SuperChickens?

May 02, 2016 by John Jackson in Microbiology, Immunology, Articles

In this final part of my series on antibiotic resistance, I want to discuss the use of antimicrobials in the food supply. If you need to review other areas of antibiotic resistance, check out “Discussing the Disappearing Miracle” (a lesson in what antibiotic resistance is and is not), “Quitting When You’re Not Really Ahead“ (how people accidentally contribute to antibiotic resistance), and “No, the Z-Pack Won’t Treat The Flu” (how overprescription of antibiotics contributes to resistance). In this article, I’ll focus on how antibiotics are used in the growth of animals destined for consumption, what that does in terms of producing resistance, and what we can do in response.

I know the article is called “SuperChickens?”, but I actually want to start by talking turkey. If you live in the United States, you’ve likely seen the president pardoning a turkey on Thanksgiving Day. This is an old tradition - you can see a photograph of Kennedy pardoning a turkey next to a similar photo of Obama doing the same thing 50 years later (1). What’s remarkable in this photo is the difference in the two birds. Kennedy’s turkey is much closer in size to wild turkeys (2), which usually weigh between 7.6 kg (toms) and 4.26 kg (hens), maxing out at 16.85kg (3). In comparison, the turkeys that grace most tables average 13.5 kg, maxing out at 39 kg (4). Wild turkeys are half the mass of modern, domesticated turkeys (2). Nor did that change happen by accident.

Until the 1950s, most turkeys were similar to the wild birds. However, with the arrival of antibiotics, the average size of the bird began to change. While this was initially done through selective breeding, the demand for meat incentivized not only breeding for size, but also speed from egg to adult. The demand for a bigger bird faster drove competition. When it was discovered that antibiotic use increased the growth rate of chicks in 1948 (chicks given antibiotics grew larger, faster, than those not given antimicrobials), it helped create a new market for the new drugs (5). Since faster growth resulting in bigger birds was the desired outcome, the animals’ feed was soon supplemented with antibiotics.

I know what you’re wondering - who even thought that feeding antibiotics to chickens was a good or necessary idea? It turns out that the introduction of antibiotics was an accident. Researchers were studying other ways to supplement growth, focusing on vitamin B12 (which includes cobalt, a trace metal important for red blood cell development, neurological function, and DNA synthesis) (6). The researchers were looking for different sources of B12, and one easily available source used was the cellular remains of Streptomyces auerofaciens (5). These bacteria were used to develop the tetracycline antibiotic aureomycin, and the cellular remains were what was left when the antibiotics were extracted from the bacteria. They used it because it was an amazing source of the vitamin for a very low cost - it was waste from another process already being done. Another source of B12 was beef liver. Researchers discovered that the chicks given bacterial remains grew 24% faster than the chicks given liver. While it wasn’t initially clear that the antibiotic residue in the cellular remains caused the growth, the vitamin was eventually ruled out as the cause of improved growth (5).

Suddenly, agriculture had an easy way to improve their product - they could grow animals faster, larger, which meant they could use less feed - the sooner an animal was an adult, the sooner it could be sent to market. Since the initial doses of antibiotics were accidental and very low, antibiotics for growth promotion also use very low doses. As a result, the bacterial population in animals are exposed to the drugs used to treat an infection in a sick animal, but over the entire course of their life. This establishes an excellent environment for the bacteria to adapt to the drug and become resistant to it.

See, resistance occurs when a bacteria is exposed to a drug, but not all of the bacteria are killed by the drug. The weakest bacteria die off, leaving those not actually susceptible. During clinical dosing of antibiotics (when used to treat an infection), high doses are used over a short course. This makes it more difficult for the bacteria to adapt. The high dose is more likely to eliminate more of the bacteria, and the short course, or amount of time involved actually taking the medication, means that any resistant bacteria don’t remain exposed to the drug long-term. That gives our rapidly multiplying bacterial population no opportunity to select for resistance. Instead, as the resistant bugs die off, random chance re-enters the evolutionary picture - there’s nothing present to make the resistant bugs more likely to survive and reproduce, so there’s no benefit to resistance.

