“Antibiotic resistance has become a global threat. But antibiotic resistance isn’t telling us the whole story when it comes to explaining why antibiotic treatment failure is so common. ”
Antibiotic resistance has become a global threat.
Microbes are quickly developing resistance to any and all antibiotics that are currently available, making antibiotic treatment failure increasingly common. In fact, the Centers for Disease Control and Prevention (CDC) recently released their updated Antibiotic Resistance Threats in the United States report for 2019, and the results are staggering.
Methicillin-resistant Staphylococcus aureus, or MRSA, is listed as a Serious Threat to public health, according to the 2019 CDC Antibiotic Resistance Threats in the United States report. Image credit: Lab Tests Online
According to this report, antibiotic resistant microbes cause almost 3 million infections in just the United States, and of those 3 million, about 10% of people die. Let’s really drive this point home: this means that every ELEVEN SECONDS someone in the United States gets an antibiotic resistant infection and every FIFTEEN MINUTES someone dies from an infection.
Y’all.
Suffice to say that these are some scary stats. But want to hear something worse? Antibiotic resistance isn’t telling us the whole story when it comes to explaining why antibiotic treatment failure is so common. To tell the rest of the story, we first need to understand how a doctor determines which antibiotic to give you in the first place.
When someone goes to the doctor with an infection, the doctor will take a sample of the infection and perform various tests to figure out which antibiotics (if any) might work. Examples of these tests include Kirby-Bauer tests and Minimum Inhibitory Concentration (MIC) tests. In a Kirby-Bauer, the bacteria taken from your body are grown on an agar plate. Then little disks containing different antibiotics are placed on top of the bacteria. If the bacteria die, there will be a “zone of clearance” around the disk, which you can see in the photo below. If the bacteria are resistant to the antibiotic, they will be able to grow around the disk. Based on the size of the “zone of clearance” doctors decide if the antibiotic will work or not.
To perform a Kirby-Bauer test, bacteria are grown on an agar plate. Small disks soaked in different antibiotics are laid over top (left). If the antibiotic is able to kill the bacteria, a “zone of clearance” (the lighter part) will form around the disk. Doctors can measure the zone (right) and determine if a bug is either sensitive or resistant to an antibiotic. Image credit: Public Health Image Library
MIC tests are very similar, but instead of disks on agar plates, the bacteria are grown in broth (basically fancy chicken broth - bacteria love it) and then exposed to decreasing concentrations of a certain antibiotic. Based on the minimum concentration of the antibiotic that prevents, or inhibits, growth of the bacteria, a doctor can determine if the antibiotic might work in a patient. These tests are really good at determining if a certain microbe is sensitive or resistant to an antibiotic.
Ok, so a doctor does a Kirby-Bauer test and, based on the results, decides that a certain antibiotic will work in his/her patient. The doctor prescribes the antibiotic and the infection goes away, right? Turns out, not always. Sometimes a doctor will prescribe an antibiotic that should work against the infection because, according to the lab tests, the microbe isn’t resistant to the antibiotic. But the patient’s infection doesn’t go away…and sometimes gets worse. Wth, right?
Well turns out there’s antibiotic resistance’s evil(er?) twin: antibiotic tolerance. Antibiotic tolerance is a conniving bastard because tolerance can’t be detected in the lab tests I talked about above. The doctor can definitely prescribe an antibiotic that the bacteria aren’t resistant to, but the bacteria might still be tolerant to the antibiotic inside the patient. How does this happen? To figure this out, let’s talk about a few things: (1) basic requirements for antibiotics to work; (2) how the infection inside the host is different than life on an agar plate or in broth; and (3) how this all comes together and leads to treatment failure.
Antibiotics target things in bacteria involved in growing and dividing, like DNA. Image credit: Getty
First things first, you can check out my other article for more information, but basically antibiotics rely on bacteria actively growing to work. Antibiotics typically target things involved in growing and dividing, like DNA replication, transcription, and translation. By interrupting these processes, antibiotics can stop the bacteria from growing and kill them. However, some bacteria are able to go into a low-energy dormant state, kind of like how bears go into hibernation in the winter. But guess what? Dormant state = not actively growing. Bacteria in a dormant state are, by definition, harder to kill with antibiotics. Secondly, you might have noticed that when I was talking about the Kirby-Bauer and the MIC tests, I mentioned taking the bacteria out of the patient and growing them on agar plates or in broth.
If you’re thinking to yourself that the inside of a person (where infections happen) is different from an agar plate and broth, you’d be very right.
Inside the patient, the bacteria are STRESSED OUT. Your immune system has a pretty impressive arsenal of defense strategies against things that shouldn’t be there, like certain types of bacteria. As you can imagine, the bacteria don’t like being under a lot of stress. Some bacteria have pretty clever ways of overcoming the stress (a topic for another time), but for other bacteria, all the stress just sends them into that dormant state that we call the “persister state”. Couple that with your doctor giving you an antibiotic, and the bacteria are all “nah, bro.” You know when you have so much going on that you decide to take a nap instead? It’s kind of like that. And when the bacteria are napping, the antibiotics don’t work very well.
1. Antibiotics might work really well at first, killing off the majority of the bacteria, but not all of them.
2. Some of the bacteria that aren’t killed by antibiotics enter the “persister state.”
3. When the stress is gone, the bacteria can wake back up and start growing again.
Now I want to really emphasize a few things. First, the antibiotic your doctor gives you for your infection might work at first, but these antibiotic tolerant cells that survive are a small subset of the initial population that is able to survive (see the blue line in the graph). Secondly, and SUPER IMPORTANT, tolerance and resistance are VERY different things.
As you can see in the graph, resistant bacteria (green line) aren’t usually present at high numbers at the start of infection. However, as the antibiotic kills some of the sensitive bacteria, the resistant ones can take over the infection. You might also notice that when the bacteria become resistant to an antibiotic, they never take a nap. They are completely unbothered by the stress from the antibiotic and just keep on growing and dividing and infecting.
When the bacteria are taken out of the patient and put onto plates or into broth, they’re happy about it. The plates and broth typically have all the yummy stuff bacteria like, and the bacteria are probably (read: almost definitely) in a higher energy state. So when your doctor does the lab tests to figure out which antibiotic to use, the bacteria being tested aren’t realllllly the same as the ones actually causing the infection. Whoops.
Alright, now that we’ve covered all that, here, my friends, is where it all comes together! Remember, inside the patient, bacteria are stressed and being stressed means the bacteria “take a nap.” The napping bacteria aren’t growing (so that’s good), but the antibiotic also isn’t killing them (not so good). This means that you end up with a small population of bacteria that are basically hiding out in your body, not being killed by the antibiotic. Even worse is that when the bacteria are hiding out and napping, it might seem like the infection is gone. So then maybe you don’t listen to your doctor (ahem) and you stop taking your antibiotic before you should (shame). Either way, stopping antibiotic treatment means some of the stress is gone. And when some of the stress goes away, the bacteria wake back up. Once they’re awake, they start growing again and can cause another infection, often in a different part of your body.
Bad news.
But good news! Lots of people (like my lab!) are studying these antibiotic tolerant bacteria. We’re trying to figure out exactly how bacteria go into the persister state and how we can either (i) wake them up in a specific way so that we can kill them, or (ii) prevent them from ever going into that state in the first place. So, stay tuned for Part 2 where we’ll chat some more about antibiotic tolerance in the context of my favorite little guy: Staph! See ya soon!
-Jenna
