Pill Pushing©

The Best of Pill Pushing - Penicillin: From battle wounds to VD - (9/14/2017)

By Dr. Ron Gasbarro
 
Society at that time
As the 1939 outbreak of World War II spread through Europe, Africa and Asia, human hardship became the norm. Soldiers and civilians died from ravaging staphylococcal, streptococcal, and pneumococcal infections. Battle-incurred wounds that became infected were not novel sequelae during the wars of Earth. In earlier conflicts, people died by the thousands from bacterial infections that resulted from their injuries. Pioneer antiseptic drugs, such as phenol, was a mediocre antimicrobial but became the drug of choice for annihilating Jews at Auschwitz by injecting in into the heart [Lifton, 2000]. Arsphenamine (Salvarsan), an arsenic-based organic compound, was the first organic antisyphilitic agent, and a tremendous improvement over the inorganic mercury compounds used previously [Gibaud, Jaoeun, 2010]. However, its preparation was complicated: the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection. Many of the side effects – rashes, hepatotoxicity, and circulatory problems which necessitated amputation and other dangerous and disfiguring surgical procedures – caused physicians to shun the drug as poisonous. 
 
The 1937 Elixir Sulfanilamide disaster
The sulfonamides, widely used by the 1930s, competitively inhibit folic acid synthesis in microbes. While they were not bactericidal, they were at least bacteriostatic against a wide variety of pathogens including some protozoa, and used enthusiastically. However, their use almost stumbled into oblivion with the 1937 Elixir Sulfanilamide disaster. 
 
This tragedy was one of the most important mass poisonings of the 20th century [Ballentine, 1981]. This event occurred shortly after the introduction of sulfanilamide, the first sulfa antimicrobial drug, when diethylene glycol, not yet known to be poisonous when taken internally, was used as the diluent in the formulation of a liquid preparation of the sulfa-based elixir. One hundred five patients died from its therapeutic use. Under the existing drug regulations, premarketing toxicity testing was not required. In reaction to this calamity, the US Congress passed the 1938 Federal Food, Drug and Cosmetic Act, which required proof of safety before the release of a new drug. The 1938 law changed the drug focus of the Food and Drug Administration from that of a policing agency primarily concerned with the confiscation of adulterated drugs to a regulatory agency increasingly involved with overseeing the evaluation of new drugs.
 
Following that debacle, sulfa had a pivotal role in preventing wound infections during World War II. American soldiers were issued first-aid kits containing sulfa pills and powder, and were told to sprinkle it on any open wound. Because many germs are now resistant, sulfonamides have largely been supplanted by more effective antibiotics, although they are still used today for urinary tract infections and dermatological conditions, such as acne vulgaris. 
 
The need for something new
Penicillin had been known about since 1928 after being fortuitously discovered by pharmacologist Alexander Fleming (1881-1955) at St. Mary’s Hospital in London, when a mold containing one of his cultures caused a variant of staphylococcus to undergo lysis [Fraser, 1984]. 
 
In Fleming’s own words: “While working with staphylococcus variants, a number of culture plates were set aside on the laboratory bench and examined from time to time. In the examinations these plates were necessarily exposed to the air and they became contaminated with various microorganisms. It was noticed that around a large colony of a contaminating mold the staphylococcus colonies became transparent and were obviously undergoing lysis. Subcultures of this mold were made and experiments conducted with a view to ascertaining something of the properties of the bacteriolytic substance which had evidently been formed in the mold culture and which had diffused into the surrounding medium. It was found that broth in which the mold had been grown like the mold broth remedies commonly applied to infections by the country people had acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more common pathogenic bacteria." [Fleming, 1929] 
 
By 1931, research on the substance was back-shelved due to Fleming’s belief that its half-life would be too short and its supply would be too small to be of any clinical usefulness. However, in 1934, he resumed clinical trials using crude materials, such as mold and sought ways to purify it. Anecdotal reports showed that penicillin was bactericidal and was recycled from the bedpans of patients to whom it was given as well as from the urine of volunteers from the Oxford (England) Police Force [Petri, 2001] By the 1940’s, production was refined so that penicillin could be synthesized in mass quantities. The modern antimicrobial age began. 
 
The good, the bad, and the ugly
Penicillin arrived just in time for World War II, saving untold numbers of military and civilians from otherwise fatal infections, such as gas gangrene. A new deep-fermentation process heralded a vital advance in the large scale production of the antibiotic. In the late 1940’s, total production soared from a few million units per month to over 200 trillion units (150 tons) a month by 1950 [Petric, 2001]. The initial cost of marketable penicillin was several dollars per 100,000 units; the same dose today costs only a few cents [Petri, 2001]. Penicillin has since been used for pneumococcal infections, anthrax, and various anaerobes. The 29% decline in age-adjusted mortality from 1935 to 1954 was almost certainly influenced by the introduction of penicillin as well as other emerging antibiotics [Moriyama, 1964].
 
