Antimicrobial-resistant pathogens cause one in five infections in OECD and EU28 nations and could kill up to 10 million people per year by 2050. What drives antimicrobial resistance and what impacts can we expect?
Antimicrobial resistance (AMR) is an increasing threat to global public health. Organisms resistant to antibiotics cause one out five infections in Organization for Economic Co-operation and Development (OECD) and EU28 countries and over 2.8 million infections and 35,900 deaths in the United States each year.
Increasing AMR is a serious threat to effective treatments, compounded by the challenge of developing new antimicrobial agents. If unaddressed, AMR can claim up to 10 million deaths annually by 2050, making it critical to develop and deploy more accurate point of care diagnostics and eliminate the injudicious use of antimicrobial agents.
What are Antimicrobials?
Antimicrobials are natural or synthetic agents used to kill or stop the growth of microorganisms. There are four types of agents: antibacterials, antivirals, antifungals, and antiparasitics.
Antibiotics are a subset of antimicrobials and defined as substances naturally produced by one microorganism that kill or inhibit the growth of another microorganism. This definition excludes substances that are synthetic, semisynthetic, or derived from plants or animals.
What is Antimicrobial Resistance (AMR)?
AMR is the microorganism’s ability to survive contact with antimicrobials designed to kill them. When this occurs, treatments become ineffective for curing infections.
Shortly after the discovery of the first antibiotic, scientists observed the development of bacterial resistance to antibiotics. In time, it was determined that in addition to AMR developing within populations of the targeted pathogen via natural selection, AMR can also be transmitted horizontally from other organisms in their environment.
When these resistance genes spread into medically relevant bacteria, antimicrobial agents with similar mechanisms of action can become dramatically less effective. When microorganisms become resistant to most antimicrobials, scientists and healthcare professionals refer to them as “superbugs” or “multi-drug resistant (MDR).” These microorganisms present a global threat to human and animal health.
How Does AMR Arise?
Bacteria have the natural ability to evolve and adapt to their environment by changing their genetic material as a survival mechanism. Antibiotics disrupt essential cellular structures or biosynthetic pathways to kill bacteria or stop them from multiplying. As a response, bacteria have developed the following strategies to defend against the toxic effects of antibiotics:
- Remove the antibiotics using an efflux pump.
- Destroy the antibiotics by producing an inactivating enzyme.
- Produce an alternative protein to bypass inhibition.
- Modify the cellular component to circumvent being a target.
- Restrict antibiotics access by changing the entryways.
Once resistance develops, exposure to antibiotics eliminates drug-sensitive competitors, allowing the resistant bacteria to survive and spread. Because bacteria grow and multiply fast, the resistant variants quickly dominate the population (Figure 1).
The resistant bacteria carry genetic mutations in their DNA, which is passed on to other organisms and spread to new generations. Bacteria transfer the encoded resistance information through the following two mechanisms:
- Vertical transmission: transfer of resistance genes from one generation to another via replication.
- Horizontal transmission: transfer of resistance genes from one microbe to another via mobile genetic elements.
Microbes can develop resistance spontaneously, but the main causes of AMR are the overuse and misuse of antibiotics. According to the CDC, 30% to 50% of all antibiotic prescriptions in an outpatient setting are unnecessary or inappropriate. With so many organisms exposed to the selective pressure of specific antimicrobial agent, the odds of one cell among them developing resistance traits increases.
The indiscriminate use of antibiotics is mostly because of the lack of diagnostic information on the causative pathogens and associated resistance patterns at the time of treatment. Resistant infections result in a longer duration of illness and treatment, increasing the economic burden on families and society.
WHO and CDC Statements on AMR
In 2014, WHO declared AMR as a serious threat to global public health:
“The problem is so serious that it threatens the achievements of modern medicine. A post-antibiotic era—in which common infections and minor injuries can kill—is a very real possibility for the 21st century.”
The Centers for Disease Control and Prevention (CDC) also warned the danger of AMR in their report on “Antibiotic Resistance Threats in the United States”. Eleven percent of the Enterobacteriaceae found in healthcare-associated infections are carbapenem-resistant, 63% of Acinetobacter is MDR, and 30% of Enterococcus strains are resistant to vancomycin, which is an antibiotic of last resort.
The CDC assessed the threat degree according to seven factors associated with resistant infections: clinical impact, economic impact, incidence, ten-year projection of incidence, transmissibility, availability of effective antibiotics, and barriers to prevention. Using these criteria, the CDC identified top 18 drug-resistant threats to the United States and classified them as urgent, serious, or concerning.
Pathogens of urgent threat to human health include:
- Carbapenem-resistant Acinetobacter
- Candida auris
- Clostridioides difficile
- Carbapenem-resistant Enterobacteriaceae
- Drug-resistant Neisseria gonorrhoeae
These bacteria cause more common diseases that are frequently treated with antibiotics.
Factors Driving AMR Acceleration
For over sixty years, antibiotics and other antimicrobial drugs have been magic bullets to cure infectious diseases. They transformed modern medicine, saving millions of lives and contributing to increase in life expectancy.
Now, resistance to a new antimicrobial drug often emerges within a few years after manufacturers introduce it to the market (Figure 2) and occurs with almost all antibiotics.
Many antibiotics are no longer effective against even simple infections. An example is Neisseria gonorrhoeae, which causes the sexually transmitted disease, gonorrhea. Penicillin could easily treat this condition in 1970’s. Today, nearly 30% gonorrhea infections are drug resistant. Even ceftriaxone, a third-generation oral cephalosporin, is not effective.
Furthering accelerating AMR is the increased selective pressure driven by widespread, unnecessary, and excessive use of antimicrobials. Increasing antibiotic consumption in the poultry and cattle industry to promote animal growth and prevent disease also contributes to the rapid spread of AMR.
To exacerbate the situation, we have seen a steady decline in the discovery of new and effective antibiotics. Over the last thirty years, pharmaceutical companies have significantly decreased R&D investment into new antimicrobial drugs due to lack of economic incentives and regulatory hurdles. In fact, researchers have not discovered new major classes of antibiotics for decades, leaving fewer options to treat resistant bacteria. The lack of new drugs could compromise the great progress made in combating infectious diseases.
How Does AMR Impact the Economy?
Research suggests that AMR can claim up to 10 million deaths annually by 2050 across the world. Significant impacts to quality of life will be experienced, along with increases in mortality, length of hospitalization, and costs of healthcare.
According to the CDC 2019 AR Threats Report, more people are dying from antibiotic resistant infections than previously reported, with at least one infection being reported every 11 seconds and one death every 15 minutes. Patients with emerging resistant infections (e.g., (Enterobacter spp.) have a 1.5-fold longer length of hospital stay and increased healthcare costs by ~$6,000 to $30,000 compared with patients without resistant infections.
The CDC estimates the total cost of antimicrobial resistance to be $55 billion every year in the United States alone because of the increase in healthcare costs and loss of productivity. These costs will increase poverty and impact low-income countries. Without intervention and AMR improvement plans, global GDP could decrease and cost the world trillions of dollars by 2050.
AMR in common bacteria has reached alarmingly high levels in many parts of the world, and awareness of the issue among veterinarians and healthcare professionals is the first step to mitigate the problem. By raising awareness and focusing on improving prescribing practices through antibiotic stewardship interventions, patient outcomes will improve, the burden of antibiotic resistance will be reduced, and healthcare savings will increase.