Pathogenic bacteria that cause infectious diseases have posed some of the greatest threats to human survivorship. These infamous bacterial diseases include tuberculosis, anthrax and pneumonia. Fortunately, modern medicine has developed a miracle drug to fight bacterial infections — antibiotics.
Antibiotics are particularly powerful because the medication targets and restricts bacterial cell functions, either immobilizing their spread or killing them completely. The first antibiotic created was Penicillin, invented by physician and microbiologist, Alexander Flemming, in 1928.
Dr. Mukherjee, the author of the Pulitzer Prize winner, The Emperor of All Maladies, concludes that, “Penicillin kills the bacterial enzymes that synthesize the cell wall, resulting in bacteria with ‘holes,’ in their walls. Human cells don’t possess these particular kinds of cells, thereby making penicillin a magic bullet”. Penicillin was revolutionary because it was the first time in history that there was a cure for infectious bacterial diseases. The efficacy of this new antibiotic had a monumental impact on World War II by controlling bacterial infections. During war, infectious diseases were often referred to as the “third army” because disease was a primary threat to soldiers. The unsanitary conditions, nutrition, overcrowding and open wounds created an ideal environment for bacterial diseases to thrive. “In World War I the death rate for bacterial pneumonia was 18% and in World War II it was less than 1%.” After World War II penicillin was being manufactured by the billions every month.
Ever since its introduction, penicillin has become the “magic bullet” in medicine. However, the medical world realized it would not last forever. Alexander Flemming accepted the Nobel prize warning generations to come that the overuse of penicillin will cause bacterial resistance. The magic bullet, antibiotics, would become an old-fashioned bayonet against modern nuclear weapons – resistant bacteria.
Bacterial infections can become resistant to antibiotics. Essentially, the process begins with antibiotics killing the microbes that are causing the infection. Then, the fraction of those microbes that survive the antibiotic treatment are naturally selected for the genes that make them resistant. As such, the presence of antibiotics increases the propagation of the surviving microbe, creating generations of antibiotic-resistant bacteria.
The new generation of antibiotic-resistant bacteria essentially outsmarts the drug through the process of evolution. Therefore, the increasing usage of antibiotics generates new strains of antibiotic-resistant bacterial infections. Many bacterial strains have not only become resistant to one antibiotic but have become multidrug-resistant.
Consequently, the world has moved into an era of pan-resistant infections, where microbes are no longer just multidrug-resistant, they are resistant to all available antibiotics. The drug that once protected and saved millions of lives has become a threat due to its overuse and misuse.
Antimicrobial resistance (AMR) and Antibiotic resistance (AR) is the global silent pandemic.
Antimicrobial resistance is a term that captures a broader range of infections caused by other microbes and is used in conjunction to antibiotic resistance. Millions of people die from antimicrobial resistance annually. The World Health Organization (WHO) published in 2019 that AMR contributed to 4.95 million deaths, including 1.27 million deaths where AMR was the direct cause of death. The WHO has declared AMR as “one of the top 10 global public health threats facing humanity.”
Antibiotics are notoriously inappropriately prescribed. C. Lee Ventola, a highly cited researcher on drug response, has uncovered that “treatment indication, choice of agent, or duration of antibiotic therapy is incorrect in 30% to 50% of cases” in the United States. He also highlights that 30% to 60% of antibiotics prescribed in intensive care units (ICUs) follow suit.
Antibiotic prescriptions and over-the-counter antibiotics are unregulated in many countries. Antibiotic resistance is largely attributed to the overuse and misuse of antibiotics. Antibiotics have become a convenient catch-all drug that is commonly prescribed for unnecessary treatments. Antibiotics accessibility, economic costs and lack of new advancing antibiotic research in the medical and pharmaceutical sectors contribute to its misuse.
The antibiotic resistance issue is defined by its complexity and is in need of progressive, multifaceted solutions that will require the cooperation of many international actors.
The fight against antibiotic resistance needs new global economic incentives for drug development, a reimagined advocacy viewpoint and an approach to stimulate awareness and cooperation.
Modern medicine has created some of the most revolutionary achievements of mankind. The twentieth century has ushered in futuristic genetic engineering, novel immunotherapies, RNA vaccines and numerous developments in all medical specialties — antibiotic resistance is threatening these achievements.
