Are we approaching a post-antibiotic era?
The introduction to a recent World Health Organization (WHO) report asks people to imagine a “post-antibiotic era,” in which common infections and minor injuries begin killing people because the antibiotics used to treat them no longer work.
“Far from being an apocalyptic fantasy, [this] is instead a very real possibility for the 21st century,” the report continues.
The reason for this dire warning: Although antibiotics have saved millions of lives since their introduction 70 years ago, harmful bacteria are evolving resistance to antibiotic drugs faster than drug companies are developing new classes of antibiotics.
Experts fear if antibiotic resistance proceeds at its current rate, in the words of Dr. Margaret Chan, director-general of WHO, it will bring “an end to modern medicine as we know it.”
Resistance: a natural aspect of bacterial evolution
Over 3.5 billion years of evolution, bacteria developed a suite of strategies allowing them to survive the assaults of antibiotics aimed at them from within their hostile microworld. These include:
1. Production of antibiotics for their own defense and enzymes that destroy or deactivate antibiotics.
2. Heritable mutations, genetic alterations that make bacteria resist the action of antimicrobial agents.
3. Non-chromosomal DNA called “plasmids,” which can replicate independently and transfer directly into other bacteria, a process called horizontal gene transfer. Many scientists suspect that horizontal gene transfer is the dominant way bacteria transmit antibiotic resistance to each other.
The risk of resistance increases each time a species of bacteria is exposed to an antibiotic agent. The widespread use of antibacterial drugs in humans, food and companion animals, and to a lesser extent, even plants, combines with the phenomenon of global travel that spreads resistant microbes around the world to explain why resistance is growing so alarmingly.
The current situation in the U.S.
The federal Centers for Disease Control and Prevention (CDC) estimates conservatively that at least two million Americans become infected with antibiotic-resistant bacteria each year, 23,000 die, and many more die of complications related to antibiotic resistance.
Experts estimate the annual economic impacts of antibiotic-resistant infections (P. 11) rise as high as $20 billion in direct healthcare costs, and $35 billion in social costs (e.g., lost wages, death of family earners).
Observers say market forces alone won’t motivate pharmaceutical companies to invest in developing new antibiotic drugs, because the return on investment is so low. Drug companies prefer to put their research dollars into drugs that treat chronic illnesses, as well as classes of so-called “lifestyle” drugs.
Animal agriculture: What’s the connection?
Around the same time antibiotics were introduced, American agriculture began industrializing to realize economies of scale. (See Report summary.)
Small-scale, diversified farms increased in size, and the larger livestock operations began specializing in a single species, often in confined settings for at least some portion of their lives.
Large-scale producers began adding low doses of various antibiotics to the feed of healthy animals to prevent diseases that could emerge and spread rapidly in concentrated operations.
Because producers found that the antibiotics also promoted faster growth and more efficient use of feed, the practice, which began in large-scale poultry operations, spread to almost all food-animal species.
Of the roughly 10 billion food animals produced each year in the U.S., many have received growth-promoting antibiotics for at least some portion of their lives.
As far back as the early 1970s, public-health advocates began expressing concern about the potential contribution of growth-promoting antibiotics in food animals to antibiotic resistance, suggesting that food animals and their environments serve as reservoirs of antibiotic-resistant microbes, accelerating the pace of resistance. They began calling for a ban on the practice, engendering a protracted debate among experts on all sides of the issue.
From an abundance of caution, the European Union banned growth-promoting antibiotics from animal feed in 2006.
No straight line from animals to humans
But veterinarians like Dr. Russ Daly, a South Dakota State University extension veterinarian and South Dakota State Public Health Veterinarian, note that science has yet to establish a direct, causal connection between the veterinary use of antibiotics and resistance in human diseases.
Daly says the widely cited figure that 80 percent of all antibiotics produced are used in food animals needs some context. “Perhaps 30 percent of the growth-promoting antimicrobials aren’t even used in human medicine,” he says.
“Plus livestock producers and vets have long felt that [the food-animal industry] might not be the main contributor to the problem, Daly continues. “For example, of all the growth-promoting antimicrobials used in swine, only about 13 percent are deemed critically important for human health.”
A 2010 Purdue Extension bulletin examining data from Denmark, which banned growth-promoting antibiotics in food animals in 1999, underscores that point of view:
“While resistance in bacteria from livestock decreased, resistance in bacteria from humans remained the same or increased in almost every type of bacteria tested. In many cases, the increase in resistance to specific drugs was likely caused by increased use of that drug in human medicine.
“Therefore, it appears that antimicrobial resistance patterns in bacteria from animals and humans are not closely related. That is, antimicrobial resistance patterns in livestock result from antimicrobial use patterns in veterinary medicine and antimicrobial resistance patterns in humans result from antimicrobial use patterns in human medicine.”
The housefly enters the equation
Dr. Ludek Zurek, a professor of microbial ecology at Kansas State University, specializes in research on the microbial contents of insect guts, particularly antibiotic-resistant bacteria that can infect humans.
Zurek’s recently published paper, “Insects represent a link between food animal farms and the urban environment for antibiotic resistance traits,” reviews studies dating back to 1990 that demonstrate common insects’ potential to acquire and pass along drug-resistant bacteria from farm to fork.
Zurek concludes that common insects such as houseflies, which develop in most forms of organic matter, including feces, and which move among farms and manure storage facilities, wastewater treatment plants, and nearby hospitals, restaurants, and homes, “likely represent a direct and important link between animal farms and urban communities for antibiotic resistance traits.”
