A 'slow catastrophe' unfolds as the golden age of antibiotics comes to an end
latimes.com
latimes.com
1) farmers everywhere are allowed to use last line/new antibiotics routinely in food production. This is utterly fucking stupid. Whats more brain dead is that its not just china its US and canada. (possibly the EU.) It could be stopped by the FDA withdrawing the license. but no. Too much money.
2) over subscription in private health.
I once listened to a co-worker phone up the Doctor and ask to have "the same antibiotics I had last time for that cold" and get it[1]. She had the fucking snuffles. No consultation, not even bothering to figure out if its even got a hint of bacterial infection.
A placebo would have been more effective. It wouldn't have given her the shits either. Paracetamol is what was needed, as its the only thing that would have made her feel better.
Seriously. yes I know that the customer is always right, but don't fucking dish out drugs like sweets. My old age, and my children's health are dependent on those drugs.
[1] yes this was in the USA, santa monica to be precise. Yes I'm british. However the prevalence of prescription medication abuse and deaths is a massive fucking warning. Something is horridly wrong with the US's health care system.
What surprises me is with the levels of litigation against doctors, this hasn't seemed to trigger any change in behaviour.
Disclosure: I live with a doctor.
Basically, it's exactly the worst thing you can possibly do, with regards to what the theory of evolution by natural selection tells us. Then add in what we know about bacteria exchanging genetic material, and it's like we're trying to inactivate all of our antibiotics on purpose.
from the half-full glass POV we are just speeding up the natural selection of bacteria resistant humans (it has been going for millenia and got, probably only temporary, delayed for the last 80 years). Also, as a side effect, it can help solve (at least temporarily) the overpopulation issue until the much more smart (wrt. health and Earth resources usage) humans evolve. Basic dialectics at work.
Often, what's good for species evolution is really bad for some individuals. What good is a half-full glass to you if you're dead?
Also, as was noted elsewhere in the discussions, evolutionary pressure for bacteria to attain an immunity is high, but pressure to lose one is usually much lower. However, bacteria are small, and such pressure is higher than in more complex celled creatures. "Shelving" antibiotics does work, but would require widespread cooperation and the curbing of feeding antibiotics to livestock.
What bad is it if you're dead?
Bacteria evolves resistance at about the same rate as people develop defenses.
So yeah, if you don't mind killing off a huge segment of the population and having women die in childbirth regularly.
Bahaha that's one way to look at it. I guess we have plenty of humans to spare.
No, they fucking aren't, especially when it comes to medicine. Antibiotics should be controlled like opiates; at least over-prescription of opiates doesn't endanger the whole species.
> What surprises me is with the levels of litigation against doctors, this hasn't seemed to trigger any change in behaviour.
Try fines - that's supposedly solved the opiate abuse problem.
Disclosure: I live with a doctor.
Irrelevant aside: Rare to find someone on HN call a disclosure a disclosure, rather than the oft-abused "disclaimer"! :)
The _crux_ of the issue is that doctors prescribe antibiotics for viral infections because the diagnosis is usually only based on a cursory examination. Their time is expensive, and you can't spend an hour on every patient with a cough and a fever. Furthermore, viral infections often precede or are concurrent with bacterial infections. So doctors are making a rational decision when prescribing antibiotics, and it's not even clear that this decision is globally suboptimal because bacterial infections are not uncommon with a cold or especially a flu.
If we're serious about overprescription of antibiotics, we should be heavily investing in improved diagnostic equipment and processes. For example, rapidly scanning mucus samples for viral and bacterial markers. The fact that we don't appear to be doing this suggests that either overprescription isn't actually a problem, or that we're not thinking seriously about the problem.
In the past, doctors heavily over-prescribed antibiotics. Often as a precaution. The government and health providers have become very aware of an upcoming problem with high restistance though, so they are working hard to change the behaviour.
Existing doctors are re-educated not to prescribe Antibiotics on a hunch, with monitoring and reprimands from health providers.
And this is also drilled into med students in University.
Change always takes time... let's hope we won't be too late to avoid a serious increase in fatalities.
What is not mentioned is a new class of antibiotics discovered in 2015 (https://en.wikipedia.org/wiki/Teixobactin) which is a big deal in that it can be used instead of antibiotics resistance to which has been acquired by bacteria during this "golden age" and as microbes evolve extremely fast, within an observable timeframe they will lose resistance to the old classes allowing those to be used again. So effectively shelving will work.
