While I find the title to be scaremongering, the recent Telegraph (UK) article on antibiotic resistance in pathogenic bacteria (The End Of Modern Medicine As We Know It) does a halfway-decent job at explaining the problem: bacteria, like all organisms, evolve resistance to environmental threats. The difference is, bacteria evolve very quickly, and some of those threats are put there by humans to protect us from disease. There is mention in the article of the evolving public health crisis in Greece (summarized nicely here by researcher Dan Bednarz) where a resistance Klebsiella has popped up in the middle of a resource shut-down, which seems to echo the proliferation of drug-resistant tuberculosis in the former Soviet Union after that country’s public health surveillance went into a similar defunding tailspin. There is also mention of MRSA, the resistant staph infection that has been bedeviling US nursing homes, hospitals, injection drug users, and just about everybody else since the 1980′s.

Antibiotic resistance in bacteria is well-discussed elsewhere on the internet. What I want to talk about it the responses that stories like this inevitable generate.

“Its A Drug Company Conspiracy”

There are few things in modern medicine and public health that our profit-driven pharmaceutical industry can’t make worse, and that’s true here as well, but not in the way that this particular statement usually implies. Antibiotics as we know them today are primarily a product of the 1950′s and 1960′s, when bacteria, fungi, plants, even random synthetic chemicals were screened for the presence of compounds that inhibited the growth of a wide spectrum of pathogens. The comprehensiveness of this survey simply can’t be overstated- when you read about the history of vancomycin (soil sample, borneo), or fluoroquinolones (failed attempt at synthesizing chloroquine) you are struck by both the thoroughness of the search and the incredible serendipity of the results.

By and large, that work is no longer continuing. Drug companies are forced by economic considerations to develop “blockbusters”- drugs that are safe and cheap to synthesize, and that provide continuing results against widespread chronic conditions in the first world. Take a disease that everybody has- heartburn, say- and find a drug that people with that disease can take every day for the rest of their lives, and you have a winner. Antibiotics tend to be short-course treatments- two weeks and you hopefully never need that medicine again- and they are disproportionately needed in parts of the world where people don’t have the kind of insurance that pays $60 per pill. Additionally, for most non-resistant infections, there are already off-patent treatments on the market for which your patients will pay pennies a day, and experience the same cure that you’re offering. Even for resistant infections there are often generic treatments, they just tend to be dicey and have horrible side effects. There’s no money in antibiotics, not like there is in viagra or boniva.

So yes, drug companies deprioritizing anti-infective therapies are part of the problem. However, all the problems in the previous paragraph also mitigate against the deliberate development and release of resistant bugs. Notwithstanding the incredible risks that some grad student, some statistician, some computer tech somewhere down the line would expose the program, any drug company would be gambling that their new resistant strep could only be treated with their new super-antibiotic- and not with amphotericin¹ or polymyxin or some other awful-but-it-works cheap alternative. Furthermore, they’d be gambling that non-treatment public-health initiatives (such as were used a few years ago against still-untreatable SARS) wouldn’t contain the disease before it spread widely enough to recoup the company’s investment. Frankly, if I were a pharma executive and somebody presented me with this scenario, even with absolute security against getting caught, I’d dock their pay and send them back to the aphrodisiac lab.

Chinese Medicine Will Save Us/Doctors Just Promote Disease/The Terrain Is Everything

I’ll pull the “chinese medicine” part out because I never get tired of giggling at hipsters who scoff at “pharmaceutical antibiotics” but drink, say, reishi tea for illness. Folks, reishi (Ganoderma lucidum) is a fungus and yes, it probably produces chemicals that inhibit the growth of bacteria.² Also, penicillium (Penicillium chrysogenum) is a fungus and it produces chemicals that inhibit the growth of bacteria. Unfortunately, there’s no reason to believe that bacteria wouldn’t evolve resistance against widespread use of reishi (or other antimicrobials from non-allopathic formularies) just as quickly as they evolve resistance against similar fungi. So, in the strict sense, TCM would “save” us only a bit of time at best.

However, there’s another sense in which these responses are intended and once again, there’s a good deal of validity to it. An organism’s primary defenses against a disease are 1) not being exposed and 2) the immune system. Every day, precursor cells in the bone marrow generate 10,000 novel clones for antibody-producing b-cells,³ virtually all of which will be destroyed within a week. In times of stress, starvation or metabolic disease, this is one area in which the body tends to economize, leading to fewer antibody isoforms “on watch” for infections, and hence a slower or less-accurately targeted immune response.⁴ This is easily demonstrable in extreme cases, but the principle probably holds closer to the median: healthier people have healthier immune systems, get less sick, and hence need fewer antibiotics.

The problem is, what are you going to do about it? Eat more vegetables, quit smoking, exercise more, avoid processed foods, make a point to engage in positive social activities, intentional relaxation, trade your car for a bicycle, blow up your television, cut the DSL, throw away your cell phone… you’re already doing this, right? We already have a long list of conditions for which these sorts of health behaviors reduce the risks, and we have absolutely no idea how to operationalize that knowledge.⁵ Sure, the people at your yoga class have better immune systems- the yoga probably helps a little, but more importantly that’s who does yoga in this country. The problem antibiotics were popularized to solve isn’t “how do we prevent incredibly healthy people from getting pneumonia,” its “how do we keep people who already have health problems from dying from it?” Health improvement plans, holistic health care, etc have a big place in the post-antibiotic world, but they already have a big place now, and nobody seems to be able to make them work.

