BTW for anyone who wants to help but thinks this is mostly wetlab/drug development work. There's quite a bit of room in the space for the computer-vision side of things to improve decision-making and time to treat. I think it's mostly based on phenotyping by imaging and identifying low-specimen cultures but I might be totally wrong.
I am trying for nearly a year to get a grant for my multi-objective drug combinations therapy optimizer, which seeks to adapt drug combination regimens for long-term robustness against emerging drug resistance. And I am getting one rejection after another.
I mean, yes, there is a crisis. We need action now. Many people are offering solutions and new research directions. But money are simply not there.
I am quite sure, that if a sufficient bounty was given out for developing new kinds of antimicrobials, they'd be developed in no time.
The problem is that cost and risk of development and trials is too large for the current rewards, and hence there is very little new antimicrobials being developed. There are very many promising leads though, and either making development cheaper (by requiring smaller or fewer clinical trials) or ensuring good prices or bounties for successful development would likely create a plethora of antimicrobials in a quite short time frame.
What if new antimicrobials do get developed? They will once again be used in massive quantities in dirty and otherwise unsanitary livestock operations, resistant bacteria will develop again and we will be where we started again. Actually we will be at a worse place from where we started because all new antimicrobials that do get developed seem ever more dangerous with ever increasing lists of ever more serious side effects.
The large livestock operations keep their livestock in horrible unsanitary conditions to save money and they create a breeding petry dish for bacteria. They rely on antibiotics to kill the bacteria but in those conditions the bacteria have all the advantages and usually are able to create resistant stains pretty quick.
This would require massive international cooperation and possibly even sanctions on countries with lax regulations.
If you have one country with lax or no antibiotic regulations then that country is going to continue breeding antibiotic-resistant pathogens. Those pathogens will pretty much inevitably escape out to more responsible countries.
This is theoretically doable, but as it stands you can't even get every country to abide by sanctions to discourage proliferation of nuclear weapons.
This is actually completely right. I believe there's some policy in the works in the US after talking to a friend who's doing some consulting work to help align the Cost-Benefit side of antimicrobial development.
I can't say if there's a plethora of drugs just waiting to be released after CT requirements are lowered, but definitely there is less of an R&D incentive currently because pts who take antimicrobials only take them temporarily and cases where you need an advanced antimicrobial to deal with an AMR case are thankfully uncommon.
There’s also pharma world wide. Seems the system is broken if only massive economic upside in the US is what leads to drug discovery and successful clinical trials.
Testing requirements are as high in other rich countries. And existing antibiotics work fine atm. Nobody’s gonna pay to use new ones unless there’s no alternative, both for cost and resistance reasons. So why bother? Might as well postpone development until there’s a real market, right?
I actually think this is good since it means we postpone usage of, and thereby resistance to, any new antibiotics.
Yes and no. Many strategies for delaying antibiotic resistance require having multiple different effective antibiotics at the same time. Thus, getting down to the point where only a few work rapidly speeds up antibiotic resistance.
Unfortunately, antibiotics are the tragedy of the commons writ large, and we’ve been wasting them for minimal gain because even minor private benefit generally outweighs long term consequences.
Edit: Apparently broad spectrum antibiotics can actually lead to antimicrobial resistance [1][2]
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> I actually think this is good since it means we postpone usage of, and thereby resistance to, any new antibiotics.
This is true if you use them in isolation but I thought broad spectrum antibiotics, aka many at once, is what is typical now to slow down development of resistance? In this case you’d want to develop a few new ones and deploy them in batch.
The reason not to postpone development is because it isn't a particularly quick solution. It would be one thing to develop and test them, and then postpone deployment of them. It's another thing to not have a backup plan and hope that one of the antibiotic candidates work out, and quickly.
Modern cities are a huge disease vector. That kind of population density lets sickness run rampant. Untreated TB has something like a 25% mortality rate, and we've already seen drug-resistant (DR) and extreme drug-resistant (XDR) strains of TB. An outbreak of TB that we have no antibiotics for would be devastating.
Seems likely there’s a fairly small number of possible classes of broad spectrum antibiotics that can be developed. Bacteria don’t just evolve resistance to a single molecule but instead to a vector of attack, and anything you’re giving to people needs to avoid harming human cells.
So ultimately the question becomes how many types of attack are possible?
The problem with developing a new antibiotic is that doctors from third world countries will prescribe them like candy - so the bacteria become resistant to it fast.
In fact Im very scared when I read that there are plans to use antibiotics "borrowed" from ants, or bees, because probably the antibiotic will be dumped by tons and become useless after 2-3 years, while all the ants or bees in the world die out.
Apart from third world countries giving antibiotics like candy, other problem are farmers, who also feed the livestock by the bucket. That's how we get bacteria resistant to everything.
The brutal reality is that new antibiotics cannot be sent to some countries, but that is very difficult to do.
Is that a third world countries issue? I’ve heard of it in the UK, there are a lot of comments on this page about it in the US. Your point about livestock is good, but that is definitely happening in the UK and US.
Your points are all entirely valid, except the "third world country" stuff: all the things you complain about are common in the richest and most developed nations. It's a systemic problem everywhere, not just in poorer countries. In fact, it might be worse in the richer countries because access to these drugs is more affordable (relative to local cost of living) there: farmers in a rich country can easily afford to pump up their livestock on unnecessary antibiotics, whereas poor farmers in some backwards country can't afford that and probably don't have access to the drugs.
