Modern medicine has seen breakthroughs in life and longer lifespans to undo this stiff resistance due to excessive antimicrobial drug use and misuse, which is pushing microbes to evolve new ways of dodging human medicine. It is a new generation of resistant pathogenic microbes that is turning some of the things that were meant to be treatable into a potentially lethal scenario. The threat of antimicrobial resistance (AMR) was prominently named one of the most important challenges to global health, placing it on the World Health Organization’s (WHO) list of the top 10 threats to the survival of humanity.¹ And as a result, antibiotic-resistant infections have grown, as have the economic and financial costs that accompany them. The steep increase of AMR is expected to lead to 10 million people’s deaths in 2050.² The possibility of a world in which a routine operation and simple infections return to be life-threatening is no more a dystopian fantasy than the current one. And it is coming sooner than we think – this is something we need to start paying attention to now.

In this paper, we articulate a detailed overall response to AMR that draws upon a One Health framing. One Health recognizes that human, animal, and environmental health are inextricably intertwined and that the causes and consequences of AMR span across fields. We explore the interplay of incentives leading to resistance, not the least inappropriate antimicrobial use in health care and agriculture, and the ecological impacts of antimicrobial pollution. Additionally, the paper shows how new technologies, such as CRISPR/Cas9 gene editing and targeted nanotherapies, can transform how we combat AMR. Finally, the paper addresses how the concepts of holistic connectivity and joint, cross-sectoral action may serve as an inspiration and a future direction for mitigating the AMR crisis and securing global health for generations to come.

It represents the biggest public health threat facing the globe now, and the threat of undoing the fruits of 20th-century medicine may be realized with a ticking back of the clock to a pre-antibiotic “dark age.” One problem that does persist with medicine is that of AMR. However, while we celebrate the curative powers of antimicrobial medicine and the new antibiotic drug, and changing what was once dubbed as “miracle drugs,” “wonder drugs,” “magic bullets,” or “panaceas,” we have grown up to realize that cure is no longer a sure thing, and many infections pose a risk of relapse. It changed the ability to treat infections and permitted life-saving surgery and organ transplantation and now complex cancer treatment where otherwise it would not have been allowed. Modern life would be impossible without them. The problem of AMR, however, according to surviving doctors born in the Victorian era, is considered to be one of the biggest and most neglected challenges to global health security, which could undo the fruits of 20th-century medicine, roll back the gains of civilization, and return us to a pre-antibiotic dark age.

A crisis of epic proportions faces us. As good an overall measure of the human impact of AMR as any study was published in 2016 in the Lancet: The authors of the paper calculated that, in 2019, AMR caused 1.27 million deaths around the world. This is an even higher figure than those found for HIV/AIDS and malaria.³ They were stark reminders that we were not talking of some distant future threat but of a present reality and its devastating implications. But who knows, if this trend continues, by 2050, the world could have its very own zombie apocalypse. This is when the WHO projects AMR will kill an estimated 10 million people annually and take its place as the leading cause of death, surpassing even cancer.³

Besides its human cost, AMR is an economic time bomb: The recently published World Bank report predicts that AMR can be expected to lead to a worldwide economic recession as dramatic as the global financial crisis of 2008, with a disproportionate impact on low- and middle-income countries.⁴ It is estimated that by 2030, antimicrobial resistance (AMR) will push an additional 24 million people into extreme poverty, further exacerbating global health inequalities. One example is an infection caused by multidrug-resistant Acinetobacter baumannii, which has developed resistance to all available last-resort antibiotics, including last-generation carbapenems (see Figure 1). This graph was created using data from the ATLAS Platform (ATLAS Surveillance, 2020–2022).

Although biological mechanisms may be quite complex, the primary causes are also in many ways all too often deeply interlinked with human behavior and practice.⁵

Overuse and Misuse of Antimicrobials: The single most important cause of AMR worldwide is the misuse of antimicrobials in human and animal health.^6,7 This includes unnecessary prescription of antibiotics – often for viral infections where antimicrobials are sneither needed nor effective to treat and cure – that allow resistant bacteria to continue to spread. Indeed, a Pew study published in 2023 in JAMA Network Open revealed that nearly a third of antibiotic prescriptions in the US were inappropriate.⁸ This issue is further compounded by using antimicrobials as growth promoters and prophylactic agents in livestock and aquaculture, creating a reservoir of resistant bacteria that can transfer to humans.⁹

Lack of Infection Prevention and Control: Inadequate infection prevention and control measures in healthcare settings and communities contribute to the spreading of resistant organisms.¹⁰ This includes insufficient hand hygiene practices, improper sterilization of medical equipment, and inadequate sanitation infrastructure, particularly in resource-limited settings. A study by Casalini et al. demonstrated the positive impact of bundled interventions on quality-of-care indicators for Staphylococcus aureus bacteremia, highlighting the importance of a multifaceted approach to infection control.¹¹ As outlined in Table 1, such an approach will be key to how we respond to these and other drivers to slow the spread of AMR and preserve the effectiveness of antimicrobials for future generations.

