Friday, August 15, 2014

A Prescription for Pestilence: Let's talk about antibiotic resistance

We are all engrossed in the current Ebola epidemic, and rightly so. However, as tragic as this epidemic is, Ebola is not the only or deadliest, Global public health concern. In fact there's some microbial trouble brewing, it's been brewing for some time and it scares me. So, without discounting Ebola, I'd like to start a new discussion. A very important discussion

For those of us lucky enough to live in parts of the world where clinics and antibiotics are easily accessible, diseases that could decimate families 100 years ago are mere inconveniences. My son had scarlet fever last year and instead of watching him suffer horribly with no assurance of his survival, I missed a couple of days of work while he recovered in relative comfort with the help of antibiotics and another modern miracle, acetaminophen.Yet I wonder for how long we will have the luxury of these medicines? We are slowly paving the way for antibiotic-resistant bacteria to rule the planet.

Seem melodramatic? I wish.

"A post-antibiotic era—in which common infections and minor injuries can kill—far from being an apocalyptic fantasy, is instead a very real possibility for the 21st century."

That is a quote from the 2014 World Health Organization report on antimicrobial resistance, and as a mother and scientist it is terrifying.

Now, before I get into antibiotic resistance, I just want to clarify: this is not meant to be a treatise on "Global microbial evolution with or without human advances in infection prevention or treatment". I know that viruses also evolve mechanisms to overcome our interference, and that introduction of resistance genes into bacteria not subject to antibiotic pressure can occur. They are independent pieces of a very large puzzle and are for another day. This post is limited to the generalized basics of our role in bacterial resistance to antibiotics. I just want you to understand why it's important and how we can begin to address it. OK.

The problem is two-fold. We are constantly warned by scientists and physicians to 1) use antibiotics with discernment and 2) take the entire course of antibiotics as prescribed. And we all know why: antibiotic resistance and other health problems could result if we don't. And yet many physicians prescribe antibiotics without actually having a definitive diagnosis, and when they are prescribed, most of us still do not take them as directed. It's a real and dangerous phenomenon and we are beginning to reap the tragic harvest that will eventually lead to that post-antibiotic era.

Let's take a minute to really appreciate what "post-antibiotic era" means. It means that the antibiotics we are using now will no longer work. It means bacterial infections will once again be able to kill and maim. It means drastic surgical intervention, such as amputation, will be used to save lives. Can you imagine the toll it would take on a preschool, elementary school, or daycare? How about a college campus fighting gonorrhea? The reality of life without effective antibiotics is frightening. Does every bacterial infection require antibiotics? No. Does every bacterial infection lead to a global pandemic if not treated with antibiotics? No. Am I fear mongering? Absolutely! I really hope you are paying close attention because this needs our attention now.

This isn't the first time you've heard this, I'm sure.So why are we still so cavalier about prescribing and taking antibiotics? Why aren't we taking this seriously?

When it comes to prescribing antibiotics, I've spoken with physicians who admit to feeling pressured to provide medicine and to do so quickly without the time and money required to run tests. For example, a sore throat could be viral or bacterial, and antibiotics won't do anything for a viral infection, they only work against bacteria, some fungi and parasites. But the parent of the sick child may want action, right? They need to get back to work, the child needs to get back to school. Life must go on!! Besides, who wants to take a suffering child to the doctor's office, urgent care or ER, wait for who knows how long, only to be told that there's nothing the doctor can do to help the child recover? No one, that's who. So either physicians feel it's the right call because, in the absence of a definitive test all signs point to the bacterial culprit, or they feel pressured to prescribe antibiotics because a parent insists on getting them, and the parent then feels like they're getting their money's worth.

When it comes to taking antibiotics, my best guess is that for the general non-scientist public, this idea of antibiotic resistance is too abstract. People don't really understand how misusing antibiotics can, and will, actually render them useless. If people really understood that concept, then I have to believe that we would not be so dismissive about requesting and using antibiotics. We are also a bit spoiled. We've either not seen first-hand how bacteria can kill (thank you antibiotics), or we're just convinced that scientists will come up with new antibiotics as "easily" as they came up with the first ones. So why worry? Unfortunately both outlooks are dangerously ignorant.

