Bacteriophages — viruses that target and kill bacteria — were one of the most promising medical treatments of the early 20th century, and were used to treat all sorts of infections, from cholera to staph, and everything in between. But by the 1950s, they had all but died out in the West. This episode tells the story of the humble phage, from its discovery in the waters of the Ganges, love trysts ending in a KGB execution, and to a resurgence of this once forgotten therapy in the 21st century as an answer to antibiotic resistance.

Sources:

• Abedon ST, Bacteriophage prehistory: Is or is not Hankin, 1896, a phage reference? Bacteriophage. 2011 May-Jun; 1(3): 174–178.
• Blair JE and Williams REO, “Phage Typing of Staphylococci,” Bull Org mond. Ste, 1961, 24, 771-784.
• Davis BM and Waldor MK, Filamentous phages linked to virulence of Vibrio cholera, Current Opinion in Microbiology 2003, 6:35-42.
• d’Herelle F, “Bacteriophage as a treatment in acute medical and surgical infections,” Bull N Y Acad Med. 1931 May; 7(5): 329–348.
• d’Herelle F.  Sur un microbe invisible antagoniste des baccilles dysenteriques.  CR Acad Sci Paris 1917,163,173-5.
• Eaton MD, Bayne-Jones S. Bacteriophage Therapy. JAMA 1934; 103:1769-76; 1847-53; 1934-9.
• Fruciano DE and Bourne S, Phage as an antimicrobial agent: d’Herelle’s heretical theories and their role in the decline of phage prophylaxis in the West, Can J Infect Dis Med Microbiol. 2007 Jan; 18(1): 19–26
• Hankin EH.  L’action bactericide des eaux de la Jumna at du Gange sur le vibrion du cholere. Ann Int Pasteur (Paris) 1896,10,511-23.
• Himmelweit F. Combined action of penicillin and bacteriophage on Staphylococci. Lancet. 1945;ii:104.
• Hicks DJ et al, “Developments in rabies vaccines,” Clin Exp Immunol. 2012 Sep; 169(3): 199–204.
• Kingwell K, Bacteriophage therapies re-enter clinical trials, Nature, Vol 14, Aug 2015, 515.
• Jensen MA et al, Modeling the role of bacteriophage in the control of cholera outbreaks, Proc Natl Acad Sci U S A. 2006 Mar 21; 103(12): 4652–4657.
• Hargreaves KR and Clokie MRJ, Clostridium difficile phages: still difficult? Front Microbiol. 2014 Apr 28;5:184.
• La Fee S and Buschman H, Novel Phage Therapy Saves Patient with Multidrug-Resistant Bacterial Infection. Retrieved from: https://health.ucsd.edu/news/releases/Pages/2017-04-25-novel-phage-therapy-saves-patient-with-multidrug-resistant-bacterial-infection.aspx
• Leitner L et al, Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 2017 Sep 26;17(1):90.
• Pearce J, Louis Pasteur and Rabies: a brief note, Journal of Neurology, Neurosurgery & Psychiatry 2002;73:82.
• Schooley et al, Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant acinetobacter baumannii infection. Antimicrobial Agent and Chemotherapy, 14 Aug 2017.
• Strathdee S, How Sewage Saved My Husband’s Life from a Superbug, TEDxNashville, retrieved from: https://www.youtube.com/watch?v=AbAZU8FqzX4.
• Summers WC, Bacteriophage Therapy, Annual Review of Microbiology, Vol. 55:437-451 (Volume publication date October 2001)
• Summers WC, The strange history of phage therapy. Bacteriophage. 2012 Apr 1; 2(2): 130–133.
• Taylor M.W. (2014) Introduction: A Short History of Virology. In: Viruses and Man: A History of Interactions. Springer, Cham
• Thiel, K. (2004). Old dogma, new tricks—21st Century phage therapy. Nature Biotechnology, 22(1), 31–36.
• Twort FW, An investigation on the nature of Ultra-Microscopic Viruses, The Lancet, Jan 10th, 1914. 101.
• Wittebole X et al, A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence. 2014 Jan 1; 5(1): 226–235.
• Ujmajuridze et al, Adapted Bacteriophages for Treating Urinary Tract Infections. Front Microbiol. 2018; 9: 1832.
• Ventola CL, “The Antibiotic Resistance Crisis: Part 1: Causes and Threats,” P T. 2015 Apr; 40(4): 277–283.