Oh, and doctors- the honest ones anyway- know this. Believe me, if you want to hear a pissed-off rant, ask a doctor about getting their patients to exercise. When people complain about allopaths only treating disease, and not promoting health, I always want to ask: what exactly do you want them to do? The path to better health does not come in a bottle, despite what Dr. Oz is hawking this week, and so far the only known force that gets people walking along it comes from within.

Phages Will Save Us!

So before applying to med school, I was very, very inspired by the virologist who taught my undergrad micro class, and considered becoming a phage librarian- one of those researchers who collect bacteriophages, test them against pathogens, and then culture them for therapeutic use. For those who don’t know, bacteriophages, or “phages” are viruses that infect bacteria and kill them. There have been several waves of research over the years to see whether phages can be developed that infect and kill the bacteria that otherwise kill us. Some of the most comprehensive work was done in the Soviet Republic of Georgia, where one of the best libraries still remains. Unfortunately, to paraphrase an old string-theory joke: phage therapy is promising- and promising, and promising, and promising…

The problems are complex and involve the life cycle of viriidae, but I’ll try to explain here. First, and most easily explained, phages tend to fall afoul of the same human immune mechanisms that attack other, less beneficial viruses. To survive long enough inside a human body to kill off a disease, a phage would have to elude the human immune system, and I’m sure we can all imagine good reasons why that might not be such a good thing.

The primary problems, however, are evolution and lysogeny. Evolution is simple and straightforward: concentrated antibiotics have only been around for a hundred years or so; phages have been around forever. Bacteria very quickly evolve resistance to any one strain of bacteriophage, and a corresponding evolutionary change in the phage to overcome bacterial resistance may come too late to save the patient. Phage libraries are enormous and require a great deal of continual screening and testing to stay “up to date” and even then tend to be dicey.

The lysogeny problem is a bit more complex. When penicillium produces an antibiotic chemical, it “wants” to kill every damn bacteria anywhere near it. When a phage infects a host, it “wants” only to reproduce itself. Our treatment goals match the fungus better than the virus. If a phage can only successfully infect one in three bacteria in a given population, or one in four, or one in a thousand, it will still be a successful organism and have little to no effect on the course of the bacterial infection. Furthermore, if instead of producing a million copies of itself and bursting the bacteria, it induces the bacteria to produce a million little bacteria babies, each of which eventually emits, say, a hundred baby phages, the phage will have become more successful- and made the infection much, much worse. This is called a “lysogenic cycle” and is one of those fascinating little tidbits every undergrad learns at some point or another. To use a human metaphor, phages don’t hunt bacteria, they ranch them.

Multiple Therapies Will Save Us!

This is a carryover from HIV, which develops resistance to antivirals even faster than bacteria resist antibiotics. What made the difference in HIV therapy was HAART- the “cocktail” approach to treatment that used so many drugs at once that the virus never got a chance to resist any of them. In principle this made perfect sense; in practice, well, lets not overlook the fact that people now can live long reasonably healthy HIV+ lives, something completely unthinkable in 1992. However, multiple resistance does eventually tend to crop up, even in well managed patients.

Importantly, though, most HIV+ people are infected with a “wild-type” virus, one that has accumulated no mutations. This is because with very rare exceptions, the resistance mutations cost the virus a great deal of its metabolic efficiency, and an unmutated virus proliferates faster and spreads faster through a new host. In other words, most HIV starts treatment-naive.

Bacteria are different, in that the resistance mutations are already out there when a person is first infected. To try the HAART model on bacteria, you would need to use two very different drugs to which no resistance yet existed, or put another way we would have to have been using multiple therapies from the beginning. Some multiple-drug combos are widely used (TMP-SMX, Augmentin) but these tend to work on similar pathways, with one drug improving the other’s binding potential. Unfortunately, this means that the resistance mutations tend to cross over as well. Overall, though, multiple treatments may be the wave of the future- if antibiotic development ever gets far enough ahead of resistance to have enough drugs to choose from.

1- Yes, amphotericin works against gram-positive bacteria. No, nobody uses it. Why would they?
2- I’m not citing the research, but I checked and there’s plenty.
3- Amazingly, I can’t find a cite for this number. I remember it from my notes last semester, and I don’t take frivolous notes, but I’m surprised I can’t validate it online. Any suggestions?
4- This is also an example of the plasticity of mammalian metabolism; anyone who says two people who eat the same food and do the same activities will have the same “caloric balance” is being ignorant. If you have a condition that leads to some of what you eat being shunted to irremovable belly fat, you won’t necessarily burn fat somewhere else to make up for it; you could just as well reduce your body temp, change the rate at which your gut lining replaces itself, impair your immune system, and never even feel hungry or tired any sooner.
5- Hint: haranguing your patients that “you’re gonna die if you don’t lose weight” does not promote healthy behaviors.