The WHO states that organ transplantations, chemotherapy and surgeries such as caesarean sections become much more risky and dangerous without effective antibiotics for the prevention and treatment of infections that arise from such procedures.
Re-imagined Awareness Platform
People from all walks of life are affected by antibiotic resistance but cancer patients are on the frontlines and are one of the most vulnerable populations.
Bacterial infections are the second leading cause of death in cancer patients. Unfortunately, many people are not strangers to the painful treatments and strenuous fights against cancer. Globally, it was estimated by the Worldwide Cancer Research Fund in 2020 that there are 18.1 million cancer patients. Cancer patients endure treatments that kill both cancerous cells and healthy cells, compromising their immune system. Furthermore, much of their care is provided in hospitals, where hospital-acquired infections (HAI’s) are a significant concern. Constant invasive visits that require puncturing skin for IV lines or the use of IV ports, surgery recovery, wound redressing and being present in an environment that treats some of the harshest multi-drug resistant infections makes cancer patients highly susceptible to HAIs.
Kevin Outterson is the Executive Director at CARB-X, Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, a global nonprofit partnership and his research focuses on global antibacterial innovation. He is also a professor of Health and Disability Law at Boston University. He published a review with other scientists that addressed the issue of HAIs and antibiotic resistance in the Clinical Journal of the American Cancer Society. In a podcast interview with the Union for International Cancer Control, Outterson discussed the increased dangers of AMR to cancer patients.
“Data shows that while antimicrobial resistant superbugs are a problem for everyone, for people with cancer, the risks are really three times higher that they’ll get a fatal infection from these superbugs,” Outterson said. He highlights that innovative cancer treatments have advanced so far that we can’t have the progress “undermined by the old foe of infection. ”
This point can be extended to how society has come so far in medical science that there is no time to be defeated by pan-resistant superbugs.
Cancer patient communities have developed many awareness groups that have contributed to the demand for new treatments. Money is being pipelined into research funds and cancer institutes. There is a lot of awareness surrounding the cancer community, which is why there is a demand for new drugs.
Cancer patient communities and advocacy groups work hard to spread awareness. Every month on the calendar is attributed to the awareness of different cancer types. The assortment of colorful ribbons divides cancers by where it was initially localized. However, that very ribbon no matter what color, symbolizes a plethora of support and unity for cancer patients.
There isn’t the same caliber of support and awareness for antibiotic resistance. The silent pandemic cannot remain quiet.
AMR poses a threat to cancer treatments and many people are unaware of this. The Union for International Cancer Control is striving to “sensitize” and educate the cancer community to the AMR threat. Cancer patients and supporters could become the global ambassadors for antibiotic resistance advocacy. They have a strong base to instill action and awareness for antibiotic resistance.
If health advocacy groups could implement AMR awareness in their programs and platforms, the impact would be monumental. Currently, there are some movements to spread awareness such as the global campaign, such as World AMR Awareness Week. However, AMR awareness requires a larger approach because it affects everyone. Imagine if every medical condition organization embedded AMR awareness in its mission. Kevin Outterson comments that not many patients identify as “I’m a survivor from a drug-resistant infection,” however, a wide range of patients would fall under this category. Countless patient groups rely on antibiotics, to unite those groups with the cancer community could change the fate of antibiotic resistance through awareness.
There needs to be a public outcry, just as the cancer community has fought for preventative measures to ensure others avoid cancer, such as HPV vaccinations, wearing sunscreen and laws surrounding cigarette usage. The mobilization of these patient groups that already have an established platform could make a significant difference in both raising awareness and mobilizing funding for antibiotic research and solutions.
Antibiotic Resistance Research Pipeline and Economy
The antibiotic research communities are described by Outterson as looking “over longingly at the pipeline and the money going into cancer, ” Outterson said. Compared to the revolutionary research being done in the cancer industry, the antibiotic industry has fallen short. The predominant cause for this discrepancy is lack of funding.
The science behind both cancer research and antibiotic research is remarkable. Science is not a limiting factor for research in the antibiotic field, it is that society does not expend money or resources for antibiotic development as if they are valuable.
Antibiotics are relatively cheap in comparison to cancer treatments as common antibiotics are mass-produced. However, the WHO states that, “just 27 new antibiotics for the most threatening infections are in the clinical trial stage of drug development. In contrast, there were more than 1,300 cancer drug trials in 2020.” To further extend this alarming condition, the WHO only recognized two antibiotics to be effective for surviving antimicrobial-resistant bacteria.
