Are we causing antibiotic resistance by trying to prevent it?

AntibioticsYou fill a prescription for antibiotics, and have 14 days worth of pills in your hand. Pop quiz: If you want to be a good citizen and prevent the spread of antibiotic resistance, how many of those pills should you take?

The sticker on the bottle is clear: all of them. In India, where Andrew Read studies infectious disease, resistance is so prevalent that standard malaria treatment includes not just the pills, but a boy who comes to your home each day to check that you’ve taken your dose. And yet, Read believes that aggressive treatment with antibiotics is increasing the spread of resistance, not controlling it.

To be clear, nobody is saying patients should decide their own dose. But there is a good argument to be made that the public health message about antibiotics, which is consistent worldwide for many diseases and drugs, deserves a second look.

I first heard about this idea in a talk Read gave at an evolutionary medicine conference in Palo Alto. (Video is online here, and here is his 2011 paper on the same topic.) He addressed one of those nagging questions I always had: if you have antibiotic-resistant pathogens in you, wouldn’t they survive antibiotic treatment no matter how long the course?

The answer is yes, at least sometimes. It’s true that some resistance is low-level, so you can kill off those bugs if you use enough medicine; sometimes the higher level resistance requires several mutations, so the sooner you can kill off your pathogens, the less likely they will find the magic combo of mutations that will let them completely evade the drug. But what if a high-level resistance mutation is already present?

Don’t think that’s so far-fetched: since most antibiotic drugs come from naturally occuring toxins, there have probably always been resistance genes. Researchers have found them in bacteria that have never been exposed to drugs, like in this 4-million-year-old cave. Friendly gut bacteria can be a reservoir for resistance genes, even years after the last antibiotic dose; and Read points out that among the 1012 individual malaria parasites in an infected person, the odds are that every possible point mutation is already present.

(By the way, we’re not just talking antibiotics for bacteria; the same issues apply to antimicrobials that target fungi, or protists such as malaria, and even insecticides and cancer drugs.)

Germ-on-germ battles

We talk of “fighting disease” as if it’s the patient vs. the germ, but there is a germ-on-germ battle too: the resistant microbes vs. others. The others may be susceptible strains of the same bug, or even commensals like your friendly gut flora. In dosing with an antibiotic, you tip the scales toward the resistant ones, so they can outcompete their antibiotic-sensitive peers. While an aggressive dose can make resistance mutations less likely to happen (good), it has a flip side of boosting the success of any resistant bugs that survive (bad).

Those resistant bugs may be few and far between, but it turns out that rare mutations benefit the most when drugs kill off their competitors. Read’s team showed, with a mouse model of malaria, that the susceptible strains win out over the resistant strains in the absence of antibiotics; after treatment, though, the resistant ones bounce back faster and in greater numbers. The boost was biggest for mutants that were rare to begin with.

This isn’t just a problem for the individual with the infection; it affects transmission rates. If you’re the patient with the newly-boosted resistance mutation, when the next mosquito bites you, she‘s going to get a mouthful of resistant bugs, rather than the susceptible ones. The next person she bites will show up to the clinic infected with a strain that’s hard to kill off.

Then there’s that huge reservoir of (hopefully) susceptible bacteria that you can’t totally kill off, and don’t want to: your normal flora.

Treating your body with antibiotics (regardless of what bugs were present – possibly none if your prescription was one of the 40% for respiratory infections that aren’t bacterial) exposes your gut bacteria to antibiotics and increases selection for antibiotic-resistant versions of those. No biggie – until one of them transfers that gene to a pathogen you do care about. The vancomycin resistance gene in VRSA (MRSA’s scarier cousin) apparently came from E. faecalis – you guessed it, gut bacteria.

Fortunately in VRSA’s case, resistant bugs often take a hit when it comes to competing outside of the influence of the drug. That’s why it never took off in the community like MRSA did (we think).

How to best use the drugs we have

New drugs are potentially a useful weapon in the fight against resistance, but the drugs often just aren’t available – leaving aside the question of whether an unlimited supply of drugs is just waiting to be discovered, there is the problem that drug companies aren’t interested in a drug that, with widespread use, could be obsolete long before it’s turned a profit; or a drug that is so good that it’s saved as a last line of defense. The few new antibiotics, Gary Taubes reports, are minor tweaks to old drugs, or have toxic side effects; some classes of bacteria aren’t getting new antibiotics at all.

