Evolution of Penicillin: The First “Miracle Drug”
“When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I suppose that was exactly what I did.”
- Sir Alexander Fleming, Scottish physician, microbiologist, and discoverer of penicillin
"A discovery is said to be an accident meeting a prepared mind.”
- Albert Szent-Gyorigi, Hungarian biochemist and Nobel laureate
Penicillin is regarded as the world’s first “wonder” or “miracle” drug. It is estimated that it has saved over 200 million lives. In this week’s Germ Gems post, I focus on the evolution of penicillin’s use with emphasis on the emergence of bacterial resistance to both penicillin and structurally related beta-lactam antibiotics. I also discuss a new approach to dealing with penicillin allergy.
Brief history of the discovery and launching of penicillin. Prior to the 1930s, there was no cure for bacterial infections such as pneumonia, meningitis, osteomyelitis, sepsis, or sexually transmitted diseases like syphilis and gonorrhea. But Fleming’s serendipitous discovery of penicillin—the first antibiotic—changed that.
In 1928, Fleming went on a vacation, inadvertently leaving an agar plate of Staphylococcus aureus sitting on a laboratory bench where it fortuitously collected the Penicillium mold, which produced penicillin. Fortunately, when Fleming returned, he noticed that the agar plate on which the mold was growing was clear of any colonies of S. aureus. He made the mental connection between the antibacterial activity of the mold (Penicillium notatum) that had floated onto the agar plate and the substance released from the fungus, i.e., penicillin, as a treatment of bacterial infections.
But it took almost a decade before the Oxford scientists, Howard Florey and Ernst Chain purified sufficient quantities of penicillin to exploit penicillin’s clinical benefit in treating bacterial infections. The issue of why it took so long is debated to this day. Some of the blame for the delay rests with Fleming’s mentor, Sir Almroth Wright. Wright had witnessed the toxic effects of an antibacterial agent, carbolic acid, used to treat war wounds of soldiers in World War I. Based on this experience, he more or less forbade Fleming from pursuing clinical applications of penicillin.
Ironically, it would be the “miraculous” benefits seen with penicillin in treatment of bacterial infections (wound infections) in soldiers in World War II that led to penicillin’s extraordinary popularity. (A poster on the door of the National World War II Memorial Museum reads, “Thanks to Penicillin. . .He Will Come Home.”) The striking clinical benefits of penicillin also figured into the enormous fame of Fleming, Florey, and Chain, all of whom were awarded the Nobel Prize for Physiology or Medicine in 1945.
Emergence of penicillin resistance. In his 1945 Nobel acceptance speech, Fleming warned about the development of bacterial resistance to penicillin. To understand the basis for antibiotic resistance, one must remember that the Penicillium mold (fungus) responsible for penicillin had been cranking out the molecule for eons to protect itself from bacterial competitors in its environment. So no sooner than penicillin was introduced into our therapeutic armamentarium, did S. aureus and other bacteria develop a number of clever mechanisms to thwart penicillin’s activity. In 1947, scientists observed the first case of penicillin resistance.
Fortunately, following the introduction of penicillin into clinical practice, scientists discovered hundreds of other antibiotics either in nature or synthesized by chemists in an effort to combat penicillin resistance as well as to expand coverage against many other kinds of bacteria. (An antibiotic is antibacterial—it is active only against bacteria, not other kinds of microbes.) Now many of these bacteria are becoming resistant to antibiotics. The question is why?
Two groups of well-meaning humans are mainly responsible for the emergence of antibiotic resistance: (1) health care providers, who prescribe antibiotics for treating non-bacterial (viral, fungal, or parasitic) infections; and (2) workers in the agriculture industry, who add antibiotics to animal feed with the hope of increasing animal growth (and thereby profitability). The formula is quite simple: the more penicillin and other types of antibiotics that we pour into the environment, the more pressure is brought to bear on bacteria to develop resistance to them.
In a March 2017 article in Yale Journal Biology and Medicine commemorating the 75th anniversary of the first administration of penicillin in humans, “Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future?,” the authors warn that “the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance.” Similarly, as I pointed out in the April 23, 2022 Germ Gems post, “Antimicrobial Resistance: the Elephant in the Pandemic Room,” a global tsunami of “multiply drug resistant bacteria” has evolved from what was a small threat in the 1940s (penicillin-resistant S. aureus), into what many infectious diseases experts consider the single biggest infectious diseases challenge facing our species.
