Part III: The terrifying realities of antimicrobial resistance that will keep you up at night

As promised, today’s post will focus on the terrifying realities of antimicrobial resistance. I'm generally not an alarmist, but these two issues are Not Good. We are on our way to a post-antibiotic age of medicine.

The terrifying realities of antimicrobial resistance that will keep you up at night

CRE: Carbapenem resistant enterobacteriaceae This week, I saw headlines about a “nightmare bacteria” that killed two people and infected at least five more. Turns out the nightmare wasn’t such a surprise—the infections were caused by carbapenem-resistant enterobacteriaceae, or CRE.

Enterobacteriaceae are a family of bacteria that includes familiar disease-causing bugs including as Salmonella, E. coli, Enterobacter, and Shigella as well as other bacteria that don’t make us sick. In fact, some of the bacteria found in this family live benignly in the digestive tracts of humans and animals. Others, however, can cause serious illness or death.

What’s particularly frightening is that carbapenems, a particular class of antimicrobials, are usually used as the last-ditch effort to fight infection when other antimicrobials have failed. Bacterial infections treated with carbapenems are nearly always resistant to multiple other drugs. This means that if bacteria are resistant to carbapenems, they’re almost certainly resistant to all other antimicrobials. There are a few drugs that are used to treat CRE, though none of them are particularly effective. If those fail, you're in big trouble.

That’s right: CRE are resistant to basically every antimicrobial. If you get a CRE infection, your chances of survival are 50-50.

CRE are a serious threat to hospital patients. People are unlikely to come across CRE in their daily lives. However, people who are receiving hospital treatment are vulnerable to CRE infections.

I haven’t found any direct evidence linking CRE directly to animal agriculture. However, because carbapenem is only used when all other antimicrobials fail, if the bacteria weren’t already resistant, carbapenem wouldn’t have to be used in the first place! If you’d like to learn more, I recommend starting with Carl Zimmer’s piece “The ‘Nightmare Bacteria:’ An Explainer.”

Foodborne illness is a direct result of animal agriculture When you get food poisoning, it doesn’t matter whether the culprit is ground beef or cantaloupe: the microbes that traveled from your salad to your stomach came from the fecal matter of an animal. Maybe it was the cow you were eating, or one of its neighbors, or maybe it was an animal whose manure runoff contaminated the ground that the cantaloupe grew on. Either way, your gastrointestinal distress is tied directly to the bugs living in the digestive systems of agricultural animals.

CDC estimates that 48 million, or 1 in 6, Americans get a foodborne illness each year. Antimicrobial-resistant infections from food cause 430,000 illnesses each year in the US. Multi-drug resistant Salmonella causes 100,000 illnesses annually. Some strains of illness-causing microbes are becoming less resistant, while others are getting stronger.

A white paper from the Center for Science in the Public Interest shows a bleaker picture. It identifies 55 foodborne illness outbreaks from 1973 to 2011 that were associated with antimicrobial resistant microbes. Foods most likely to be implicated in these outbreaks were dairy, ground beef, and poultry. More than half of the outbreaks were due to multi-drug resistant microbes.

Maybe even more concerning is the fact that 58% of the outbreaks in that 38 year period occurred between 2000 and 2011. That’s right—more than half of foodborne illness outbreaks caused by drug resistant microbes since 1973 have occurred in the 21st century. The number of human illnesses caused by food contaminated by resistant microbes is on the rise.


This series has raised a lot of questions for me, and I plan to continue exploring this issue. Are there any related questions you’d be interested in having me research? I’ll totally do the work for you!


Special thank you to John Phillips for setting me straight on carbapenems. He's going to be a great pharmacist.

Part II: Evidence of the link between animal agriculture and antimicrobial resistance

Yesterday, I wrote about the basics of animal agriculture and antimicrobials. Today, I’ll dive deeper into the issues.

Part II: Evidence of the link between animal agriculture and antimicrobial resistance

What is antimicrobial resistance and why should I care about it? Antimicrobial resistance occurs when microbes have developed the ability to evade antimicrobials, survive antimicrobial treatment, multiply, and infect others. Microbes are able to survive partly because antimicrobial treatment may kill off the sensitive microbes and leave the more adapted ones to adapt to the antimicrobial and multiply.

