The Much Hyped End to Antibiotics is Nowhere in Sight

[cosmicalstorm]

Is antibiotics going to be another peak oil crisis? I hope so.

The Much Hyped End to Antibiotics is Nowhere in Sight
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Antibiotics are the drugs used to control bacterial infections. Here I'll point out a couple of recent articles relating to antibiotics research, as counterpoints to the prevailing view that we're in danger of running out of antibiotics that work at some unspecified future date. That would be an existential threat to our desired future of extended healthy longevity, were it to happen, but fortunately I think it is a mirage, as are so many of these predictions of doom. As a general rule predictions of doom rely upon people doing nothing to prevent said doom, and that is never the case.

We humans have trouble thinking rationally about progress. We live in an age of profound technological change: it is everywhere, fast enough to see sweeping differences from decade to decade, and yet it is human nature to look at the present state of things and predict a future that is just today with a few of the deckchairs shuffled around. You have to think carefully on a topic to step beyond this instinct, to consider how the fundamental aspects of the picture will change, not just the fiddling details. The moment that you stop paying attention, you'll backslide into making assumptions that are, in essence, based on the belief that nothing important is going to change.

This aspect of our nature gives rise to Malthusian visions of an end to present resources, and a dismal future world that falters because of it. In practice this end never comes to pass because people react to the threat of scarcity, far in advance, by creating new resources and more efficient ways to use existing resources. The moment that price increases due to scarcity emerge as a possibility on the horizon, scores of entrepreneurs start on their varied visions for a better replacement resource. So we have progress, and in our age that is self-evidently continual, rapid, driven progress.

Present popular views on the future of antibiotics are essentially Malthusian in nature: a trend in drug-resistant bacterial species is observed, and if continued it leads to a scarcity of effective antibiotics in the future. That trend is then projected all the way down to zero, to no working antibiotics and a world of rampaging bacterial infections. That grim result will never happen, however, just as any number of other predicted grim results failed to emerge over the past few hundred years. In this case, as always, entrepreneurs both inside and outside the scientific community have been at work for years on varied solutions to bacterial resistance to antibiotics. A few are mentioned here:

Antibiotics Are Dead; Long Live Antibiotics!

Quote:

We've been hearing the tales of doom for quite a few years now: the breathtaking promiscuity of bacteria, which allows them to mix and match their DNA with others' to an extent that puts Genghis Khan to shame, has increasingly allowed them to accumulate genetic resistance to more and more of our antibiotics. But this pessimism rests entirely on one assumption: that we have no realistic prospect of developing new classes of antibiotics any time soon, antibiotics that our major threats have not yet seen and thus not acquired resistance to. And it now seems that that assumption is unwarranted. It is based on history - on the fact that no new antibiotic class with broad efficacy has been identified for decades. But very recently, a novel method was identified for isolating exactly those - and it seems to work really, really well.

Antibiotics are generally synthesised in nature by bacteria (or other microbes) as defences against each other. We have identified antibiotics in the lab, and thus necessarily only those made by bacterial species that we can grow in the lab. Yet almost all bacterial species cannot be grown in the lab using present day practical methods. Knowing these points, researchers built a device that allowed them to isolate and grow bacteria in the soil itself, with molecules freely moving into and out of the device, thereby sidestepping our ignorance of which such molecules actually matter. And then they were able to isolate the compounds that those bacteria were secreting and test them for antibiotic potency. And it worked. They found a completely new antibiotic that has already been shown to have very broad efficacy against several bacterial strains that are resistant to most existing antibiotics.

And as if that were not enough, here's the kicker. This was not some kind of massive high-throughput screen of the kind we so often hear about in biomedical research these days. The researchers tried this approach just once, in essentially their back yard, on a very small scale, and it still worked the first time. What that tells us is that it can work again - and again, and again.

Viral Soldiers

Quote:

Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a closer look at the many different viruses that attack bacteria. Bacteriophages (literally, "bacteria eaters") punch holes through the microbes' outer covering and inject their own genetic material, hijacking the host's cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay. Phages are picky eaters that only attack specific types of bacteria, so they're unlikely to harm the normal microbiome or any human cells. And because phages have coevolved with their bacterial victims for millennia, it's unlikely that an arms race will lead to resistance. This simple biology has led to renewed interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill their bacterial foes.

While most research is still in the preclinical phase, a handful of trials are underway, and a growing number of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory oversight at the time. "Bacteriophage therapy will have its day again. It sort of had one, before antibiotics came along, but it wasn't well understood then."

On that topic, what to do about the many types of viruses that we don't want to engage with? This is a very different area of research in comparison to the matter of controlling bacterial infection, but again there are numerous promising strategies that look capable of fundamentally changing the picture for the treatment of viral infections. One of those you might be familiar with is DRACO, double-stranded RNA activated caspase oligomerizer, a technology that can in principle control near any type of viral infection by destroying infected cells before viruses can multiply effectively.

