Of course, there’s a lot to say about the issue of antimicrobial resistance, but we’d like to focus on resistance that originates from bacteria in animals and then appears in humans. To discuss this issue in the spirit of One Health, we’ve invited Editorial Board members from the human MSD Manual and the MSD Veterinary Manual. We have Matt Levison, MD, former Professor of Public Health, Drexel University School of Public Health and Adjunct Professor of Medicine, former Chief, Division of Infectious Diseases, Drexel University College of Medicine, and Kris Carter, DVM, MPVM, DACVPM, Epidemiologist, Center for Preparedness and Response, Centers for Disease Control and Prevention (CDC).
Q: What’s the scope of the problem?
Dr. Carter: The World Health Organization (WHO) reports that resistance to 1st-line antimicrobials for common infections has been increasing and even approaches 100% for some pathogens. The CDC reports that in the US each year about 23,000 deaths and 2 million illnesses are due to antimicrobial-resistant infections.
Dr. Levison: Included in these are over 300,000 cases of resistant campylobacter and 1.2 million resistant pneumococci; and between 8 and 65% of E. coli associated with urinary infections are resistant to ciprofloxacin.
I’d also like to emphasize that antibacterial resistance is a threat to modern medical care. So many of our advanced procedures, such as cancer chemotherapy, organ transplantation, and prosthetic devices depend on the ability to prevent and treat infections and would be nearly impossible.
Q: What are the corresponding data in animals?
Dr. Carter: We don’t really have similar quantitative data for animals but reports of antimicrobial resistance in animal pathogens leading to therapy failures are increasing as well. Outbreaks of disease caused by antibiotic-resistant organisms have cost some individual veterinary hospitals hundreds of thousands to millions of dollars.
Q: Obviously, resistance can develop and spread completely within a human population. But when resistance spreads from animals to humans, what microorganisms are we talking about?
Dr. Carter: The classic ones are gut flora, particularly Salmonella and Campylobacter. We’ve also learned that some strains of methicillin-resistant Staphylococcus aureus (MRSA) originated in animals. Advances in genomic testing have improved our ability to determine the origin of a given organism.
Dr. Levison: Yes, genomic testing has been extremely useful. For example, it’s recently shown us that a certain troublesome, new strain of vancomycin-resistant enterococcus originated in animals. And organisms from one location can quickly travel around the world. Colistin resistance that began recently in China, where colistin was used as a prophylactic agent in animal husbandry, has since spread around the world.
Dr .Carter: And let’s not forget viruses. Influenza is probably the best example of a virus that can pass between animals and humans.
Dr .Levison: And although antiviral drugs are used less often in animals than antibiotics are, use of amantadine in Chinese poultry has led to resistance to this drug among lethal influenza strains.
Dr. Carter: And we’re also seeing that certain parasites are becoming resistant to anthelmintic drugs. For example, triclabendazole resistance in Fasciola hepatica is increasing worldwide, which is a problem for both animals and humans.
Q: How do antimicrobial-resistant bacteria get from animals into the human population?
Dr. Carter: Primarily by fecal-oral transmission. Intestinal microorganisms can contaminate meat or other animal products directly when food processing is suboptimal. Or fecal material can contaminate water and be ingested by humans who drink untreated water or eat uncooked plants irrigated by that water. We also know that people who work in direct contact with animals may have a higher likelihood of being colonized by resistant microorganisms than people who don’t. For example, a study found that Dutch pig farmers were much more likely to be colonized by MRSA (a non-enteric organism) than the general population (1, 2).
Dr. Levison: But it’s not just these specific resistant microorganisms from the gut microbiome that we need to worry about. Because bacteria can share genetic material with other bacterial species by transferring plasmids or even DNA segments, these animal bacteria can spread resistance to other unrelated microorganisms in the environment. This opens the door very wide to the dissemination of resistance.
Q: So how do organisms become resistant?
Dr. Carter: Genes that confer antimicrobial resistance are thought to have emerged in microbes a billion years ago.
Dr. Levison: Microorganisms themselves produce antibiotics locally in their environment. In response, neighboring microorganisms develop genes for resistance mechanisms that ensure their survival. However, humans now produce antibiotics on an industrial-scale.
And resistance is accelerated immensely by exposure to these man-made antibiotics. For example, in the US in 2015, providers wrote about 270 million outpatient antibiotic prescriptions for humans (3). And a large US survey showed that between 2006 and 2012 (4), over half of hospitalized patients received antibiotics. In the rest of the world, a rapidly expanding middle-class population is now demanding access to antibiotics previously available only in the developed world.
Dr. Carter: We don’t have the same information for animals, but in 2016, about 8.4 million kg (18.4 million pounds) of antibiotics considered important for human use were sold for use in animal agriculture (3).
Dr. Levison: Similar data on sales by weight in humans are not tracked routinely, but in a 2011 letter to House Rep. Louise Slaughter, the FDA cited statistics from 2009 estimating about 3.3 million kg of antibiotics were sold for human use. Although using different methodology and coming from different years, it seems reasonable to conclude that the majority of antibiotics in the US are sold for animal use. Both human and animal use of antibiotics has markedly increased the selective pressure on microorganisms to develop resistance.