According to a 2019 report from the Centers for Disease Control and Prevention, “More than 2.8 million antimicrobial-resistant infections occur in the U.S each year, and more than 35,000 people die as a result.” That same year, the UN ad hoc Interagency Coordinating Group on Antimicrobial Resistance reported that globally “at least 700,00 people die each year due to drug resistant diseases, including 230,000 people who die from multidrug-resistant tuberculosis.” As Ms. Amina Mohammed, then UN Deputy Secretary-General and Co-Chair of the Interagency Coordinating Group on Antimicrobial Resistance said: “Antimicrobial resistance is one of the greatest threats we face as a global community.”
New approach to penicillin allergy. Despite the widespread emergence of bacterial resistance to penicillin (and related antibiotics, like amoxicillin, augmentin, anti-staphylococcal penicillins, and a host of broad spectrum cephalosporins), penicillins remain some of the most commonly used antibiotics globally. Their popularity is rooted in their long history of efficacy and safety. Plus, when compared to many newer antibiotics, penicillins are far less expensive.
One of the most common reasons for not prescribing penicillins is a patient report of a history of “penicillin allergy.” Many studies have shown, however, that while 10% of the population reports a penicillin allergy, less than 1% of the population is truly allergic.
A common reason for over- or mis-diagnosis of penicillin allergy is that many people who think they’re allergic to penicillin are not. They are simply not aware of the meaning of the term “allergy.” According to the NIH, an allergy is an exaggerated response from the body’s immune system to otherwise inert substances present in the environment. That is, penicillin allergy is an immunological disorder. (Often patients wrongly associate development of gastrointestinal symptoms, such as nausea, vomiting, or diarrhea or lightheadedness after receiving an antibiotic, with an allergy.)
An allergic reaction to penicillin can either be “immediate” (occurring within 15-30 minutes of exposure to the drug) or “delayed” (for hours and sometimes days). Immediate allergic reactions are immunoglobulin E-mediated. These reactions can be very serious, even fatal, whereas delayed allergic reactions are caused by other elements of the immune system and are usually characterized by an itchy rash.
In a 2022 National Institutes of Health (NIH) article, “Penicillin Allergy,” the authors point out that identification of true penicillin allergy is critical as 80% to 90% of people once considered allergic are ultimately able to tolerate penicillins, thus resulting in a decreased need for broad-spectrum antibiotics and reduced development of multi-drug resistant bacteria.
The good news for patients and medical practitioners alike is that this is now being sorted out. Within the past few months, a spate of articles, such as “Implementing Delabeling of Bet-Lactam Allergies: Getting to the ‘Why’” as well as “The Who, What, and Where’ of Inpatient Direct Oral Penicillin Challenge—Implications for Health Services Implementation,” both in the July 1, 2023 issue of Clinical Infectious Diseases and another, “The Penicillin Allergy Decision Rule—Something New for Penicillin Allergy” in the Journal of American Medical Association suggests that given the increased recognition of the importance of accurate assessment of penicillin allergy, hospital antibiotic stewardship teams are increasingly responsible for implementation and monitoring of penicillin allergy and, when appropriate, desensitization.
The science of good luck. Both Fleming and Louis Pasteur articulated the idea that “chance only favors the prepared mind.” A 2006 article in Science News supports this idea. An Association for Psychological Science study, “Sudden Understanding: Aha! Favors the Prepared Mind,” shows specific patterns of brain activity appear before people see and solve problems.
Just think how lucky we are that Alexander Fleming picked a week for a vacation in September 1928, and left an agar plate of S. aureus sitting on a bench where it collected the Penicillium mold that did its business by producing penicillin. And how lucky we are that Fleming’s mind was prepared for an “Aha!” moment leading to the discovery of penicillin.
Let’s hope that some creative minds that are working on solving the mounting problem of antibiotic resistance are prepared and that they experience “Aha! Moments.” It would be hugely lucky for us all.