Microbes can become resistant to multiple drugs. This makes the infection difficult or impossible to treat. By its very nature, an infection will spread to others, endangering more people with resistant infections.

The FDA has a pretty great video explaining the process of antimicrobial resistance.

Is there any evidence of association between antimicrobial use in animal agriculture and antimicrobial resistance in humans? Yes. Most of the evidence is based on studies of foodborne illness such as Salmonella and Campylobacter because the foodborne route is the most common way that resistant microbes are transferred from animals to humans.

Some resistant bacteria will themselves endanger human health. Others which cannot make humans ill will share their resistant genetic code with microbes that can make humans ill. These previously vulnerable, pathogenic microbes become resistant when they receive the resistant genes.

Using antimicrobials at sub-therapeutic levels to enhance growth means that all bacteria in an animal’s body is regularly exposed to low levels of antimicrobials. The most susceptible microbes will be killed or incapacitated, but the surviving ones will become increasingly resistant to the antimicrobial used.

How does using antimicrobials in animal agriculture contribute to human foodborne illness? The CDC report “Antibiotic resistance threats in the United States, 2013” outlines exactly how these two issues are related:

  1. Antimicrobial-resistant microbes may be formed through biological (e.g. selective pressure, mutations) or human (e.g. antimicrobial misuse, inadequate diagnostics) avenues.
  2. Antimicrobials used in animal agriculture kill off susceptible microorganisms while allowing resistant microbes to survive.
  3. Resistant microbes can be passed from animals to humans through fecal or other forms of contamination of food.
  4. When humans eat contaminated food, they develop infections (e.g. coli) that cannot be treated with antimicrobials. For generally healthy people, this may not be problematic, as their immune system will fight the infection itself. However, some people will need a boost from antimicrobials—antimicrobials that are now useless.

Beacause of this strong connection between animal antimicrobial use and human illness, CDC recommends that antimicrobials are used only to treat infections rather than to enhance growth. The CDC calls this antibiotic stewardship. 

What are some other ways animal agriculture-induced antimicrobial resistance affects human health?

  • Infections that would not have otherwise occurred
  • Treatment failures
  • Increased severity of infections (Source.)

Is animal agriculture the only cause of antimicrobial resistance? Definitely not. The other major contributor to antimicrobial resistance is improper human medical use. For example, when doctors prescribe antibiotics for a viral infection, the antibiotic will not treat the viral infection. However, the antibiotic may kill off a few bacteria from a minor bacterial infection, leaving only the remaining bacteria resistant to the drug.

 

Come back tomorrow for Part III: The Stuff That Will Keep You Up At Night

Part I: The basics of animal agriculture + antimicrobial resistance

Before antimicrobials, strep throat could be fatal. Nearly every child who had bacterial meningitis died. A small cut, once infected, could kill a person. In my mind, antimicrobials are neck-and-neck with vaccines and basic sanitation as the most important health and medical discoveries. And yet we are quickly losing our grasp on treating infections. Multi-drug resistant tuberculosis is on the rise, as is drug resistant gonorrhea, and MRSA strikes fear into anyone working or staying in a hospital.

Animal agriculture may have something to do with this. Antimicrobials are used extensively in the livestock and poultry industries. This piece is Part I of my exploration of the links between animal agriculture and the looming public health crisis of antimicrobial resistance.

The basics of animal agriculture and antimicrobial resistance

What is the difference between antibiotics and antimicrobials? Strictly speaking, an antibiotic is a substance produced by a microorganism that is used to kill or inhibit the growth of other microorganisms. Penicillin, grown from fungus, is an antibiotic.

An antimicrobial can be naturally-occurring, semi-synthetic, or entirely synthetic compound that it used to kill or inhibit the growth of other microorganisms. Antimicrobials include sulfonamides and amoxicillin. Antimicrobials can be used against bacteria, viruses, fungi, and protozoa such as malaria and toxoplasma gondii.

When discussing animal agriculture, the term antibiotic resistance is often used. However, because it doesn’t include synthetic or semi-synthetic antimicrobials, I’m going to follow the lead of the United Nations, the World Health Organization, and the World Organization for Animal Health and use antimicrobial resistance.

