Executive summary

Antimicrobial resistance (AMR) is a growing global health crisis that threatens the effectiveness of treatments for infections in humans, animals, and plants.  Although it receives significant attention in the context of global health, its relevance in the context of biosecurity and pandemic preparedness is less frequently discussed.

This post aims to explore the growing threat of antimicrobial resistance through the lens of biosecurity and pandemic preparedness.

Basic concepts of AMR are discussed, including how microorganisms evolve resistance to drugs and how human overuse and misuse of antibiotics accelerate this process, as well as the current global impact of AMR. Its importance as a global health threat, already causing millions of deaths, and its projected future trajectory, which could result in 10 million deaths annually by 2050, will be highlighted.

The post explores the importance of AMR in the context of pandemic preparedness by discussing whether AMR could lead to a catastrophic bacterial pandemic and how antibiotic resistance may amplify the severity of viral pandemics through secondary infections.

It concludes that while AMR is unlikely to directly trigger a catastrophic bacterial pandemic, it could exacerbate the impact of viral pandemics by making secondary infections harder to treat.

Improving diagnostics, strengthening surveillance, and developing robust (“pandemic-proof”) antibiotic stewardship programs were highlighted as important components to address both the slower moving threat of antibiotic resistance and the sudden emergence of pandemic pathogens.

Understanding the AMR crisis - What is AMR and why does it matter?

What is Antimicrobial resistance?

Antimicrobial resistance (AMR) occurs when disease-causing microorganisms evolve to survive the medicines designed to kill them or stop their growth. This affects our ability to treat infectious diseases in humans, animals, and plants, as microorganisms can become resistant to antibiotics (for bacterial infections), antivirals (for viral infections), antifungals (against fungi), and antiparasitics (against parasites). Without effective treatment these infections are more likely to spread, cause severe illness, disability or death.

AMR is considered a "One Health" challenge because microbial infections affect humans, animals and plants.  When resistance develops in one setting – whether in human healthcare, livestock farming, or crop agriculture – it can spread to affect all others. This interconnected nature means that addressing AMR requires coordinated surveillance and action across human medicine, veterinary care, and environmental health sectors.

The development of resistance is a natural evolutionary process. Microorganisms can acquire resistance genes from other microbes or randomly develop genetic changes that sometimes help them survive antimicrobial drugs.^[1] They might for example develop ways to destroy the drug, to pump it out of their cells, or to modify their structures so the drug cannot affect them anymore. Human overuse and misuse of antimicrobials, particularly in healthcare and agriculture, creates strong selective pressure that favors resistant organisms which leads to increased resistance rates, which means an accelerated development and spread of resistance (O'Neill, 2016). 

When considering the treatment of patients,  it is important to distinguish between primary resistance,  which occurs when a microbe is resistant to a drug from the very beginning of an infection, and secondary resistance, which develops during the treatment and is often associated with incomplete or inappropriate use of antibiotics. This distinction highlights the need to identify the pathogen causing the infection in order to make informed decisions about which antimicrobial to prescribe by quickly determining whether an infection is likely to respond to specific treatments.

How antibiotic resistance is affecting us today

While antimicrobial resistance includes various types of microorganisms becoming resistant to different drugs, bacterial resistance accounts currently for the biggest share of the problem and the problem assessment and strategies for antibiotics can on a general level be applied for other antimicrobials as well (O'Neill, 2016).^[2] 

In 2019, bacterial antimicrobial resistance was associated with 4.95 million deaths globally, including 1.27 million deaths directly attributable to bacterial AMR^[3].  The impact beyond mortality was evaluated to 192 million disability-adjusted life years (DALYs) associated with resistance and 47.9 million DALYs directly attributable to antibiotic resistance. This puts the DALYs estimates that are associated with antibiotic resistance in a comparable order of magnitude to those for ischaemic heart disease (188 million) or COVID-19 (212 million) in 2021. 

