• Before penicillin, post-exposure prophylaxis with sulfathiazole was used.

• Following reports of an unpublished trial during the Korea War with penicillin prophylaxis given to troops before liberty period and a resultant marked reduction in STD rates, penicillin prophylaxis was authorized for general use.

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Streptomycin• In 1940 Selman Waksman, a soil

microbiologist isolated an antibiotic called actinomycin.

• Actinomycin was bacteriocidal, but it was too toxic for a clinic trial.

• In 1944 he discovered another fungal species with bacteriocidal properties, Streptomycin.

• Streptomycin proved to be active against a variety of gram negative and acid fast bacteria, as well as gram positive organisms resistant to penicillin.

• Most importantly, it was the first antimicrobial used in treatment of tuberculosis.

Nobel Peace Prize Winners

Gerhard Domagk(1895-1964)

ReferencesBroughton, George, Janis, Jeffrey et al. A Brief History of Wound Care. Reconstructive

Journal. Volume 117, Number 7S, p. 6S-11S.Crillo, Vincent J. Perspectives in Biology and Medicine. Chicago: Winter 2008, Vol 51,

Iss 1:p121-133.Henderson, John W. The Yellow Brick Road to Penicillin: A Story of Serendipity.

History of Medicine. Volume 72(7), July 1997, p.683-687.Porter, Roy. The Greatest Benefit to Mankind. W.W.Norton & Company LTD, 1997, p.

428-461.Prain, David. Penicillin in War Wounds. The Lancet, April 1, 1944.Rasnake, Mark, Conger, Nicholas et al. History of U.S. Military Contributions to the

Study of Sexually Transmitted Diseases. Military Medicine. Volume 170, 4:61, 2005, p. 61-65.

Tansey, E.M. Medicines and men: Burroughs, Wellcome & Co, and the British drug industry before the Second World War. Journal of the Royal Society of Medicine. Volume 95(8), August 2002, p. 411-416.

Waksman, Selman. Streptomycin: background, isolation, properties, and utilization. Nobel lecture found at www.waksmaninstitute of microbiology.