Another point is that other new methods of searching for new drugs are being researched (http://www.theverge.com/2016/5/18/11686268/new-antibiotic-dr...) and the future is not at all gloomy.
Sure, new methods of finding antibiotics are in the works, although the article you link has plenty of experts recommending caution about their potential. The bigger point is that in 2016 there is a looooooong road from antibiotic "candidate" to FDA-approved drug. That road involves decades of trials and costs billions of dollars per approved drug.
The larger problem is that there is little if any incentive for pharma companies to invest in antibiotics compared to traditional blockbuster drugs that are supposed to be taken chronically (and therefore have better ROI). It's the same reason little R&D goes into making new vaccines. It doesn't matter how many candidates are found if they can't make it to market in a timely fashion (the point of the CDC bar graph), and this is what the "slow catastrophe" really is. It is not that scientists will never figure out new ways to kill bacteria.
I used to joke that there were so many groups with a Gram+ antibiotic drug discovery program going that my parents were probably running one out of their cellar.
Gram- are tough.
That's freaking fascinating, I'm in bioinformatics myself, I'd love to hear more about this- I wasn't aware that an antibiotic discovery startup was/is/could be a thing at all- If you can tell me anything more or put me on the right track to reading more about your old employer in that space or whatnot, I'd appreciate it! :)
But these startups do exist: look up Achaogen (achaogen.com) and Tetraphase (tphase.com).
Cubist Pharmaceuticals was a big antibiotic developer that was recently purchased by Merck. Cubist itself bought another startup called Trius Pharmaceuticals, which had developed a newly marketed antibiotic.
So, there is $$ to be made in antibiotic drug development, but as many people on this thread have pointed out, there is more $$$$ to be made in other therapeutic areas (e.g., oncology).
For example, fluoroquinolones can kill both Gram+ and Gram- microbes, but they are generally better at killing Gram-.
Other classes have the reverse characteristics.
I don't know much about the types of microbes that cause periodontal disease.
However, my company was initially interested in treating Community Acquired Pneumonia (CAP). The problem with CAP (and many other bacterial infections) is that they can be caused by either Gram+ or Gram- pathogens. This means that if you're making a drug to treat CAP, you need an antibiotic that can "hit" both types.
A common occurrence when we were looking for a candidate drug that could treat CAP was that the candidate would be powerful at killing Gram+ CAP microbes and weak at killing Gram- CAP species. If we improved the drug's ability to "hit" Gram- species, we would always seem to lose potency against Gram+. It was extremely tricky to find something that was powerful enough against _all_ the relevant microbial pathogens.
Only because we've had time as a luxury in the past. I imagine new variants will get fast tracked. FDA bureaucrats hoping to lazy their way to retirement will be under a lot of pressure to actually get things done quickly when there's so much social need. No one wants to be the POTUS who didn't fast track life saving antibiotics if they're shown to be generally safe in early testing. The FDA is a government organization and as such is subject to the politics of our leadership and indirectly, the electorate.
The FDA has a page about this process here:
http://www.fda.gov/forpatients/approvals/fast/ucm20041766.ht...
At least 774 drugs have gone this route:
Basically. Humans are horrible at cost/benefit calculations on an abstract level that may not directly affect them for years or even ever on an individual scale. I've known people who won't wear seatbelts because someone they know got trapped by one in a freak accident, despite overwhelming statistical evidence that's a dumb approach. The industry also has a long history of fighting regulations that require safety features but make cars more expensive.
http://www.nytimes.com/1986/07/20/weekinreview/the-give-and-...
> Last month, Ford proposed weakening the transportation department's 1984 rule in exchange for faster introduction of air bags in its cars. The company offered to install the bags on the driver's side of a majority of its cars by the 1990 model year if the department would drop its requirement that the front seats of all cars be equipped by then with automatic or so-called passive belts, designed to restrain the passenger as the car door closes.
http://blog.esurance.com/seat-belt-history/
> A Federal Motor Vehicle Safety Standard proposes that all vehicles made after January 1, 1973, include an automatic restraint system, i.e., air bags or automatic belts. The auto industry, knowing that it would have to increase production costs to meet the new standard, balks, leading to a decade of argument and delay.
https://en.wikipedia.org/wiki/Unsafe_at_Any_Speed
etc.