Not only a third world country issue of course…but also, I had the reverse experience in Madagascar for instance where doctors were a lot eager to narrow down what you actually needed and how much you need it to avoid throwing the kitchen sink at you.
Depending on the country and situation medecine can be pricy and in limited supply, wasting it away becomes a disaster in many more ways than long term resistance.
Yeah, many urgent care doctors here will prescribe antibiotics just to get the patient out of there as fast as they can even when they almost certainly have a viral infection
Not my experience. Many doctors seem very hesitant to prescribe antibiotics. Even 10 years ago I was in the ER for a deep flush wound from shop accident, almost killed myself. Had a large open wound from a dirty saw. They made sure I was up my my tentis shot but no antibiotics. When I asked about them, they said they would treat if an infection presented itself but not before
Anecdotally, from two (albeit leading) microbiologists, an additional risk if the cultural one. The thinking being, if you work on a semi-marginal anti microbial, it’s less important, but nobody will protest your margins. Versus if you develop something game changing, chances are the powers that be will take it from you.
As we just saw with the COVID-19 vaccines, you may develop game changing drug, almost skip the testing phase and profit hugely off it, if the demand is high enough.
The mRNA vaccines were tested on 10ks of people before they were released to the general public. While the timelines were sped up and access to larger bodies of test subjects, the testing phase was not skipped by any stretch
You need to kill bacteria, not kill humans and print money. The optimal strategy is to wait as long as possible as the value of a novel drug goes up as resistance goes up.
Hot take, but I actually think this is good since it means we postpone usage of, and thereby resistance to, any new antibiotics. The second there’s a new antibiotic, poor countries are going to over-use generics of it and create resistance.
If the economics were rational, I’d agree with you.
Humans inability to effectively organize doesn’t matter to the bacteria. As a species, we have the ability to understand that what happens in impoverished areas impacts us all. The smart move would be to rethink healthcare, globally.
Otherwise, those bacteria, who can’t argue, will just relentlessly keep evolving.
> The problem is that cost and risk of development and trials is too large for the current rewards,
This kind of invesment has been traditionally done by governments. But with a reduction of taxation governments do not have animore money to do this. And for private companies it makes more sense to spend that kind of money in advertisment than in developing new products.
> ensuring good prices or bounties for successful development would likely create a plethora of antimicrobials in a quite short time frame.
If one woman has a child in 9 months. How many months takes to 9 women? More money may accelerate development, but there is a limit on how much faster one can go. Give a big enough reward and you will find more corporations cheating and lobbyng to get that money without delivering any actual antimicrobials.
Public research institutions seem a very good middle ground. Give pasionate scientist funding and they will come with solutions. Give passionate CEOs money and you get the next big scam.
> Give passionate CEOs money and you get the next big scam.
This has been the case for decades, yet we still seem to have not learned this.
This is my observation, from having seen this happen in a couple of industries, and hearing of it happening in others.
There seems to be a "sweet spot," in new money-making stuff, where real value is produced, rewards are reaped, and scamming is low.
The industry starts off with small-scale passion projects, and relatively low rewards. Virtually no scamming, but also modest financial gains, as the passion-players start to establish the infrastructure.
Then it starts to "catch on," and a more professional approach is applied. The industry starts to scale, and the first folks on the upswing start to make some good money.
Then, after that, the scale goes up exponentially, the quality of the work nosedives, the rewards pile up, and the scamming becomes more prevalent. Many of the originators fall down, because they can't adapt to the new darwinian order.
Eventually, the whole thing becomes so corrupted, that it collapses under its own weight.
i think you’re hitting the nail on the head emphasizing passion.
so often people entirely disregard passion for the work when theorizing that no one would be a ceo for less than $40million.
i haven’t ever seen studies done surrounding the issue, but i’d bet far more innovation comes from people doing something because they’re passionate than it does from monetary reward.
there’s a tipping point somewhere when innovation takes a backseat to greed.
often greed directly leads to a willingness to destroy a things essence or just chip away at the thing completely ignoring the passion which brought it about in the first place.
edit: forgive me if this seems a bit heavy handed—just watched Its a Wonderful Life with the family for Christmas so maybe i’m feeling a bit jaded towards greed.
I’m pretty sure government tax revenue is still at or near all time highs. As the population grows there’s more and more taxes to spend for this purpose. It’s just a matter of priorities.
This feels like a misdirection, though. Revenue may be high, but the same forces that drive this being a trivial statement also mean that expenses are at an all time high.
Any increase in general tax revenue generated by an increase in population is going to used for the new population. For example NASA's budget didn't increase just because of an increase in population
If you have reasonably honest people who are not starting from scratch, and honest trials, you likely are going to get a real thing. Case in point: mRNA vaccines against COVID.
> The problem is that cost and risk of development and trials is too large for the current rewards, and hence there is very little new antimicrobials being developed
If that is so, then that research should be done by the state. The well-being of entire human race cannot be tied to monetary incentives of profiteering.
The ENTIRE technology core of the US. The government channels taxpayer money to state research organizations like DARPA. They invent things like the Internet. Then they turn over those to the private sector for profit.
The majority of core research has been backed by government funds for a while now. Commercialization and mass market adoption is typically where private enterprise steps in.