Even though the threat is global, low-income countries are affected more seriously. While high-income countries experienced about 56 AMR-associated deaths per 100,000 deaths, this rate nearly doubled to 99 deaths per 100,000 in Sub-Saharan Africa. This disparity reflects differences in healthcare infrastructure, access to appropriate antibiotics, and infection prevention capabilities.

AMR has implications for medical treatments that leave patients more vulnerable to bacterial infections - implications that many might not directly associate with antibiotics. When antibiotics lose effectiveness, cancer treatments and organ transplants become more dangerous due to increased infection risks for immunosuppressed patients. Similarly, invasive surgeries, including routine procedures like cesarean sections, carry higher risks. The situation is particularly critical for intubated patients in intensive care facilities, who face elevated infection risks from ventilation systems (Antimicrobial resistance Factsheet 2023; O'Neill 2016).

The economic impact is already substantial, with excess costs estimated at 20 billion USD annually as of 2013. Due to these severe global health impacts but more gradual and less visible spread compared to acute disease outbreaks AMR has already been described as a "silent pandemic”. However, these current challenges may pale in comparison to future projections if AMR continues to spread at its present rate.

Tomorrow’s crisis: Projecting the future impact of antibiotic resistance  

If AMR continues to spread at current rates, projections suggest a dramatic increase in both human and economic costs. The influential O'Neill report estimates that by 2050, AMR could cause approximately 10 million deaths annually - surpassing cancer (8.2 million deaths) as a leading cause of death globally. The same report projects cumulative economic damage of 100 trillion USD by 2050.

However, it is important to note that these estimations received some critique pointing out the inherent complexity of long-term forecasts about AMR and the challenge to quantify the associated excess morbidity and mortality.^[4]

Even though the exact numbers might be debated, there is broad scientific consensus that AMR poses a growing threat to global health systems. Without effective interventions, there is the risk of entering a "post-antibiotic era" where common infections once again become life-threatening and many modern medical procedures become too risky to perform. AMRs implications for biosecurity and pandemic preparedness are less frequently discussed. This article explores AMR through the lens of pandemic preparedness by examining two questions: first, whether AMR itself could trigger a catastrophic bacterial pandemic, and second, how antimicrobial resistance might amplify the severity of viral pandemics through secondary bacterial infections.

AMR and pandemic preparedness  

Could drug-resistant bacteria trigger the next pandemic?

To understand whether antibiotic-resistant bacteria might cause catastrophic pandemics^[5], we need to understand what characteristics a pathogen with pandemic potential has and assess to what extent these characteristics are fulfilled by antibiotic resistant bacteria.

What makes a superbug? Understanding pathogens with high pandemic potential  

There are several properties that enable quick and widespread transmission of pathogens which enhances their pandemic potential^[6].  

The most essential feature is an efficient transmission mechanism, with respiratory transmission routes being particularly effective in human to human transmission due to the difficulty of containment (inevitability of breathing). While water-borne pathogens or pathogens following fecal-oral transmission routes like Vibrio cholerae can cause serious outbreaks, these can generally be contained through modern infrastructure and public health measures that improve sanitation. 

To have a high pandemic potential the pathogen must also be able to establish infection in a significant portion of the population, which typically requires the ability to utilize common human cellular receptors, the ability to overcome or evade host immune responses and a lack of pre-existing immunity in the population.

Pre-symptomatic transmission, which means the pathogen can spread before the onset of symptoms, dramatically increases pandemic potential, because it makes traditional containment strategies like symptom-based screening ineffective.

Viruses, particularly RNA viruses, possess many of these properties. They typically demonstrate rapid replication rates, fast transmission and genetic plasticity, which allows swift adaptation to new hosts and evasion of immune responses. Their small size and simple structure often enable efficient airborne transmission, as seen with influenza and SARS-CoV-2. Additionally, many viruses can spread during a pre-symptomatic phase, making containment particularly challenging.