Transcript

This is Adam Rodman, and you’re listening to Bedside Rounds, a monthly podcast on the weird, wonderful, and intensely human stories that have shaped modern medicine, brought to you in partnership with the American College of Physicians. If you are a member of the ACP, you can get CME/MOC points for listening to this episode by going to www.acponline.org/BedsideRounds.This episode is called “The Phage,” and it’s about one of the great missed opportunities of 20th century medicine — the discovery of bacteria-destroying viruses called bacteriophages that were used to treat infections in the days before antibiotics, and about how scientific squabbles and Cold War politics conspired to end research in the West, at least until the past decade or so. Along the way, I’m going to talk about the holy waters of the Ganges, a controversial treatment for rabies, the origins of our understanding of the immune system, love trysts ending in a KGB execution, and a possible way to avoid the oncoming tide of antibiotic resistance. That’s all a lot for one podcast host to tackle, so I’m joined by my friend and colleague Dr. Andy Hale, who first told me about bacteriophage therapy while we were eating lobster and drinking beer at the Mount Desert Island Laboratory in Maine where we spent a week recreating classic medical science experiments. And yes, I know, my life is absurdly difficult. Anyway, first, an introduction, to both Andy and bacteriophages:

16: I am Andy Hale, I’m an infectious disease doctor at the University of Vermont …

I’m a hobbyist in evolutionary medicine and comparative medicine (330).

How did you become interested?

So I learned about htem as an infectious disease fellow. One of those moments where I completey dove into the rabbit hole. 

57: The history of them is fascinating. It’s a whole other approach to treating infection that we’ve totally forgotten about. So many tidbits that are promising. Tempting to think about possibility for patients going forward.

And what are bacteriopohages?

Literally means a “bacteria eater”. This is a virus that infects and kills bacteria.

How does it do it?

Are extraordinarily diverise. Likely millions and millions. And each would be unique.

2:06 If you think of the tree of life, by far the most diverse is bacteria. SUCH A SMALL SLICE OF LIFE. If you were a virus, the opoprtunity to infect is much higher. Probably millions and billions more than infect bacteria.

How old are bacteriopages? 2:40

I think whether you can call a virus a living organism is a matter of debate. But prokaryotic cells, precurosors to bacteria, came around a billion year ago. Eukaryotes 1.8. I would suspect soon after te advent of the prokaryotes 3 billion years ago. 

We’ll zoom a couple billion years forward to the official beginning of human contact with bacteriophages, with the mystery of the Ganges River. The Ganges, or Ganga, River starts high in the Himalayas, coursing 2,500 kilometers through the Indian subcontinent. Along with the Tigris and Euphrates in the Middle East, and the Indus to the West, the Ganges has nurtured the beginnings of human civilization. Cities, and later Empires have flourished on its fertile floodplain. With its long history, the Ganges has become interwoven with Hinduism. Its water purify, not only spiritually, but physically. Akbar the Great, the polymath who ruled the Mughal Empire at its height, would only drink water from the Ganges, and insisted on bringing with him as he traveled. He called it the “water of immortality”. Hundreds of years later, as another empire carved up the subcontinent, the British East India company insisted on only using water from the Ganges for the three month trips back to England as it stayed “sweet and fresh.”

By the late 19th century, water from the Ganges had become a fascination for science. It was generally understood by this time that the great cholera outbreaks that had burnt their way across the globe in the nineteenth century had their origin in the Ganges river basin, yet the water was renowned for its cleanliness. In 1896, Ernest Hankin was a British bacteriologist — a new field, as bacteria had only been discovered two decades prior — working for the British Colonial government. While testing the waters from the Ganges and the Yamuna (or Jumna) River, he discovered that something in the water appeared quite remarkable — when added to cultures of cholera, it eviscerated the bacteria. Clear spots would appear in the culture, eventually overtaking all the microorganisms. When he poured the river water through Chamberland filters — millopore filters made of diatomaceous earth, the glassy remains of tiny creatures making it impossible for bacteria to pass through — the killing effect remained. But when he boiled the water, it would no longer kill cholera. So there must be something smaller than a bacteria in the water of the Ganges that was able to kill cholera — but that was disabled by heat. Hankin had no idea what this was, but published his results in the Annals of the Pasteur Institute — in French, notably for a British scientist. 

