No issue in the past 15 years logged more space in agriculture, veterinary or public health-related press than antimicrobial resistance (AMR). No single topic appears more often on conference and seminar agendas than the one addressing prudent use and abuse of antimicrobials in humans and animals. Despite the attention AMR has received, we have not diminished, even subdued, the evolution of antimicrobial resistance. We appear to be losing the war.
The throngs of professionals examining AMR and all the negative ramifications AMR brings to human and veterinary medicine seem to have reached the threshold where the quest for information is confused with understanding. Moving beyond today’s dependence on antimicrobials and the negative impact AMR has on human life calls for astute decision-making. The key to good decision-making on AMR is not reams of finite knowledge about the mechanics of resistance, but understanding why it’s happening because of the way antimicrobials are being used.
The issue is complex and global in nature with no easy answers. No subject touches modern livestock production more fully than antimicrobial use in animal-based food production and the relationship it has to AMR in humans. The assignment of cause for the growing dilemma of highly resistant, life-threatening bacterial infections on hospital wards stimulates arduous debate and finger pointing over what represents judicious use and where responsibility lies related to preserving the shrinking inventory of effective antimicrobials. Agriculture is in the game. The livestock industry must approach the future with a remit to be proactively engaged in finding answers to AMR, or stand suspect and untrustworthy.
Within the context of this article the terms “antibiotic,” “antibacterial” and “antimicrobial” are used synonymously as drugs used against micro-organisms, bacteria in particular, although by scientific definition antimicrobial compounds can be classified, produced and used in different ways.
Since the 1940s, antimicrobial drugs saved millions of lives in both animals and people despite a biological flaw shared by them all — the innate ability to become resistant. Alexander Fleming, the scientist credited with discovering penicillin, knew antibiotics were a unique class of drug. He recognized very early that antibiotics underwent a transmissible loss of efficacy over time. The more we use them, the more we lose them. For this reason, Fleming considered antibiotics a public trust in that every individual’s use of antibiotics affects the efficacy of antibiotics for everyone else. “The thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.” (Alexander Fleming, 1945)
The fact we may be approaching an era without antimicrobials is frightening. Predictions that the real predators of the 21st century will be the microbes grow hauntingly real. It’s very difficult to give simple, sound bite answers for issues that we know have evolved over thousands of years as naturally occurring antimicrobials in our ecosystem played the Mephistophelian dance of adaptation. Bacteria exist in microbial communities that interact with each other. At a molecular level, antibiotic-like compounds act as signalling devices, informing all community microbes that changes are happening. Bacteria, being highly sensitive, adapt. Bacterial communities associated with air, water, soil, humans, and animals are all involved. To blame any single player in the mix as being the “major” contributor to AMR might seem a convenient answer, but it’s not a real one.
Bacteria are living creatures and as such adapt and mutate. Change is perpetual and makes antimicrobial resistance a moving target. AMR is not new. Going back to undo errors of the past is simply not doable. All this generation possesses is the wisdom learned from poor judgment through much of the last century. Finding a way forward rests with a full understanding about changes induced through our use of antibiotics, and the imprudence that brings us to this point. In the search for answers, we need to factor in the adaptation industry requires to sustain food production and adjustments needed to maintain human medical systems.
On a personal note, I’ve shifted from one side of the fence as a practising veterinarian at one time unconcerned about industry’s ability to discover new antimicrobials, to sitting on the fence realizing there were limits to invention, to the side of being afraid. The fear factor materialized after losing a dear friend, a mother and nearly a brother following open-heart surgery to bacterial septicemias caused by garden-variety bacteria that had grown resistant. All this, in spite of the armament of potent antibacterials sitting on shelves within reach.
It’s real folks. The following is an attempt to provide the inside skinny on AMR; underlying issues we need to collectively deal with; opinions why we’re not further along the road than we should be; and hopefully, insight into solutions.
AMR’s complexity is a complement of the many ways bacteria interact with antibacterials, and with each other to exchange genetic material between species giving rise to multiple patterns of resistance. The multitude of ways bacteria spread between animals, people and the environment, and the innate ability bacteria possess to reproduce, multiply and protect themselves add to the complexity.
Basically, antibiotics inhibit or kill susceptible bacteria in four general ways:
- Disruption of microbial cell wall synthesis
- Inhibition of DNA replication
- Inhibition of protein synthesis; and
- Inhibition of cell division, development, and differentiation.
Bacterial infection is typically a numbers game. They possess the ability to grow exponentially, which means 10 cells dividing once per hour become a million cells in 16 to 17 hours. The infective dose (number of bacteria required to produce illness) varies widely among pathogens. For example, E. coli O157:H7 requires an infective dose of only about 10 cells. By contrast, other pathogens, such as Vibrio cholerae, require a large number of cells (hundreds of thousands) in the inoculum to successfully infect a host. Immune systems must be functioning and fully equipped to fight infection or defence mechanisms are overwhelmed very quickly.