Bacteria, while generally more robust in the environment, typically spread less efficiently person-to-person through respiratory routes. Their larger size makes airborne transmission more difficult, and their replication rate, while still rapid, is slower than that of viruses. However, bacteria possess other concerning characteristics: they can form protective biofilms and share acquired resistance genes, contributing to the emergence of multiresistant bacteria.

Lessons from history: When bacterial plagues changed the world

Even though bacteria generally have a lower pandemic potential than viruses, they demonstrated their ability to cause devastating pandemics with lasting impact throughout history. The most prominent example of a bacterial pathogen with pandemic potential is Yersinia pestis, which can manifest in different forms of plaque (bubonic, septicemic and pneumonic) depending on route of infection (Yang, 2018). While each plague pandemic had significant death tolls, the second plague pandemic during the middle ages prominently known as the “Black death” illustrated the potential of bacteria to cause catastrophic pandemics best. Within only 4 years between 1347-1351 the “Black Death” killed an estimated quarter to third of Europe's population influencing major social, economic and religious transformations.

Since scientists identified that the disease spreads primarily through fleas from infected rodents, targeted prevention through pest control and insecticides was possible. Furthermore, medical advancements provided both preventive measures (vaccines) and treatments (antibiotics like streptomycin and tetracycline).

Today plague is classified as a re-emerging infectious disease because the occurrence of large scale epidemics in countries without animal reservoirs for Yersinia pestis is unlikely. However, in affected countries there is a risk for the emergence of antibiotic resistance.

Another prominent example of a bacterial pathogen with pandemic potential is Vibrio cholerae, a water-borne pathogen infecting people via contaminated food or water. Thanks to basic improvements in sanitation - like proper sewage systems - its ability to spread has been dramatically reduced in many parts of the world.

Both examples illustrate that severe bacterial pandemics are possible, however less likely today. Modern infrastructure and improved hygiene help to prevent transmission and with antibiotics infections can be treated when they occur. However, rising antibiotic resistance threatens to render infections untreatable.

Superbugs Unleashed: Assessing the risk of a “superbug pandemic”

To understand the risk of a “superbug pandemic”, we first need to understand what is meant with "superbugs." It is a term used to describe microbes that developed a resistance to multiple drugs which were previously effective in treating infections. The level of resistance can vary^[7]:

• Multidrug-resistant (MDR): Bacteria are resistant to at least one agent in three or more antimicrobial categories. While concerning, these infections often remain treatable with alternative antibiotics.
• Extensively drug-resistant (XDR): Bacteria are resistant to at least one agent in all but one or two antimicrobial categories, which severely limits treatment options.  
• Pan-drug-resistant (PDR): Bacteria are resistant to all available drugs in all antimicrobial categories, making these infections untreatable with current antibiotics and thus most dangerous.

Currently, the most concerning resistant bacteria, like the so-called ESKAPE pathogens, primarily spread in healthcare settings rather than in communities. This inefficient human to human transmission in healthy individuals makes antibiotic resistant bacteria rather unlikely to cause a sudden, explosive pandemic like respiratory viruses.

This could change though if bacteria would acquire more efficient transmission capabilities allowing rapid spread in community settings instead of being confined to healthcare environments. While natural evolution of these capabilities seems unlikely, advances in genetic engineering could allow the design of bacteria with enhanced transmission capabilities. Nevertheless, the risk of a catastrophic pandemic caused by antibiotic-resistant bacteria appears to be lower overall compared to the threat by viruses.

But even during a viral pandemic antibiotic resistance should not be dismissed. During the COVID-19 pandemic resources were diverted from AMR surveillance and control, while at the same time the antibiotic use increased, which increased the risk to accelerate antibiotic resistance development even more. Studies investigating a direct link between COVID-19 and accelerated antibiotic resistance however have not been conclusive so far.

The Hidden threat of Bacterial Secondary infections

Thinking about pandemics, the focus is often on single pathogens. However, the interaction between different types of infections – particularly viral and bacterial infections – can impact the severity of the pandemic.

