“The world is facing an antibiotic apocalypse.” - Dame Sally Davies, British physician, Chief Medical Officer of England (2010-2019)
“Antimicrobial resistance may not seem as urgent as a pandemic, but it is just as dangerous.”
- Tedros Adhanom Ghebreyesus, Director-General, World Health Organization
In early December 2019, many experts considered antibiotic resistance to be the number one infectious disease threat in the world. It was a global crisis killing 700,000 people a year and, if the situation didn’t improve, was predicted to cause 10 million deaths per year by 2050. Back then, no one knew that an outbreak of pneumonia (soon to be named COVID-19) was just emerging in Wuhan, China and would subsequently sweep the globe, killing an estimated 3 million people in its first year. Also, nobody could foresee then how the COVID-19 pandemic would exacerbate the menace of antibiotic resistance. The convergence of COVID-19 and antibiotic resistance caused a perfect storm and is the topic of this week’s Germ Gems post.
Synopsis of antibiotic resistance. The Center for Disease Control and Prevention (CDC) monitors 18 different types of antibiotic-resistant bacteria and fungi. These microbes are also referred to as “superbugs” because they are resistant to two or more classes of antibiotics or, in some cases, to all antibiotics. Leading the list of these antibiotic resistant microbes is methicillin-resistant Staphylococcus aureus (MRSA), a gram-positive bacterium, followed by a number of gram-negative bacteria, including Escherichia coli, Klebsiella, Acinetobacter, and Enterobacter. Candida auris, a yeast that is resistant to multiple antimicrobials, is the main fungal superbug.
Antibiotics are effective against bacteria. They are not effective in the treatment of viral infections, nor were they intended to be. Doctors and other medical professionals unwittingly have played a role in creating the environment that permitted the emergence of antibiotic-resistant bacteria by prescribing antibiotics for people with viral infections such as upper respiratory tract infections (colds and bronchitis), acute sinusitis, and serous otitis media (inflammation of the middle ear).
The price that is paid by overprescribing antibiotics to treat viral infections is that bacteria are wizards at dealing with threats in their environment, like antibiotics. Mutants emerge with elegant mechanisms to inactivate or otherwise circumvent the activity of antibiotics. Development of antibiotic resistance by bacteria is an excellent example of evolution in action (the “survival of the fittest”—that is, those with the best workarounds.) Studies have shown that roughly half of all antibiotics given to adults and children in an outpatient setting were unnecessary and unwarranted because the patients had viral infections. Such inappropriate antibiotic use is a global emergency, one that according to the World Health Organization (WHO) is increasing in low and middle-income countries.
The use of antibiotics in animal feed for the purpose of growth promotion is also a global problem. According to the Food & Drug Administration (FDA), in the U.S. in 2014 more than 20 million pounds of medically important antibiotic drugs, amounting to about 80% of all antibiotics sold, were used on livestock farms to fatten poultry, cattle and hogs. While antibiotics given to animals may increase their growth, we pay the price by our exposure to more antibiotic-resistant bacteria.
The good news is that inroads into stemming the overuse and misuse of antibiotics in both humans and animals were being made prior to COVID-19. This hopeful trend was fostered by antibiotic stewardship programs promoted by the CDC, WHO, and FDA. In hospital and clinic settings, antibiotic stewardship teams (comprised of infectious diseases physicians and pharmacists) educated their colleagues about the hazards of antibiotic-resistant bacteria, leading to more thoughtful prescribing.
Antibiotic stewardship also spilled over to farms. In 2018, the FDA announced a five-year plan to curb the spread of antibiotic-resistant bacteria, which included a commitment to ensuring that medically important antibiotics used in animals had limited and defined durations of use. Moreover, interest in antibiotic-free foods by consumers caught the eye of major food (poultry and beef) companies, grocery stores, and restaurant chains.
How COVID-19 is fueling antibiotic resistance. In the early months of the COVID-19 pandemic, alarm began surfacing about increased overprescribing of antibiotics. Research from one of the earliest studies by the Pew Charitable Trusts found that of 6,000 hospital admissions for COVID-19 between February and July 2020, at least one course of antibiotics was given to more than half (52%) of patients. And 36% of these patients were treated with a course of multiple antibiotics or received two of more courses of antibiotics.