But when the exposure is low, more of the bacteria survive, giving a larger population the ability to adapt (versus the much smaller population of resistant bacteria that exist after the rest are killed off). What makes this worse is when that exposure occurs over a long period of time. The benefit of remaining resistant continues, which ensures that the larger population is more likely to retain resistance. Random chance is thus limited when mutations occur - the pressure to remain resistant persists within the bacterial community, producing more resistant bacteria in greater numbers.

Growth promotion isn't the only use for antibiotics in agriculture. When one or more animals is ill, or when stress is high within the population (such as weaning the young or transporting them), farmers use antibiotics to prevent illness in the entire community. This preventative use makes use of higher doses than those used for growth promotion, but still lower than needed to treat active infection. This subclinical dosing (lower than needed to treat an infection) in both cases increases the exposure of bacteria to the same drugs used to treat disease in both animals and humans. While this preventative use need not be used over an extended period time, not all farms as judicious as they could be in their use. However, this use of antibiotics creates a similar selection pressure on the bacterial populations within the animal - it's still high enough to eliminate the most susceptible bacteria, but because no active infection is present, the animals' immune system never activates to eliminate the remaining, resistant population. Worse, because this dose is higher than the one used for growth promotion, the percentage of the population that remains is made up of mostly resistant bacteria (as opposed to resistant and non-susceptible bacteria that remain with the very low doses involved in growth promotion).

The least controversial use of antibiotics in food production occurs when an animal is actually ill. In these cases, sick animals are given clinical doses of antibiotics, just as the rest of us are. Since the animal is reliant on another to dose them, either in feed, water, or via injection, the risk of forgetting a dose is reduced. Some farmers do this by adding the medication to the water supply, but if it is only supplied to the infected animals, the risk of resistance drops. Since it’s illegal (and unprofitable) to sell sick animals, very few object to clinical uses in these settings (although some farms ban the use of all antibiotics, or won’t sell animals that required treatment).

OK, so animals can develop resistant bacteria just like people do. You may be asking yourself why that matters. We can’t give animals cold medicine when they get sick - surely we’re not using “people” medicine for animals, right? Wrong. In fact, farmers are more likely to use the inexpensive generic drugs that are less beneficial for human use due to increased resistance. This might not seem like a problem - if we can’t use them anyway, why not get some benefit? Sadly, some of these old medications are held in reserve to treat bacterial infections that are resistant to almost all antibiotics, but that were never exposed to these older drugs. As a result, using these “last line” drugs can create bacteria that are not only resistant to the drugs commonly used to treat infections, but also to these older drugs (7,8).

You’re wondering how, if sick animals can’t be sold, resistant bacteria transfer from healthy animals to people. There are a few ways, but nearly all of them are tied to food safety practices. The possibly grossest method is via feces: the animal passes stool, and water washes the resistant bacteria into a water source. This contaminated water is then used to water fresh vegetables that are likely not cooked before consumption. In fact, this is exactly how the Escherichia coli outbreak in 2006 occurred. A cattle farmer leased land to a spinach farmer, which became contaminated by infected cattle feces in the water supply. Because spinach is often consumed raw, the bacteria were able to reproduce without adequate control and without being eliminated when the food was cooked.

That last point - that the food wasn’t cooked - is the key to most of the remaining transferrals. Contaminated raw meats can spread bacteria to people as well. Meat that isn’t cooked to a temperature that kills the bacteria can lead to consumption of viable bacteria. This is why menus note that eating meat or eggs can cause problems in certain groups - undercooked eggs are another possible source of viable bacteria. But even if you’re careful to always cook your food to the right temperature, if you don’t cool it correctly and keep it out of the danger zone (4° - 60° Celsius), the bacteria can grow to a dangerous population after cooking. More than that, putting hot food into the refrigerator or freezer can raise the temperature of surrounding foods (including those that are pre-cooked) long enough to allow bacterial growth.

“Oh,” you say, “but I’m always careful to have my meat well done, my eggs over-hard, and to put leftovers away immediately without letting them heat surrounding food.” That’s awesome, but you’re not out of danger yet. There’s still cross-contamination to consider. This can occur if you cut or handle raw meat with the same hands or tools that you then use to handle fresh, uncooked food. This is why cutting boards for designated purposes have increased in popularity - keeping your raw chicken on one board, your red meat on another, your fruit and veg on yet another, helps reduce the risk of putting fruits and veggies into a pool left behind by raw meat. But if you don’t change your knife or wash your hands, you may still have cross contamination issues.

