In 4 years, the field of medicine will celebrate the 100^th birthday of an important discovery. It fueled a century of medical marvel and innovation in medicine: Penicillin! The first of many antibiotics discovered by humans. But… will we have reason for celebration in 2028? Penicillin still saves countless lives today but the magnificence of antibiotics have long been overshadowed by the doom and gloom of antimicrobial resistance (AMR). Up to 10 million deaths per year caused by superbugs in 2050! Up to 4.9 million deaths directly associated with antimicrobial resistance in 2022! One trillion dollars of extra healthcare costs linked to antimicrobial resistance by 2050, according to the World Bank. One to 3.4 trillion dollars loss in gross domestic product (GDP) by 2030. BIG numbers! Numbers… with little value for a single individual. Why use those numbers if they have little value to people? Well… they are simple and measurable. Yet, how do you translate those numbers into a story that everyone can relate to? Do those numbers not have a different value depending on who you talk to? Often, those numbers are simply used to create an emotion of ‘concern’ and ‘fear’ to drive a ‘call to action’ and for policy makers to take notice. And they work… somewhat. However, others might want an in depth dialogue and education. A personal message is needed. Do we really need those numbers? I don’t think so, we need tailored content to inspire people to introduce simple changes. That the missing link today: a yet to be defined statistic that describes how many people can relate and understand antimicrobial resistance to such an extent that it inspires individual action. Do we really need this? Maybe… or maybe not. In the end, we should think of it as a story. A story can create a unique emotion and view with the reader. However, the most common emotion triggered by the story will not resonate with everyone… but all readers read the book and got something out of it. That’s the goal… How to tell the AMR story so everyone gets something from it?

I argue that we need more storytelling in the field of AMR. That’s why today we are going back to 1928. To the very beginning: the origin of penicillin. But… there’s a plot twist. We’ll not only look at penicillin through the eyes of humanity. The microscopic world of microbes was equally, if not more, impacted by Alexander Fleming’s work. Does this really matter that much? Debatable… but the reality is that we tend to emphasize the marvels associated with the discovery of penicillin. The flipside of the coin is often neglected: humanity unintentionally started to meddle with the normal evolutionary processes of microbial survival. A different perspective that deserve some time in the spotlight.

Echoes of Ancient Battles: How Penicillin Reshaped Human and Microbial Worlds

The year is 1928. Alexander Fleming makes the groundbreaking discover of penicillin. Yet, the discovery didn’t equate to clinical utility for years to come. The initial antibiotic properties of penicillin were described in 1928 but the following years were focused on additional research. A more detailed description of those antibiotic properties was needed. Did penicillin work against multiple bacteria? Was it safe? Simple questions critical for translating penicillin’s interesting properties to clinical applications. The first ‘safety data’ became available in 1929: penicillin was found to be non-toxic for animals. Although the science developed quickly, there was one major challenge that proved difficult to overcome: large scale manufacturing of penicillin in sufficient quantities. It was effectively keeping the door to human medicine applications shut. Only in the 1930s did change start to occur when the Clever men at Oxford got involved. Penicillin was purified in high amounts, it’s efficacy got demonstrated and the first patient treated. Despite all of this, it would still require the urgent medical needs seen during World War II to shift the gears and accelerate development. Deep-tank fermentation techniques were developed in a US-UK partnership and by 1943, mass-scale production started to save lives. An unprecedented 15-year journey of scientific research and novel technology developments to effectively bring penicillin to market. Nobel prize winning progress for humanity! But on a microscopic scale… chaos erupted. Microbial communities in disarray. A declaration of war and a fight for survival ensued.

It’s some year before the dawn of civilization. The mold penicillium rubens is having another skirmish with the surrounding bacteria in the local community. It tends to get ugly, poisonous darts of penicillin are thrown. The bacteria shield themselves and luckily, balance gets restored in the end. Once the dust settles, the darts and shields are put on the shelf and life continues as normal. It’s a process of adaptation and evolution long before Alexander Fleming first observed these events under his microscope. We don’t know for sure how long penicillin has been around in nature but genetic analysis suggest it could be around 400 to 600 million years. When exactly doesn’t really matter. What matters is the continuous microscopic warfare between antibiotics and resistance way before humanity came into the picture. But there was balance… even if it was a never ending war raging for millions of years. Globally, but not a global scale. Neither sides gaining the upper hand and a stalemate occurred.

