Antimicrobial Resistance: the Elephant in the Pandemic Room

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body."

- Alexander Fleming, Scottish microbiologist, discoverer of penicillin

“Earmarked as a ‘silent tsunami’ because the general public is largely unaware of the threat, AMR [Antimicrobial Resistance] could undermine pharmaceutical developments from the past century, potentially undoing decades of work in antibiotic development—and regression can ill be afforded.”

- Nicholas Witts, science journalist, South Wales

Concern about antimicrobial resistance (AMR) is not new. In the first six months of writing Germ Gems, I published two posts that dealt with AMR (September 30, 2019, “The Antibiotic Discovery Pipeline: Will It Run Dry?” and December 8, 2019, “The Antibiotic Arms Race: Are We Gaining Ground?”). Then, the COVID-19 pandemic struck, and as with many other crises, this viral pandemic became a distracting influence. Nonetheless, many public health experts continue to sound the alarm suggesting that AMR is as big a threat to human health as is climate change. My goal in this Germ Gems post is to unearth key aspects of AMR, so everyone knows something about this “hidden pandemic.”

What is AMR? The World Health Organization defines an AMR as “when bacteria, viruses, fungi, and parasites change over time and no longer respond to medicines making infections harder to treat and increasing the risk of disease spread, severe illness and death.” Often the resistance of bacteria to antibiotics (termed “antibiotic resistance”) is stressed because bacterial infections exact a larger toll on human health than infections caused by other kinds of microbes.

Of major concern to medical and public health practitioners are microbes called “superbugs.” Superbugs are strains of bacteria, viruses, parasites, and fungi that are resistant to most of the antimicrobial drugs and to other medications commonly used to treat the infections they cause. Bacterial superbugs are the most worrisome. These bacteria are resistant to several types of antibiotics, and sometimes to all antibiotics. Notorious examples of bacterial superbugs are:

· Carbapenem-resistant Enterobacteriaceae (CRE)

· Methicillin-resistant Staphylococcus aureus (MRSA)

· ESBL-producing Enterobacteriaceae (extended-spectrum β-lactamases)

· Vancomycin-resistant Enterococcus (VRE)

· Multidrug-resistant Pseudomonas aeruginosa

· Multidrug-resistant Acinetobacter

According to the Centers for Disease Control and Prevention (CDC), each year these drug-resistant bacteria infect more than 2 million people nationwide and kill at least 23,000.

Why does AMR occur? AMR is a naturally occurring phenomenon that can be slowed, but not stopped. Over time, germs (bacteria, viruses, parasites, and fungi) adapt to the drugs that are designed to kill them and develop mechanisms to ensure their own survival—this is an example of evolution in action. This “evolution” makes previously standard treatments for some infections less effective, and sometimes totally ineffective. As I pointed out in my earlier Germ Gems posts on AMR, the two biggest forces underlying development of AMR are: (1) physicians who prescribe antibiotics to treat viral infections (antibacterial drugs don’t work against viruses); and (2) people in the food industry who add antibiotics to the feed of farm animals.

What’s the cost of AMR? Two years ago, the CDC predicted that without radical changes to antibiotic use practices, drug-resistant pathogens, which at that point were estimated to cause 700,000 deaths globally every year, could kill 10 million people per year by 2050. (For comparison, as of April 5, 2022 COVID-19 had killed 6,180,128 people worldwide.) A landmark study published in the February 2022 issue of The Lancet, however, indicates that the toll from AMR is worsening even faster than expected.

In this Lancet article, titled “Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis,” Dr. Christopher Murray, Director of the Institute for Health Metrics and Evaluation at the University of Washington, and his colleagues report on the global impact of AMR. Their study includes data on 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. Their results show that AMR is now among the leading causes of death worldwide, exceeding the toll of HIV/AIDS and malaria.

While HIV research attracts close to $50 billion per year in funding, the global spending on addressing AMR is, in all likelihood, far less. Governments and other funders face huge challenges to incentivize companies to develop new antibiotics especially because the process is long and complex and the opportunity for profit limited. In the article “The hidden epidemic” in Vox on February 16, 2022, Miranda Dixon-Luinenburg reported that since 2014 “more than half of the drugs being tested were discontinued before reaching the approval stage” and that according to a 2017 estimate “a single successful antibiotic costs $1.5 billion to bring to market, whereas the expected annual revenue per drug is less than $50 million per year.” Perhaps this is why the development pipeline of new antibiotics to fend off superbugs has fallen off and drug-resistant infections pose a growing threat to public health.

Global strategies to slow AMR. Established in 2020, the AMR Action Fund (AMR Fund) is the world’s largest public-private partnership investing in antimicrobial treatments. On April 4, 2022, the AMR Fund announced its first investments in companies developing new treatments for superbugs. The two companies receiving AMR Fund support—Ventorx Pharmaceuticals and Adaptive Phage Therapeutics—represent different approaches to combatting AMR. Ventorx is advancing an antibiotic combination (cefipime-taniborbactam) to treat multidrug-resistant urinary tract infections (UTIs) and pneumonia. Adaptive Phage Therapeutics is expanding access to bacteriophages (viruses that selectively target and kill bacteria, including superbugs) to treat chronic prosthetic joint infections, chronic wound infections with osteomyelitis, and complicated UTIs that are caused by bacterial superbugs. The funding provided by the AMR Action Fund is considered a short-term solution while governments consider additional strategies to delay the emergence of AMR, such as changing how antimicrobials are paid for.

Established in 2002, “the Global Fund to Fight AIDS, Tuberculosis and Malaria” is another source of funding that is being considered for possible repurposing to help stop AMR. Although donor investment to this fund is likely to remain on the three diseases that have been the hallmark of its success, the Global Fund is actively considering widening its focus to include other urgent global health crises, including AMR.

What can you do to help slow AMR? As I’ve already mentioned, the two biggest drivers of AMR are human behaviors—the misuse of antibiotics (prescribing and taking antibiotics to treat viral infections) and adding antibiotics to animal feed. To counter the former (mis) behavior, “antibiotic stewardship programs (ASPs),” usually led by doctor/pharmacist teams, have sprung up at many hospitals throughout the U.S. The intent of these programs is to provide advice for antibiotic prescribers on the best choice, dosage, and duration of antibiotic use for bacterial infections. And the good news is that ASPs work. According to the PEW Research Trust, “A large and growing body of research shows that hospital-based antibiotic stewardship programs reduce antibiotic resistance, improve patient outcomes and save money.”

But an estimated 80-90% of the volume of human antibiotic use occurs in the outpatient setting and is often influenced by patient pressure. I recommend that when an antibiotic is prescribed for you, you ask for information about the nature of your infection. If your practitioner doesn’t prescribe an antibiotic because they think you have a viral infection, say thank you.

Although detailed information about antibiotic use in animals is lacking, available data show that around 70 percent of the total volume of all medically important antibiotics in the U.S. is sold for use on the farm. How to thank workers in the food industry for not adding antibiotics to animal feed is more difficult. But you’ve likely seen an increase in advertising at grocery stores and restaurants of “antibiotic-free” foods (chicken, pork, beef, etc.). The food industry often responds to the desires of their consumers. So, consider rewarding purveyors of antibiotic-free foods by purchasing their products. Prevention of AMR is one of the clearest examples of a “One Health” approach to public health, that is, we humans, along with other animals, as well as plants, are “all in this together.”