The underlying issue is that there is not enough research going into the solution for antibiotic resistance. Internationally, there was only one antibiotic, “cefiderocol, that was approved to treat the superbugs on WHO’s most critical list.” The recently published urgent threat multi-resistant bacteria and fungi include Carbapenem-resistant Acinetobacter, Candida auris, Clostridioides difficile, Carbapenem-resistant Enterobacteriaceae and Drug-resistant Neisseria gonorrhoeae. Carbapenem-resistant Acinetobacter, which cause pneumonia, bloodstream infections, urinary tract infections and wound infections, especially in patients receiving care in intensive care units. It is also one of the many resistant strains cancer patients are susceptible to. The Carbapenem-resistant Acinetobacter carries “mobile genetic material” that can produce enzymes that inhibit the effect of antibiotics.
There are limited incentives to produce new innovative antibiotic drugs to combat these threats. The cancer research industry has fantastic reimbursement through selling cancer treatment drugs. The economic model for pharmaceutical companies is to invest upfront and reap the rewards from sales once approved. This model is not applicable for antibiotics and it stems from its market nature. Negative externalities arise as the production of new antibiotics results in a cost to a third party. Antibiotics may help a group of patients but then create resistant bacteria for the rest of the population.
It is an unusual market condition because companies invest time and money to produce antibiotics that are then used sparingly to reduce antibiotic resistance.
Antimicrobial resistance escalates when there is an increased use of antibiotics; it creates a cycle of developing smarter microbial infections. That is atypical for the general medicines used today. For example, anticoagulants, antihistamines and antiepileptics will not lose their efficacy over time and only affect the individual patient prescribed.
According to Doctor Venkatasubramanian Ramasubramanian, president of the Clinical Infectious Diseases Society of India, “with a new antibiotic, we say, ‘don’t use it,’ or ‘use it sparingly so it lasts longer… It is not an attractive proposition for anyone in the industry,” Ramasubramanian said.
Antibiotics need to be conserved to prevent the evolution of more antibiotic resistant bacteria. This is why newly developed antibiotics are typically used sparingly for five to fifteen years to ensure its efficacy.
The flipside to this situation is that companies “developing one new antibiotic can take up to two decades and usually costs $568 million to $700,” according to Pharmaceutical Research and Manufacturers of America’s, Medicines in Development for Antimicrobial Resistance 2021 report. After all, the resources and money is put into approving a new antibiotic drug; it is then not used for as long as possible until necessary. Therefore, a large majority of antibiotic companies have gone bankrupt or abandoned the antibiotic field. Big Pharmaceutical companies are fleeing, such as Melinta Therapeutics, a large antibiotic developer warned the regulators they were running short of funds. Achaogen, a biotech company, went bankrupt after dedicating 15 years to develop a new antibiotic that was then added to the WHOs list of essential new medications. This market exit is a terrible trend as antibiotic resistance becomes more exacerbated.
Antibiotic resistance is a massive global financial burden worldwide and the highest burden is for low-resource countries. The United Kingdom’s AMR policy paper mentions that the World Bank predicts that “28 million people will be forced into extreme poverty by 2050 unless AMR is contained.” The World Bank also highlighted that there will be a global cumulative cost of $100 trillion by 2050 if the issue of antibiotic resistance remains under the radar for most people.
There is a need for new global initiatives to stimulate more money into researching not only new antibiotics, but innovative solutions targeting antimicrobial resistance.
The United Kingdom has pioneered an incentive payment model that could be emulated globally. In 2019, the United Kingdom’s Department of Health and Social Care launched an AMR project titled “UK 5-year action plan for antimicrobial resistance 2019-2024” that aims to contain AMR in the UK by 2024.
The UK is the first country to create a subscription-based payment model for antimicrobial pharmaceutical companies where the government pays a fixed fee upfront to companies developing new antibiotic drugs. Since this model makes profits independent of prescription volume, it could dis-incentivise part of the reasons for antibiotics overuse .
In 2022, Shiongi, a Japanese discovery-based pharmaceutical company signed an agreement with the National Health Service to begin a “subscription payment model for reimbursement of cefiderocol in England,” and Shionogi commented the company welcomed the “introduction of pull incentives to help bring urgently needed new antibiotics to market.” Although the UK’s initiatives have been attracting international pharmaceutical companies, they recognize that their actions to combat AMR need to be coupled with a global response where countries implement this model or their own variation of incentives into their domestic markets.