Q: Obviously physicians and veterinarians both treat bacterial infections with antibiotics, which is an obvious source of exposure. Are there other ways that animal microbes are exposed to antibiotics?
Dr .Carter: Besides treatment of individual animals for infection, antibiotics may be used for mass treatment and mass prophylaxis, and some animal producers routinely include subtherapeutic amounts of antibiotics in animal feed to promote growth.
Dr. Levison: Also, remember that many of these antibiotics are excreted in urine and stool and enter the environment where they can cause resistance to appear in environmental microbes that are not part of the animal gut flora. And because of the ability to transfer genes that are located on mobile genetic elements, those organisms that carry these mobile genes may transfer resistance to completely different organisms that are human pathogens.
Dr. Carter: Yes, we see “hot spots of resistance” in microbial populations in some locations where antibiotics have entered the environment. These include places where sewage treatment plants discharge wastewater effluent or sewage sludge is applied to land; where aquaculture is practiced (sometimes involving distribution of antibiotics into the water); areas where manure or farm waste water is applied to crops; and even adjacent to antibiotic manufacturing plants that don’t strictly control their waste water.
Q: Let’s talk about mass administration of antibiotics. Does it even work? Does it promote growth? Does it prevent illness? We don’t typically give prophylactic antibiotics to closely packed human populations such as in prisons or military camps.
Dr. Carter: Interestingly, increased growth in animals treated with subtherapeutic doses of antibiotics is seen, although it’s not clear whether this is due to a decrease in subclinical disease or some other effect of the antibiotics.
Dr. Levison: In terms of preventing illness, we’ve long taught that there’s no evidence in humans that mass administration of antibiotics to large populations lowers the incidence of disease. However, a recent small study in Africa did show that mortality declined by 13.5% among children who received 2 annual doses of antibiotics from birth to age 5 yr. Children aged 1 to 5 months had a 25% decrease in mortality (5).
Dr. Carter: And we do give prophylactic antibiotics to close contacts of people who have invasive Haemophilus influenzae b disease, meningococcal infection, or pertussis.
Dr. Levison: But that’s only to close contacts, not the “herd.” Although I suppose that it could be argued that animals in densely packed production facilities are all “close contacts” of any sick animal in that facility. And we do routinely give antibiotics to those undergoing certain surgical procedures to prevent post-operative infection.
Dr. Carter: Certainly, many farm managers continue to believe that mass administration of antibiotics improves their production. But even if it does, what really needs to be asked is not “Is there a benefit?” but, “What is the risk/benefit ratio?”
Dr. Levison: Yes, even if the farm manager and meat purchaser receive a benefit in terms of greater production and thus cheaper food, they don’t see the cost of resistant microorganisms—that’s borne by my patients on the infectious disease service and the health system that pays to treat them. I haven’t seen calculations comparing the costs of resistant infections to the consumer savings of cheaper food, but even if it were comparable, the costs are concentrated in a relatively smaller number of people who suffer immensely or die, whereas the savings are spread over a large number of consumers who each gain only a little. Also, antibiotic resistance puts the entire modern medical system at risk; antibiotic resistance, for example, threatens to impede advances in cancer chemotherapy, use of prosthetic devices, and organ and tissue transplantation, to mention just a few. Increased antibiotic resistance threatens to put us back to the pre-antibiotic era when common bacterial infections were deadly because effective treatments were not available. To my mind, the trade-off is not worth it.
Q: What needs to be done?
Drs. Levison and Carter: The bottom line is that we must decrease the use of antibiotics in both humans and animals. These valuable drugs should be used only when absolutely necessary—and that’s most commonly for an active bacterial infection that cannot be treated by other means.
Q: What other means?
Dr. Carter: Potential non-antibiotic treatment methods include the use of bacteriophages, immunoglobulins, and modified zinc. There’s also research into novel methods to re-sensitize bacteria to antibiotics through the use of gene editing, antibiotic adjuvants, and metabolic boosters (6, 7).
Dr. Levison: Interestingly, bacteria can even evolve resistance to non-antibiotic antimicrobials such as certain metals. For example, copper, zinc, silver, mercury, arsenic, and antimony all have antimicrobial activity and were used in the pre-antibiotic era; silver-based burn creams still are used as antibacterial agents. Unfortunately, bacteria have begun developing resistance to these metals and, more disturbingly, the genes encoding resistance to these metals have been found linked to genes encoding resistance to antibiotics. Thus, exposure to the metal may result not only in resistance to the metal, but also resistance to antibiotics genetically linked to the metal resistance (8). After Europe banned antibiotic growth promoters, livestock feed supplementation with zinc increased and was followed by emergence of antibiotic-resistant E. coli (9).
Dr. Carter: Preventive measures are more likely to be helpful in the short term, including things such as
- New vaccines
- Selective breeding of animals with greater disease resistance
- Food processing methods that eliminate more pathogens before the point of sale
- Better testing methods, such as multiplex PCR screens, that can diagnose specific pathogens and thus help distinguish viral from bacterial infection and also identify infected animals quickly so they can be isolated and treated without treating the whole herd or flock
- Using probiotics and organic acids for growth promotion
Dr. Levison: And elevated serum procalcitonin levels may also be a biomarker of bacterial infection.