The economic burden associated with AMR is large and multi-faceted, transcending immediate healthcare expenditure implications to affect productivity, economic growth, and global security. The failure to tackle this crisis is dire, affecting individuals, health systems, and the global economy.

The economic burden of AMR is large and multi-stakeholder; it goes beyond immediate healthcare costs to include foregone economic productivity and impediments to economic growth and global security. The failure to tackle this crisis has dire consequences for individuals, health systems, and the global economy.¹² This is further compounded by exorbitant healthcare costs related to the treatment of resistant infections, longer hospital stays, and increased morbidity and mortality – all threatening the sustainability of health systems and the economies relying on them.¹³ It also predicts that the long-term economic impact of AMR will increase rapidly and, if the present trends continue, will incur a death toll of 10 million people per year by 2050. In this regard, the important need for policy responses cannot be overemphasized in the battle to prevent this crisis from growing and to ensure a brighter future for all.¹⁴

Direct Costs: The financial strain of AMR is first felt within healthcare systems grappling with the increased costs of treating drug-resistant infections. More extended hospital stays, often required for patients battling resistant pathogens, significantly burden hospital resources and contribute to rising healthcare expenditures.¹⁶ This is further compounded with the usage of more expensive last-resort antibiotics, which are also often related to a higher level of toxicity and side effects. A 2022 Clinical Infectious Diseases study concluded that the annual cost of treating antibiotic-resistant infections in the US alone exceeded $4.6 billion.¹⁵ However, this only scrapes the tip of the iceberg.^16,17 In addition to direct healthcare costs, the overall economic implications of AMR include lost productivity due to illness and early death and significant economic costs associated with increased morbidity and mortality in the workforce, which could result in loss of gross domestic product (GDP) and a national security threat.^13,17,18

Indirect Costs: The true economic cost of AMR is much broader than just the cost incurred within the walls of the hospital; it affects individuals, communities, and national economies. Lost productivity due to prolonged illness and premature death is an enormous but generally invisible cost. The World Bank estimates that in 2050, AMR could lead to a loss of $3.4 trillion in global GDP.¹⁹ This economic fallout will be projected upon low- and middle-income countries, compounding isting inequalities and blocking development. Moreover, the threat of untreatable infections can upset global trade and tourism, as the fear of contagious outbreaks curtails travel or disrupts trade. This situation is only worsened by the fact that the economic consequences of AMR typically result in increased premiums by insurance companies and higher healthcare costs passed on to consumers, which, in the end, further straddles families and communities with financial burdens.¹³ In addition to the fact that infections resistant to treatment are increasing the financial burden on healthcare budgets, the development of new antibiotics and other therapies to treat resistant infections represents a significant investment with a great risk for sponsors in view of the many market dynamics and regulatory challenges. In addition, these antibiotics offer no immediate financial returns in a high-risk environment.²⁰ In this way, tackling the economic aspects of AMR is not just a healthcare issue but also an imperative global economic issue, and it needs collective action and investment at international, national, and community levels to avert potential collapse, thus safeguarding public health systems for future generations. As the costs of inaction mount and threaten global stability, this will also show the need for innovative financing mechanisms since the public and private sectors will have to come together to prioritize research and development for new antimicrobial agents, similar to the strategies used in other critical areas of public health.^4,13,17,21 However, the rapid growth of AMR without timely intervention and investment in antimicrobial stewardship jeopardizes decades of medical progress and puts us at risk of a world where routine procedures may become life-threatening, making it necessary to radically reconsider certain policies and strategic investments in order to avert this impending crisis and secure a more prosperous and sustainable future. Concomitantly, the economic implications of AMR go beyond the health sector and will pervade the global workforce, as the emergence of resistant infections is marked by lost productivity and increases in rates of absenteeism, and, therefore, further the problems of economies in recovering from the COVID-19 pandemic. Furthermore, the potential of AMR to cause drastic disruptions of the health workforce and general economic status should underline the urgent need for integrated approaches that include increased public awareness, education about the responsible use of antimicrobials, and robust strategies for the prevention of infection at all levels to avert these wide-ranging effects and ensure the health and general well-being of human beings, communities, and nations. The multiple effects of AMR on health systems, economies, and individual lives emphasize the need for immediate global action, including work towards sustainable strategies to prevent and manage AMR and to drive innovation in antibiotic development, including campaigns to raise awareness for the responsible use of antimicrobials, all of which will ensure the continued effectiveness of these major medical breakthroughs.^17,22–24