I thought of that too. I don't know enough about it to know if it's a legit counterpoint. My view is that real competition is necessary to efficiently and effectively get to a solution, versus focusing on the bureaucratic mechanics of running the machine that's supposed to be building the solution, which is what happens when government takes things on.
But the space program, and maybe the Manhattan project, actually had real, credible competition, even if it wasn't economic, so maybe were able to escape the bureaucratic trap. Something less urgent (even if it is on paper) like antibiotic resistance, I'm not convinced presents the kind of competition that would actually substitute for a competitive market.
> I don't know enough about it to know if it's a legit counterpoint.
Its a gigantic counterpoint. A large swath of the technology used today was developed by NASA and then turned over to the private corporations for them to profit. Socializing the costs. Privatizing the profits.
The Internet iself an argument. It was developed at DARPA with taxpayer money. Then turned over to the private corporations so that they could profit. Another case of socialism for the corporations.
I think this is overstatement as to 'turning it over.' DARPA paid for research and operated communications systems in furtherance of a standardized packet network. This was done largely with privately developed tech like commercial telephone wires, commercial modems, commercial minicomputers, commercial solid state RAMs, commercial storage tech. The benefit of DARPA's big funding boost was consolidation, sharing, selection of objectively reasonable choices like tcp/ip, and allowing international collaborators. This sped up the process of having a viable, unified internet wherein other researchers who were not even in the United States contributed tech like the web (on Next computers, with Next software stacks, Motorola chipsets, Sony CRT tech, etc).
> This was done largely with privately developed tech like commercial telephone wires, commercial modems, commercial minicomputers, commercial solid state RAMs, commercial storage tech
Same happened with all of those. The government created the tech, then paid private corporations to implement it, literally funding the everything from scratch while the private corps grabbed the profits.
> This sped up the process of having a viable, unified internet
That's false. Chile's Socialist president was at the point of launching their Internet in mid 70s. Which was ended by the US backed coup.
With the Internet the government got their pound of flesh through taxation of all the new enterprises that sprung up because of their investments , so I wouldn’t make it sound so negative.
> With the Internet the government got their pound of flesh through taxation of all the new enterprises that sprung up because of their investments
Really. With all the tax breaks and ongoing lowering of the top tax bracked for corporate profit. Even as they offshore their legal entity to dodge taxes...
Even if the capital gains taxes were 90% like back in Eisenhower era and it was actually enforced, that still wouldn't justify handing over publicly funded research to private actors to profit. Publicly funded everything should be made publicly available and usable.
Not sure I agree. Take a look at recently developed antimicrobials. It’s not like there haven’t been any new ones. The problem is this: they are very expensive compared to older antimicrobials (so don’t get used at all except in wealthy healthcare systems) and they are tightly held in reserve for only the most resistant cases (so very small market). The latter point is particularly insurmountable, since widespread use will make the new antimicrobial less useful. It isn’t really worth it for a drug maker. The article talks about this, indicating that public-private partnerships are the way forward.
They also tend to not be new families of antimicrobials with novel mechanisms of action, which is what's needed for more significant gains against resistance.
Another factor to consider is it’s much better for social good to wait until you have 2-3 working new antibiotics to mix together to reduce the survival rate exponentially. But that would require delaying the short term profits of selling the single-cocktail twice.
If this ends up being the approach, I really hope it will be led by a country with a few decades experience in successfully being socialist. The US really has no business doing this, the government departments and oversight boards that exist today are much too compromised by the pharmaceutical industry to pull this off.
A national laboratory is not a socialist idea. If it were then the US would actually be an extremely socialist country given its government spending. Doesn't the US put out the most research in the world, and have the most Nobel prizes? That hardly seems like a country that can't manage this. Nowhere is free of bureaucracy.
Nationalization of research laboratories is a very socialist idea. That doesn't make it bad or inefficient, but government takeover of research and education has pretty solid roots in socialism, Marxism, and fascism.
The US does spend the most and that leads to output, but that doesn't mean it's the most efficient or does the best job of prioritizing the populations best interests over political or business concerns.
The selection process of awards like the Nobel Prize is also at risk of bias given that many of the people involved in picking the winners are themselves part of the national laboratory machine.
Regardless, my point was simply that we probably have a better chance at a Swedish effort leading to less biased and more efficient research than one from the US right now. I wasn't aiming for a debate on the relative political roots or leanings of publicly funded research labs.
A 'national lab' does not have anything to do with 'nationalisation'. Nationalisation means to take over an existing privately run lab, whereas a national lab can be established from scratch without even the hint of a takeover of any private organisation. In the post you replied to there was zero suggestion of nationalisation.
That said, nationalisation is sometimes the correct move as the opposite of privatisation which is also sometimes the correct move, so attaching labels like 'socialist' to it to tar the policy is not productive (just as tarring something
as 'capitalist' also does not beget good thinking about policy).
Phage therapy seems like it's gonna become increasingly important (we've been using static munitions against increasingly dynamic enemies for far too long).
Keyhole and robotic surgeries (already advancing rapidly) are going to be significant and useful.
We also need to investigate, understand and classify symbiotic organisms with the same zeal with which we've approached pathogens.
We've spent so long glaring at the invisible enemy that we've completely ignored the invisible allies (who we regularly nuke with broad spectrum soaps, gels and other microbicides).
All we're really doing is creating monopolies for pathogens.
Maybe it's me, but a lot of these article seem to advocate for magical solutions; when there's both enhancements to current technologies and unexploited low-hanging fruit that they aren't even bothering to consider.