So if our antibiotic use strategy is actually encouraging resistance, what should we do instead? Many guidelines still stand, like preventing disease transmission in the first place (think hand washing) and eliminating antibiotic use where it’s not necessary: viral infections, for example, and use in livestock. When it comes to treating an individual patient, though, aggressive antibiotic use (finishing all your medication) may make that person feel better but ultimately pass the risk on to the community.

One suggestion, supported by Read and others, is this: rather than killing off all the pathogens, we could help the immune system with the smallest dose possible. That would reduce the microbes’ numbers temporarily so the patient’s natural defenses can do their job. (The immune system seems to be equally effective against antibiotic-resistant and sensitive bugs.) This could mean pulses of treatment, or even the heretical advice to take the drugs until you feel better, then stop. Of course, you may need them again later on.

Evidence shows that many infections clear with less than a typical course of antibiotics, which is good since the longer the course, the more chances bugs get to develop resistance. Richard Everts identifies several infections where short courses are effective; they include (depending on the exact drug and dose) UTIs, bacterial meningitis, strep throat, and others. The short courses he reviewed were often along the lines of 3 days; for gonorrhea, a single dose was effective. He concludes that symptoms should guide the length of treatment, except for particular diseases where symptoms don’t reflect the true pathogen load. Quoted in the Taubes article, Louis B. Rice argues that long courses of antibiotics benefit the physician’s peace of mind more than the patient or public health.

Back to those pills in your hand: the evidence isn’t strong enough, yet, for anyone to feel comfortable telling your pharmacist to trash the sticker. Read et al also consider the idea that the right drug regimen may change over time: aggressive treatment with fresh drugs, then shorter pulses of treatment once resistance develops. This means that different drugs would have different dosing regimens, subject to change. If that’s the case, public health officials will need to consider the spread of information as well as the spread of resistance genes. They write: “Such a switch may be difficult in practice. Health messaging may require constancy, or it may be that by the time unambiguous evidence of high-level resistance has been obtained and policy changed, it is already too late.”

Do you think we could realistically change the public health message about antibiotics? Would it be too confusing if the rule was different for different drug/pathogen combinations?

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2 Responses to Are we causing antibiotic resistance by trying to prevent it?

  1. Pingback: The Messy Machine » Antibiotic use as a tragedy of the commons

  2. Oliver H says:

    I see a couple of problems with the rationale. First, if “taking until you feel better” would actually do something, then all those people not taking the full dose of antibiotics had actually been doing the right thing. Given that we can expect a lot of people NOT to follow the message, it begs the question – how did we arrive where we are?

    The answer in my eyes is that just looking at antibiotics given against a specific treatment against which it might even work is too short-sighted. The problem is much wider: We use antibiotics even in a lot of cases in which they will not help, period, and often without checking for resistances before application. The end result is not only that we reinforce existing resistances, but that we also introduce a lot of antibiotics both in the body and in waste and sewage that need not be there – and possibly end up being there in dilutions not effective at killing off bugs. And that’s not even starting about preventative use of antibiotics in livestock…

    Considering the public health message is really besides the point while primary care physicians and clinicians don’t even follow recommendations stringently. I’ve been talking to a lab doctor in a hospital who said he recommended not using a certain antibiotic empirically in the hospital because resistance was already high. But clinicians still used it, not the least because it was cheap and they wanted to give patients something and checking for resistances takes time…

    How do we expect the public to act sensibly, whatever that may mean, when not even the medical community does?

    The problem cited in the article essentially restricts itself to selecting for the resistant clones if they are already present. In my eyes, the best way to tackle this is to make sure you know what bugs you are dealing with and what antibiotics they are resistant against. Yes, that takes time. But the time it takes is being reduced steadily by developing diagnostics technology. And the notion of giving the body’s immune system a hand looks good on paper. But it presupposes that the people at issue have a working immune defense to begin with. When we look at MRSA cases on intensive care units, that’s quite a long shot.

    In some countries, antibiotics are already now strictly prescription-only. In others, less so. And even where they are prescription-only, practitioners all too easily give in to hand out antibiotics in viral infections. Add to that the lack of resistance testing, and we have plenty of areas for improvement.

    Experimenting with patient adherance is in my eyes not a good approach. There are too many diseases in which it is a life-or-death factor.

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