I've spoken to 5 people within my circle of friends and family in the last week who admitted to never following the instructions for taking antibiotics. The most common logic for their decisions was that the person taking them had "recovered", so why use them all? The leftovers were saved for the next time someone got sick. Seems reasonable until you learn a little more about how this all works.

So how does it work? Well. Let's consider an infection with the bacteria that causes scarlet fever: Streptococcus pyogenes. This bacteria is fascinating. It not only causes strep throat and scarlet fever, it also causes impetigo, acute glomerulonephritis (inflammation of the tiny filters in your kidneys), and most notably, necrotizing fasciitis - a pretty nasty flesh-eating infection. It's also on the rise, especially in the UK. The current standard treatment of care for this infection is penicillin, or for those allergic, erythromycin.

OK, so now you're infected with  S. pyogenes. Generally speaking, and with the right conditions, a population of bacteria can double in 20 minutes. Scarlet fever has an incubation period of about 2-3 days, which means you will feel symptoms between 2-3 days after you're infected. During that incubation time, the bacteria is reproducing in, and spreading throughout, your tissues. By the time you start feeling sick, you've got quite a load of bacteria in you and a rash that makes the people in the clinic congregate on the other side of the waiting room. The doctor examines you and scarlet fever is  clearly the diagnosis and he sends you off with explicit instructions to take penicillin for 10 days. The penicillin prescription bottle reiterates his instructions: "take all medicine as directed". In case you were wondering, this translates to "Take every single pill in this bottle, at the time you are supposed to take it, you buffoon!" And yet...

You start taking the medicine and 24 hours later the rash is gone and you feel so much better already! You continue taking the antibiotics for four more days, but by then the fever's been long gone and you feel fine. So you quit taking them and save the rest of the bottle in case it turns out that you had infected someone in your family.

But what's really going on inside of your body during those five days you're taking the antibiotics, and what happens when you stop? As I mentioned, by the time you start taking those antibiotics, you have a substantial population of bacteria festering in you. This population of bacteria is not homogeneous. By that I mean that the individuals making up the population are not all the same; there are differences among them, genetic differences as are seen in any large population of an organism. Not all differences are relevant to antibiotic tolerance but those are the ones we care about today. So within this population of S. pyogenes that's making you sick, there is an entire spectrum of antibiotic susceptibility, including some that are really susceptible to penicillin and some that are more tolerant. Take note here, I said "more tolerant", not "resistant".  So you begin the course of antibiotics and it takes time for them to get into your system at the concentration needed to fight the infection. When it does, the first bacteria affected are those that are the most susceptible. As the antibiotics continue to remain in your system at the needed dose, i.e., you are taking them every 6 hours as prescribed, more bacteria are killed. These would not have been as susceptible as the first ones, but they are more susceptible than others among them. As the bacteria population dwindles you feel better! Of course you do! There are fewer bugs! Yay antibiotics!

This goes on day after day as the antibiotics and your immune system continually attack the bacteria, slowly chipping away at those that are less susceptible until the remaining bacteria are those that are hardly susceptible at all. Those remaining are the really nasty ones and we do not want them to get away. If they do, they will continue replicating and more mutations will occur and it is only a matter of time before they get that mutation that will shift their "strong tolerance" of antibiotics, to total resistance. However, if you continue the antibiotics for as long as prescribed, at the intervals indicated in the directions, you will kill even those most tolerant bacteria. If you stop after only several days, then you have not only allowed those most nasty ones to survive, you've provided an environment for them in which to grow without competition. You've killed all the other bacteria, so now the nasty ones have all the nutrients and space they need to really explode, which means even more replication and opportunities for mutation. Basically you've set them up to become completely antibiotic resistant and you've also set yourself up to spread them to other people, because even if you don't get sick again, you will be transmitting them. 

Way to go.