Aubrey de Grey
Gerontologist; Chief Science Officer. SENS Foundation; Author, Ending Aging
Antibiotics Are Dead; Long Live Antibiotics!
https://edge.org/response-detail/26701
The Much Hyped End to Antibiotics is Nowhere in Sight
https://www.fightaging.org/archives/201 ... -sight.php

[ArmorPierce]

One of the main issues which is cited in this article with people predicting outcomes is folks taking current trends and extrapolating it to infinite. I've seen folks guilty of it in general and on this board.

[Guardsman Bass]

One quibble -

And then they were able to isolate the compounds that those bacteria were secreting and test them for antibiotic potency. And it worked. They found a completely new antibiotic that has already been shown to have very broad efficacy against several bacterial strains that are resistant to most existing antibiotics.

This isn't even close to being something resembling a viable antibiotic. It's not enough to show that the compound works against bacterial strains - it also has to be something that won't kill the human beings taking it, and won't require an onerous level of dosage to work. That's not a minor problem - one of the reason why the "last line" antibiotics are last line is because the side effects are often severe.

The pharmaceutical field is littered with countless compounds that seemed initially promising, but which failed safety tests, failed to work out when actually tried in human beings and test animals, and so forth.

[Napoleon the Clown]

In relation to what Bass said, I reference xkcd.




The problem at hand for new antibiotics is that testing takes many years and is very expensive. New antibiotics wouldn't be the first choice in 99% of cases (number pulled directly from my ass) because insurance companies will drag their feet over something that would be so damned expensive. So sales would be miniscule, making it difficult as hell to get any sort of return before the patent expires.

The potential issue pointed out by Bass is, in fact, a real problem. Yeah, bacteria produce stuff that can kill other bacteria. But it's also bad for you. You don't get horribly ill from these various bacteria just because your immune system is getting angry over foreign invaders. Many pathogenic bacteria release compounds that are toxic to humans.

Killing bacteria is easy. Killing bacteria in a way that won't harm the person you're treating more than letting their immune system try and fight it off all on its own? A lot more difficult.

[jwl]

In relation to what Bass said, I reference xkcd.




The problem at hand for new antibiotics is that testing takes many years and is very expensive. New antibiotics wouldn't be the first choice in 99% of cases (number pulled directly from my ass) because insurance companies will drag their feet over something that would be so damned expensive. So sales would be miniscule, making it difficult as hell to get any sort of return before the patent expires.

The potential issue pointed out by Bass is, in fact, a real problem. Yeah, bacteria produce stuff that can kill other bacteria. But it's also bad for you. You don't get horribly ill from these various bacteria just because your immune system is getting angry over foreign invaders. Many pathogenic bacteria release compounds that are toxic to humans.

Killing bacteria is easy. Killing bacteria in a way that won't harm the person you're treating more than letting their immune system try and fight it off all on its own? A lot more difficult.

I can't see this argument applying to the section of the article on bacteriophages though, they should generally be harmless to humans. I imagine (without actually looking into this) the main problem would be getting the bacteriophages to spread when the bacteria are distributed over a wide area of the body.

Regardless to this, isn't the main argument put forward that antibiotics will end if we do nothing? Doing scientific research into bacteriophages and new methods of finding antibiotics is not doing nothing, it is exactly the kind of thing the people raising these issues are calling for.

Also, re: no new antibiotics in decades, what about that rediscovered medieval remedy I posted a thread on a while back? That's not going to have problems with safety because it is made of stuff like wine and garlic.

[Napoleon the Clown]

You immune system also targets the bacteriophages because it sees them as foreign invaders. They also tend toward being specific about what they will attack. They're not some magic bullet that kills all bacteria dead and leaves you alone. Yeah, they leave you the hell alone. But they're pretty specific about which bacteria they go after, and administering them isn't as simple as "take this pill" because most won't survive the digestive process. They can be damn effective, but they still take a lot of effort. I did some research on them for an end-of-term paper for a class last semester, and the easiest use is surface wounds. Instead of a pill, if you need to get them into someone's blood stream you've gotta go the injection route. And because they do replicate, they are very effective. Downside of ones that self-replicate (they have engineered kinds that don't) is that they still cause the bacteria to rupture and release toxic compounds into your bloodstream. If this happens on a large enough scale, that could be a problem. The non-replicating ones don't cause the bacteria they infect to rupture, but they do kill those bacteria leaving an easy clean-up job for your immune system. Downside there being, the immune system's also going to go to town on the bacteriophages, so you'll need repeated treatment. And there's the issue of your immune system building antibodies for bacteriophages used on you, so we'd need to continually change their surface proteins to buy them more time.

My entire point comes down to there being relatively little interest from pharmaceutical companies in researching new antibiotics because it doesn't strike them as being profitable.

If we want to get more out of what we already have, we need to eliminate putting antibiotics in livestock feed when not actively treating ongoing disease, doctors have to stop writing antibiotics prescriptions for a kid with the sniffles no matter how upset his mommy gets, and people need to finish the fucking bottle as ordered. If we don't take care of those parts, all we're left with is engineering new strains of bacteriophage as bacteria evolve to be "invisible" to those already there. Viruses "look" for specific surface proteins before binding to a cell, which is why they can be so specific about what they'll target.