Hankin had no idea what he had stumbled on. How could he have? The last few episodes of Bedside Rounds have been microbiology heavy so I’ll do a quick review. Koch’s discovery of the anthrax bacillus in 1876 had caused a true paradigm shift in medicine. It’s remarkable, if you think about it. In 1875, there was still active debate on whether tuberculosis was hereditary, or caused by the rebreathed air in crowded cities. The Yellow Jack that decimated the Caribbean and Southern U.S. was blamed on noxious smells coming from the docks. Cholera too was treated with quicklime in the streets, or by perversely draining human excrement into drinking water, with the thought that these foul smells caused the disease. 

Less than a generation later, tuberculosis was shown to be caused by a difficult-to-grow rod shaped bacteria, cholera by a small comma, erysipelas by small chains of spherical bacteria called streptococcus. The implications for physicians was enormous. Treating foul odors? Clearing the docks? Pushing waste into drinking water? A waste of time at best, and possibly incredibly harmful. Bacteria were living creatures, and anything that was alive could be killed. New medicines could be identified that could specifically target bacteria. No matter that nothing existed yet; the practice of medicine had fundamentally shifted almost overnight. A new field was born — bacteriology, of which Hankin was an early practitioner.

Almost as soon as anthrax had been identified, scientists began to work on clever ways to kill bacteria. The first was stumbled upon by chance. Louis Pasteur at this point was famous in the scientific community for his work on disproving spontaneous generation of life, and for helping to popularize germ theory, and also for his prickly temperament and secrecy which led to well-publicized feuds with the likes of Robert Koch. But he had not yet achieved worldwide fame, to the point that there are over 2,000 streets named after him in France alone. Pasteur was working with chicken cholera, which required repeated inoculations of the bacteria into the hapless chickens. However, his assistant, Charles Chamberland — who had invented the filter that Hankin used of the Ganges river water — had left a culture sample out prior to going on holiday. When he returned, the chickens were inoculated — and they showed only a very mild form of the disease. Pasteur then gave them a fresh culture, which had slaughtered flocks of chickens prior, but these chickens did not become sick. Pasteur immediately realized what had happened — he had created an attenuated bacteria. It was weak, too weak to cause serious disease, but still strong enough to cause the host to be immune. Just like Edward Jenner and smallpox a century before, Pasteur had stumbled upon a way to protect humans from infectious disease. He set to work trying to adapt this to protect humans, and not just animals. Pasteur ultimately decided to work on developing a rabies vaccine. Why rabies? Today rabies is exceedingly rare in high-income countries, and was decreasing in frequency even in the late 19th century as standards of living increased across Europe. But Pasteur was interested in rabies because of the incredibly long lag between inoculation by animal bite, and developing symptoms — almost a month, and sometimes even longer. This would give plentiful time for a rabies treatment to work. 

Pasteur developed a method of serially infecting dogs and rabbits with rabies, then removing their spinal cords, drying them out, and using that material to infect other animals, hoping that this process would select for a weaker organism. After five years of experimenting by this process, he had developed a live concoction that could protect against the disease in dogs. But in the process of working on his treatment, he had discovered some odd fact about rabies. It was clearly infectious, and could transfer between organisms. But nothing was ever grown in culture, and nothing was seen under the microscope. This wasn’t too odd in and of itself; many bacteria were notoriously difficult to culture. But when a solution of rabies was passed through one of Chamberland’s filters, it still could cause the disease. We now know that is because rabies is caused by a virus — the rabies lyssavirus, far too small for the filter to stop. Ultimately, this “filterable agent,” as he called it, didn’t bother Pasteur much. He had greater things to worry about. In 1885, a nine year-old boy named Joseph Meister was attacked by a rabid dog. His desperate parents had brought him to Paris. On July 6th, 1885, Pasteur — a chemist by training, mind you, not a doctor — and two physicians gave the boy the “Pasteur treatment”. And it worked — the boy never developed rabies. Pasteur decided to honor Jenner and call this new treatment “vaccination” — remember that vaccination comes from the root word cow, and prior to this only referred for inoculation with cowpox (or sometimes horsepox) to protect from smallpox. Within a decade, vaccines had been introduced for diphtheria and plague. Pasteur, who had placed himself at legal liability by treating Meister, was now honored as a world-wide hero. The Pasteur Institute was started in his honor, with Pasteur at its head. And his method of vaccination went on to save countless human lives. It’s almost understandable that the mystery of what rabies actually WAS fell to the wayside. 