In addition to cleaning up an S. pyogenes infection quickly and preventing its spread, antibiotic treatment of scarlet fever prevents complications like rheumatic fever which can develop when S. Pyogenes is left untreated or is insufficiently treated. Rheumatic fever is an inflammatory disease; excess inflammation in the wrong places can cause severe tissue injury. Rheumatic fever can permanently damage the heart.

One of the most amazing things about modern antibiotics is their specificity: they specifically target bacterial cells. And while yes, this means they affect the populations of beneficial bacteria that we all have and need, they do not kill our own cells. This is one of the most critical traits for a good antibiotic. Bleach is a great antibiotic right? It really kills those little buggers. Well, sure, but you can't drink it or wash with it without serious injury to your own tissues or death. Generating new, safe and effective antibiotics is not going to be easy and research to that end is limited. Tim Sandle gives a nice rundown of this research in a recent blog post. [Edit: 8/18/14: Tim just published a review of two new antibiotics. This is great, but still not enough.] While there may be some hope with these, our best chance is to make sure that the effective antibiotics we already have, stay effective for as long as possible. The only way to do that is to be responsible about prescribing and taking them. If you are concerned about losing your own beneficial bacteria, replenish them! There are bacteria supplements you can take and yogurt works too. Talk to your pharmacist about it!

So please. Make sure your physician is positive that what you have is treatable with antibiotics, before you ask for them and before he prescribes them.  If your physician suspects a virus, ask him or her why that is. Ask them to explain it to you until you understand. Also ask if there are any tests to help differentiate between a bacterial or viral infection. There are quick tests that can verify if you have the flu or strep. Ask for them if they are suspected. If the doctor finds a lot of evidence to support the idea of a viral infection then ask what you can do to alleviate symptoms and help your immune system fight it. Resting, staying hydrated and controlling pain are important and will help your body heal itself. There are also successful anti-flu medications, and many over the counter drugs that can help. Communicate with your doctor, he does actually know a thing or two. Also ask what to expect during recovery so you will know if you are getting better or if something else is going on. Viral infections can often weaken us and make us more susceptible to bacteria so if you are feeling worse when you should be feeling better, get back to the doctor ASAP. Once you've been told that antibiotics are indeed necessary, then take them responsibly. Take them all, on the specified schedule. Protect your family and generations to come by following the instructions carefully. It's up to each of us to make the changes that will help prevent or at least delay the onset of a post-antibiotic era.

Finally, don't forget that an ounce of prevention really is worth a pound of cure. Hand washing and covering our mouths when we cough are still the best ways to prevent infection of transmissible illnesses. For your children, remember to find the balance between preventing disease and encouraging the development of their immune system. Vaccination prevents a wide range of diseases, some of which really are life-threatening. If you or your family members don't get vaccinated, and the antibiotics aren't effective, then you've set yourself (& others in your community) up for tragedy. So please don't let celebrity propaganda influence important decisions about your health or the health of your family. Get vaccinated. OK. Enough of that. That topic deserves a post all its own.


Pathogen Scribe

[edit 8/19/14: P.S. just came across a great blog post by Sarah Hird that explains this with really cool graphics. Check it out.]


WHO 2014 Antimicrobial Resistance Global Report on Surveillance

Understanding the basis of antibiotic resistance: A platform for drug discovery. Piddock LJ. Microbiology. Aug 13, 2014 

Origins and Evolution of Antibiotic Resistance. Julian Davies and Dorothy Davies. Microbiol. Mol. Biol. Rev. September 2010 74:417-433

Antimicrobial resistance: A Primer. Laura A. Stokowski, RN, MS 2010

Evolutionary consequences of antibiotic use for the resistome, mobilome, and microbial pangenome. Michael R. Gillings. Front. Microbiol., 22 January, 2013

Natural antibiotic resistance and contamination by antibiotic resistance determinants: the two ages in the evolution of resistance to antimicrobials. José L. Martínez* Front. Microbiol., 13 January 2012

2011 Feb 3 Eurosurveillance report on increased S pyogenes and S pneumoniae infections

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