The question isn't can we find new treatments (we can), but will we do it fast enough? And with profit-driven research, general human stupidity in taking medication, and farms being able to give healthy animals a steady diet of antibiotics... We've got cause for concern. Cause for wanting to change some goddamn policies. Those who discuss the possibility of returning to the time where we didn't have effective antibiotics aren't saying "We're doomed!" they're saying we need to stop being so damn careless in how we use them.

[Ziggy Stardust]

The only reason bacteriophage treatment can be so effective at the moment has less to do with it being an inherently better way to treat bacterial infection (though in some ways it certainly is), and more to do with the fact that standard anctibacterial treatment is so complicated by the fact that it has been used so long for so widely that bacteria have had the time to react. If the development of the two approaches had happened in reverse of what it did in real life (by act of Q), we would now be talking about using antibiotic chemicals to replace standard bacteriophage treatment.

The trick isn't going to be to just switch everyone from antibacterials to bacteriophages, but to control and moderate the use of both to ensure the right balance between treatment people who need it and not breeding super-bacteria. And, honestly, more than anything else, increased study of the way bacteriophages work will give us more insight into the particularities of the way bacteria respond to threats, which has the potential to lead to entirely new methods of treatment.

[madd0ct0r]

Are there limits to bacterial multi resistance? I appreciate that resistance to two different drugs probably isn't independent and I also appreciate the molecular design space that meets the "dosent kill humans" criteria is also limited, but within that space do bacteria get to the point that resistance type Z means losing resistance type B, or the energy strain of providing both means the immune system has an easier time?

[Terralthra]

Fundamentally, if there's no selection pressure to be resistant to a particular antibiotic chemical, increased energy cost would drive the genes which code for that resistance to be selected against pretty heavily. Since we still use antibiotics on a tiered "front line" system, the pressure to maintain resistance against e.g. meticillin-family antibiotics in gram-positive bacteria remains high. Basically, a *cillin is the first drug those bacteria encounter, so there isn't a huge pressure in the bacterial gene pool to select toward efficiency and away from resistance. If there was a worldwide ban on *cillins, I'd expect the meticillin-resistant gene to disappear in somewhere on the order of a decade or two. The problem is that *cillins are still so darned useful.

[SCRawl]

I find it interesting that the OP (and the cited documents) came out at almost exactly the same time as this article, which is well summarized in its first paragraph:

The alarming drug-resistance gene MCR-1 that was first detected in China in November has been found in meat sold in Ontario in 2010, the Star has learned. The gene grants bacteria like E. coli resistance to colistin, a powerful antibiotic of last resort.

If this isn't evidence that the "antibiotics era" might be coming to an end, I'm not sure what else might qualify. And although the drug of last resort, colistin, is very rarely prescribed in humans -- it's pretty damn toxic, apparently -- it's still used extensively in animal agriculture, which has led us to this point:

...global surveillance for mcr-1 resistance is now essential to try to prevent the spread of polymyxin-resistant bacteria. China is one of the world's largest users and producers of colistin for agriculture and veterinary use. Worldwide demand for the antibiotic in agriculture is expected to reach almost 12,000 tons per year by the end of 2015, rising to 16,500 tonnes by 2021, according to a 2015 report by the QYResearch Medical Research Center.

(Emphasis mine)

[Me2005]

My entire point comes down to there being relatively little interest from pharmaceutical companies in researching new antibiotics because it doesn't strike them as being profitable.

I saw a very good show on this, but can't remember where or what it was called. I'm 99% sure it was on PBS though, in which case it'd be available online.

It boiled down to this: As bacteria become more and more resistant to existing antibacterials, it becomes more expensive to research new effective, safe, antibacterials. And by their nature, antibacterials are less desirable to a pharmaceutical company than drugs which treat chronic diseases. This is because a patient on an antibacterial needs it for a short time and is then cured, while a patient on a drug treating chronic disease is on it as long as the chronic disease lasts (possibly life).

Oh yeah, and they only get an 8 (I think?) year period of exclusivity before it goes generic. Since doctors/insurance drag their feet on accepting new drugs, and (rightly) prefer to try all the existing options before trying new ones, the pool of possible uses for the drug during the researching company's ownership period shrink. That makes it so that, in order to make enough money off the antibacterial to even afford researching it, the company would need to charge so much that no insurance or patient could pay for it. Add to that the high rate of drug research failure, requiring higher profits to pay off, and you start to see the problem. A private company cannot afford researching new antibacterial drugs; as evidenced by all of the private pharmaceutical companies dropping the research.

Until these scientists can show how they plan to scale the experiment and apply it to humans, I'm still concerned. It's good to know there are other avenues to treating infections though.

Myself, I see this as a valid place for government work. It is in the public interest to have antibacterials available.