Antibiotics have driven a revolution in modern medicine. Before the 1940s and the introduction of penicillin and other antibiotic treatments, an infected wound could be a death sentence. Tuberculosis, food-borne illnesses, and more – these once-dire microbe-caused diseases have been made treatable by antibiotics, which are key elements in modern medicine’s toolbox.
And yet we now inhabit a world in which many microbes are resistant to the very antibiotics that have saved so many people’s lives. Microbes are tiny organisms with fast, short life cycles; as a result, microbial populations are quick to adapt to their environments. Every generation ends up with possible mutations that can be inherited and put to the test by the next. Given our frequent use of antibiotics, individual microbes that develop genes resistant to those antibiotics are favoured by natural selection. They and their offspring thrive, taking over a population that might otherwise be under threat from antibiotics.
While tiny, microbes are also highly diverse and as a whole make up a complex global community, so there is more at play here than this simple explanation. But the short and sweet version is that more use of antibiotics equals more resistance in microbes. And we have been using a lot of antibiotics, in healthcare, agriculture, and beyond.
Antimicrobial resistance is extremely dangerous and risks undermining global development, researchers have recently argued.1 1. Jasovsky, D., Littmann, J., Zorzet, A., Cars, O., 2016. Antimicrobial Resistance - A Threat to the World’s Sustainable Development. Uppsala J. Med. Sci. 121:159–164. DOI: 10.1080/03009734.2016.1195900 How did we get here? Part of the answer is that we failed to identify how microbes support human life. The solution might be a global shift in mindset, from seeing microbes as supervillains to recognising their superhero role in our planet’s life support system.
We have the opportunity to make a transformation to a “pro-microbial” planet, systematically focusing on enhancing the benefits we get from microbes, while reducing their negative impacts on human health – which means rethinking antibiotics.2 2. Søgaard Jørgensen, P., Wernli, D., Folke, C., Carroll, S. P., 2017. Changing antibiotic resistance: Sustainability transformation to a pro-microbial planet Antimicrobial. Curr. Opin. Environ. Sustain. 25:66–76. DOI: 10.1016/j.cosust.2017.07.008 To help us understand what this would entail, let’s take a fast tour through the history of antibiotics, and look at what we can do in the future to keep them viable while protecting ourselves and the microbes on which we depend.
From the golden age to non-renewable resources
After the introduction of antibiotics for soldiers in the 1940s during the Second World War, the treatments quickly became widespread in the general populations of developed countries. The 1950s and 1960s were a golden era in the development of antibiotics. When resistance became widespread to one drug, pharmaceutical companies introduced another to take its place. However, the innovation boom soon subsided due to a combination of economic incentives and the difficulty of coming up with new drugs with long-lasting efficacy and minimal side effects. Of the antibiotics available on the market now, the most recent class was discovered in the 1980s.
In 2016, a patient in the United States died of an infection that made headlines in many countries – and not just because it was one more death in a developed country caused by a microbe known as CRE NDM Klebsiella pneumoniae.3 3. Chen, L., Todd, R., Kiehlbauch, J., Walters, M., Kallen, A., 2017. Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae — Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 2017;66:33. DOI: 10.15585/mmwr.mm6601a7 This bacterium could withstand all 26 antibiotics available for treatment. And while the patient’s doctors knew about its antimicrobial resistance, they were still unable to successfully treat her. That’s what made this case alarming: the doctors had no drugs available to them that would work against CRE, even in a wealthy, well-supplied medical setting.
In developing countries, millions of people die from illnesses that could have been treated with access to care – whether for bacterial, viral, or other diseases. Among them are hundreds of thousands of people who die from diseases caused by antibiotic-resistant bacteria, parasites, and fungi.4 4. Laxminarayan, R., Matsoso, P., Pant, S., Brower, C., Røttingen, J.A., Klugman, K., Davies, S., 2016. Access to effective antimicrobials: A worldwide challenge. Lancet 387:168–175. DOI: 10.1016/S0140-6736(15)00474-2
International health codes do not distinguish between susceptible and resistant infections as a formal cause of death, so the exact toll of antimicrobial resistance remains unknown, but it is obviously large and growing. Meanwhile, some countries are adopting modified versions of codes from the World Health Organization (WHO) to provide an increasingly detailed account of the toll of drug resistance.