These researchers also determined that only 29% of the patients who were treated with an antibiotic(s) were diagnosed with a suspected or confirmed bacterial pneumonia. Similar reports appeared subsequently from a number of U.S. and U.K. hospitals. All of these reports documented that while a majority of COVID-19 patients are treated with antibiotics, less than 10% of the time a bacterial infection was confirmed. Thus, while the underlying basis for antibiotic overprescribing during the COVID-19 era hadn’t changed—that is, doctors were ordering antibiotics with little or no firm evidence of a bacterial infection—the setting had shifted largely from outpatient clinics to in-hospital treatment.
The Doctor’s Dilemma. In the hospital, antibiotics are commonly administered intravenously, and they are selected to target the bacteria that a doctor considers the most likely cause of an infection. Most COVID-19 patients requiring hospitalization are seriously ill (many are in an intensive care unit), and doctors are appropriately concerned that their patients may have a deadly bacterial infection.
Because SARS-CoV-2 commonly causes lung infection (pneumonia), clinicians often worry that an associated secondary bacterial infection of the lungs has occurred. They know that SARS-CoV-2 is a virus, and as such, won’t respond to antibiotics. But what if, their patient has a secondary (or superimposed) bacterial pneumonia?
Or, what if their patient’s clinical picture fits the criteria for sepsis, a condition that is often fatal. (See the October 27, 2019 Germ Gems post, “Sepsis: What Everyone Needs to Know,” for a discussion of this entity, defined by the CDC as a “life-threatening medical emergency caused by the body’s extreme response to an infection.”) The symptoms and signs of sepsis (fever, chills, loss of appetite, fatigue, and confusion) are non-specific. The mortality rate of sepsis is 40%-50% if it is accompanied by shock. Therefore, doctors often initiate a course of antibiotics for patients with sepsis before the results of tests, such as blood cultures, have returned.
Many experts fear that the large-scale use of antibiotics in COVID-19 patients, especially antibiotics with broad spectrum activity against many types of gram-negative bacteria, will fan the fires of what already was recognized as a global health emergency—antibiotic resistance. But it’s too soon to know the magnitude of the COVID-19-driven antibiotic overuse.
Confronting antibiotic resistance beyond the COVID-19 pandemic. Antibiotic stewardship teams are ramping up and clinical investigators, together with CDC and WHO researchers, are gathering data to define the burden of COVID-19 on antibiotic resistance. It is also good to know that at the same time progress is being made on the crisis of antibiotic resistance independently of COVID-19.
A new 20-member international group on antibiotic (antimicrobial) resistance, “The One Health Leaders on Antimicrobial Resistance,” was launched last year. Given the contribution of farm animals to antibiotic resistance, this group includes members from veterinary medicine. Also in 2020, a pharmaceutical collaboration—the “AMR Action Fund,” which includes over 20 pharmaceutical giants—pledged more than $1 billion to bring two to four new antibiotics to patients by 2030. On September 20, 2021 the Infectious Diseases Society of America praised the Biden administration’s plan to allocate more than $2 billion to build infrastructure to fight antibiotic resistance.
An article in the August 15, 2021 issue of Clinical Infectious Diseases, “Antibacterial resistance leadership group 2.0: Back to Business,” outlines three overarching research priorities: infections caused by antibiotic-resistant gram-negative bacteria, infections caused by antibiotic-resistant gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. Of these priorities, I’m in strong support of the third because it speaks to the need of doctors for better tests to confirm when antibiotics are necessary.
I know that most physicians worry a great deal about the side effects of antibiotics, their cost, and the emergence of antibiotic resistance. And I can understand why those on the front lines of clinical decision-making and patient care in this time of COVID-19 may overprescribe antibiotics. Their judgment is heavily influenced by the desire to treat “treatable conditions,” such as, bacterial infections. Viewing the overprescribing of antibiotics in this light makes me more sympathetic to their plight. Nonetheless, the next time you develop symptoms of an upper respiratory tract infection and your doctor doesn’t prescribe an antibiotic say “Thank you.” Your physician is not only doing the right thing for you but is also doing their part in the fight against antibiotic resistance.