Q: What about an outright ban on adding antibiotics to animal feed?
Dr. Carter: The European Union banned the use of antibiotics as growth promoters as of 2005, and in 2018, is poised to ban routine mass prophylactic use of antibiotic-medicated feed. Many studies have shown decreases in antimicrobial-resistant organisms in food animals following the 2005 ban. The US has been implementing better regulation of antimicrobials in food-producing animals— since January 2017, the US Food and Drug Administration has disallowed the use of medically important antimicrobials for growth promotion in food animals, and the FDA’s veterinary feed directive regulations have transitioned medically important antibiotics from over the counter purchase by producers to requiring veterinary oversight. And some states have even stricter rules on antibiotics in food animals, but none have approached an outright ban. And legislative action alone is unlikely to work without education, enforcement, and the means to implement better management practices.
Dr. Levison: Better some action than none.
Q: Those are certainly interesting approaches. But they’re all top-down, academic or governmental solutions. What can the average practitioner do?
Dr. Levison: Well, top-down approaches, such as limiting the over the counter sale of antibiotics (to patients and farmers), better oversight of antibiotic manufacturing facilities and hospitals, and regulating farm waste runoff, are quite important; at the individual level, practitioners can be local advocates for such interventions. And physicians have slowly been educating themselves and their patients that antibiotics are not the solution to every illness. This has taken time, but we’re seeing progress. Such education is particularly important in countries where antibiotics are available without a prescription.
Dr. Carter: Yes, the same with veterinarians and their clients. And there are a number of professional guidelines and resources to educate and remind ourselves and our clients about when antibiotics are indicated. Here’s a list of resources and policies on antibiotic resistance for physicians and veterinarians:
CDC:https://www.cdc.gov/drugresistance/about.html
FDA: https://www.fda.gov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/default.htm
American Veterinary Medical Association (AVMA): https://www.avma.org/KB/Resources/Reference/Pages/Antimicrobial-Use-and-Antimicrobial-Resistance.aspx
WHO: http://www.who.int/antimicrobial-resistance/en
World Organisation for Animal Health (OIE): http://www.oie.int/for-the-media/amr/
We can also point out to food producers that consumers are increasingly coming to demand antibiotic-free foods.
Dr. Levison: And our preventive health measures in the physician’s office can certainly include education on food safety, particularly proper handling and cooking, and hygiene measures such as hand washing, especially in health care settings. We can at least interrupt the chain of transmission while we’re trying to limit the development of resistant organisms.
Dr. Carter: Veterinarians can similarly talk to their clients about farm practices that prevent introduction of disease and transmission of disease within the farm, called “biosecurity” and “biocontainment.” USDA and OIE have several publications on biosecurity for a variety of animal producers and disease agents; some states are adopting some of these practices as regulations.
Q: What’s our take-away?
Drs. Carter and Levison: We’re encouraged by the spread of information that’s been enabled by increased access to digital resources. We do hope to see continued progress in limiting the use of antibiotics and slowing the development of resistant pathogens.
References
- Voss A, Loeffen F, Bakker J, et al: Methicillin-resistant Staphylococcus aureus in pig farming. Emerg Infect Dis 11:1965–1965, 2005.
- McKenna M: “Pig MRSA” came from humans, evolved via farm drugs. Wired Feb. 23, 2012.
- Pew Research Center: Trends in US Antibiotic Use, 2018. Philadelphia, Pew Charitable Trusts Aug. 1, 2018.
- Baggs J, Fridkin SK, Pollack LA, et al: Estimating National Trends in inpatient antibiotic use among US hospitals from 2006 to 2012. JAMA Intern Med 176(11): 1639–1648, 2016.
- Keenan JD, Bailey RL, West SK, et al: Azithromycin to reduce childhood mortality in Sub-Saharan Africa. New Engl J Med 378: 1583–1592, 2018.
- Marquardt RR: Antimicrobial resistance in livestock: advances and alternatives to antibiotics. Animal Frontiers 8(7):3037, 2018
- Ali J, Rafiq QA, Ratcliffe E: Antimicrobial resistance mechanisms and potential synthetic treatments. Future Sci OA 4(4): FSO290.,2018
- Pal C, Asiani K, Arya S, Rensing C, et al: Metal resistance and its association with antibiotic resistance. Advances in Microbial Physiology April 1, 2017. DOI: 10.1016/bs.ampbs.2017.02.001
- Bednorz C, Oelgeschläger K, Kiennmann B, et al: The broader context of antibiotic resistance: Zinc feed supplementation of piglets increases the proportion of multi-resistant Escherichia coli in vivo. Intl J Med Microbiol 303(6–7):396–403, 2013.
Disclaimer: The opinions expressed in this editorial are those of the authors and do not necessarily represent the views of Centers for Disease Control and Prevention or any other entity of the US government.