Therefore, it was the plant pathologists, and not doctors, who would first discover viruses. Tobacco mosaic disease is a big deal in parts of the world that grow tobacco, like my home state of North Carolina, and causes crop loss even today. It causes mottling on the plants before it kills them — hence the “mosaic.” In 1890, Adolf Mayer used sap from an infected plant to infect healthy plants.  Tobacco mosaic disease must be infectious! But he was unable to culture any organism or see anything under the microscope. Like Pasteur and rabies a few years before, this didn’t bother him much. In 1892, Ivanovski repeated these experiments and found that, like rabies, it was filterable — it was not blocked by a Chamberland filter. But he too assumed that it was either just really hard to grow bacteria, like TB, or a spore former, like anthrax. Finally, Martinus Beijerink put these observations together and realized that tobacco mosaic disease was actually caused by something fundamentally new to science — a “contagious living fluid.” He opted for a catchier name than contagious living fluid — “virus,” from the word poison in Latin. In 1897, Friedrick Loeffler, who had worked closely with Koch, repeated this methodology with foot and mouth disease in cattle, and realized that like tobacco mosaic disease, it too was caused by a virus. Soon after, it was speculated that yellow fever was caused by a virus, and by the early 20th century it was generally accepted that there was a mysterious sort of infectious disease called a virus, far smaller than bacteria. 

With that context, it’s clear why Hankin had no idea what he was observing. This mysterious killer of cholera that lived in the water of the Ganges would be discovered twenty years later, independently by two different scientists. 

The first was a British microbiologist named Frederick Twort. In 1915, he was working with micrococci and the vaccinia virus, the virus thought responsible for vaccination. He discovered glassy lesions in some of his micrococcus cultures — areas of bacteria that were spontaneously dying and lysing. Curious, he experimented, and realized that he could transfer this glassiness to other cultures, where it would cause the same problem. He passed the glassiness through a Chamberland filter, and it retained its killing ability. He called this a “transmissible glassy transformation”. He had no idea what he had discovered — he thought it might be a fermentation factor secreted by the bacteria for some unknown reason. He didn’t investigate further, and hadn’t realized the significance of what he had discovered.

That would fall to Felix d’Herelle, who independently made the same discovery the next year. d’Herelle was a French self-trained scientist, with quite an interesting backstory himself. He only had a high school education, and had largely taught himself science. An adventurer at heart, he decided to study fermentation and traipsed across Central and South America when he was young. He had a strong affinity for what we today would call LMIC, and spent much of his life either working in them, or trying to improve health in them. He was also something of a superfan of Louis Pasteur, and tried to model his life on the famous scientist. At first, he studied fermentation, just like Pasteur had. By 1916, d’Herelle had returned to Paris and took an unpaid job at the Pasteur Institute — literally a single stool at a lab table. He was studying the stool from patients who had recovered from bacillary dysentery, a form of bloody diarrhea caused by the Shigella bacillus. He noted that if he added the stool from a cured patient to a pure culture of Shigella, the culture would initially appear cloudy, turbid with the bacteria. But over the period of several hours it would gradually become glassy and then clear up, until all the bacteria had been destroyed — “dissolved” as he put it. Was this not the same phenomenon that had been observed in the Ganges decades before? That had been observed by Twort the year before? d’Herelle repeated the process, taking this new liquid, and inoculating it again into a culture of dysentery. The bacteria died ever more quickly this time. He could cross-inoculate as many times as he wanted, and the killing power never went away. In fact, even infinitesimally small amounts of this factor would still enjoy the same amount of killing. d’Herelle called this new discovery a “bacteriophage” — bacteria eater. 

Unlike Twort, d.Herelle immediately recognized the significance of what he had discovered. He had discovered an “ultramicroscopic” being that secreted a ferment used to kill bacteria. It must be alive. Out of necessity, he wrote, it must be one of these mysterious viruses, a virus that preyed on bacteria. And if the bacteriopage killed deadly bacteria in culture — might it not also kill bacteria inside the body? d’Hererelle came to believe that bacteriophages might actually be the cause of recovery in patients, that they played an important in why some people were more resistant to different organisms and recovered faster. 

d’Herelle knew what he had to do. He started with chicken typhus, using the same method to isolate a chicken typhus bacteriophage. He then used this phage to successfully treat chickens infected with the disease, who recovered at a higher rate. It was time for human trials. He first tested his dysentery phages on himself and his family, and with no ill effects he used them to treat patients suffered from high grade dysentery. He reported the dramatic results: ““In all cases, without exception, all of the morbid symptoms disappeared within a few hours, from 4-20 according to the case, and the next day the patient was definitely convalescent.

