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Comment by HillaryBriss | Hacker News Reader

...for most superbugs, health departments and the US Centers for Disease Control and Prevention (CDC) don’t track who acquires them, nor do they know how many recovered or died. The most recent CDC report estimates that 23,000 people die in the U.S. each year from superbug infections, based on data from 2010. But a recent report estimated that at least 153,000 people died from superbug infections the same year, an estimate that is nearly seven-fold higher. We are allowing most superbugs to maintain their invisibility under the radar, where they are spreading quietly. Unreported. Undetected. And, increasingly, untreatable.

this isn't really scary at all. i'm not scared. are you scared? why be scared?

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Extremely scared, especially in light of barriers to drug approval killing off interest in antibiotics development. Just take a look at what happened to Achaogen: http://www.bioworld.com/perspectives/2019/04/24/a-decade-of-...

The FDA granted Fast Track designation for their antibiotic, only later refuse to approve it for use in bloodstream infections due to quibbling over study size (which was admittedly smaller than it could have been, largely in part due to the Fast Track designation). The antibiotic has been relegated to on-label use for complicated UTIs. Though it can still be used off-label, this isn't enough to attract further investment or keep sales strong enough to sustain ongoing operations. Achaogen was forced to lay off nearly all staff, and is now entering bankruptcy.

Unfortunately, this sort of thing is hardly unique among early stage pharma companies focusing on antibiotics, and it's steering investors away from such companies. It's also driving pharma professionals away.

But they could still get approval in other countries.

Wouldn't have mattered previously, won't matter going forward. The USA is the most important and lucrative market, whether we like it or not.

As I understand it, other countries are not very profitable as pharmaceutical markets, so they probably won't get developed in the first place there.

The point of her article wasn’t to push despair, but rather to urge the Western medical establishment to get moving on phage research.

Bacteriophages as a solution to our antibiotic resistance crisis have been largely ignored in the West due to unpatentability, research mainly performed in Eastern Europe, etc — but her story is that a bacteriophage cocktail saved her husband’s life where antibiotics failed...and the only reason they even were able to go that route was because she’s an epidemiologist who pulled some strings, pulled research teams together, got approvals, and managed the project herself.

So, why isn't government funded research being done on it then? I often hear about how the government funds a lot of medical research, so this seems like the perfect thing for them to fund.

What makes you think they're not?

From the article:

Alternatives to antibiotics are desperately needed.

She's not pushing phage research per se, just research into alternatives generally.

Did you stop reading there, by chance?

Shame on whoever downvoted you. The full last 5 paragraphs are devoted to bacteriophages, which are what ultimately saved the author's husband. The author is "Co-Director of the Center for Innovative Phage Applications and Therapeutics" at UCSD (https://profiles.ucsd.edu/steffanie.strathdee)

It closes on

"The possibility of living in a post-antibiotic era where simple surgeries or scrapes could lead to an infection that requires limb amputation or results in death means we need to improve AMR surveillance, diagnosis and treatment. This includes antibiotics, but should also include phage therapy. We can’t afford to bury a promising alternative to antibiotics for another hundred years."

She is absolutely pushing phage research. Not exclusive to any alternatives, but that is basically the point of the article.

I've heard that phages have a narrow target. They are not broad spectrum like antibiotics. Most of the time you don't know they exact bacteria that is causing the infection and to figure out may take days.

This is the major problem, in my view, with phage. You cannot treat until you've not only diagnosed the infection, but tuned the phage library being used. That's slow, even at major hospitals, and a major problem in places where diagnostic availability is limited.

Having seen her speak in person at IDWeek, I think an important thing to recognize is that the amount of work that went into treating her husband was pretty damned heroic - and it's not clear that that's not the standard for phage therapy.

I literally have a standard "Why phage are a problem", from the perspective of an infectious disease epidemiologist whose been super-interested in phage for like...a decade.

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, 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 tenure-track 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.

Also, I would like to note that phage therapy wasn't only ignored due to unpatentability. A couple other reasons:

1) Antibiotics were superior in basically every respect. It's hard to justify decades of sustaining research into the fussy, expensive, edge-case alternative to something that works amazingly well.

2) Phage therapy was used in the West. Due to the technology at the time, it had a tendency to, well, kill people, due to contamination with bacterial endotoxins.