Phage comes up a lot here - it seems to be on of HN's favorite biology topics.
I have a deep and abiding fondness for phage, but they're not quite as awesome as they seem at first glance. From the perspective of an infectious disease epidemiologist who has been super-interested in phage for my whole career (literally tried to get a job out of undergrad with a phage therapeutics startup):
1) There's no such thing as a "broad spectrum" phage. They're organism specific, and that means not only would you need to keep a phage library on hand, but you'd have to do a lot of diagnostic tests. That's going to be both expensive and tricky. There are treatment guidelines for things like sepsis right now that are basically un-doable with phage therapy because of the time it takes to tune a phage library.
2) Phages are living things. Not only is that a weird regulatory framework to be in for a drug, but it also means that you need to be able to keep phage alive. In contrast, antibiotics are inert.
3) Phage therapy is also relatively new in the West (after being abandoned for some very real, very serious safety concerns back in the day), which means there's just less of a R&D infrastructure behind it.
There have been people working on commercializing phage therapy since I was in undergrad (I'm now a tenured professor). The problem is it's hard, and antibiotics are so much better as a treatment that there's kind of a ceiling on the excitement that they can generate, especially when trying to treat at scale.
Some of the most interesting applications are currently combination antibiotic and phage therapy - it's much harder for bacteria to maintain resistance mechanisms for both simultaneously.
Phages are great when they work, but they too are yet another tool that bacteria can evolve to survive. I can’t find the article right now but there are bacterial strains that evolve so quickly that you can’t usually subdue them with just one strain of phage - you need to go at them with multiple strains at once.
Like many slow moving disasters, it doesn't feel like one while you live through it.
An example: gonorrhea has no golden standard cure anymore. 40 years ago a single large dose of oral antibiotics was an effective cure. It made controlling it relatively easy. In the 90s, resistance to most of the common oral antibiotics became prevalent. Through the 2010s, a single dose of an intramuscular cephalosporin was effective. Now resistance to that is also common. Gonorrhea remains curable in almost all cases, but cultures and strain-specific targeting and second-line antibiotics in combination may be needed. Repeat testing to be sure it worked is necessary.
From one pill cure in 99%+ of cases, to something requiring multiple clinic visits and lots of lab work and possibly IV infusion antibiotics. The complications for public health, in terms of patient compliance, containing spread, as well as just the labour hours and case management complexity, are awful.
No matter how many new, different, or even radical antibiotics we develop, unless we get ahead of over-prescribing and under-treating (not taking all of a prescribed treatment course) we will continue to rapidly evolve more successful micro-organisms, to our own detriment.
I think it's utterly hopeless. With billions of humans, there's no way to get everyone to agree to do the right thing, both with doctors and especially patients. You just need a small fraction doing the wrong thing for something bad to evolve: look at Covid, for instance. That simply evolved somewhere at one point in time in one place, and then spread like wildfire.
Good thing nobody gets cheated on, lied to, or raped.
As advice, this is like saying we don’t need airbags because people should drive safely. Provably millions of people will have adverse effects due to this and moralizing won’t shift that rate anywhere near enough.
It is difficult to understand what you are trying to say with this comment. What are you trying to communicate with it? Could you express your intent in some other way which might make it clearer?
Traditional morality around sex, dating, and marriage, is one solution to reducing the prevalence of STDs. It doesn't eliminate it, and there will always be edge cases, but it does "flatten the curve" so to speak, as much as people may not like to admit it.
It has happened. My child got a resistant strain of Shigella causing severe dysentery. After a stool assay it was found only 3 kinds of IV antibiotics were effective, with only 1 being safe for children at effective dose. And it still took a week of 3x per-day IV infusion for it to clear. The doctors said only 5-10 years ago there were still oral antibiotics that worked, but now there aren't any.
But it does. Both my grandfathers died as a result of infections with resistant strains, one of them after surgery, and the other after an extended hospital stay. Cause of death for both of them was persistent diarrhea over a few weeks. It’s quite common for tissue to become infected after major surgery (eg hip) with resistant bacteria, often necessitating another round of surgery and/or Dr-House-esque search for a particular antibiotic that will work. Older patients might not survive for long enough.
Older or sicker folks who end up in a hospital or nursing home / rehab are very vulnerable to stuff like TB or c.diff. Cdiff is huge now as hospitals purge support staff and are filthy. If you’re old or immune compromised, you’re gonna pick up a severe, hard to treat infection if you spend time in the ER or general medical area of a hospital. The “money areas” of the hospital are usually better.
Supposedly MRSA kills like 100k people per year (although maybe a good chunk of those 100k aren't getting any antibiotics at all, so it's not entirely due to resistance)
> And yet the crisis hasn’t happened. Why is that?
I used to think this, too (and this is coming from someone who worked at an antibiotic drug-discovery startup in the early 2000s).
I think it's not that there will be a comprehensive event in which "this bacterial pathogen is now unassailable by any antibiotic in our arsenal."
It's more that, if you are on the front lines of a hospital, you'll come across many (but not all!) patients with bacterial infections for whom antibiotics won't work.
If you are an MD with enough of those types of patients, it will fuck with your decision making process. It will also cause a lot of prolonged health issues as well as death. It just won't be a wall-to-wall comprehensive type of antibiotic resistance.
