Last week, Europe, Australia and the U.S. all launched their 5th Antibiotic Awareness Weeks, spreading the word about bacterial resistance to antibiotics. I heard of the event during a conversation about the death of a New Zealand man who had been infected with pan-antibiotic resistant bacteria. According to reports, the infection was not the cause of his death, but it made news because his doctors found that no known antibiotic could stop his infection.
On her blog, Superbug, writer Maryn McKenna closely follows the growing issue of antibiotic resistance. She also recently wrote a report about what the world might look like without any working antibiotics. Recall any time you’ve taken antibiotics for an ear infection or after a root canal or a simple surgery. Those simple infections and procedures could become a lot more dangerous without the ability to kill off bacteria. After all, the first test case for penicillin was a gardener who was dying of an infection caused by a small cut from a thorn.
A very well illustrated CDC report estimated that 2 million people are infected with antibiotic resistant bacteria in the U.S. each year. In an effort to bring some organization to the overwhelming issue, the report ranked 18 resistant organisms as “urgent,” “concerning” or “serious” threats.
What does resistance mean exactly? And what does this have to do with immunology?
Our immune systems have a variety of techniques to address bacterial infections. We have cells called phagocytes that eat bacteria and digest them, we have specialized T cells, natural killer cells and neutrophils that secrete molecules and proteins that damage bacteria or kill infected cells. Proteins in our blood (complement proteins) stick to bacterial cell surfaces and then build upon each other like blocks until they make what’s called an “attack complex” that drills a hole in the bacterial cell membrane.
{Did you know we need free radicals to fight infections and kill cancer cells? Phagocytes use them to kill the bacteria that they engulf. Many people think of free radicals as “bad” molecules and take antioxidants hoping to prevent cancer, but free radicals are one way our bodies destroy rebellious cancer cells. In fact, many cancer treatments activate free radicals to target cancer cells and patients receiving these treatments are instructed to avoid antioxidant supplements.}
If a species of bacteria is good at avoiding one tactic, there are plenty of others, and a healthy immune system will usually contain an infection and eliminate it. If someone has an unhealthy immune system (immunocompromised) or the inflammation from the immune response starts to damage tissue, antibiotics are a great way give the immune cells a fighting chance and spare the infected person.
Unlike the immune system, an antibiotic is just one compound with one tactic or mechanism. So it’s possible for just one mutation to give a bacterium resistance to that one compound’s tactic. If a drug targets a protein needed for bacterial cell membrane construction, the bacteria may alter the protein, change its construction method or make a different protein that pumps the drug out of the cell.
DNA mutations are common at the rate that bacteria divide. Staphylococcus aureus, for example, can divide every half hour. I grow S. aureus in the lab, and when I put an amount that could fit on a pen point into a tube of special broth at 37° C (the same temperature as the human body), the next day I end up with enough bacteria to fill about a quarter of a teaspoon.
Life for bacteria is tougher inside a human body since they are always being attacked by the immune system. But say the bacteria get the upper hand inside an infected person, we’ll call her Amy. Amy goes to the doctor and gets an antibiotic prescription, perhaps methicillin or vancomycin—enough pills to take one a day for 7 days. When she starts taking them many bacteria will die or stop dividing and her immune cells will be able to make headway against the infection. S. aureus can accumulate hundreds of mutations a day and even though most of the mutants will die, there will likely be individual bacterium inside of Amy with mutations that make them resistant to the drug she is taking. Those resistant mutants have an advantage over the other bacteria and will take over as all of their siblings get killed off by the drug.
Imagine the image shown on a kitchen cleaner commercial as it touts “kills 99.9% of germs.” On one side of the screen the “before” shot shows lots of wiggly cartoon “germs” and on the other side, after the cleaner is used, there are one or two wiggly little guys left. By “99.9%,” the commercial means that their product kills most known household species of bacteria, but if those were all the same species infecting a person and the cleaner was an antibiotic drug, those two little guys left behind would multiply with a vengeance and birth a resistant strain. There is a potential for that to happen every time a person takes antibiotics.
Ideally, even if mutations do arise, the antibiotics slow down the bacteria enough to let the immune system completely eradicate the infection (including the resistant mutants). But say Amy takes her prescription for 4 days and feels like she’s back to normal so she decides not to finish the whole 7 day course. By this time, she may be harboring resistant mutants and when she stops taking the drug, her immune system will suddenly have a lot more to deal with, and the mutants may expand. When she feels sick again a day or two later and starts to take the antibiotics again, they may not work at all since the resistant mutants have outgrown the other bacteria. She may end up having to get a different antibiotic injected into her bloodstream in the hospital and while she’s there, she may spread the resistant bacteria to other patients.
That’s the story of one mutation giving rise to a bacterial strain resistant against one drug. The man who passed away in New Zealand was infected with a strain of Klebsiella pneumonia that was resistant against every drug. How did that happen?
The short answer is we don’t know the history of every resistant strain. One interesting example that scientists are following is vancomycin-resistant S. aureus (VRSA). VRSA has been isolated about a dozen times from individual patients. Most of them were diabetic patients with methicillin-resistant S. aureus (MRSA) infections that coincided with the presence of vancomycin-resistant Enterococcus sp. (VRE). It’s thought that the VRE transferred its genes for vancomycin resistance to the MRSA, resulting in a strain of S. aureus that is resistant to both methicillin and vancomycin. This sort of gene transfer can happen inside an infected person or out in the environment.
Scientists are also monitoring how the use of antibiotics in agriculture and aquaculture may promote development of antibiotic resistance. According to a 2010 review, less than half of all antibiotics are used to treat human infections. Most farm animals are constantly on antibiotics and are known to harbor resistant strains of bacteria, making foodborne illness a potential route to spread resistant bacteria or genes to humans. To microbiologists, chronic use of antibiotics in agriculture is an obvious route to resistance, but it’s difficult to track exactly where resistant strains originate, so the issue is still controversial. A study published a few days ago found that MRSA infection rates were statistically correlated with how close Pennsylvania residents lived to livestock feedlots or to fields where swine manure was used as fertilizer.
There is a large gap in our knowledge about the link between antibiotics and agriculture, but it is an active area of research. Whether you buy antibiotic-free meat or whether you cover your house with Lysol, the one non-controversial and vital thing we can all do is always complete the full course of an antibiotic prescription.
Sources
NZs first ‘superbug’ victim? Siouxsi Wiles Nov 2013
The real story behind penicillin. Howard Markel, MD Sept 2013
Antibiotic resistance threats in the United States. The CDC, November 2013
Antibiotic resistance, mutation rates and MRSA. Pray, L. Nature Education, 2008
The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. Appelbaum, P. Clin Micr and Inf Jan 2006
The Origin and Evolution of Antibiotic Resistance. Davies, J. and Davies, D. Microbiol Mol Biol Rev Sept 2010
A call for antibiotics alternatives research. Stanton, T. Trends in Microbiology March 2013
MRSA: Farming up trouble. Mole, B. Nature July 2013
High-density livestock operations, crop field application of manure, and risk of community-associated methicillin-resistant Staphylococcus aureus infection in Pennsylvania. Casey, JA et. al. JAMA Intern Med Nov 2013
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