Cross-contamination can even occur before you bring your food home. If your meat and your fresh food aren’t stored correctly, the meat may contaminate the fresh food in your supermarket buggy or in your refrigerator. Meat stored above a crisper drawer may leak into the crisper drawer, especially if it isn’t wrapped well. Food put into the fridge without cleaning where the raw meat had been can then be infected as well. It’s also possible that food handlers (before it ever reached you) could be the cause of cross contamination.

Once you’ve consumed the contaminated food, the bacteria have the perfect host in which to grow and reproduce. As they grow, they interact with other bacteria in your body (remember the lesson in “Discussing the Disappearing Miracle”). The plasmids that contain the genes for resistance are then shared with bacteria present in your body, and now those bacteria are resistant to the drugs coming from the animal population.

Many have suggested that this sort of cross contamination between agricultural and human bacteria is incredibly unlikely. Sadly, a recent study in China (7,8) illustrates that resistant bacteria in animals are present in food and have caused disease in humans. Worse, the drug resistance is to a drug-of-last-resort. Colistin is an old antibiotic (developed in 1959), meaning it is now available in a generic formulation and thus cheap. It was also not widely used in humans due to the tendency to cause kidney problems, limiting the ability of bacteria common to humans to develop resistance to it. Because it is cheap, colistin has been widely used in agriculture, particularly in Asia, where it makes up 73.1% of colistin production. However, because so few things have had opportunity to develop resistance, infections that are resistant to other treatments are treated with colistin (when your choices are maybe develop kidney problems or die of the bacterial infection, medical professionals tend to opt for risking the kidney problems over death).

The study in China found colistin resistant bacteria in animals, raw meat in stores, and in 1% of hospital treated infections. Worse, this resistance has already spread from China and is now present in Malaysia. This means that patients are already seriously ill from antibiotic resistant infections that are also resistant to our last defense (7). We’re already seeing the first waves of a time when antibiotics may no longer be available. And while 1% may not seem alarming, remember that resistance spreads fast because bacteria share.

At the start of this article, I suggested that I would include information on how you, as an ordinary person, can help fight antibiotic resistance from agricultural use. I’ve already told you that safe food handling can help prevent the spread of bacteria to you and those you love, but that’s only one way to fight this growing threat. Many companies are already taking the steps necessary - Denmark (9) has outlawed the use of antibiotics in animals destined for market, and two turkey producers (10) have outlawed them either entirely or for subclinical usage. You can help make it more profitable for companies to take the longer road to growth by buying from trusted brands or demanding that your favorite brands eliminate subclinical use. You can demand better living conditions for animals bred for market - I didn’t even discuss how the terrible living conditions trigger preventative use of antibiotics or lead to sicker animals. The eggs that came from free-range hens are far less likely to have had antibiotics, because those hens are less likely to need them. But free-range hens require more land and more time and more food to grow, which increases the cost to the producer and the consumer.

Antibiotic resistance didn’t happen overnight. Many smart people are working on how to solve it, to keep our miracle intact for generations to come. Fixing a problem this big isn’t going to be easy or cheap. But you can help. You can demand that your food be antibiotic free, you can insist on only taking antibiotics when they’re actually necessary, and you can take every pill on time, to the end, even when you feel better (by the way, that’s actually a decent test to determine if your infection is viral or bacterial: viral infections last 7-10 days before the immune system can wipe them out. Bacterial infections treated by antibiotics will improve in a day or two. So if your doctors writes you a script for antibiotics, and you take them, and you aren’t better in a day or two, odds are your infection wasn’t bacterial. I give you permission to remind your doctor about the risks of antibiotic resistance). You can also educate others, like I did here. Understand the risks, do the hard work to help reduce them, and encourage others to do the same. Together, we might just be able to win.

NB: I included not only the sources I cited here, but also several that I used as I prepared this article. Watch for a video from “In A Nutshell” to explain this very topic, as well. It isn’t cited here, but it’s coming.

Sources:

No, the Z-Pack won't treat the flu...

December 08, 2015 by John Jackson in Immunology, Microbiology, Physiology

No, the Z-Pack won’t treat the flu.

