[pak]

Teixobactin is cool, but if it's only active against gram positives, it's never going to work against most of the bacteria listed in the article: E. coli, Salmonella, Klebsiella, N. gonorrhoeae, etc. Most of the terrible new drug resistance genes are showing up in gram negatives.

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.

[busyant]

I used to work at an antibiotic discovery startup.

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.

[Fordrus]

An antibiotic discovery startup, eh?

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! :)

[busyant]

I'd rather not mention my recent employer.

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).

[mrfusion]

Say are there any compounds that fight only gram negative and leave positive untouched? I'm thinking that might be useful for periodontitus?

[busyant]

Many antibiotics classes seem to be partially selective at killing either Gram+ species or Gram- species.

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.

[drzaiusapelord]

>That road involves decades of trials and costs billions of dollars per approved drug.

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:

http://www.bmj.com/content/351/bmj.h4633

[djschnei]

Am I the only one that would prefer that politics and lazy bureaucrats didn't have the ability to get in the way of my well being in the first place?

[iheartmemcache]

It's not as easy as that. Take the meat/poultry/milk products industry. In the EU, legislators have done a net-good for humanity by aggressively issuing legislation restricting antibiotics and growth-hormones. This is widely accepted as good for humanity as evidenced in this seminal article[1]. The sword cuts both ways.

[1] http://jac.oxfordjournals.org/content/53/1/28.full

[ceejayoz]

See also: vehicle safety features like airbags, seatbelts, crumple zones, child car seats, safety testing, etc. Collectively, they've helped drop car crash injuries and fatalities enormously.

[djschnei]

Because humans, without regulation, don't value vehicle safety. Gotcha.

See also: https://en.wikipedia.org/wiki/Totalitarianism

[ceejayoz]

> Because humans, without regulation, don't value vehicle safety. Gotcha.

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.

[coldtea]

>Because humans, without regulation, don't value vehicle safety.

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...

[djschnei]

And I can almost guarantee that this has negatively effected the purchasing power of those least well off in the EU. Along with other various detrimental unintended consequences. Which is why, morally, this is wrong through force. If I want to eat growth-hormone free meats, that's my choice. This "net-good" talk is nonsense.

[coldtea]

>And I can almost guarantee that this has negatively effected the purchasing power of those least well off in the EU

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.

[Retric]

All I see when I read that is, it should be my choice to kill hundreds of millions of people. This is about more than say the deaths from say the Holocaust, this is about more lives than where lost in all of WWI and WWIII combined.

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.

[katbyte]

Can you honestly say cheap meat is morally worth the antibiotic resistance and animal cruelty it often leads too? When did cheap meat become a right?

[djschnei]

And, as usual, you are quickly pulled into the straw-man: "well if you don't want government to solve it, than you don't want it solved". I don't want to forcefully deprive the poor of food, that is true. I don't really want to forcefully do anything.

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.

[Mz]

Sigh.

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.

[matt4077]

Sure.

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))

[BurningFrog]

Discussing FDA type regulation you need to consider both costs and benefits. As with everything else, of course.

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.

[matt4077]

Having worked a bit in the industry, changes in regulation aren't actually the main problem. There are two trends combining: some tightening of the rules, yes (although the 'hockey stick phase of regulatory interference' was after WW2) and, much more importantly, a complete collapse of research success.

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).

[Fomite]

We do however have both historical examples of pre-regulation pharmaceuticals and the supplement industry to examine, and neither one is a shining light of efficacy or safety.

[drzaiusapelord]

You can't cherry pick victories and ignore the failures. Hell, I was on Vioxx for a while and now have to worry about heart attacks and strokes more than the average person. Gee thanks FDA!

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.

[gonzo]

> Oh! You never had a chance to get that in the US.

There were 17 "thalidomide babies" born in the US.

[ceejayoz]

We tried that, for centuries.

https://en.wikipedia.org/wiki/Snake_oil https://en.wikipedia.org/wiki/Medicine_show https://en.wikipedia.org/wiki/Patent_medicine

[djschnei]

There is a huge difference between preventing fraud and what we have today, and you know that.

[ceejayoz]

The differences largely result from stuff like that fraud, ethics failures, and other issues we've run into in the past.

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.

[nnf]

No.

[djschnei]

Oh, good.

[baq]

issues with trust re government? who would you suggest to trust then, because i assume free market businessmen aren't trustworthy either?

[jbigelow76]

Theranos approves this message!

[coldtea]

No, every snake oil merchant in the planet wants that too.

[JunkDNA]

You're right about incentives being wrong, but I disagree with the preference for chronic drugs being a primary factor. In my opinion, the primary incentive killer is that agencies like the FDA will not approve a truly new antibiotic for general use. It gets approved as an antibiotic of last resort. So for the time that a new antibiotic is under patent protection, the company can't recoup their R&D because they can only address a tiny part of the market. When the day finally comes when the wonder drug can be standard of care, it's well off patent and generic competition torpedoes any real profit. Why develop a great new antibiotic if the FDA forces you to keep it locked away? From the company perspective it makes no sense.

[pak]

Hmm, well as a counterpoint to your point about the FDA, fidaxomicin was approved in 2011 for general use against C. difficile colitis, because it showed certain outcomes that compared favorably against the current standard of care (oral vancomycin) [1]. The reason it isn't used more often is probably because it is one of the most expensive antibiotics available. Antibiotics aren't typically approved only as "last resort"; it remains at the discretion of the physician to jump straight to the big guns before drug susceptibility test results are available (which is part of the problem).

[1] https://en.wikipedia.org/wiki/Fidaxomicin