don't call it a comeback - I've been here for millions of years

May 21, 2018 9:17 AM

Three months earlier, on the last night of a Thanksgiving vacation in Egypt, Patterson had suddenly fallen ill, so severely that he had to be medevaced to Germany and then to UCSD. There were several things wrong—a gallstone, an abscess in his pancreas—but the core of the problem was an infection with a superbug, a bacterium named Acinetobacter baumannii that was resistant to every antibiotic his medical team tried to treat it with. Patterson had been a burly man, 6-foot-5 and more than 300 pounds, but now he was wasted, his cheekbones jutting through his skin. Intravenous lines snaked into his arms and neck, and tubes to carry away seepage pierced his abdomen. He was delirious and his blood pressure was falling, and the medical staff had sedated him and intubated him to make sure he got the oxygen he needed. He was dying. ... “We are running out of options to save Tom,” she wrote. “What do you think about phage therapy?”

Phage therapy: An alternative to antibiotics in the age of multi-drug resistance, Derek M Lin, Britt Koskella, and Henry C Lin, World J Gastrointest Pharmacol Ther. 2017 Aug 6; 8(3): 162–173.

Phage therapy gets revitalized, Sara Reardon, Nature, 2014

For decades, patients behind the Iron Curtain were denied access to some of the best antibiotics developed in the West. To make do, the Soviet Union invested heavily in the use of bacteriophages — viruses that kill bacteria — to treat infections. Phage therapy is still widely used in Russia, Georgia and Poland, but never took off elsewhere. “This is a virus, and people are afraid of viruses,” says Mzia Kutateladze, who is the head of the scientific council at the Eliava Institute in Tbilisi, which has been studying phages and using them to treat patients for nearly a century.

Phage Therapy—History from Twort and d’Herelle Through Soviet Experience to Current Approaches [PDF], Nina Chanishvili

‘They’re Not a Panacea:’ Phage Therapy in the Soviet Union and Georgia, Anna Kuchment, from The Forgotten Cure, excerpted:

Phages are no magic bullet. Critics point out that they can cause disease as well as cure it. By mingling their own genes with those of bacteria, phages have given rise to some of our deadliest pathogens, including toxin-producing Corynebacterium diphtheriae, which cause diphtheria; and E. coli 0157, which causes severe food poisoning. Proponents counter that they have the technology to screen out these rogue phages. Like antibiotics, phages breed resistance, though isolating a new phage can be faster and cheaper than synthesizing a new antibiotic. Finally, some see phage therapy as a cultish phenomenon backed by weak science. But the current crop of biotech startups is beginning to prove them wrong.

Soviet Doctors Cured Infections With Viruses, and Soon Yours Might Too

A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens, Xavier Wittebole, Sophie De Roock, and Steven M Opal, Virulence. 2014 Jan 1; 5(1): 226–235.

Despite all the advantages summarized above, we are far from describing phages as the “magic bullet” to treat any type of infection. Actually, the optimal dose, route of administration, frequency, and duration of treatment still need to be defined before widespread clinical trials are contemplated.

The major disadvantage of phage therapy is the need to rapidly determine the precise etiological microorganism causing infection with accuracy. The exquisite specificity of phage therapy against specific pathogens is a major advantage, but also a liability. A clinical sample has to be isolated and cultured, using standard microbiology diagnostic procedures, to identify the pathogen before a specific bacteriophage solution may be defined and later on administered to the patient. Innovations in rapid bacterial diagnosis with genomic methods or the use of mass spectroscopy might help. Nonetheless, this is a time consuming process in most clinical microbiology laboratories and in resource-limited health care settings.

Why Bacteriophage Therapy Won't Solve The Problem Of Antibiotic Resistance

In Vitro Characteristics of Phages to Guide ‘Real Life’ Phage Therapy Suitability, Eoghan Casey, Douwe van Sinderen, and Jennifer Mahony, Viruses. 2018 Apr; 10(4): 163.

posted by the man of twists and turns (11 comments total)

The history of development of medicine has been full of "well, let's throw things at it until we find something that works."

I fully support the throwing of more things if the previous things are starting to fail.
posted by delfin at 9:22 AM on May 21, 2018 [4 favorites]

(paging Blasdelb...)
posted by clawsoon at 9:34 AM on May 21, 2018 [8 favorites]

I remember reading about phage therapy in Russia in the 1980s, and it had a tone of "those wacky Soviets" back then, but it sounds like it had been regular practice for many years and nobody had caused a zombie apocalypse by then, so it seemed to me like a reasonable treatment plan.
posted by AzraelBrown at 9:47 AM on May 21, 2018 [1 favorite]

previously
posted by the man of twists and turns at 9:58 AM on May 21, 2018 [1 favorite]

it had been regular practice for many years and nobody had caused a zombie apocalypse by then, so it seemed to me like a reasonable treatment plan.