So far, in our discussions on antibiotics, we’ve discussed what antibiotic resistance is and isn’t (Discussing the Disappearing Miracle) and how ordinary people accidentally contribute to this growing problem (Quitting When You Aren’t Really Ahead). While there is growing awareness that antibiotics in our protein supply (see SuperChickens?) can contribute as well, an area that becomes increasingly frustrating is over-prescription of antibiotics. This happens in two ways: patients, unaware of the difference between the causes of infections, may ask for antibiotics for illnesses even if they would be ineffective. Doctors, unwilling to see their patients suffer, offer something, anything, in an attempt to help. Unfortunately, neither scenario is truly harmless.

In order to understand why prescribing antibiotics all the time isn’t harmless, we must first understand a little bit about pathology, or how disease impacts the body, a little bit about epidemiology, how disease spreads in a population, and a little bit about microbiology and immunology, how the body defends itself from disease (and the causes of disease). I will point out that it is possible to get doctoral degrees in each of these fields and to go into far more depth than I intend to explore here. My plan is to just skim the surface and help you piece everything together to make a complete picture.

Raz and Aisha are a young couple working hard to make a home. When their new baby joins the family, they become familiar with all the sleeplessness that accompanies a new baby, the late night feedings, the endless diaper changes, and the wonder of rediscovering the world through the eyes of new life. It isn’t long before their new baby becomes an older sibling as the parents welcome their second child and everything is repeated. Raz and Aisha learn what every new parent learns at this point: Someone is always sick.

This is normal in homes with small children, even healthy children. In the first five years of a child’s life, the immune system is learning and growing as much as the child is. During prenatal development (while the fetus was in the womb, connected to mother via the umbilical cord), the child had the benefit of mother’s antibodies, circulating immunoglobulin G (IgG). As soon as that cord is cut, however, so is the supply. Now it is baby’s turn to make antibodies.

If mother can breastfeed (and not all mothers are able to, for a variety of reasons, but if they can, it is best), then baby gets another boost of antibodies from a secreted antibody known as IgA. This is excellent, because by about 4-6 months, mother’s supply of IgG is gone, but if baby is getting a constant supply if IgA, it can provide a boost of protection. Even at 12 months, baby’s first circulating antibodies are likely only around 80% of what they will ever reach at their best - little baby Sarah just doesn’t have the protection that her body needs to fight off everything that Raz and Aisha can. A year later, when baby Abram is born, Sarah will have grown, her body will have learned more, but there is still so much to learn - but Abram is starting from zero, just like Sarah did.

So we have a young family, mother and father and two precious small children with growing immune systems. They get vaccines for themselves and their children. Dad’s vaccines ensure that his strong immune system is ready to defend his body and keep disease from gaining a foothold - he provides a fence around his family. Mom’s vaccine is another link in that fence - when parents go to work, they encounter microbes, bring them home, but inside of Mom & Dad’s body, the microbes encounter strong immune systems capable of eliminating the microbe before it can cause disease, and thus removing the threat to the children. But if Mom can breastfeed, Mom adds another layer of defense: the antibodies she makes are passed on to her children in her breast milk, and the children get that defense as well (see why this is so important to breastfeed if you can?) The children are getting a carefully timed sequence of vaccines as well. Each is a very specific dose, in a very specific sequence, aimed to teach their growing bodies how to protect them against illness.

It’s also worth noting that vaccines are non-infectious, dead, weakened, or parts of viruses and bacteria. Vaccines can not cause the illness they protect against. Let me say that again. A vaccine cannot cause the illness it protects against. What vaccines accomplish is to allow the body to encounter pathogenic particles (bits of disease causing agents) in a controlled manner that stacks the deck in favor of the immune system. Instead of encountering wild viruses or bacteria that can and do cause disease in the human body with little to no preparation, vaccines train the body via the immune system so that when the body does encounter the wild pathogens (disease-causing agent), the body knows how to defend itself.