Judging from everybody I've seen texting while driving, NO, they don't.
You keep using this word, totalitarianism. I don't think it means what you think it means.
I mean, seat belt laws are totalitarian? That's kind of insulting to the victims of totalitarianism everywhere...
No, you should just avoid the slippery slope fallacy.
And I can guarantee absolutely that purchasing power is not the be all end all, and that leaving it all to the free market and "if I want X, it's my choice" creates more issues than it solves. For example, nobody labelling what they sell as X (but as X+, the better variety), without legislation to prevent them.
And the same argument goes to BS like avoiding vaccination and people teaching Creative Design to their kids.
Antibiotics have already saved ~200 million lives, 80% of their use is in livestock, and they are of limited long term value. A reasonable guess is a Billion+ lives hang in the balance.
We convinced millions of people they'll feel better if they don't eat gluten. An entire cottage industry created. All without force. All without the influence of politics and fallible men.
How do you make the logical leap from "a big diet fad happened" to "the FDA is redundant and evil?"
I have read all your comments -- including the doozy "all...without fallible men" -- and I will suggest that:
A) If you are incredibly savvy, you can already sidestep government regulation by pursuing remedies outside the scope of what they control.
B) Most people are not that savvy and, unfortunately, need the protection provided by government regulation.
C) There is zero means to remove the fallibility of "men" from the equation. (I am a woman. As much as I would love to joke that things would be so much better if women ruled the world, the reality is that the fallibility of humankind is inescapable. Also -- cough -- Theranos.)
D) Antibiotic resistance is not due to lazy bureaucrats. It is due to lazy humans. It's lazy humans all the way down. They are hardly confined to government.
E) Even in alternative med circles, you get social pressure and people with a profit motive and conflict of interest and on and on.
F) The path to solve this will never catch on. It is too much work. It can be done now. The research into how to break up biofilms is already at a useful stage, if you are sufficiently motivated.
G) Gosh, I wish you would step away from this discussion. You aren't adding any value here.
Would you like some Thalidomide with that?
Oh! You never had a chance to get that in the US.
(For those who don't know her: https://en.wikipedia.org/wiki/Frances_Oldham_Kelsey was the filthy lazy bureaucrat we all wish we could be (i. e. heroic))
The Thalidomide argument points out the benefit: These regulations avoid releasing medications with bad side effects to the population. Nobody denies this is a good thing.
The costs are more rarely discussed. I think these are the main ones
1. When approval of a medication is delayed 10 years, everyone who would have been cured/helped by it during that time pays. Often with their life.
2. The high cost of FDA level trials makes medication more expensive. It also makes some medications economically unviable, with similar costs as in 1.
I'm not aware of any study trying to quantify these effects, but my wild guess/gut feel is that the costs are ~100 times bigger than the benefits.
The PR problem is that victims of bad medications are seen. The Thalidomide sufferers became world famous. But the ~100k Americans who died while the FDA took 17 years extra to approve beta blockers had no idea why they died.
We're still basically following the process established in 192x (Bayer, sulfa drugs) of throwing any structure we can think of onto some essay, into some mice, then humans. Educated guesses have become more educated, but not much better.
Regulation has only become a burden because we're chasing ever-decreasing improvements. Even placebo got better over the last decades, which may have doomed a few potential blockbusters.
It's obviously a problem of the lower-hanging fruits having been picked, and not all is bleak (kicking HIVs butt these days). But a cell just happens to be 35mill lines of self-modifying, multi-layered, self-evaluating, quantum-effects-using complexity and we're far away from a rational, hypothesis-driven drug discovery process.
Deregulation wouldn't actually help. While it is possibly attractive for a patient now, that comes at a certain and significant disadvantage for future patients: If you could sell everything you wanted, there'd be no incentive for studying efficacies – it'd just be random stuff that may work, competing in a dysfunctional marketplace.
Dysfunctional because nobody would know anything. Even with the somewhat professional studies we have today, and even for professionals, it is a major undertaking to form a solid opinion on a drug. Throw in patients who have nothing to lose and it'd probably be worse than it ever was.