In the United States, the Pioneering Antimicrobial Subscriptions To End Upsurging Resistance (PASTEUR) Act introduced in 2023 follows a similar suit where companies would be paid contractually. The PASTEUR Act begins to address the broken marketplace for developing antibiotics and would authorize the Department of Health and Human Services to “enter into subscription contracts for critical-need antimicrobial drugs, providing $6 billion in appropriations for activities under the bill”.
The PASTEUR Act is being debated, and if passed, it would fund vital antimicrobial stewardship programs as well. The UK serves as a role model for the rest of the world by taking a step in the right direction to solving the interdisciplinary issue of antimicrobial resistance.
COVID 19’s Impact on Antimicrobial Resistance
In the CDC’s 2022 Special Report on COVID-19’s impact on antimicrobial resistance, they state that Antimicrobial resistance was the “greatest public health concern prior to the COVID-19 pandemic, and it remains so.” The CDC also released that antimicrobial resistance is a leading cause of death globally.
COVID-19 taught the world that viruses are a threat to human vitality, and preventative measures were crucial to combat the contagious spread of COVID-19 as it continued to mutate and create new strains. Even countries with strong healthcare infrastructures suffered from the fatal virus.
The pandemic overshadowed the antimicrobial resistance pandemic. During COVID-19, patients upon admittance to the hospital would be prescribed antibiotics. This was an overuse of antibiotics when patients frequently did not have bacterial infections. This was due to the fact that healthcare professionals did not have any cure for COVID-19 and had to be greatly cautious. Patients that had weakened immune systems from COVID-19 were more susceptible to bacterial infections. In the US, “from March 2020 to October 2020, almost 80% of patients hospitalized with COVID-19 received an antibiotic.”
COVID-19 should serve as a lesson that the international community must invest in the preparedness to fight the next pandemic. Antimicrobial-resistant will have severe, long-term consequences and it is our “silent” pandemic. The best way to fight this pandemic is to be preventative. This is why funding in antimicrobial resistance research is crucial and should be at the forefront for the scientific community. For example, there is a need for specialized laboratory tests to efficiently identify bacterial infections and new effective stewardship programs for infection prevention measures.
The COVID-19 pandemic created a race to find curative measures against the virus. The novel vaccine restored the world. However, it is important to note that antibiotics are a “shared resource” drug, one person’s use of antibiotics impacts the efficacy of the drug. This is why global cooperation is so important to combat AMR. The WHO created the Global Antimicrobial Resistance and Use Surveillance System (GLASS) to inform, collect data and connect global actors on solution strategies. This is a representation of global cooperative measures that are needed.
Vaccine development is at the forefront of antibiotic resistance research fields and serves as a new hope to decrease antibiotic use. Drug-resistant S. pneumoniae is the only bacterial pathogen that has an effective vaccine, pneumococcal conjugate vaccines (PCVs) listed in the CDC’s special report. This vaccine “prevented more than 30,000 cases of invasive pneumococcal disease and 3,000 deaths from 2010 to 2013 alone.” Vaccines such as this help safeguard antibiotics from overuse that creates resistance.
COVID-19 required an international response, and collective action was taken to combat it. COVID-19 taught the world that we are not immune to viruses or infections. The virus evolved into new strains which required global action to combat its rapid evolution into more contagious strains, such as Omicron.
The CDC’s 2022 report stated that much of the progress was lost in regard to antimicrobial resistance in the US due to the impacts of COVID-19. They stated that the “pandemic pushed healthcare facilities, health departments, and communities near their breaking points in 2020, making it very hard to maintain the progress in combating antimicrobial resistance.” Now that the COVID-19 pandemic is more controlled, the world must face and focus on the pandemic of antimicrobial resistance here and on the horizon.
Valeria Gigante, a member of the WHO’s antimicrobial resistance division states that people who die from antibiotic resistance outnumber the deaths from HIV, tuberculosis and malaria combined. There has been great mobilization for all three and similar mobilization occurred during COVID-19.
It is time to see the same call for action for antibiotic resistance because we live in an age with an upsurge of pandemics and superbugs.
We are no longer strangers to superbugs; we must reimagine a world where our priority is to combat antibiotic-resistant microbes because if we don’t they will always be evolving one step ahead of us.