OK, so Raz and Aisha have been doing everything they can, and they take Abram and Sarah out to play. Maybe they go to their local house of worship. Maybe both parents work, and the children are in daycare. However it happens, Abram and Sarah encounter the great big world, where there are other people. It isn’t too long before one of the children wakes up Mom with a snuffly nose, a cough, and a fever (of course they wake up Mom. Even if they woke Dad, even if Dad is a pediatrician, they still asked for Mom and wouldn’t calm until they got Mom. That’s just how we are. We want our Mommies. It’s ok. Or maybe you prefer they want Dad. The point is that parent is disturbed by sick child).

Sick child cannot join other children. One of the parents must miss work, even if they decide that this isn’t worth a doctor visit yet. However Raz and Aisha decide, the decision is made, and the parents adapt to the needs of their child. Of course, the next day, the other child is ill, as well. Another day missed from work. Perhaps the parents opt to trade who misses. Maybe they’ve made other arrangements. But clearly whatever the children encountered in the wider world has defeated their own growing immune systems. Remember - these are small children, whose immune system hasn’t learned all the things that Mom and Dad have. It’s getting better all the time (as The Beatles said), but there just hasn’t been enough time yet.

But there’s another race going on: as the children’s bodies race to grow and learn from the world around them, inside their bodies are all the Sue Streptococcus and Reeking Jim and other bacteria. And the kids have a cold, a virus we can’t vaccinate against because there are just too many varieties making too many changes. The most common cold virus, rhinovirus, is effectively a protein instruction manual inside a protein coat looking for a factory, and everyone is a factory. Worse, while there’s really one kind of Sal, even if he does mutate and change, there’s 99 kinds of rhinoviruses, and they don’t get along. Even if we figure out how to deal with one of the 99 rhinos, there’s 98 more waiting, and that’s just the most common kind. You probably have more than one virus at a time, too, so you’re not just dealing with Sal and his copies going crazy, or a single rhinovirus setting up shop in the factory that is your nose, but as many as 200 different viruses possibly causing your cold.

So Abram and Sarah have a cold, which means they have multiple viruses that found their noses and mouths and decided to set up shop and start making copies. In response, their immune system has tried a few different things to protect them. To help kill the viruses, the immune system increases the temperature. Our body has a very specific temperature we like, but pathogens are even more picky. Often, a change in temperature can help kill the virus or bacteria causing illness. So up goes the body temperature, and up goes the misery. There’s viruses in the nose, so the immune system tries getting them out. Immune cells called neutrophils rush to the site, causing swelling and redness, which brings more heat and pain with it. This helps trigger mucus production and gives the kids runny noses. As the mucus runs down the back of the throat, it triggers a cough, too. In fact, if virus is in the airways, the immune response may continue there, causing sore throat and more cough. In fact, all the misery you feel from the cold is actually the result of your body fighting the cold. But if your body didn’t fight the cold, the virus would gradually take over enough of your cells to kill you. I think we can agree that given the choice between the misery of the cold and death by cold, death by cold virus is worse.

From start to finish, it takes 7-10 days for the human body to fight off a viral infection. Some take longer - if there are more viruses, it may take longer, for instance, or if you don’t give your body the tools it needs, like rest and fluids, it may take longer. But there is really nothing that can be done to shorten the length of time you have a cold. Because viruses have to get into your cells to work, anything that would shorten the length of time you are sick must first attack your own body, and finding a way to kill a virus without killing the cell it infected is incredibly difficult. This, by the way, is why the side effects for anti-viral medications like tamiflu sound incredibly like more of the flu but worse. It actually is. This is also why some anti-virals have such a narrow window of effectiveness - once the virus is inside the cell, medication aimed at keeping the virus out of the cell is far less effective.

Let’s get back to poor Abram and Sarah. Neither of them have the flu, right? They’ve got colds. And because colds are contagious, of course Raz and Aisha get colds and no matter how careful they are, Raz and Aisha share their colds, and everyone’s temper gets short because they’re discovering that when small children are present, someone is always sick. That’s how epidemiology works in families. Once the kids get older, that will happen less, but while they grow up, it will feel like someone is always sick, especially the more children there are and the more social the family is. This is actually good - their bodies are learning and growing and they will, in general, be stronger, healthier adults.

As the family recovers, just as the last of them starts to feel better, things get worse. One of Raz’s coworkers decided to share his flu, and Raz shares with the family without realizing. The family goes to the doctor who mistakes flu for an ongoing sinus infection and prescribes Z-Packs for the lot of them.