How are antimicrobials used in animal agriculture? Antimicrobials are primarily used as growth promoters and are given to livestock and poultry at sub-therapeutic levels, meaning that the levels at which the antimicrobials are administered are below the threshold that would fight off infection. Using antimicrobials as growth promoters is a direct result of the ever-increasing demand for meat and animal products.

Antimicrobials increase animal growth rate by 2-10% and feed conversion efficiency 3-9%. It’s unclear how or why this happens, but some researchers suggest that cytokines released when the immune system fights off infection may stimulate growth-inhibition hormones. Others suggest that antimicrobials keep animals’ gut bacteria in check, allowing the energy that would have been used to stave off infection to instead be used for growth.

Because nearly all animals raised for food are kept in cramped, stressful conditions, antimicrobials are also used for disease prevention and control (metaphylaxis). The animals live in such a way that makes infectious disease likely—packed in very closely, standing their own excrement—and rather than make changes to their living conditions, the various industries choose to feed the animals preventative antimicrobials.

Antimicrobials are also used when animals get sick, or after an injury or surgery. However, these uses make up just a small portion of the antimicrobials used.

Does animal agriculture really use 80% of the world’s antimicrobials? This statistic is often cited. However, there doesn’t seem to be much evidence to support it. However, this figure includes ionophores, which are not used in human medications but are used as growth promoters.

Which antimicrobials are used in animal agriculture? This table shows a selection of the antimicrobials identified as both critical to human medicine and regularly used in animal agriculture in the Congressional Research Service brief “Antibiotic use in agriculture: Background and legislation” by Geoffrey S. Becker. I added the columns “Common drugs in this class” and “Human infections treated by this class (selected).”

Antimicrobial class Common drugs in this class Human infections treated by this class (selected) Use in animal agriculture Level of importance for human medicine as defined by the FDA, based on level of difficulty of transmitting resistance across genera and species
Cephalosporin (3rd generation) Cedax, Fortaz, ceftriaxone Gonorrhea; urinary tract; respiratory; pelvic inflammatory disease; pneumonia Disease treatment in cattle and swine Critical
Fluoroquinolone Cipro, Floxin, Avelox Anthrax; hospital-acquired infections, especially pneumonia; urinary tract Disease treatment in cattle Critical
Penicillin penicillin, amoxicillin, flucoxacillin Meningitis; syphilis; Lyme disease; strep throat Disease treatment in cattle; growth and disease treatment in swine High
Macrolide Zithromax, erythromycin Legionnaire’s Disease; chlamydia Disease treatment and prevention in cattle; growth, disease treatment and prevention in swine Critical
Tetracycline doxycycline, tetracycline, Chlamydia; acne and rosacea; typus; plague Disease treatment and prevention in cattle; growth, disease treatment and prevention in swine High
Lincosamide clindamycin, lincomycin Toxic Shock Syndrome Disease treatment in swine High
Streptogramin pristinamycin, quinupristin Vancomycin-resistant Staphylococcus aureus (VRSA) and enterococcus (VRE) Growth, disease prevention in chickens High

How does antibiotic resistance happen? The National Institute of Allergy and Infectious Disease (NIAID) cites seven ways that microbes can become drug resistant:

Biological causes

  • Selective pressure: only the microbes with genes that make them resistant to antimicrobials are able to survive
  • Mutations: random changes in the genetic code protect some microbes from antimicrobials
  • Gene transfer: microbes can get genes from other, drug-resistant microbes

Human causes

  • Inappropriate use: prescribing antimicrobials for a disease that cannot be cured by them—for example, prescribing an antibiotic for a cold
  • Inadequate diagnostics: using a broad-spectrum antimicrobial when a specific one may be more effective, or being unsure of the underlying cause of illness and prescribing a drug “just in case”
  • Hospital use: hospital patients are susceptible to infections, but giving them high doses of antimicrobials puts them at risk for resistant infections
  • Agricultural use: NIAID states that agricultural use of antimicrobials is still debatable as a public health issue.

Now that we’ve covered the basics, check out Part II!