Since their advent in the early twentieth century, antibiotics have saved countless lives, curing human beings of diseases caused by harmful bacteria. But from the beginning of the antibiotics era, in the middle of the twentieth century, scientists warned that misuse or overuse of the drugs would render them less effective, or even useless as bacteria evolved into drug-resistant forms. Only prudent use of the precious medicines, they warned, could guarantee their utility in the twenty-first century. Political leaders have generally reasoned that as dire as the forecast of incurable diseases might seem, such profound drug resistance was unlikely to arise on their watch, allowing them to kick the can down the road to the next generation. Policies responding to the threat have amounted to urging the pharmaceutical industry to invent new drugs and asking medical associations to issue guidelines on how to limit the use of antibiotics in health-care settings.
Meanwhile, since the 1950s, these drugs have steadily become less effective, the range of diseases proving difficult and costly to treat has broadened, the scale of resistance has grown worldwide, and the speed with which new mutant forms of resistant bacteria pop up globally has hastened.
Four years ago, the U.S. Centers for Disease Control and Prevention (CDC) reckoned that antibiotic resistance caused at least two million infections and twenty-three thousand deaths annually in the United States, costing $20 billion directly and an additional $35 billion in productivity losses. In May 2016, Lord Jim O’Neill, an economist and member of Britain’s House of Lords, issued the landmark Review on Antimicrobial Resistance, estimating that “700,000 die each year of drug resistance in illnesses such as bacterial infections, malaria, HIV/AIDS or tuberculosis,” and “50,000 lives are lost each year to antibiotic-resistant infections in Europe and the US alone.” The review predicted that by 2050 up to ten million people will die yearly from drug resistant infections, costing a cumulative $100 trillion worth of economic output by that time.
Although more than a hundred brands of antibiotics are marketed for human use, they all boil down to just fifteen classes of drugs that attack bacteria, by damaging either the microbes’ outer membranes or their ability to reproduce. When, for example, bacteria evolve the ability to resist a drug that blocks their formation of protective cell walls, that attribute applies to all the drugs that kill bacteria using the same mechanism. As a result, antibiotic resistance arises at first as a response to a specific drug, but over time comes to apply to an entire class of drugs.
Bacteria are one-celled creatures that far outnumber visible plants and animals. The first life-forms on Earth, they emerged in the seas to convert sunlight to oxygen, creating the air we breathe. Every system on the planet, including the human body, thrives because of the bacteria within it, though some bacteria species are pathogenic, or even deadly, to their hosts. Bacteria always compete against their larger foe, fungi, which emit countermeasure chemicals to kill the smaller microbes. Scientists in the early twentieth century discovered how to use those fungal chemicals as drugs, or antibiotics. Yet bacteria have developed ways to leapfrog through evolution, scouring their environs for useful genetic material known as plasmids, which may give the microbes the ability to resist antibiotics. Plasmids are promiscuous, jumping from one bacterial species to another, giving them capacity to resist. Scientists have long warned that use of man-made antibiotics would hasten this plasmid sharing, and the evolution of ultraresistant, or even incurable superbacteria.
Those prognostications have now tragically come true. In 2008 a plasmid emerged out of India named New Delhi metallo-beta-lactamase-1, or NDM-1, giving all bacteria that absorbed it, such as E. coli, the ability to resist the most powerful class of antibiotics, carbapenems. Today sixteen forms of NDM plasmids have been identified, mutating from the original Indian strain and spreading to more than seventy nations including the United States. Seven months ago, a seventy-year-old woman who had recently returned from a stay in India died of Klebsiella pneumonia despite receiving twenty-six different antibiotics in a Nevada hospital. Her death was caused by an incurable bacterial strain loaded with NDM-1 plasmids, prompting CDC Director Tom Frieden to label the mutant Klebsiella “the nightmare bacteria.”
A similar case in 2016 involved an otherwise healthy forty-nine-year-old Pennsylvania woman suffering from what at first seemed to be a routine urinary tract infection of the sort eight million Americans suffer, and usually recover, from every year. Her infection came from a highly resistant E. coli that fourteen antibiotics had failed to cure. Her doctors resorted to prescribing colistin, a drug rarely used in humans due to its high toxicity. She recovered, with scientists describing the new antibiotic-resistant plasmids—one of which, mcr-1, had never been seen in a U.S. patient—as heralding “the emergence of a truly pan-drug resistant bacteria.”