Here’s the thing. Streptococcal infections aren’t something to be ignored. If you have strep throat, take your antibiotics as prescribed, take every pill on time, finish the entire prescription, even when you feel better, and take them all. It’s very easy for your body to get confused and look at Sue and look at parts of you, like your heart, or your kidneys, and get mixed up. It’s called molecular mimicry, and when it happens, your immune system goes from being your best buddy to being a serious problem. It causes autoimmune problems like Scarlet Fever, where your body attacks itself instead of the bacteria. Before we had antibiotics, Streptococcal infections could be deadly even if you survived them. So we’re very eager to treat them, and it’s not a bad thing.

But antibiotics can’t treat a viral infection. Remember the talk about resistance versus susceptibility? If a bacteria never had a weakness to a drug, it could never become resistant to it because it was never susceptible to it. Viruses are not susceptible to antibiotics. They will never be susceptible to them. Viruses are instruction manuals inside of a coat (sometimes wrapped in armor). They lack the mechanisms that antibiotics target. This, too, is a good thing; if viruses could live outside of a cell, if they could copy themselves without needing us, they would wipe us out in no time. We want viruses to lack those mechanisms, to effectively be in suspended animation when they’re not inside cells.

So what happens when our little family makes the mistake of taking the Z-Pack for the flu? No harm, no foul, right? The have a viral infection that will wipe itself out in 7-10 days, so they’ll feel better if they take the pills or not (and we’ll pretend that they’re really good about taking them like they should). No big deal?

Except there are friendly Sues that live with the Reeking Jims and another organism, a fungus we’ll call Difficult Claus. Good ol’ C. difficile. Just like the viruses aren’t susceptible to the azithromycin in the Z-Pack, neither are Jim or Claus. But unlike the viruses, Jim and Claus live in our bodies, serving an important function, growing with us. And they can live inside or outside. They don’t go into suspended animation like the viruses do.

Normally, our Sues and Jims and Claus live with other organisms and with us in our intestines where they teach our immune system the difference between us and other, living off the food we eat and don’t need (all the food you eat has stuff you can’t use - that’s what they use). It’s a commensal relationship, not just between us and organisms, or microbiome, but within the microbiome itself. The Sues and Jims and Clauses all make sure everyone takes up just the right amount of space, that no one hogs all the best intestine. But when you take antibiotics, the Sues and the Jims start to lose, and Claus might grow out of control. In our happy little family, only Sue dies off. Jim and Claus stay behind, and now the children have unhappy tummies.

Oh, and Sue keeps making copies of herself, remember? Just like Sal did. And the Sues that survive are the SuperSues. So when the children get Strep throat, and they need that Z-Pack to kill the bad Sues, the ones that are making them sick, guess what’s going to happen? If you guessed resistance, you guessed right. And what happens when we can’t fight strep infections? Molecular mimicry can happen. The risk of very bad things start to increase.

So no. No Mom, No Dad, no, you may not have antibiotics for your cold, flu, or seasonal allergies. No, Doctor Meanswell, you may not prescribe antibiotics to help your patient feel better, even if you know it’s probably not bacterial. What you may do instead is insist on the test that will confirm that the infection is the bacteria or virus that will be treated by the drug you want, and then prescribe the most effective drug for that infection. Your future you will thank you.

Using Viruses to Fight Bacteria?

June 17, 2013 by Heather Jackson in Articles, Immunology, Microbiology

In Tbilisi, Georgia (the country, not the state), Dr. Revaz Adamia is trying something different in the war against bacteria: instead of using antimicrobial drugs, he's treating infections with a special class of viruses instead. Why use viruses? The class in use, bacteriophages, target only bacteria, not the human infected. As a result, the virus infects and kills the infection that was making the patient sick. When the bacterial infection is gone, the virus, now without a host, dies off.

This solution is an alternative to the increasing problem of antimicrobial resistance. Many bacteria are increasingly resistant to the drugs used to treat patients infected with them. The most well-known case of resistance is MRSA, or Methicillan-resistant Staphylococcus aureus, a bacteria that frequently causes skin and respiratory infections or food poisoning. Resistant bacteria no longer respond to the drugs once used to treat infections, making treatment of patients increasingly difficult.