3) It's not clear phage can be turned into anything other than a pretty bespoke, custom tailored product. Even in the East it's not doable "at scale" in the way we talk about antibiotics.

Are you saying there might be some survivor bias in this article?

Maybe 100 other equally qualified spouses tried equally ambitious programs to save someone, they all died, and we never heard about it...

Not necessarily as much as...

Right now, antibiotics are a point-and-shoot, frontline treatment for things, and phage therapy is a sort of "treatment of last resort" bespoke therapy.

Are phage super-useful for cases like the one in the article, where you have something super-resistant like Acinetobacter? Yes.

Is there much hope, near term, that they'll work as a drop-in replacement for the antibiotics we're losing? No.

Agree!

As the author of the op-ed you are referring to, allow me to chime in. It's true that a huge effort went into saving my husband's life with phage therapy but as a result of that, it's getting easier to treat other cases. I'll comment on your other points too:

1) Broad spectrum phages don't exist in nature but gene-editing techniques can be applied and this technology now exists. Several biotechs are now working in this space.

2) Phages are not hard to keep 'alive'. They need to be refrigerated and kept away from sunlight.

3) True that phage therapy is relatively new in the West but the field is exploding. There are very few pharmas still developing antibiotics and very few in the pipeline, esp for gram-negatives, so there is an imperative to have alternatives to antibiotics.

With an ever-expanding phage library of well characterized phages, it is possible to generate personalized phage cocktails in days. An antibiotic takes a decade to develop, at around a billion $, and has collateral damage on the microbiome. For more on the story, check out ThePerfectPredator.com

For the record, your talk at IDWeek last year was one of the highlights of the conference.

To touch on a few of your points:

1) I'm hopeful about these, and have been sort of idly following them, but I think they're a long way from anywhere close to the utility the average HackerNews reader is hoping to get out of them.

2) When compared to "There's an inert, shelf-and-temperature stable blister pack of these living at the bottom of a bag" they're hard to keep alive.

While not relevant in your husband's case, the vast burden of AMR is going to end up falling on the global poor, and in those cases, solutions that require a cold chain aren't reliable solutions.

3) It is exploding, but I've been following phage research for 15 years now, and it's one of those technologies that has lived in the "any day now" space that whole time. So I tend to try to temper the expectation of folks because I fear that it's going to end up, at best, as a supplemental solution to a very complex problem, rather than the "a new technology will get us out of this" path the popular media sometimes portrays it as.

To me, the really scary thing about antibiotic resistance is not necessarily random infections in the hospital (as bad as that is) but the fact that antibiotics are what made surgery possible, and if they don’t work, all these medical procedures we’ve gotten used to as harmless suddenly carry a very serious risk-reward tradeoff. Imagine C-sections, biopsies, hip replacements, etc. all having a one-in-four chance of death. That’s what we’re heading back to.

For operations, sterilizations are carried out with a mixture of means like chemical disinfectants, subjecting instruments to extreme heat (Autoclaving), etc. but they don't rely on antibiotics. Instruments can be put into environments toxic to both human and bacterial cells. The big difference of antibiotics is that they are toxic to bacteria but not to human cells so they can be put directly into the system. Some bacteria are also developing resistance against chemical disinfectants but here we have a much larger choice.

It's defense in depth.

Yes, sterile technique is used to minimize the occurrence of surgical site infections. Sterile technique, when performed 100% correctly, isn't perfect and prophylactic antibiotics are standard to help mitigate any remaining risk.

Oh, TIL. Thanks for the info! It won't throw us back to the pre-semmelweis era though only to the pre-fleming area.

The field uses "Swiss cheese" as a term for a reason - you can have holes in each layer (and will), but if you have enough layers you'll be okay.

agree. and my next fear is that all of the medical establishment, suppliers, and practitioners who depend upon surgical procedures for their profitability downplay the additional risks and continue to encourage all of us to undergo surgery

Surgeons are already the bane of many infection control specialists.

Not scary at all. This is just life, and we must endure it.

Keep in mind at the same time this is happening we also have to deal with climate change and not blowing ourselves up in all out Nuclear War. And even if we avoid all that you could still step outside and be shot or stabbed by a ruffian who leaves you dead all the same.

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