At a basic level, One Health recognizes the intricate interconnectedness of health for humans, animals, and our environment, and the mutuality of their well-being.²⁶ The methodological approach is underpinned by transdisciplinary collaboration and information-sharing among health scientists, veterinarians, ecologists, policymakers, and communities to mitigate or alleviate shared health threats, such as AMR.²⁷ By maximizing the health of humans, animals, and our environment, One Health aims to achieve the optimal health outcomes for all stakeholders.

A critical pillar of the One Health approach is fostering a culture of responsible antimicrobial use across all sectors. This requires comprehensive education and training programs tailored to different target audiences. Healthcare professionals need ongoing education on evidence-based prescribing guidelines, infection prevention and control measures, and the importance of antimicrobial stewardship.²⁸ Similarly, veterinary experts require training on prudent antimicrobial use in animal care, emphasizing reduced unnecessary antibiotic use in livestock and aquaculture.²⁸ Public awareness campaigns can empower individuals to make informed decisions about antibiotic use and understand their role in mitigating AMR.

This can be achieved through effective policy interventions that create an enabling environment for responsible utilization of antimicrobials, such as framing and enforcing regulations on antimicrobial use in human and animal health, incentivizing and accelerating research and development of new antibiotics and alternatives, and strengthening surveillance to monitor the emergence and spread of resistance organisms.²⁴ Given the globalization of AMR, global collaboration becomes imperative to approach these issues in a unified manner. For example, the WHO’s Global Action Plan on Antimicrobial Resistance provides a roadmap for joint action and resource-sharing among nations.²⁹

Following a One Health approach and incorporating these holistic strategies will move us closer to a future where antimicrobials are still valuable tools for safeguarding human and animal health.

Scientists are actively investigating a range of promising alternatives to conventional antibiotics:

Antimicrobial Peptides (AMPs): These small proteins are found ubiquitously in nature. They are broad-spectrum antimicrobials and so would help address the problem of antibiotic resistance.³⁰ Because of the multivalent action of AMPs on their bacterial targets, it is difficult for resistance to occur.

Phage Therapy: In this strategy, viruses that infect and kill bacteria (bacteriophages) are utilized against bacterial infections. This therapy loses out by a hair because it still depends on antibiotics to get rid of bacterial exotoxins. However, the virus/bacteria combination is a potential response to multidrug-resistant infections, and, in theory, allows for targeted elimination of only the bad bacteria.³¹

Anti-virulence Strategies: Unlike the anti-bacterial approaches described above, these therapies do not kill bacteria, but rather impair pathogenic bacteria by disarming their virulence factors so that they are no longer harmful to the host,³² an approach that could reduce antibiotic selection for resistance.

Cutting-edge technologies are revolutionizing the development of new antimicrobial agents:

CRISPR/Cas9: This revolutionary gene-editing tool holds immense potential for combating AMR. CRISPR/Cas9 can be used to develop highly specific antimicrobials that target essential genes in resistant bacteria, potentially overcoming existing resistance mechanisms.³³

Nanotechnology: Nanoparticles offer a versatile platform for delivering antimicrobial agents with enhanced efficacy and targeted delivery. Nanoparticle-based therapies can improve drug solubility, enhance penetration into bacterial biofilms, and reduce off-target toxicity.^12,34

The role of public awareness-raising in promoting appropriate antimicrobial use and limiting the occurrence and spread of AMR cannot be underestimated. Responsible practices should be promoted through microbial-ecology-based educational campaigns concentrating on:

Value and Threat: Why antibiotics are precious and how AMR poses a threat.

Ensuring Appropriate Antibiotic Use: Enlightening people on what illnesses require antibiotics and the need to stick to professionals’ instructions.

Preventing Infections: Stressing the importance of handwashing, vaccination, and other sources of infection, reducing the demand for antibiotics.

The WHO offers some valuable resources and guidance for public awareness campaigns relating to AMR.³⁵

In addition to establishing behavioral protocols to mitigate the development of resistance, healthcare professionals must educate patients about the proper use of antimicrobials:

Shared Decision-Making: Involving patients in decisions about antibiotic use, considering their preferences and values.

“Adherence”: Focus on the emphasis of the necessity of completing the course of antibiotics, irrespective of symptom improvement.

