Two years ago, the CDC made a disturbing prediction: Without radical change 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.
A recent report published in The Lancet, however, found that the toll from antibiotic resistance is worsening even faster than expected.
Last month’s Global Research on Antimicrobial Resistance (GRAM) project report estimates that, in 2019, about 1.27 million people died directly due to antimicrobial resistance (AMR), which means cases where the patient wouldn’t have died had their infection been treatable with standard antibiotics. The total rises to 4.95 million deaths once fatalities associated with a drug-resistant infection, meaning that a patient died while having an identified antibiotic-resistant infection but it wasn’t clearly the immediate cause of death, are also included.
The report includes data on 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019, with statistical modeling used to produce estimates for regions missing data.
The new numbers means that AMR is now among the leading causes of death worldwide, exceeding the toll of HIV/AIDS and malaria (864,000 and 643,000 deaths in 2019 respectively, according to the Lancet’s Global Burden of Disease study). HIV research attracts close to $50 billion per year in funding, but as Ramanan Laxminarayan of the Center for Disease Dynamics, Economics and Policy noted in a commentary published along with the Lancet study, “global spending on addressing AMR is probably much lower than that.”
In the last century, antibiotics have revolutionized medicine, massively cutting down mortality from common infectious diseases, while drastically improving the safety of major surgery and recovery rates from trauma. By one estimate, antibiotics have extended average human life expectancy by more than 20 years since their discovery over a century ago.
But the overuse of antibiotics, whether in human patients or in livestock, results in bacteria adapting to the drugs, leading them to become less effective over time. If the pace of resistance isn’t halted — whether through more judicious use of the drugs or through the development of new classes of antibiotics — it will likely lead to soaring deaths from common infections and surgical complications, sending us back to a world where a minor cut could potentially once again be lethal.
We can avoid this fate, but it will require coordinating a global response before it’s too late.
Antibiotic resistance, explained
Antibiotics are drugs that kill or prevent reproduction of disease-causing bacteria, without directly harming the patient’s cells. The invention of the first antibiotics changed everything, offering nothing short of a miraculous cure for severe pneumonia or wound infections that might have otherwise left patients dead.
But due to their ability to rapidly reproduce — staphylococcus, for example, can double every two hours when colonizing the human nose — and to directly exchange fragments of genetic code, bacterial pathogens evolve far more rapidly than multicellular organisms like humans. When a mutation arises that conveys resistance to an antibiotic, a large population of resistant pathogens can rapidly result, and the mutation can then be shared with other lineages of pathogen if they come into contact with each other.
Every time a patient is treated with antibiotics while a given pathogen is present, it’s a roll of the dice for a new resistance mutation to emerge. This isn’t just for human patients; the use of antibiotics for disease prevention and faster growth of livestock, which accounts for two-thirds of the total medically important antibiotics sold by weight in the US, is also a major contributor to AMR.
Resistance can develop with remarkable speed. Methicillin-resistant staphylococcus aureus, or MRSA, was first documented in 1961, just one year after the antibiotic methicillin was introduced. MRSA is actually something of a misnomer, as the pathogen is resistant to two major classes of antibiotics, penicillins and cephalosporins.
The first outbreak was documented in a Boston hospital in 1968, and for several decades most MRSA infections were seen in hospitals or other health care settings. However, by the early 2000s, community-acquired cases were rising even as hospital spread decreased. In 2019, according to the Lancet report, MRSA directly caused more than 100,000 deaths.
Resistance is the inevitable result of using antibiotics. The best we can hope for is to delay it, mitigate the consequences, and buy time for the development of new antibiotics that bacteria haven’t yet evolved resistance to.
How to resist antibiotic resistance
The Lancet study identifies three ways to slow the march of antibiotic resistance: more selective use of antibiotics, tighter infection control measures, and rapid investment in new treatments.
While the best practices for antibiotic usage in medicine are well established, they’re not always followed. Antibiotics are only effective against bacterial infections — meaning they’ll do nothing for a viral illness like influenza — and should be given only when medically necessary for an identified bacterial infection. However, a 2016 study estimates that 30 percent of the antibiotic prescriptions given in clinic visits are unnecessary.
Treatment should always start with the most narrow-spectrum antibiotic, saving for later the “big guns” — broad spectrum antibiotics, which are important to keep in reserve so they remain effective with the sickest patients, as well as newer drugs with less established resistance. Once treatment is started, it’s important for patients to finish the full course; incomplete treatment can result in a surviving population of the disease pathogen, selected for resistance, which can then infect others and spread.
Cutting down on the use of antibiotics in farming is also essential. The low-dose, prolonged regimens given to increase the rate of growth in farm animals creates ideal conditions for pathogens to evolve resistant strains, at which point these pathogens can spread to affect humans. Denmark has been a world leader here, drastically restricting non-therapeutic use of antibiotics in healthy animals solely for disease prevention and faster weight gain, but the US has yet to follow suit.
Preventing the transmission of infections within hospitals is also an essential measure to minimize the death toll from resistant bacteria; hospital-acquired infections are a major concern, with an estimated 650,000 cases annually in the US alone, and drug-resistant pathogens are much harder to treat, so maintaining isolation measures and the appropriate use of protective equipment is key.
One complication is that patients can be asymptomatic carriers without being sick, unknowingly spreading resistant bacteria. US hospitals will often test all newly admitted patients for MRSA and vancomycin-resistant enterococcus (VRE), two of the most common community-transmitted antibiotic resistant pathogens, so that carriers can be isolated from patients at risk of severe illness.
This means that reliable testing and data collection is essential to keep track of and slow the spread of resistant bacteria. That’s a particular challenge for lower-income countries; they lack the resources to test and screen patients as reliably, and they often have a shortage of and sanitation supplies. Those failings matter for rich countries as well — a globalized world means that novel resistant pathogens anywhere will present a risk elsewhere.
These control measures can buy time for pharmaceutical research companies to invest in developing new generations of antibiotics to replace existing treatments as pathogens acquire resistance to them. But progress on new antibiotics has been slow. Truly novel options — not simply tweaks on existing drugs — are what is most needed to stop drug-resistant pathogens, but the last entirely original class of antibiotics, lipopeptides, was discovered in the late 1980s.
Despite the desperate need, pharmaceutical companies are less incentivized to overcome the scientific, regulatory, and financial challenges involved in approving a new antibiotic — especially when the opportunity for profit is limited. Successfully developing an effective and nontoxic new antibiotic is a long and complex process; since 2014, more than half of the drugs being tested were discontinued before reaching the approval stage. 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.
Since the most powerful antibiotics are held in reserve as much as possible and then prescribed only as short-term treatment for acute infections, they bring in much less revenue than drugs for chronic conditions such as high blood pressure or Type 2 diabetes.
As Kevin Outterson, a Boston professor who studies antibiotic resistance, told my colleague Sigal Samuel, the problem is that “this is a product where we want to sell as little as possible. The ideal would be an amazing antibiotic that just sits on a shelf for decades, waiting for when we need it. That’s great for public health, but it’s a freaking disaster for a company.” Governments and other funders need to respond by implementing financial incentives for companies, funding academic research, or other significant changes to the current regulatory framework.
There is some good news on this front. The use of animal antibiotics decreased by 3 percent between 2019 and 2020, and the EU recently banned antibiotic administration to healthy animals. But this is far from enough.
Antimicrobial resistance has been a hidden epidemic, less visibly front and center than Covid-19, but the world cannot afford to wait to act until it reaches a crisis point.