Mcr-1, the mobilized colistin resistance gene, was first found in China in pigs in February 2016, and then in people, some of whom acquired their infections from the animals or from eating pork. Over the last year, scientific and medical literature have exploded with reports of mcr-1 infections in livestock and humans now spanning twenty-nine countries and at least five bacterial species, including E. coli, Klebsiella, and the most common cause of food poisoning, Salmonella. A recent survey of China’s pigs showed a startling 21 percent of seemingly healthy animals carried bacteria with mcr-1, as did 15 percent of tested chicken and pork meat and 1 percent of all hospitalized Chinese patients. This should not have been a surprise given the sheer quantity of antibiotics, including colistin, used in the Chinese swine industry. Worldwide about three-quarters of all antibiotics are used for nontherapeutic purposes: not to treat diseases in animals or people, but to fatten up animals through livestock or aquaculture feed. By one estimate, China uses a third of all growth-promoter antibiotics fed to livestock worldwide.
A new, disturbing study testing domestic pets—cats and dogs—in China discovered that many carry E. coli bacteria harboring the mcr-1 gene. Worse, the pets were getting infected by eating meat-rich pet food that is sold in the United States, and some of their human owners acquired the dangerous infections from them.
Inaction and Loose Regulation
Though political leaders have long noted their concern about antibiotic resistance, action has been lacking. Rising antimicrobial resistance (AMR) is a classic long-tail problem; it presents a grim ultimate prospect that is reached incrementally over a long period of time. In the late twentieth century, the forecast of AMR and incurable disease prompted regular calls for the prudent use of antibiotics to slow the evolution of superbugs in hopes of buying time for pharmaceutical breakthroughs. Yet other crises always loomed with greater immediacy, pushing AMR to the political back burner.
Meanwhile, the pace of pathogen evolution has accelerated as the global production and use of antibiotics has soared, especially in Asia. Public demand for meat and medical care has grown in China and India with their economic rise. Antibiotic use in animal feed for growth promotion has soared accordingly, as has the manufacture of drugs in both countries, which are the world's most populous. Not coincidentally, the occurrence of NDM and mcr-1 rose. Drug manufacturing and use are regulated loosely, if at all, and both livestock and medical consumption are skyrocketing. In China alone in 2012 470 million pigs and 660 million livestock swine were reared, and one estimate from that year suggests 84.9 million pounds of antibiotics were used on livestock. Colistin is not used in Chinese clinics; the only source of mcr-1 in that country is livestock use.
While few Indians eat pork, the consumption of chicken and poultry fed with antibiotics is rising rapidly, increasingly resulting in human acquisition of drug-resistant infections. Worldwide demand for livestock antibiotics is expected to soar 67 percent above 2010 levels by 2030, with 99 percent of that growth driven by China, India, and other major emerging economies.
The U.S. livestock industry uses an estimated twenty-nine million pounds of antibiotics annually, twenty-five million of which is nontherapeutic. The U.S. Food and Drug Administration has long sought to stop its nontherapeutic use in animals, but been thwarted by the U.S. Department of Agriculture and the food industry. The Obama administration tried to coax the industry into stopping feed application of the compounds, but in 2015 agricultural use rose 2 percent. American hog workers commonly develop drug-resistant skin infections.
In both China and India, antibiotic manufacturing has soared, along with human consumption of the drugs. Their health-care systems provide poor care for most citizens, proffering antibiotic pills and injections for everything from headaches and fatigue to childbirth and bona fide bacterial infections. In China, for instance, many hospitals rely on selling drugs for the bulk of their revenue. Indian patients take more medicinal antibiotics than any other population in the world and powerful drugs can be purchased without prescriptions. As many as fifty-eight thousand newborns die in Indian neonatal centers annually from drug-resistant infections. Indians on average take 10.7 units of antibiotic treatment every year, compared to 7.5 among Chinese and 6.8 among Americans.
Stopgap Measures Won’t Work Anymore
For years, U.S. and European physicians have tried to limit the spread of antibiotic-resistant disease by discouraging medicinal overuse of the drugs and tracking down infected patients and staff in hospitals. But fear of losing patients to resistant bacteria has, perversely, prompted increased use of broad-spectrum drugs, prompting even wider resistance in the United States and Europe, according to the CDC.