There are alternatives to antimicrobials being developed. Instead of directly killing bacteria and therefore putting selective pressure on them, you can prevent their ability to bind to host surfaces and wash them away. The best example is probably mannosides, which are high affinity mannose analogues currently in clinical trial in humans for UTI treatment.
Not OP, but it's kinda like boiling or alcohol versus poisoning (which is essentially how most drugs work). Certain attack vectors are literally unevolvable, as they would require fundamentally different building blocks to be able to be able to handle, which is too big of a leap for evolution to make.
The challenge is:
1) finding something that kills mostly/only cells we don't want in or around our cells
2) kill them in such a ruthlessly efficient way that there are no survivors
As a sibling points out, the vacuum of space does #2 quite well. Actually we have a lot of stuff that handles #2 quite well. But #1, differentiating between "good" and "bad" with our murder machines, is pretty much an unsolved problem.
We need to create nanides: nano-scale machines that can differentiate between microbes and destroy the bad ones. Just don't piss them off with a phaser blast when they get into the ship's computer core.
Look into immunology, it's a biologically mostly solved problem with the mammalian adaptive immune system.
...In the sense we're here because an implementation evolved, however, the physics and minutiae of the problem domain are so numerous that even nature with billions of years of time, and the happy accident of intelligent tool using life haven't been able to make significant inroads on nailing down the problems space in an "ahead of the machine" sense yet.
The Covid pandemic shows that immunology is very much not a "solved problem". Any time someone dies of a disease caused by a virus, bacteria, or even cancer, this shows that immunology is very much unfinished.
But that's the thing, it's not very intuitive but selection pressure doesn't distinguish between dead and banished. Selection pressure means "instead of 100k bacteria, there are now only 100 bacteria that are the best at surviving this environment, and there is enough food for 100k, so they are going to grow back to 100k very quickly, all of them with the better survival skills"
Interesting point! I was thinking washed away germs remain in the gene pool so they aren’t selected out, but I guess the odds that they creep all the way back into the hospital to reproduce with the general population is quite low.
AIUI, a "gene pool" is much more of a thing with sexually reproducing organisms, where mutations either quickly spread across the gene pool, or they get diluted out, because you keep mixing everything together every generation. However, with bacteria, you just have both old and new bacteria each doing their thing.
If we start killing everyone by sending them to the vacuum of space, will we evolve to survive those conditions? Some solutions just defy what adaptation is capable of
Last Wednesday night, I drove a torx bit right through the first knuckle on my left index finger. Since I type all day this seemed serious enough to go to the emergency room. When I see the doctor, I am sure I sounded like a fiend looking for a hit but in this case for antibiotics. He tells me that he does not want to give them to me because if I didn't really need them that it could make it so they don't work for me later in life when I have a real need. Instead he gave me an xray, a tetanus shot and sends me on my way. Since then the swelling has gone down and my finger looks nasty but healthy and I am so far glad that I did not get the antibiotics.
I will not say that there is no possibility that I misunderstood him but if I understood him correctly the act of taking the antibiotic will make it less likely to work for me personally in the future.
In hindsight I wish I had ask him to clarify if he was talking about not working for me or in general. If he was talking about in general, I would have pushed harder for my drugs.
I think if it had been any other part of the finger it would have been real bad. I was working and typing with it until getting the call from the PA mid-morning the next day. Really it came at the perfect time with my Christmas break giving me time to heal up.
I’ve received a ton of medical advice from people in the field, and it varies - some docs say “do X”, some say “no, do Y”. Probably the only unanimous medical advice I’ve received is this: if you live in a non-rural area you have one or more orthopedists nearby specializing on the hand. Call them for a hand emergency first.
The hand is a complicated appendage. There’s a ton that can go wrong treating it or things that can be missed. Early intervention from a hand surgeon could potentially make a significant difference in long-term outcomes.
Honestly, you might take your X-rays & get a second opinion. Don’t mess around with injuries to your hands, especially if you use them to make your living.
There anti-pneumonia vaccines, though the effectiveness is iffy. (For starters, many species of bacteria can cause pneumonia. The species not covered by the vaccine she got will not magically avoid infecting her.) If your wife hasn't gotten one recently, and has no contra-indicating medical conditions or...
Phage therapy is already used in Eastern Europe and Russia. I received phage therapy there myself against an antibiotic-resistant GI infection about 15 years ago. It has been effective. Of course, this is a sample size of 1.
I genuinely believe that ideological and political stigma still stands in the way of phage research and use in the West as it did in the cold war when phages were considered "Soviet". More thoughts on this - https://www.theguardian.com/science/2019/may/09/cold-war-pol....
Soviets, Russian and Georgian scientists did a lot of good work; I'm ashamed to see it shunned in Western medicine when I know it can already be effective and save lives if an industry developed around the medical use of phages. Lives lost to antibiotic resistance in the West will be the price of politicizing science.
Another reason why phages aren't used in western countries is that it is difficult to make money off of them. As I understand it, phages are bred uniquely for each strain which means it is difficult to patent them. The strains change all the time, therefore the phages have to change, by the time you get a patent for one, it is already likely to be ineffective.
Furthermore, the process of breeding phages for each disease is something drug companies really do not want to do. They want to manufacture pills, ship them in boxes to hospitals and get their money. Doesn't work with phages. You have to take samples at the hospital from a patient of the bacteria, breed a phage that eats that bacteria and then send that phage back to the patient.