It's not like experimental treatments aren't available today. Almost every cancer patient is enrolled in one or more trials, unless she immediately responds to existing drugs. Quite a few people have traveled to Asia for some stem cell snake oil (less money, nice tan, no improvement, life-threatening complications being the usual outcome).
The FDA also has a long history of whistleblowers to fight FDA corruption. Drugs like Avandia and Rezulin should give you pause.
Yes, lazy bureaucrats, rubber stamping, politics, and monied interests work together to make FDA approval a crap shoot. I never understood this whole "worship the state" aspect millennials subscribe to. The state has its own agenda and its usually counter to yours.
There were 17 "thalidomide babies" born in the US.
Just like Bitcoiners rediscovered the reasons our financial system has the various moving parts it does, healthcare regulations tend to have good reasons behind them.
I absolutely agree that it won't be as gloomy as outlined in the article. The search for novel antibiotics has been pretty much neglected (Teixobactin is more of an exception to the rule) because the currently employed drugs work quite well. As this is changing, the possible market for novel antibiotics will increase and thus funding will shift into this direction.
"Strains of bacterial pathogens that have acquired mutations conferring antibiotic resistance often have a lower growth rate and are less invasive or transmissible initially than their susceptible counterparts." http://aac.asm.org/content/54/5/2085.full
If evolutionary logic holds (and there's little doubt about that, though research on the rate of resistance lose with time varies), switching to new classes of antibiotics and not using old ones until resistance to them de-evolves is a viable strategy.
The problem is China loves to pump their livestock full of it to boost production, and now we're starting to see bacteria strains that are resistant to it.
http://phenomena.nationalgeographic.com/2015/11/21/mcr-gene-...
The WHO simply do not have any teeth to enforce shelving, and it's probably going to take a major health crisis before it's even on the table.
The use of common antibiotics isn't good, by any means, but last-defense drugs being used is far worse.
At least two cases have been detected in the US, the first was earlier this year, the second as of yesterday.
https://www.sciencedaily.com/releases/2016/07/160711150939.h...
As mentioned in the article, the colistin resistance is being transmitted via plasmid, so it is capable of diffusing quite widely into different types of bacteria.
Too long. You can get significant mileage out of a 3 year ban but resistance will return very quickly afterwards. You'd need to wait decades to truly reset the clock.
> After three years of banning the use of that antibiotic, the resistance of the bacteria dropped significantly. But because there were resisitant strains that persisted right through the end of the study in 2008, it was likely that the resistance would surge once again if the antibiotic were reintroduced. To safely reintroduce the antibiotic, Townsend said, you have to kill off all the pathogens.
> Considering how important antibiotics have become to human health — from the treatment of strep throat to MRSA to tuberculosis — Townsend says a 45-year ban on most antibiotics would be impractical. Doctors estimate it takes about that long for the resistance to disappear.
Ideally you have enough different classes of antibiotics that you can maintain a constant rotation and always have new antibiotics coming off shelved status so you can retire antibiotics that've formed resistances. Even better, a larger library of antibiotics directly improves the effectiveness of this strategy - in the short term, introducing a new class means you can shelve an old, resisted class; in the long term, more classes means each class can spend longer on the shelf and we reduce antibiotic resistance further.
My crazy theory is that somebody with drug resistant TB could be deliberately infected with regular TB, which will replace all the DR TB, and then you treat the patient normally. Assuming they survive.
The funding purse is open for antibiotic research and I find it hard to believe its a dry well. I think we'll see more discoveries like these in our lifetime.
Call us when any of them survive the valley of death that kills 99%+ of substances with interesting in vitro activity to reach clinical use and the hypothetical becomes actual. In the mean time, real people are dying real deaths.
It's nice to get paid to solve a problem you created in the first place.
The current free market approach is completely failing this. It's not particularly profitable to invest many years in a drug people only need to take once to cure a disease when compared to developing a drug people need to take for 5-10+ years to manage a disease.
Phage therapy should be further developed as well, which has been proven to work against some resistant strains.
Why couldn't their payment scheme be identical even if it's a one time dose? Instead of $1000 per year for a drug you need to buy every year for ten years, make it so it has an up front cost of $12,000 or whatever with a ten year payment plan available for people who don't have that kind of cash on hand. This suggestion obviously inspired by the real world good that is a one time purchase that people make all the time: houses.