In the past we have used the language of war in talking about microbes – they arm themselves against our drugs, we find ways to wipe them out. Or we have framed resistance as an obstacle to achieving health for all, or a challenge to innovation when it comes to creating super drugs.5 5. Wernli, D., Jørgensen, P. S., Morel, C. M., Carroll, S., Harbarth, S., Levrat, N., Pittet, D., 2017. Mapping global policy discourse on antimicrobial resistance. BMJ Glob. Heal. 2:e000378. DOI: 10.1136/bmjgh-2017-000378 But that language is slowly changing as the threat grows.
Some medical personnel and researchers have been sounding the alarm about the waning effectiveness of antibiotics. They do not assume that all antibiotics will continue to be effective in the future. Instead, they have begun to talk about antibiotic effectiveness as a non-renewable resource: once resistance to an antibiotic is developed, that treatment will gradually stop being effective and it is unlikely to be as effective ever again.
The recent attention devoted to antimicrobial resistance has focused largely on creating incentives for the continued development of new antibiotics. Recent insights into the importance of a diversity of microbes for human health, however, suggest that it might be time to turn this strategy on its head. To maintain the efficacy of antibiotics, we need to pay attention to maintaining the diversity of good or harmless microbes that inhabit the planet and our bodies – and which happen to be treatable with antibiotics. These microbes are, in fact, the non-renewable resources on which we greatly depend, in the same way that we depend on productive soils and the provision of clean water.
The good, the bad, and the context-dependent
When we think about human health principally in terms of the effectiveness of antibiotics, it narrows our perception of the solutions. Such thinking focuses on disease control and does not allow for other ideas that could be crucial for reaching the full potential of human, animal, and environmental health. What’s more, focusing on antibiotic effectiveness ignores the fundamental fact that we as humans need microbes. To illustrate this point, we need to go to the place in the human body with the largest abundance of microbial life – the human tropical rainforest if you will: our guts.
We humans ourselves are a rich ecosystem made up of hundreds if not thousands of species of microorganisms.
While antibiotics are lifesavers when given at the right time in the right situation, they also cause major disturbances in our gut microbial ecosystem. Most antibiotics kill not only the “bad” bacteria but also the species in our bodies that at first appear to have no critical function, but actually help keep other “bad” microbes in check. For adults, such disturbances can, ironically, cause temporary dips of the immune system and secondary infections. In infants, growing evidence indicates that antibiotics can have long-term health effects, such as increasing the risk of autoimmune diseases.6 6. Schulfer, A., Blaser, M. J., 2015. Risks of Antibiotic Exposures Early in Life on the Developing Microbiome. PLoS Pathog. 11(7):e1004903. DOI: 10.1371/journal.ppat.1004903
Consider Clostridium difficile, sometimes called C diff, a bacterium that sickens half a million people and kills around 30,000 every year in the United States. The species, which lives in soil, water, and sometimes food, takes advantage of a weakened community of gut bacteria to colonise and infect the gut, causing severe diarrhoea. With this in mind, perhaps it is not surprising that most of the people who suffer from C diff infections do so after having taken antibiotics, when their usual assortment of gut bugs is completely off balance.
For a long time, the only tool available to treat C diff infections was more antibiotics. That solution can lead to a self-reinforcing loop of continuing infections, antibiotic prescriptions, and a degraded gut microbiome. However, in the past decade, a method long used in veterinary medicine finally broke through the barrier of social taboos and made it into human medicine: faecal transplants.7 7. Bakken, J. S., Borody, T., Brandt, L. J., Brill, J. V., Demarco, D. C., Franzos, M. A., Kelly, C., Khoruts, A., Louie, T., Martinelli, L. P., Moore, T. A., Russell, G., Surawicz, C., Fecal Microbiota Transplantation Workgroup, 2011. Treating Clostridium difficile Infection With Fecal Microbiota Transplantation. Clinical Gastroenterology and Hepatology 9(12):1044-1049. DOI: 10.1016/j.cgh.2011.08.014 Carefully transferring treated faecal matter, or “poo” if you prefer, from a healthy donor to a patient suffering from a C diff infection can restore a healthy microbiome, making the gut once again able to withstand and crowd out the C diff bacteria.
Addressing C diff required thinking outside the box, shifting the focus away from antibiotic effectiveness to other solutions. Such a shift should also increase the emphasis on disease prevention, through ensuring access to clean drinking water, improved sanitation, or vaccines, and that has implications for development organisations and global development.
Investments in these measures should lower the rates of infectious disease and are key to reaching the UN Sustainable Development Goals. In 2015, 2.4 billion people still defecated in the open, 400 million people lived without access to basic healthcare (including preventive healthcare), and 20% did not have access to the measles vaccine, according to the UN Development Programme. That year, 9% of the global population lived without access to safe drinking water; that amounted to 580 million people in Asia and Africa. Making progress in closing these development gaps is one crucial way of ensuring that the diseases we cannot prevent remain treatable.