This kind of back and forth seems way to expensive and complicated to the modern drug company. They do not want to build infrastructure around all the country's hospitals to ship contagious samples and to have labs all over the country to breed and manufacture phages.
I don't know how the economics can or would work out for a modern drug company. It's agreeable that Western personalized medicine seems to lag behind Europe and Asian countries like China.
However, this Georgian phage producer does sell patentable boxed-up phages that consume common bacteria, like S. aureus, which has been discussed for its antibiotic resistance in academia a lot - https://phage.ge/products/pyo-bacteriophage/?lang=en. Years ago, I stumbled across some online stores that used to sell these products in Europe and the US, but now I can't find them.
This makes me think that a traditional distribution model for these drugs can work. But there is too much medical skepticism for phage demand. And phages are often slower to work than antibiotics, so the latter option is more practical in treatment... when it works.
The problem with phages is that our immune system can recognize them easily and flush them out of the body. It doesn't stick around long enough to do the work. It could work if the dose is massive or if the infection is localized to one specific area.
Btw this is what I learnt from reading a blog from someone who has worked with this stuff. I'm not a biologist and it's been a long time since I read that article so I can't seem to find it. So take the above stuff with a grain of salt
> The problem with phages is that our immune system can recognize them easily and flush them out of the body.
The problem with phages is that they are finicky to administer. There is no "get this phage and it will kill all bacteria in and around you" treatment. They are specific. This of course has its own benefits too, but makes the process of administering harder.
With antibiotics the doctor comes to the conclusion that it is a bacterial infection. Then they write a prescription. And then you can buy the drug from any drug store. Antibiotics are largely shelf-stable and there is only a handful of different ones, so any drug store can keep all the major ones.
With phages the pipeline is more complicated.
You need to take a sample from the patient, you need to cultivate it, and then you need to check which phage or phage cocktail gets rid of that specific bacteria the best. That is a lot of lab work. Won't work at scale unless we automate it. And then there are questions like: How do they keep the phages healthy and happy? Are they working with a fixed selection of phages (a phage library if you will) or do they try phages based on the symptoms? Once they know which phage is the right one how does the patient get them? Can we stock them in our existing drug stores? Are they shelf-stable / can they be made shelf-stable? Which phages should the drug stores stock?
All of this can be of course answered and the problems ironed out. We put a man on the moon after all. We can do hard things if we want to. It is just a lot of faff.
The reason I explained in my previous comment deals with the interaction between our body and the phage. A lot of drugs fail in this phase. What works in a cell culture need not work in the body. Even if you find the right phase for your infection it still might not work. All this might be solved with genetic engineering. But there a lot of work to do.
Also as an aside, physics is easier than biology. Once you figure out a solution that works, it always works in the future. The moon is not actively changing its orbit to survive. Bacteria or cancer for that matter always end up finding a way to overcome
This is not necessarily true. Our gut has trillions of bacteriophages. They are actually really useful as they keep bacterial populations under control.
Many bacteriophages are not immunogenic, i.e. our immune system will ignore them. Others are very immunogenic, and are actually used as vaccine platforms.
Bacteriophages in the bloodstream is different from our gut. Our gut has a lot of bacteria too but the immune system rarely bothers with them till they start popping up outside the guy. We've coevolved with phages for a long time. So our immune system knows that they are mostly benign but don't like them hanging around the bloodstream and flush them out pretty quick
Phage comes up a lot here - it seems to be on of HN's favorite biology topics.
I have a deep and abiding fondness for phage, but they're not quite as awesome as they seem at first glance. From the perspective of an infectious disease epidemiologist who has been super-interested in phage for my whole career (literally tried to get a job out of undergrad with a phage therapeutics startup):
1) There's no such thing as a "broad spectrum" phage. They're organism specific, and that means not only would you need to keep a phage library on hand, but you'd have to do a lot of diagnostic tests. That's going to be both expensive and tricky. There are treatment guidelines for things like sepsis right now that are basically un-doable with phage therapy because of the time it takes to tune a phage library.
2) Phages are living things. Not only is that a weird regulatory framework to be in for a drug, but it also means that you need to be able to keep phage alive. In contrast, antibiotics are inert.
3) Phage therapy is also relatively new in the West (after being abandoned for some very real, very serious safety concerns back in the day), which means there's just less of a R&D infrastructure behind it.
There have been people working on commercializing phage therapy since I was in undergrad (I'm now a tenured professor). The problem is it's hard, and antibiotics are so much better as a treatment that there's kind of a ceiling on the excitement that they can generate, especially when trying to treat at scale.
US doctors have to do everything to keep patients happy. CMS rules their careers with satisfaction metrics. Hospital ADMINS really push it on them. Complaints lead to job loss.
The way it was explained to me is that the physicians know it very well but they're exhausted from arguing with patients who demand antibiotics anyway.
This is just weird. Not living on the US and people here take taking antibiotics seriously, because they often have nasty side effects like messing around with digestion, making you otherwise feel like shit. People don't ask for strong antibiotics just for a common cold or the flu.
I saw a Dr the other week (to rule out Covid and strep) and despite testing negative for both and telling me I just had a cold she offered me antibiotics. I declined, not wanting to be part of this problem, but was taken aback that she would basically try to push them on me.
The biggest risk factor when it comes to infection in general is agriculture:
- We encroach ever closer and closer to reservoirs of animal illnesses, which is how we got OG SARS, MERS and Covid.