In 2013 the CDC reckoned that most human-to-human spread of superbugs occurs inside hospitals, increasing health costs by $20 billion per year and causing a U.S. productivity loss annually of $35 billion. Hundreds of millions of dollars are spent by U.S. hospitals to scour facilities after resistant strain have sickened patients. Worse, the antiseptics commonly used to scour hospitals and to clean health-care workers’ hands seem to promote the emergence of drug-resistant bacterial strains. Harvard’s William Hanage says that no matter what cleansing measures they take, patients carry wild assemblages of genetically resistant microbes that spread, unnoticed by disease detectives, to other patients. Hanage argues, “If it is right that we are missing a lot of transmission, then only focusing on cases of disease is like playing Whac-a-Mole; we can be sure the bacteria will pop up again somewhere else.”
Chemicals used in antibacterial products such as paints and scrubs also promote the growth of drug-resistant microbes. Similarly, chlorine treatment of sewage waste selects for tougher, drug-resistant bacteria, filling water systems with concentrated populations of dangerous bacteria. The Whac-a-Mole problem extends from Hanage’s hospital setting all the way to coastal waters and rivers, which are filling with plasmids and resistant bacteria thanks to the very treatments intended to eliminate the microbes. This is dangerously altering ecosystems, killing off bacteria vital to ecological balance. In the absence of those competing bacteria, dangerous ones, such as cholera, are able to surge unchecked.
Plasmid Paranoia Prompting New Action
Top health and political leaders appear well aware of the threat of returning to pre-antibiotic-era treatments of infections, such as amputations, contagion isolation, and the surgical removal of festering cysts and pustules. In March 2015, President Barack Obama released the National Action Plan for Combating Antibiotic-Resistant Bacteria, a $1 billion multiagency scheme to tackle the crisis with reduced use of antibiotics in both people and animals, stronger animal surveillance, nationwide education, basic research on entirely new potential antibacterial drugs, development of new vaccines, hospital strategies, and the creation of AMR programs in all fifty states. In 2016, the White House requested $1.1 billion more for the effort for U.S. fiscal year 2017, with an emphasis on training laboratories across the nation to detect dangerous plasmids. It is not known what stance the Trump administration may favor for the AMR problem.
In September 2016, the UN General Assembly unanimously passed a political declaration from the High-Level Meeting on Antimicrobial Resistance that called for the UN secretary-general to create a high-level AMR panel. The group launched this March, but its charge is limited to preparing a report for the General Assembly session this September.
The AMR crisis cannot be tackled by any one nation, and economic incentives that encourage livestock industry behavior and antibiotic uses can only worsen the situation. On February 27, the World Health Organization took an unprecedented step, naming twelve bacteria as top priorities for research and drug development due to antibiotic resistance. The list drew fire for its failure to include leprosy and tuberculosis, both diseases caused by slow-growing but deadly mycobacteria for which few drugs are available and fully drug-resistant, incurable forms of the bacteria have emerged.
Last year the Pew Charitable Trusts identified thirty-seven new antibiotics in the pharmaceutical pipeline, holding out the promise that the long drought in new medicines might be ending. But the only products likely to soon see the light of day, Avibactam and Aztreonam, relied on subsidies under the Obama administration’s AMR scheme. Developed by AstraZeneca, the drugs moved through the pipeline thanks to a federal infusion of $220 million in 2015.
One area in urgent need of reform is the livestock industry. There are inexpensive ways to raise fattened animals without adding antibiotics to their feed, but the FDA’s attempts to promote these alternatives have been ignored by the livestock industry. At most the growth promoters increase animal size by 3 percent, a margin that has been eclipsed by proper animal rearing and feeding in Sweden, where the use of growth promoters was phased out more than two decades ago.
The time for dithering and timidity has long passed. In less than eighteen months, NDM-1 spread to every continent and mutated into sixteen forms, and in one year, two forms of mcr arose from the pig industry and spread around the world. To avert a global health crisis and protect the utility of precious medicines, the Group of Twenty and General Assembly should set a target this year of 2020 for the complete global cessation of all growth-promoter uses of antibiotic chemicals.