If a more stodgy and unimaginative one than, say, the T-virus.
posted by Naberius at 10:18 AM on May 21, 2018

I remember learning about phage therapy from Greg Bear's SF, including a little of the history in Georgia. It's nice to read about the real-life implications and context.

The phage resistance is something I have thought to myself before ("surely bacteria could just evolve to resist those too?"); I guess it is a thing after all. So, like monocultures in agriculture, is the only solution to keep diverse options on hand at all times and not rely too heavily on any one thing?
posted by inconstant at 10:50 AM on May 21, 2018

zombie apocalypse

Not zombie apocalypse of people, but rather of the bacterium that phage therapy intended to destroy (see Corynebacterium diphtheriae in the FPP).

Also, see CRISPR - genetic recombination events leading a bacterium to be able to recognize a specific phage/ virus and stop it in its tracks. One genetic recombination anomaly and all of that bacterium's offspring carry that resistance. Of course, it's a two way fight and another phage (through mutations via low fidelity reproduction) may not be susceptible to that particular resistance mechanism (nucleic acid sequence detection and cleavage).

The major problem is that phage therapy requires classical microbiology - sure you can culture all kinds of microbes (bacteria, fungi) from a sick (or even non-sick) person. Then you have to figure out which one of those is causing problems.

Modern molecular techniques such as rapid high throughput sequencing can shorten the amount of time required to identify the microbes, but picking out which one is the problem is... a problem.

Then you have to grow up the microbe of interest - no mean feat. Lots of microbes are difficult to culture outside of a body. Even if you manage that, it can take time for the microbe of interest to multiply to useful quantities.

Then you have to screen that cultured microbe against (in practice, likely many different) panels of phages. This takes time, especially if the microbe of interest grows poorly in culture.

Then you have to wait to see which phage actually inhibits the growth of the microbe of interest. Sometimes you won't get a hit. Or you get several partial hits. Then you have to decide which one to use, or to administer it as a cocktail.

Then you run into problems of getting the phage to where it can actually get to the microbe that's causing problems. In sufficient quantities. In a formulation where your body doesn't break down the phage virions.

All this time, the pathology causing microbe is still in your human subject wrecking shit up.

If you choose the wrong phage (through misidentifing the causal microorganism) one could potentially reduce a non-pathological population that had been competing with (and thus inhibiting the full destructive power) of the actual causative microbe.

--

Phages are cool, phage therapy is a great idea. Implementation is hard.

Phages are also used in antibody discovery (a bit of a misnomer - phage display techniques allow for high throughput production of libraries of "artificial" (recombinant) antibodies) which have very wide range of uses.
posted by porpoise at 10:52 AM on May 21, 2018 [8 favorites]

Kurzgesagt had a really cool video on phages last week. It's a nice explainer if video is your thing.
posted by explosion at 11:07 AM on May 21, 2018 [1 favorite]

Tom Patterson's partner is a friend of mine and so I followed all of the phage drama via her fb at the time. It's really fascinating medical science, as well as a testament to her public health training and persistence.
posted by gingerbeer at 11:51 AM on May 21, 2018 [2 favorites]

In the linked article explaining why Phage Therapy will never work, I really honestly share the dude's frustration with how terrible and almost word for word plagiarized most popular 'science journalism' about phage therapy is. Journalists are rarely ever even aware of genuinely exciting developments and are almost to a person content to just rip off the last article while keeping their thesaurus handy. He is also absolutely right that phages will never be a panacea appropriate to all contexts that antibiotics filled before, but they don't need to be to save lives by the million. The hole being left by antibiotic resistance will be a bigger deal than the all of cancer mortality by 2050, and filling even just a significant part of that hole is worth some investment. It bugs me too just how uncritically phages are always sold to the public by the idiots tasked with telling the public what to think, but this dude clearly doesn't really know enough about the field to meaningfully critique it.

"1. Antibiotics work most of the time. And they are cheap. This means that the market is small (phage would be used only as second- or third-line therapy) and pricing power would be low. There is not much hope of making money in phage therapy."

Sure front line antibiotics are cheap, but secondary and tertiary ones aren't necessarily, and the value of treating an otherwise intractable nosocomial infection can more than pay for the real cost of providing phage treatment in either a pret a porter or sur measure context. Phages won't need to be hoarded like tertiary antibiotics but will still be able to command at least their prices, changing the economic dynamic. This is also ignoring all of the other medical markets phages can fill, like hospital decolonization that have significant economic value. Phages are already being used profitably in food safety applications. If anything, the market is one of the few things that won't be a significant challenge.

"2. Phage are intrinsically narrow spectrum agents. Not only are they restricted to a single bacterial species, but usually to a subset of strains within that species. Dozens of phage strains are thus needed to cover the likely sources of any given infection. The same level of coverage can be attained with 1–2 antibiotics."