It’s 1943. Two independent stories intersect. A balance gets disrupted. The macroscopic world invaded the microscopic stalemate. Humanity started to use penicillin in medicine ignorant of the potential microscopic impact. Medicine at first but other penicillin applications followed quickly. Excessive use, unaware of the consequences. Celebrated as a golden age of fighting infectious diseases. But… in the microscopic world it started to rain. Acid rain. Penicillin falling from the sky. Microbes seeking shelter wondering what’s happening. Accidental environmental pollution of the microscopic world. A dark age followed… frequent penicillin use by humans implied stronger and more frequent acid rains. However, as the existence of bacteria became threatened they turned to their strongest skill: adaptation. As the stalemate was disrupted and microbial communities started to dissolve, a resistance started to brew to restore the equilibrium. The bacteria that survived shared their tale with others and soon penicillin use started to reshape microbial diversity. The outcome? Survival of the fittest and the survivors became more abundant.

By the time humanity caught wind of the penicillin resistance brewing in the bacterial communities, the damage was already done. So, what did we do? Nothing… at first. The benefits of penicillin strongly outweighed any sense of responsible use. What followed  was a global ecosystem of widespread penicillin use which couldn’t be reset… even when awareness on resistance became more abundant.

Antibiotics Beyond Medicine: Growth, Greed, and Resistance.

Initially penicillin had a pure medicinal function: treating infections. During World War II, many soldiers suffered from wound infections. Penicillin saved lives. A few years later, things started to change. In the late 1940s and early1950s, penicillin use spilled over to the agriculture sector. Initially for treating bacterial infections in livestock: a revolutionary way to protect animals from diseases. What would be the benefit? Improved food yields through massive reductions in livestock losses. But that’s a good thing right! Yes… if penicillin was only used to treat infections. The reality… penicillin use shifted to a prophylactic application: prevention rather than treatment. With this shift came a profound new knowledge: animals got ‘big’, and ‘big’ faster. It turned out that low doses of antibiotics in animal feed acted as a growth promotor. Routine prophylactic use of antibiotics in livestock, poultry and farmed fish followed swiftly. It’s intriguing as someone once told me that when you got a common cold, you need chicken soup not antibiotics. This might be true in concept. But what if the chicken in your soup consumed more antibiotics in their live compared to what we might prescribed unnecessarily for a common cold? It makes me wonder: do we truly understand the consequences of some of our daily actions? Besides animals, humanity also briefly experimented with antibiotics in plant agriculture practices. Same concept: treating plant infections to improve agriculture yield. Luckily, this never really caught on. At least not for penicillin…

Such non-human antibiotic practices lasted until regulations were put in place due to concerns of both antibiotic resistance and antibiotic residues in food products impacting human health. Which makes me wonder about our previous blog… why do those concerns not apply to glyphosate today? But let’s stay on track. Antibiotic use in livestock has dramatically reduced and most countries to date limit antibiotic use just to treating animal infections. A great success, but why did it take so long? Only in 2006 did the EU ban antibiotics for use as growth promoters. The FDA originally proposed a withdraw approval for this application in 1977. Today, the FDA makes use of a set of guidelines introduced in 2017 to ensure judicious use. A guideline 40 years in the making…

So what happened in the microscopic world in those 40 years? Well… originally the impact of penicillin was confined to individual patients. Disease causing bacteria got killed, but the good bacteria in and on our body got affected as well. Not great, not terrible. Things took a turn for the worse when humanity used penicillin and other antibiotics elsewhere. Animal use implied we were changing their microbiomes as well. Plus the environment got contaminated through animal feces and rainwater runoff. Plants & trees use followed swiftly. Ecological changes in soil and water followed. Did this have any consequences? Yes… strong selective pressure for development of antibiotic-resistance emerged. Everywhere. We slowly started to change the composition and diversity of microbial communities. Ask yourself: what would you do if you had to endure continuous acid rain exposure? Do you migrate? Or… do you find a way to adept as the grass isn’t necessarily greener on the other side.

Beyond the Cure: Rethinking Our Relationship with Penicillin and Bacteria.

Today, penicillin remains a tremendous asset to human health. So why tell such a story if we have things under control and regulations in place? Well… to me a story will inform more than quoting AMR statistics. One story won’t make a difference! I tend to agree, but we’ve only uncovered penicillin’s story. Penicillin has many sisters and brothers who’s stories are yet to be told. By simplifying penicillin’s role in AMR, we revealed a near century learning curve of what penicillin is and where we should and shouldn’t use it. Did it truly take us that long to figure things out and use a new medication responsibly? Maybe not but… it does reveal how we also don’t properly understand the true impact of new medications either.

So what to remember? Penicillin is a great medicinal wonder which saves patient lives. However, we need to cherish it. At the same time, we need to change our relationship with bacteria. Not all bacteria are bad, on the contrary. We don’t want all of them dead. Let’s celebrate the good ones and protect the tools we have to kill the bad ones. This is something that everyone can take action on. Doctors are amazing people but next time they start talking about giving antibiotics it is ok to ask questions and to start a dialogue. Do I really need them doc? Sometimes you do, sometimes you don’t. Shared decision making and patient-doctor dialogue can help.

So cherish penicillin! Once we do that maybe we can look at the history of another class of antibiotics on a different day in the future.