The human-animal link
Resistant bacteria can contaminate the human food supply at processing or become environmental contaminants through manure and water run-off. Food safety issues arise whether bacteria are resistant to antibiotics or not. Resistance adds another dimension to illness caused by human pathogens in food. Preventing human infections with resistant bacteria that potentially arise from the food supply is particularly complicated, and in many ways, not fully defined.
The role antimicrobial use in livestock plays against the backdrop of food safety and AMR requires careful analysis to ensure the right things are done for the right reasons. The notoriety of food safety issues is heightened by modern food distribution systems that channel outbreaks of food poisoning across jurisdictional boundaries. Recent outbreaks of multi-drug-resistant salmonella traced to ground beef and poultry demonstrate the relationship of animal and human health.
Results of a study published in the journal Clinical Infectious Diseases drive increased discussion of antibiotic use in livestock and emergence of antibiotic-resistant pathogens. Work conducted by researchers, from the University of Iowa, Kent State University and the National Cancer Institute, Rockville, Maryland, showed that workers in swine barns are six times more likely to carry MDRSA (drug-resistant staphylococcus) than those without swine exposure. In an article from Reuters, the National Pork Producers Council pointed out that other studies have shown hog farming does not create an increased risk for staph infections.
Researchers at Texas Tech University are now suggesting that airborne dust could be a pathway for antibiotic-resistant bacteria to travel from feedlots to human environments.
The complexity that food safety concerns add to the AMR challenge is particularly problematical requiring a multi-faceted approach by many stakeholders. The controversy surrounding agriculture’s role in AMR isn’t helped by contrasting opinion within the research community.
Many bacteria in the environment carry antibiotic-resistant genes developed as a result of exposure to naturally occurring antibiotics produced by soil fungi and bacteria. Laboratory-made versions of naturally produced antibiotics are used to treat infection in humans and animals. Others, not used in human medicine are produced commercially to promote growth in livestock. Manure itself is known to change the composition of bacterial communities in soil. A team led by microbiologist Jo Handelsman (Yale University, New Haven, Connecticut), showed that manure treatment helped natural bacteria grow and in doing so promoted proliferation of antibiotic-resistant genes in soil. The manure was particularly beneficial for Pseudomonas species. Highly resistant P. aeruginosa is a leading cause of death among cystic fibrosis sufferers and a cause of other resistant infections in hospital patients. By putting antibiotics into soil where bacterial populations have been altered by manure, can exacerbate problems with resistance. Some feel strongly that taking a closer look at organic agriculture techniques using manure instead of nitrogen-based fertilizer requires review. Use of manure may inadvertently enrich soil-enhancing growth of drug-resistant bacteria that eventually span the gap from agriculture to human medicine.
The extent to which use of antibiotics in farm animals contributes to antibiotic resistance in human medical clinics is still controversial. A U.S. government release published in September 2014 concluded further investigation is still needed, but stopped short of recommending a ban on all medically important antibiotics for humans in farm animals.
Antimicrobials commonly used in humans and administered to companion animals (dogs, cats, horses) add another field to the AMR quandary. Companion animals, especially cats and dogs, through their close contact with humans, are potential sources of spread of AMR between animals and people. Antimicrobials like cephalosporins and fluoroquinolones are a particular concern. In 2002, companion animals accounted for 37 per cent of pharmaceutical product sales in the EU. Drug-resistant infections in companion animals include methicillin-resistant Staphylococcus pseudintermedius and Schlieferi; methicillin-resistant Staphylococcus aureus; and multi-drug resistant Klebsiella and E. coli. A dog park study conducted by the University of Minnesota showed 27 per cent of samples were positive for E. coli — many multi-drug resistant.
In response, to these concerns, national and state professional veterinary associations have actively promoted antimicrobial stewardship in companion animal practice. There has been an effort to better understand practitioner prescribing behaviour and laboratory practices. Associations have encouraged development of practice guidelines and promote educational programs with web-based training modules.
The choice of antibacterials used in food animal agriculture is only one part of the AMR equation, the other major component being the historical use of antibiotics in humans. A report to President Obama on combating antibiotic resistance from the President’s Council of Advisors on Science (PCAST) in Sept. 2014 stated, “While it is clear that agricultural use of antibiotics can affect human health, what is less clear is its relative contribution to antibiotic resistance in humans compared to inappropriate or overuse in health care.”
Antibiotics in the health-care system have been inappropriately used in the absence of bacterial infection and for prophylaxis (prevention). Not uncommonly, improper dosage instructions are issued with a lack of attention to appropriate duration of administration. Owner finances, AMR concerns, side-effects and client expectations are cited as influential reasons for choosing a specific antimicrobial.