Addressing AMR requires a One Health approach that fosters collaboration across sectors:

Health care: Develop antimicrobial stewardship, enhance infection prevention and control, and incorporate judicious prescribing.⁵

Agriculture: Cutting antimicrobial use in livestock and aquaculture, introducing biosecurity to stop pathogen spread, and developing alternative growth promoters.⁵

Environment: Recovering and mitigating antimicrobial residues in the environment, finding ways to improve sanitation and hygiene, and increasing appropriate waste management pathways.⁵

Perhaps, one of the greatest ethical challenges going forward will be how to accommodate individual patient interests with the need to preserve the effectiveness of antimicrobials for the community. On the one hand, a necessary response to drug resistance is to restrict antibiotic use. However, it can still be a wrench when there is an individual patient who might possibly benefit from the use of an antibiotic (even if the indication is debatable). This highlights the fact that we also need more fine-tuned ethical frameworks, which are able to help us guide decision-making in the face of uncertainty. They will have to weigh up potential benefits for the individual when a patient treatment option becomes available, against the possibility that such use will compromise future treatment options for us all.³⁶

The overall ethical complexity of the situation is deepened by the unequal distribution of the burden of infectious diseases and access to health care across the globe. High-income countries are grappling with overprescribing and healthcare-associated infections, while low- and middle-income countries often suffer from poor availability of existing antimicrobials, thus perpetuating an undertreatment vicious cycle that leads to increased resistance.³⁷ Both equitable distribution of existing antimicrobial therapies and shared collaboration to foster access to new antimicrobials are crucial, especially in light of healthcare infrastructure inequalities and affordability concerns. This again requires international collaboration and researching of resources to enable the distribution of new therapies in scenarios where access to healthcare systems is not guaranteed.

The appearance of AMR brings home the need for stewardship – for all of us to use antibiotics responsibly. This includes individual stewardship of using antibiotics as directed by your healthcare provider and taking full courses prescribed (yes, even if you start to feel better), and the stewardship of healthcare providers to prescribe antibiotics judiciously and to ensure proper stewardship for their patients.³⁸ The stewardship responsibilities of the agricultural community include a reduction in the use of antimicrobials in livestock and in sustainable farming practices that reduce the spread of resistant organisms.³⁸

Ethical issues figure prominently in the development of new antimicrobial therapies. The desperate need to discover new treatments must be balanced with the need for appropriate development and clinical uses – access to new drugs around the world, reducing clinical trials conducted in developing countries, and maintaining transparency in research funding and data sharing.³⁹

Public education has a place in the ethical response to AMR, too. Broadening societal awareness of the problem, its implications if nothing is done, and the value that might be gained through collective action promotes responsible antimicrobial use and supports AMR mitigation policies.⁴⁰

There are no simple answers to the ethical challenges posed by AMR. Resolving these issues calls for continuous discussion, interdisciplinary collaboration, and the development of a social justice agenda. By bringing ethical reflection to bear on policy development, research, and clinical practice, we might someday achieve the goal of a world where antimicrobial therapies continue to protect human health.⁴⁰

AMR is also an endemic global health problem, exacerbated by a perfect storm of antibiotic overuse and misuse, poor infection control, and the paucity of new drug antibiotics.

The costs of doing so are huge: Hundreds of millions of lives, trillions of dollars of economic activity and, most importantly, massive disruption to society.

There are no silver bullets – we need a multi-pronged approach: AMR demands an approach that encompasses antimicrobial stewardship, infection prevention, new drug development, international collaboration, and public education.

Innovative solutions are key: Maintaining our capacity to produce novel antimicrobial therapies, such as phage therapy and AMPs, and the development of novel technologies, such as CRISPR/Cas9 and nanotechnology, are of utmost importance.

It is important to emphasize public awareness: Training the public about the need for judicious antibiotic use, hand and cough hygiene, and the significant threat posed by AMR will help cultivate a culture of stewardship.

No more declaring an end to communism. We must work together globally. AMR does not respect national boundaries, and we need international collaboration on discovery, surveillance, and policy to tackle this shared menace.

What is needed now is a collective awareness of the threat posed by AMR, a willingness to learn, a spirit of cooperation, and momentum. Governments, care providers, equestrian athletes, industry leaders, researchers, and civilians have all invested heavily in the preservation of these medicines that save lives. Sustainability demands a holistic, One Health approach also mindful of the connection between human, animal, and environmental health. Our response must recognize the shared burden – and take collective action – before it is too late.

The post-antibiotic future is not written but one that we can help shape. If we act boldly, collaboratively, and with mutual responsibility, we can help ensure that our critical weapons in the battle against infectious disease remain with us for the coming decades.