Yet, as early as 1942, penicillin-resistant staphylococci were recognized, first in hospitals and ultimately in the community [Rammelkamp, 1942]. By the late 1960s, more than 80% of both community- and hospital-acquired staphylococcal isolates were resistant to penicillin [Chambers, 2001]. This pattern of resistance, first nosocomial and then spreading to the community at large, is now a fixed pattern that recurs with each new surge of antimicrobial resistance. Acute anaphylactic or anaphylactoid reactions constitute the most immediate danger of penicillin use. While the incidence of anaphylactoid reactions is believed to be 0.004% to 0.04% in persons treated the penicillin, approximately 0.0005% of such patients will die from this rare adverse reaction – about 1,500 Americans annually [Kucers & Bennett, 1987]. The manifestations of penicillin allergy include maculopapular or morbilliform rash, fever, urticaria, exfoliative dermatitis, swelling of the throat, difficulty breathing, eosinophilia, serum sickness, Stevens-Johnson syndrome, and anaphylactic shock [Idsoe, 1968]. In patients found to have penicillin allergy, the frequency of positive results on skin testing decreases by 10% per year of avoidance [Gonzalez, 2015]. Thus, 80% to 100% of patients are expected to test negative for penicillin allergy by 10 years after their reaction.
 
Impact of drug on culture
Aside from its value in curing infections caused by direct assaults on the body from bullets and shrapnel, the use of penicillin during World War II may have instigated the sexual revolution of the 1960s. Syphilis was the fourth leading cause of mortality in the United States prior to World War II, following only tuberculosis, pneumonia, and cancer [Stokes, 1944]. Overall, the prevalence among recruits in 1942 was 4.5 cases per 100 individuals [Stokes, 1944]. By 1999, the rate of syphilis among the military was comparable to the US civilian rate of 0.0025 cases per 100 persons [CDC, 1999]. 
 
The drug was also effective against gonorrhea. A 1944 study in which investigators that examined 1,686 patients with sulfonamide-resistant gonorrhea showed a 92.5% cure rate using total penicillin doses of 160,000 units or less [Sternberg, 1944]. Thus, the use of penicillin, along with many other factors, including education, eventually led to greater control of syphilis and gonorrhea in the United States, such that new recruits are no longer screened for the disease [Gaydos, 2000]. 
 
The reshaping of modern sexuality 
Debate continues as to whether the sexual revolution of the 1960’s was attributable to the oral contraceptive or to the cure of sexually transmitted diseases. One study investigated the hypothesis that a decrease in the cost of syphilis due to penicillin spurred an increase in risky non-traditional sex. Using nationally comprehensive vital statistics, a recent study implied that the era of modern sexuality originated in the mid to late 1950s, with a rise in risky sexual behavior during that same period [Francis, 2013]. This trend evidently coincided with the containment of the syphilis epidemic. Syphilis incidence dipped to an all-time low in 1957 and syphilis deaths fell rapidly during the 1940s and early 1950s. Regression analysis demonstrated that most measures of sexual behavior significantly increased immediately following the collapse of syphilis and was significantly associated with the decline in the syphilis death rate. These findings supported the supposition that the discovery of penicillin decreased the cost of syphilis and thereby played an important role in shaping modern sexuality. 
 
Where the drug is today
In 1942, Anne Miller was the first patient whose life was saved by penicillin [Saxon, 1999]. Already hospitalized for 4 weeks with beta-hemolytic streptococcal sepsis and accompanying delirium and temperatures as high as 107°F (42°C), she was given a small dose of penicillin. According to her New Haven (CT) Hospital chart, now housed at the Smithsonian Institution, she registered a sharp overnight drop in temperature, and by the next day she was no longer delirious and was soon eating full meals. She died in 1999 at the venerable age of 90. More than 60 years after its breakthrough, and despite the fact that more than 200 antibiotics now exist, penicillin is still one of the most widely used antibiotics today. Because ordinary penicillin has a limited spectrum of effectiveness, many offshoots have been developed. From penicillin, the ß-lactam class has branched out into many derivatives: This includes penicillin derivatives (penams, such as ampicillin and amoxicillin), cephalosporins (cephems), monobactams, and carbapenems [Holten, 2000]. Working by inhibiting cell wall biosynthesis in the bacteruim, ß-lactam antibiotics are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were ß-lactam compounds [Elander, 2003].
 
Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Write him with any ideas or comments at ron@rx-press.com.

References
 
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Centers for Disease Control and Prevention: Primary and secondary syphilis: United States, 1999. MMWR 2001; 50: 113–7.
 
Chambers, HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect. Dis. 2001. 7:178-82. 
 
Elander RP. Industrial production of beta-lactam antibiotics. Appl Microbiol Biotechnol. 2003;61:385–92. 
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Rammelkamp, CH, Maxon, T. Resistance of Staphylococcus aureus to the action of penicillin. Proc Royal Soc Exper Biol Med. 1942. 51:386-389. 
 
Saxon W. Anne Miller, 90, first patient who was saved by penicillin. New York Times. June 9, 1999.
 
Sternberg TH, Turner TB: The treatment of sulfonamide resistant gonorrhea with penicillin sodium. JAMA 1944; 126: 157–61.
 
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US Food and Drug Administration. The Federal Food, Drug and Cosmetic Act. Available at: www.fda.gov 


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