- We give farm animals prophylactic antibiotics to promote growth or, worse, keep them alive in completely unsanitary conditions, and the conditions in slaughterhouses are often horrible as well. That is not just plain horrible from an animal welfare aspect, but risks breeding superbugs on one side and severe complications should someone not properly cook their meat and not kill off all the bacteria.
- We spread manure from farm animals over produce fields, which regularly causes e.coli / EHEC outbreaks
Antibiotic overuse in humans is only a small part of the problem, simply because the agriculture scale is so much bigger, and even people who go vegan/vegetarian because they want to avoid all the issues with meat production still can't avoid their produce being contaminated.
>We spread manure from farm animals over produce fields
You do not want to stop this. Topsoil is a damn complicated thing, and bacteria and other decomposers are critical to freeing up and breaking down organic material to keep the nutrient cycle going. Try growing a plant in a sterile soil, and you end up having to maintain it on artificial fertilizers instead of being able to let microbiota do their thing.
I've got a hunch part of our degradation in crop nutrition and loss of topsoil quality is probably stemming from overuse of chemical fertilizer, as well as fundamental microbiome depletion from overuse of antibiotics in industrial farming processes. The unfortunate part being there may not be much to be done about it if there is a desire to maintain our current population carry capacity, because replenishing of it would require reversion to less short-term efficient agriculture, but more long term sustainable methods.
Even in the US, pre COVID, every time I went to to doctor with a bad cold/flu, they'd just give you a Z Pak(antibiotics) and say...if it's bacterial this will kill it, if it's viral it'll work itself out.
So I can definitely see how they're overprescribed.
Z-pak (azithromycin) is not the recommended antibiotic for bacterial sinus infections nor pneumonia (common bacterial infections associated with upper respiratory infections) per most guidelines. Interestingly though, it does have anti-inflammatory properties in addition to its main antibacterial effect. When I see a clinician prescribe a Z-pak (urgent cares are notorious for having a low threshold for prescribing Z-paks), part of me wonders if it's to avoid overuse and potential resistance to appropriate antibiotics and placate patients who want a quick fix.
The downside is that since they feel better from the anti-inflammatory effect, its supports their initial thought they needed antibiotics and in the future will always think they need them, even though they very likely only have a viral infection.
And yet, people will demand an antibiotic from their doctor even with a test showing it's viral. Partially because school science ed doesn't cover that topic at all, partially because of "folk tales" aka learning from parents who didn't know better, partially because of placebo effect... and ultimately, because people want/need to feel better soon because they can't afford being too sick to work or having to take care for sick children.
In the end it dwarfs against antibiotics in agriculture anyway, but if we want to fix the issue of antibiotic overusage on humans, we need to completely re-think our relationship to work and sickness.
Death from COVID, and other pneumonic (pulmonary) diseases, can be commonly a result of secondary infection by bacteria. Our bodies are not the best at handling two different types of threats at the same time. See https://www.nature.com/articles/s41598-021-92220-0 for instance.
P.S. Note that the situation was unclear in 2020-2021 -- for instance from a quick lookup see https://pubmed.ncbi.nlm.nih.gov/34354682/. So patient management was different per region -- as it was a guess.
Same deal in Japan, every time my kid has a cold her mum takes her to the doctor and comes home with antibiotics. When I get a cold the first thing anyone asks is whether I went to the doctor yet. For what? “Medicine.”
AMR is actually a SOLVED problem at this point. If we threw money at it like we threw them at Patriot missiles, we wouldn't run out. But... here we are.
Rant on why things are why they are:
1. Making antibiotics is hard and expensive. The "low-hanging fruit" are all gone, and in the last few decades we've just been rehashing different variations of the same classes of antibiotics. We're seeing bacteria become resistant to entire variations within classes so quickly that, it doesn't make sense to develop those variations anymore.
2. Making antibiotics is harder, and more expensive than it needs to be. This is because of regulations, and mostly it's a good thing. It protects us from getting sick(er), and from scams and grifts. Clinical trials are expensive: https://news.ycombinator.com/item?id=33545209
3. We expect antibiotics to be cheap to buy. We expect them to be cheap, and if the price gets jacked up, people (doctors, patients, ppl on social media) complain. Because it's a pill we think it should be free (and it should; gov't should subsidize) but it's not free to make. If we required iPhones to sell for $5 each by law, they wouldn't be around either.
4. New antibiotics are "not allowed" to be sold. This is because we're afraid of resistance developing against them, which makes sense! But this means no company is allowed to recuperate the hundreds of millions of dollars of up-front development costs it takes to new versions of these things.
5. No one expects to make profit. Few expect to recuperate costs in antibiotics, at this point. It's not profitable (or cost-recoverable). If we treated bacteria like the Russian invasion of Ukraine, and we called antibiotics "Patriot" then we'd get more funding. Yes there's GARD-P and CARB-X etc. but look... the total amount of money raised in antibiotics funding is like less than half what Bird scooters raised before getting acquired by their Canadian subsidy.
6. Gov't has "more important things to do": new funding for AMR didn't pass congress, and Pasteur Act in general has been in a holding pattern. Basically it introduces more funding and allows for new ways to sell antibiotics. (Higher ups call it a "Netflix model" but it really is a "Doordash model" because Netflix has near-zero distribution costs. But it didn't matter bc it didn't pass)
7. It's not a real crisis yet. It's not really anyone's problem. Since we're not staring down the barrel of a real crisis. It's like going to the gym or eating healthy — yes we should probably do it, but let's put it off til next year, and make a resolution for it. Kick the ball down the road.