He adds, “However, insects also represent a link in intraurban spread of resistance in cities far removed from any livestock operations.”
Flies don’t just mechanically transfer bacteria from one food source to another, Zurek notes. The bacteria they ingest during feeding not only proliferate wildly, but readily share resistance traits within the insects’ foregut.
“Flies are more than just a nuisance,” Zurek says. “They aren’t taken seriously enough among food safety people.” When a fly lands on your freshly cooked hamburger, “It delivers from both ends,” he says. “Wherever they land and begin feeding they regurgitate the contents of their crop [foregut] and defecate from the other end.”
“The practice of feeding growth-promoting antibiotics to food animals is short-sighted,” Zurek says, “a matter of short-term gain, not looking down the road.” He even suggests that we may need to add the cost of antibiotic resistance to the costs of our food long-term.
Zurek acknowledges his paper “is no smoking gun, and offers no silver bullet” to solve the antibiotic resistance threat. He advises employing rigorous pre- and post-harvest insect control and “adopting prudent use of antibiotics in the food-animal industry.”
“[Zurek’s] work is valuable,” says South Dakota veterinarian Russ Daly. “But what we’re not seeing is that direct line from food-animal antibiotics to resistance in humans. When I see people making that leap, I get a bit distressed.”
“What I’ve seen [in all the published literature on the topic] is disjointed chunks attempting to link antibiotics in animals to increased resistance in humans, but it’s still disjointed chunks. Give me a paper with hard evidence that ties them all together, if that’s even possible.”
FDA sets guidelines for removing antibiotics from animal feed
Last December, the federal Food and Drug Administration issued a “guidance” document outlining its planned phase-out of the use of antibiotics important in human medicine as growth-promoters in livestock.
The ruling won’t affect antibiotics used to treat sick animals or to control or prevent an outbreak of disease. Farmers will still be able to get the feed additives, but only under the oversight of a veterinarian with whom they have an ongoing relationship.
Daly of South Dakota lays out the changes in a news bulletin, Using Feed-Grade Antibiotics for Livestock: Changes are coming:
“This means that before a producer can obtain [a listed drug for use as a feed additive] he will have to obtain a [Veterinary Feed directive] VFD form filled out by his veterinarian. The form will specify the farm and animals to be treated, the duration of treatment, and which drug is to be used. The feed mill or distributor would need to have a properly completed VFD before they could supply the feed.”
“Yes, the guidelines are voluntary,” Daly says, “but I have confidence the industry will comply. Twenty-five of 26 pharmaceutical companies have already told FDA they will remove growth promotion from their labels [as acceptable uses of the antibiotics].
“The drug companies have three years to make the label changes, so livestock producers currently using antibiotics for growth promotion will have time to adjust, depending on how quickly the companies switch over.
“There are many growth-promoting antibiotics not on the FDA’s list of drugs medically important for humans,” Daly says. “Plus, in the last 20 years, changes in hog management have created such improvements in health and productivity that many farms are no longer seeing the benefits of (growth-promoting) feed additives, so they’re not using them.”
Dr. Larry Hollis, the extension beef veterinarian for Kansas State University, also predicts the voluntary program will succeed.
“Virtually all animal-health pharmaceutical manufacturers are small branches of the same companies that provide drugs for human use,” he says. “They will play by FDA rules, because [the agency] has tremendous leverage and the drug companies won’t jeopardize their ‘human business’ by doing something stupid.
“And when the drug company pulls [growth-promoting] claims off the label, producers will have to comply. It’ll be illegal not to,” Hollis says.
“If you want to see where resistance is occurring in animals, look across the pond to China. They play by a whole different set of rules,” he says.
“Whenever a new antibiotic is developed, the Chinese see the patent filings, figure out how to make it, and without any regulatory structure, it goes straight to animals. By the time it’s available here, the antibiotic is already showing resistance.”
Hollis suggests, “Most antibiotic transfer is coming from human side of the equation. Bacteria don’t care who the host is. Anything that’s mobile has the potential to move resistant bacteria from one place to another. With the speed and intensity of global travel, [bacteria] come in with the people.”
To underscore his point, consider that although 40 years of research shows antibiotics aren’t effective for bronchitis (and 15 years since CDC began urging physicians not to prescribe them for the condition), 71 percent of bronchitis patients are still receiving them.
Justin Waggoner, an extension beef specialist for K-State works with producers at every scale of operation.
“Right now, we’re still early in the process; people are still learning.” he says of the response to the FDA directive. In meetings with producers, Waggoner says, “There’s not a lot of opposition to it. However, you can definitely detect an undertone of, ‘Oh, boy, here come more regulations.’
“The initial response is typically, ‘What exactly is gonna change? And how will it impact me?’ he says. “One question routinely does comes up: Because a veterinarian is involved, will there be a fee involved?”
Industry will adapt
Daly says, “We’ve learned so much about raising pigs in the past 20 years that has contributed improvements in both health and productivity. Based on my conversations with hog farmers, many just aren’t seeing the benefits of growth-promoting antibiotics–the [weight] gains from antimicrobials aren’t as dramatic as they once were, so they’ve stopped using them.”
“We’re going to take a look at management protocols, nutrition, genetics and other methods of growth promotion,” he says. “If we phase out growth promoting antibiotics, I don’t think it’s going to affect their bottom line.”
Hollis offers a similar prediction. “As long as we don’t have to give up the therapeutic uses of antibiotics, the removal of growth-promoting antibiotics from feed will have zero impact on the beef industry. With improvements in management, breeding, nutrition, and management, the industry will adapt.”