During viral infections like influenza or COVID-19, patients often become vulnerable to bacterial infections, which can occur simultaneously (Co-infections) or one after the other, meaning bacteria infect someone who is already weakened by a viral infection (Secondary infections).

Viral infections can damage protective barriers in our respiratory system and weaken our immune response, creating opportunities for bacteria to establish infections that might not have occurred in a healthy person. The virus weakens the body's defenses e.g. by damaging the cell lining in the respiratory tract, and bacteria like Streptococcus pneumoniae (which normally cannot get past these defenses) can then slip through these breaks and cause a secondary infection (in this example pneumonia).

The potential deadly impact of bacterial Secondary infections became apparent looking at an analysis of the 1918 influenza pandemic, which observed that the majority of deaths were likely caused by secondary bacterial pneumonia. During the 2009 H1N1 influenza pandemic, bacterial infections were found in 30-55% of fatal cases. And also during the recent COVID-19 pandemic bacterial secondary infections (often by multidrug resistant bacteria) were significantly correlated with severe and deadly cases.

These examples show that bacterial secondary infections can exacerbate the impact of a viral pandemic by increasing the risk for severe morbidity and/or mortality.

While antibiotics are available today, unlike in 1918, that help reduce the impact of bacterial secondary infections, rising antibiotic resistance might lead to critical situations where secondary bacterial infections cannot be treated effectively, leading to higher morbidity and/or mortality during a viral pandemic. Thus, it is important to consider antibiotic resistance also in the context of pandemic preparedness.

Fighting back: Solutions to combat drug resistance and implications for pandemic preparedness

As we have seen, the relationship between AMR and pandemic threats is multifaceted. Current evidence suggests that while antibiotic-resistant bacteria pose a very serious global health threat, they are less likely than viruses (especially RNA viruses) to cause a catastrophic pandemic. This is primarily because bacteria generally spread less quickly and efficiently, and modern hygiene and sanitation effectively minimize bacterial pathogen transmission. However, this risk assessment would change dramatically in case of genetically engineered bacteria with more efficient transmission capabilities. The likelihood of such a scenario though remains unclear.

The importance of AMR in pandemic preparedness extends beyond the direct threat of resistant bacteria. Historical data showed that secondary bacterial infections can exacerbate pandemic mortality, and antibiotic resistance could make these infections harder to treat. While the exact contribution of resistant bacteria to pandemic mortality remains uncertain, this connection has important implications for preparedness efforts.

These findings help explain why the biosecurity community, especially groups focusing on global catastrophic biological risks, prioritize preparation for RNA viral threats and prevention of genetically modified pathogens with enhanced pandemic potential.

Still, the impact of a less sudden but nevertheless severe "silent pandemic", which makes routine medical procedures increasingly risky, is not negligible and should be addressed. There is a range of possible solutions: the development of new antibiotics (using artificial intelligence), bacteriophage therapy, vaccines, CRISPR-based antibacterials, microbiome-based approaches or antimicrobial peptides. Developing these solutions requires robust partnerships across research, industry, and policy. This is especially true for the development of new antibiotics which needs political incentives, because it is a scientifically challenging and expensive process with low expected investment returns (as antibiotics should not be used on a large scale according to stewardship programmes and may become obsolete due to developing resistance quickly).

Beyond these solutions, three crucial areas of our health infrastructure need strengthening: diagnostics, surveillance, and antibiotic stewardship.

Rapid and accurate diagnostics are the foundation of effective response to both routine infections and pandemic threats. As diagnostic technologies improve, their implementation and use should become standard practice globally. During a pandemic, the ability to quickly distinguish between viral and bacterial infections and identify the exact pathogen becomes crucial for proper treatment decisions. Next-generation diagnostic tools, including whole-genome and metagenomic sequencing, should be viewed as essential components of pandemic preparedness infrastructure, not merely clinical tools.