Just how wide the host range of phages are is very dependent on both the host clade we're talking about, where genetically homogenous clades like Staphylococcus have phages that infect between 80% to 95% of clinical isolate while diverse clades like coliform bacteria have phages that infect just one serotype or up to 40%. It is also very dependent on how the phage was isolated to begin with and how the phage has been 'trained', where clever microbiologists can select against narrow host range phages and we've been playing with expanded host range mutants since the '40s. Companies, at least well advised ones, are really talking about cocktails of one to four phages max, not dozens. The relevant limitation isn't really the work involved in isolating and characterizing lots of phages, but in producing each phage as an Active Pharmaceutical Ingredient to a purity that will remain safe even when they're all mixed together.

"3. Phage are cleared rapidly from the bloodstream and provoke a response from the immune system. Using them for a systemic infection would be challenging, and you couldn’t use them a second time on a patient."

I see this quoted as gospel, or some other kind of received truth, all the time; but never with citations. While the relationship between phages and the human immune system still has a lot of fascinating and important mysteries to it, we have regularly seen reasonable persistence in both tissues and the gut since Dubos' observation more than half a century ago, at least when the bacterial hosts remain present. Phage propagation appears to generally be more than capable of outrunning innate immune clearance, at least when the conditions are right, but most applications being explored don't involve counting on it anyway. The idea for most applications is that when enough phage are applied they'll encounter enough of the bacteria in the wound to kill them before the adaptive immune system encounters them, particularly in the kinds of wound systems where the immune system isn't particularly present anyway. While the reasons why are still unclear, phages in general appear to be a lot less immunogenic that you'd think based on theory for routes of administration from topical to intravenous, and phages can be evolved to avoid immune surveillance at all through serial passage.

"4. The phage efficacy data from Russia and elsewhere are crap. Just because a lot of treated patients get better, as most phage “clinical trials” purport, means absolutely nothing. Most infections resolve even without treatment. Placebo-controlled antibiotic trials are rarely done now, due to ethical concerns. But trials from the 1930s and 1940s show 40–80% resolution of infections in the control arm.

5. Let’s agree that supportive care (these were mostly pneumonia patients) is much better now, so that these numbers are lower bounds. A convincing demonstration of efficacy requires very careful trial design, and no one has come close to meeting a modern standard of proof with phage therapy."

We are not currently trying to treat standard pneumonia, but the bugs phage therapy is being pitted against now are for the most part intractable chronic infections that have persisted in patients for the months to years it took them to access phage therapy. There are a lot of microbiological contexts where historical controls have real value, but this dude hasn't really seen our most relevant problem. There are a number of well designed trials being conducted now, like this one that I am very excited to see unblinded, but if anything the bigger more fundamental limitation is in protocol design and physician experience. It doesn't matter how good the phages are or how well designed the trial is if physicians don't have a good idea of how to use them.

"6. Phage therapy is technically feasible, but probably only for certain applications, like diabetic foot ulcers and ear infections. If someone can figure out how to make the economics attractive, it could definitely happen. But it is never going to be a significant alternative to antibiotics, or a solution to the resistance crisis."

I appreciate that he approves of my work and the excellent stuff happening in Novosibirsk, diabetic ulcers really are the perfect model system for this, but what makes it particularly attractive to us is how adapted it is to productive and ethical experimentation. That is not the goal though, ESKAPE pathogens especially absolutely do have a market for phage therapy, and the economics of it absolutely do make sense once we as a global community get the scientific, regulatory, and medical challenges solved.
posted by Blasdelb at 12:51 PM on May 21, 2018 [25 favorites]

inconstant: "The phage resistance is something I have thought to myself before ("surely bacteria could just evolve to resist those too?"); I guess it is a thing after all. So, like monocultures in agriculture, is the only solution to keep diverse options on hand at all times and not rely too heavily on any one thing?"

This is the subject of an expert opinion statement we just published last month. Phage resistance evolves quite readily. In fact it is pretty trivial to select for phage resistant mutants in a lab environment, and depending on the phage and host generally arises in one in every 10^6 to 10^9 cells exposed to phage predation. At least in a lab environment, these mutations almost always involve simply losing the cell surface receptor that the phage binds to and usually carries a meaningful fitness cost. Oddly enough these fitness costs are often relevant for virulence suggesting that it might not be as big of a deal in vivo as it is in vitro.

Although some implausibly claim that phages will adapt to resistant mutants in vivo, the real big advantage of phages antibiotics with regards to resistance in the long term is that there will always be new phages to isolate by dangling phage-resistant mutants in front of sewage and we can always generate expanded host range mutants in vitro.
posted by Blasdelb at 1:27 PM on May 21, 2018 [9 favorites]