But to elaborate, aside from the obvious ethical implications, there are also practical differences. You are usually not forced out-of-the-blue to buy a house, no matter if you can afford it or have just bought a house last month. Also, houses can be sold, so people have ways to back out of a purchase when they realize they cannot pay back the loan. None of this works for drugs.
Trying to apply the same logic to drugs would make the the debt problem of medical bills even worse than it already is. It would also lead to a strong inequality in medical care.
The problem with that approach is the way that hospitals are reimbursed for antibiotics in the US. There is no room for those prices. I know Congress is trying to change that by making antibiotics separately reimbursed.
[Source: I worked at a biotech firm that has a number of antibiotics in development]
- There is no such thing as a "broad spectrum" phage. You can't do empirical treatment using phages, and there's not really "off the shelf" phage therapy - it tends to be a bespoke creation for a particular infection.
- There's some serious regulatory problems, similar to those experienced by fecal transplant treatments. We're not yet really equipped to think about handling evolving, custom microbes as a treatment.
- Because of the first, it's going to require a considerable amount more lab capacity than most clinical settings currently have, and considerable delays until treatment.
- There's also some biosafety issues around phage prep, but those are easily solvable.
It's a great way to treat particularly resistant or hard to treat infections, but it's not a particularly great general solution. There's a reason it was abandoned in countries with easy access to antibiotics - they're just roundly superior in basically every respect.
> To offset the millions of dollars they pour into research, clinical trials and the FDA approval process, pharmaceutical companies aim to develop blockbuster drugs, said Dr. Anthony Fauci, director of the National Institute for Allergies and Infectious Diseases. An ideal candidate would be used by millions of people every day for the rest of their lives, like pills to keep cholesterol or blood pressure in check.
> Antibiotics won’t pay the freight. They should be prescribed sparingly and only used for about a week.
Hmmm. Natural selection of humans, in an environment partly controlled by Pharma.
Pharma needs lots of patients that consume a drug every day for life. (I take three of them, plus an arguable fourth.) People who take one or more of these drugs are valuable. Such people who live longer lives are more valuable.
By not discovering low revenue new antibiotics and making them available, what we're left with is people who take daily drugs for life, and somehow survive or avoid bacterial infection.
I want to believe that no one in Pharma has thought of this.
Teixobactin is 2015 and is probably a member of a new class of antibiotics.
Also note that retrospective studies have shown that first observed resistance to an antibiotic appears about six months after it is introduced. We are producing new antibiotic families far slower than this rate.
http://jac.oxfordjournals.org/content/70/8/2177.full
My experience with kids is that here in Spain they are using older antibiotics now to preserve the newer ones for serious infections trying to limit evolutionary pressure on the bacteria.
There is probably a huge array of such things out there. They are unlikely to be as broad-spectrum as traditional antibiotics, but with research we should be able to find ones to apply to the right situations.
At the same time as this crisis unfolds, our ability to know exactly what someone is infected with improves. Soon sequencing of bacterial infections will be the first step in patient triage. This will help us apply precisely the right toxin to rid the body of the problematic type(s) of bacteria.
> Artificially constructed plasmids may be used as vectors in genetic engineering. These plasmids serve as important tools in genetics and biotechnology labs, where they are commonly used to clone and amplify (make many copies of) or express particular genes.[12] A wide variety of plasmids are commercially available for such uses. The gene to be replicated is normally inserted into a plasmid that typically contains a number of features for their use. These include a gene that confers resistance to particular antibiotics (ampicillin is most frequently used for bacterial strains), an origin of replication to allow the bacterial cells to replicate the plasmid DNA, and a suitable site for cloning.
I think that the problem would be coming up with a delivery method.
We already know. There are four main mechanisms for horizontal gene transfer:
1. Free DNA uptake 2. Phage transfer 3. Conjugation 4. GTA
Preventing any of these is near impossible.
We have however had some success in using phage therapy against some MDRs.
Might be a bit rough on gut bacteria, though...
From what I have read and experienced firsthand, you are far better off strengthening your gut flora, not undermining them.
Even in a hypothetical case where a random enzyme mutation confers resistance with no real obvious cost or side effect to the cell, unless there is specific environmental pressure to keep that mutation, it can easily revert in subsequent generations.
You'd potentially have to take whole classes of antibiotics out of circulation, for a long time. And even then, some of them will maintain resistance genes because these compounds are present in the environment.