Surveillance systems, which are closely related to fast and accurate diagnostics, represent another critical area where AMR and pandemic preparedness efforts overlap naturally. Sustainable worldwide surveillance of antibiotic consumption and resistance trends helps to anticipate emerging threats and prevent antimicrobial shortages. The Global Antimicrobial Resistance and Use Surveillance System (GLASS) is a global WHO initiative aiming to standardize the collection, analysis and interpretation of AMR surveillance data, including epidemiological, clinical, and population-level data. Since effective global surveillance data is also a critical component of defense against emerging viral pathogens there are efforts to establish a global disease surveillance infrastructure to support pandemic preparedness. As surveillance is central to the control of any infectious disease, it would be exciting to explore potential synergies between the different surveillance infrastructures.

Another important implication of AMR for pandemic preparedness is the need to maintain effective antibiotic stewardship even during crisis situations like pandemics. The COVID-19 pandemic, leading to increased antibiotic use and potentially accelerated resistance, revealed how easily stewardship programs can be disrupted. Robust stewardship protocols that balance immediate patient needs with long-term resistance concerns need to be developed as part of pandemic preparedness plans.

While AMR may not be the most likely cause of a catastrophic pandemic, its potential to exacerbate pandemics and its ongoing toll on global health make it a crucial consideration in biosecurity and pandemic preparedness. By viewing diagnostic, surveillance, and stewardship programmes as integral parts of pandemic preparedness rather than just tools for managing routine infections, investments in these crucial areas can be better justified and coordinated. This integrated approach strengthens our defenses against both the slow-moving threat of antibiotic resistance and the sudden emergence of pandemic pathogens.

Acknowledgements

I wrote this post as my BlueDot Biosecurity Fundamentals course project. I am grateful for the valuable opportunity to acquire an interdisciplinary overview of the field of biosecurity and pandemic preparedness. And I want to thank everyone in my cohort for the engaging discussions and the valuable feedback and encouragement during the project phase.  

1. ^{^}

    Additionally to this developed resistance, it is important to note that different types of bacteria are naturally non-susceptible to certain antibiotics simply because of their basic structure. Just as different locks need different keys, different types of microbes require different types of drugs. For instance, some antibiotics can't penetrate the outer membrane of certain bacteria, making these bacteria non-susceptible to those drugs, not by developing resistance but by their very nature.

2. ^{^}

    While antiviral resistance is also important for pandemic preparedness - particularly if an emerging virus develops resistance to previously effective treatments - this text focuses on antibiotic resistance as the currently most prevalent form of AMR. The impact of antimicrobial resistance during a pandemic can be modeled as: drug availability × degree of resistance × proportion of preventable deaths × baseline mortality, highlighting how resistance could severely compromise our ability to respond to viral outbreaks.

3. ^{^}

    Associated deaths are determined using a counterfactual of no infections, while attributable deaths are defined by a counterfactual of treatable infections.

4. ^{^}

    A recently published systematic analysis of AMR burden came to an estimate of 8.22 mio deaths associated with AMR in 2050.  

5. ^{^}

    The term catastrophic pandemic is not strictly defined. Here it refers to a pandemic that could lead to “sudden, extraordinary, widespread disaster beyond the collective capability of national and international governments and the private sector to control” resulting in a “great loss of life, and sustained damage to national governments, international relationships, economies, societal stability, or global security". Following the John Hopkins Center for Health Security’s working definition of global catastrophic biological risks.  

6. ^{^}

    For a detailed discussion of pandemic potential see “The Pathogenic Potential of a Microbe”.

7. ^{^}

    In the clinical context it is also important to consider the toxic side effects of antibiotics that are used to treat infected patients. To account for different toxicity levels of different antibiotics the term Difficult-to-treat resistant (DTR) was introduced for Bacteria that are resistant to all standard first-line, lower-toxicity antibiotics.