The examples of C diff and the gaps in basic hygiene and sanitation show the potential value of viewing development from a pro-microbial perspective. That pro-microbial view may not only contribute to addressing the challenge of antibiotic resistance, but a whole set of development issues. Reframing microbes could even lead to a fundamentally different way of viewing our own species.
Microbes were the first group of species to exist on the planet. They live in our guts, on our skin, in our mouths, in places we don’t even think about all over our bodies. Microbes help our immune systems and researchers are looking for connections between our gut microbiomes and our brains, and even our moods. When we are healthy, and our microbes are healthy, everybody wins.
Researchers have been turning their attention to this symbiosis over the past decade. Among other efforts, Robb Dunn and his research group at North Carolina State University started the Belly Button Biodiversity project, exploring the rich and diverse microbe communities that inhabit our belly buttons. Their study found that an average person harbours more than 60 types of microbes in their belly button. And despite a small sample size of only 60 belly-button habitats, the team identified more than 2,000 types of microbes.8 8. Hulcr, J., Latimer, A. M., Henley, J. B., Rountree, N. R., Fierer, N., Lucky, A., Lowman, M. D., Dunn R. R., 2012. A jungle in there: bacteria in belly buttons are highly diverse, but predictable. PLoS ONE 7(11):e47712. DOI: 10.1371/journal.pone.0047712
On a larger scale, microbes are present in all environments, and not only in all animals, but also in water, soil, and plants. Plants, for example, require microbes that colonise their root systems, or rhizome, to get nutrients from soils, as well as microbes inside some of their cells. Microbes help decompose biological material, clean water, and produce almost half the oxygen we breathe. Ecologists would refer to these things as ecosystem services.
We humans ourselves are a rich ecosystem made up of hundreds if not thousands of species of microorganisms. That understanding could be a possible game changer in how we think of microbes and antibiotics.
New studies highlight not only the intimacy of human-microbe interactions, but also that our knowledge of how the microbiome impacts our health is far from complete.9 9. Lloyd-Price, J., Mahurkar, A., Rahnavard, G., Crabtree, J., Orvis, J., Hall, A. B., Brady, A., Creasy, H. H., McCracken, C., Giglio, M. G., McDonald, D., Franzosa, E. A., Knight, R., White, O., Huttenhower, C., 2017. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. DOI: 10.1038/nature23889 The studies suggest a more complex way of thinking about human-environment interactions, one that resilience researchers would call a social-ecological systems perspective, based on complex adaptive systems thinking. So, what can social-ecological resilience thinking offer for counteracting antimicrobial resistance?
Reconnect to your microbes
Overuse and misuse of antibiotics have eroded the resilience of the microbe microcosm.2 2. Søgaard Jørgensen, P., Wernli, D., Folke, C., Carroll, S. P., 2017. Changing antibiotic resistance: Sustainability transformation to a pro-microbial planet Antimicrobial. Curr. Opin. Environ. Sustain. 25:66–76. DOI: 10.1016/j.cosust.2017.07.008 10 10. Jørgensen, P.S., Wernli, D., Carroll, S. P., Dunn, R. R., Harbarth, S., Levin, S. A., So, A. D., Schlüter, M., Laxminarayan, R., 2016. Use antimicrobials wisely. Nature 537, 159–161. DOI: 10.1038/537159a Our capacity to respond to new disease outbreaks, globally and locally, is now severely threatened. The scale of international travel across the planet makes this an issue of global concern – microbes travel as fast as the rest of us, as they usually travel with us, in our guts or goods.
We know of several interventions that might work to rebuild this resilience and safeguard our microscopic companions, but there is no silver-bullet, one-size-fits-all solution. A combination of approaches can help turn things around.
For now, no organisation systematically monitors the impact of antibiotic resistance. There is no record of resistance-related deaths or of how the use of different antibiotics is contributing to microbial resistance to antibiotics. It is difficult to prevent resistance if societies are not clear on how it is developing and where it is spreading.
Research capacity to invent new treatments has dwindled. Rather than finding new antibiotics, the focus on preventing diseases needs to be front and centre. Prevention is the best cure, after all, and in that regard, sanitation and hygiene are crucial.
A number of taboos in society need to be broken to make way for new thinking around treatment. For example, faecal transplants – inserting the poo from a healthy person into the colon of a sick person – are an efficient way to restore the health of our gut microbes. But the “yuck” factor tends to prevent people from wanting to use such treatments.