Ending on a slightly happier note:
1. Old school antibiotics development take many years to develop. Hopefully with AI, ML, genome sequencing, we might be able to find new classes!
2. Phages definitely work. We work with them! We've been treating some very hard-to-treat patients at Phage Australia, as a five person team, out of Westmead Institute.
3. Does phage therapy work at scale? We're shifting our answer from "is this crazy? Will it even work?" to "will this be sustainable?" It costs around $70k+ AUD per patient (time, labor, equipment, for labs and paperwork) but we have no systems in place. Lots of room to bring it down.
4. Does it work at scale, with good unit economics (and to Western standards)? We TGA to figure out regulations, and we're figuring out how to get them reimbursed for the long run. Ideas include using them as compounding pharmacy ingredients (like "Magistral Phage" out of Belgium)
5. There's no money in phages - even with our success, it's hard, and we're always scrambling for money to keep the lights on. But hopefully the Aussie gov't will keep the project running for long enough that we can get a better understanding of running this with "lifestyle business" unit economics (it's probably not venture scale).
6. Going to market is very tricky. Phages are a service, not a drug. Each person's phage treatment is different than the other, so this doesn't fit the clinical trial pathways currently available. It's also different in each country, and we're open to ideas.
Final note:
What we REALLY want is to provide a "concierge service" to wealthy clients and hospital systems that always want "insurance" to treat some of the worst pathogens lurking around the hospital or their region. AMR infections can strike quickly, but usually it's strains that we've seen before — especially in hospitals. It's always the "most wanted" strains that have previously caused problems. We're able to create "countermeasures" for any bacterial threats using phages. Pretty much like Patriot missiles (and with similar costs). This would also follow the Tesla playbook for ("a rich people toy" before releasing a cheaper version).
This would really help us fund us to find ways to lower our production and get it into more hands.
We need help on that front!
If you're able to help, or have ideas, please find me on my twitter (same as my handle here) or on the Phage Australia website)
I have half a mind to study deep sea microbes and how the immune system might react when presented with them using AI/ML and see if that helps this any. Following you on Twitter.
Its a topic that comes up again and again. We are getting resistance against modern antibiotics. There are a ton of old antibiotics that have been out of use for decades that should be retested as possible weapons. Evolving resistance comes at a cost for bacteria and over time they might loose resistance against previous antibiotics.
The problem is no pharmaceutical wants to spend money on qualifying an out of patent antibiotic that can be copied by any generics manufacturer.
We need a joint governmental founding initiative across the eu and us and any other countries to fund qualification of old antibiotics as well as developing new ones.
> Evolving resistance comes at a cost for bacteria and over time they might loose resistance against previous antibiotics.
This is known as the "ecological fallacy".
> reversion to sensitivity is neither an immediate nor necessary outcome of selection simply because a resistant pathogen is no longer in an antibiotic-laden environment [1]
Epidemiology and disease ecology, particularly of antimicrobial resistant pathogens.
The Wikipedia entry for it gives the definition I've always seen: "An ecological fallacy is a formal fallacy in the interpretation of statistical data that occurs when inferences about the nature of individuals are deduced from inferences about the group to which those individuals belong."
My mistake, this is not an example of “ecological fallacy”, but instead a line of reasoning that explains the assumptions that led to an “ecological fallacy” type of error.
An antibiotic is something that kills something you don't like while not killing things you do like. The survival strategy for hostile bacteria is to evolve towards not having vulnerabilities to things which have that antibiotic property. A century of antibiotics has pushed evolution in that direction. Antibiotics thus get harder to find. There may be a fundamental limit here.
The golden age of simple, broad-spectrum antibiotics is behind us.
An offering of ill-informed conjecture/prediction from afar: no progress in future antibiotics—things shift to understanding human biome, at least in significant parts of not whole. Antibiotics are an Industrial Age approach that got humanity across some hurdles, similar to hydrocarbons, but are a dead end.
I was hospitalized to have an operation recently and before they admitted me they tested my nose for MRSA. Apparently pretty common but not a concern as long as they are aware of it
Well we better deal with it now. If the threat becomes too dire we’ll reach the critical level above which people begin to believe the threat is fake news.
Just like global warming, ridiculous wealth inequality and housing crises, outdated primary education systems, air and water pollution, diabetes and obesity crises, increasing prevalence of autism, and still ongoing COVID need action.
I think the pandemic gave us a good reality check about how much is going to actually get done about an urgent crisis: not much.
Another way to slow the pace is to not get infected in the first place.
When I was a kid, cleaning oneself and your environment was emphasised. Scrub your nails, use hot water snd soap. You would smell lysol/dettol often. And bleach. Also, iodine and phisohex.
Now, not so much. Even the phisohex you buy today has no hexachlorophene in it. It's triclosan like ever other damn thing - due to a California law I believe.
I just don't believe these new green clothes and dishwashing liquids are as effective either.
I suppose I'm saying "an ounce of protection is worth a pound of cure"
Some competitions:
- https://longitudeprize.org/
- https://dpcpsi.nih.gov/AMRChallenge/Finalists
Some previous work using various ML piplines:
- https://phastdiagnostics.com/
- https://acceleratediagnostics.com/publications/
- https://talisbio.com/