It is 1919, and there are very few effective treatments for infectious disease. Salvarsan, the first chemotherapeutic agent, had started to be used for syphilis and other infections, and pyrotherapy, including malariotherapy, was routinely used as well. Both of these, as you can imagine, were risky and with high mortality. So a safe, effective treatment for bacterial infections should be viewed as a panacea, right? That, of course, is not what happened. Almost immediately, attacks on bacteriophage therapy started. 

d’Herelle’s heretical beliefs about bacteriophages certainly didn’t help. He became convinced that bacteriophages were a fundamental part of both recovery from an illness, as well as lasting immunity. Administration of phages appeared to confer lasting immunity in his experiments. The recently described cellular and humoral immune system, he argued, were only part of the picture. He argued, “Immunity, far from being the cause of recovery, is a consequence of recovery”. He pointed to statistics from India, where the lowest mortality rate from cholera — 27% — was in the poor hospital, while the Campbell Hospital, sanitary and clean for the rich, had the highest rate of mortality at 86%. The lack of sanitation in the poor hospital, he argued, was what accounted for the lower mortality rate — while it allowed for faster spread of the disease, it also allowed for faster spread of bacteriophages.

The attacks came swiftly, mostly from the “Belgian Group,” associated the Jules Bordet. Bordet was the head of the Pasteur Institute in Brussels, and had just won the Nobel Prize in 1919. Bordetella pertussis, the organism that causes whooping cough, is named in his honor. This Belgian Group was especially affronted at d’Herelle’s claims about the immune system. Their experiments, many on animals, had begun to show a complicated system of immunity. Since the late nineteenth century, it had been shown that the body contained two types of cells, then called macrophages and microphages, that enveloped and destroyed bacteria. But by the turn of the 20th century, things became even stranger — the body appeared to have a non-cellular defense mechanism, with antibodies, complement, and opsonins. In fact, Bordet had won his nobel for working of the role of complement. This new understanding of this second immune system — which these researchers playfully called humoral, referencing old ideas about essential body fluids — had already paid huge dividends by 1919 — especially in allowing for blood typing and the first blood transfusions.  

That immunity might be primarily due to a virus was anathema to this emerging view of the immune system. They argued instead that bacteriophages did not exist — they were most certainly not viruses, and were probably an anomalous enzyme from the bacteria themselves. While we know today that this is wrong, at least this was a generally scientific argument.  But their most effective argument was also the most unfair — they accused d’Herelle of viciously stealing the credit for bacteriophages from Twort. Modern historiography has shown that d’Herelle actually went out of his way to give credit not only  to Twort but also to Hankin and his Ganges water. It appears that this line of attack probably came not because of actual concern of d’Herelle stealing Twort’s ideas, but because Twort himself had advocated a view more similar to the Belgian Group. In any event, these attacks seemed to work, and every medical textbook of the day agreed with the Belgian Group — bacteriophages were certainly not viruses, played no part in recovery or immunity, and were abberancies made by the bacteria themselves. And who was d’Herelle to fight back? He was a volunteer at the Pasteur Institute. His laboratory assistants were his wife and two children. It didn’t help that he had a very “unscientific” flamboyant personality, and was given to argumentation — he called Bordet’s work a “monstrosity.” And he was an outsider — self-taught in an era where institutions began to dominate science. This hostility from the medical establishment, and the Pasteur Institute in particular, would last his entire life.

Undaunted, d’Herelle returned to perfecting bacteriophage therapy. He quickly discovered that there were bacteriophages to every bacteria that he studied — little armies ready to do battle against essentially every human pathogen, and even in bacteria that only affected plants. Throughout the 1920s, he criss-crossed the world, experimenting on new phage treatments. He started in Brazil, where he claimed 10,000 successful treatments of dysentery, and only 2 failures. He repeated this in Sudan, where he wrote, “the results of treatment of bacillary dysentery with it have been little short of miraculous”.  Other trials started to trickle in. In India, a trial was performed in cholera patients. The mortality among the control group was 63%; in the bacteriophage group mortality was only 8.1%. In a prevention trial in Bihar, India, cholera bacteriophage was introduced directly into the drinking water in some villages, with the standard of care in the others. Cholera season came, and in the control group the average length of the epidemic was 26 days; in the phage group, less than 48 hours. Similar, though small, studies were repeated with bubonic plague, with plague phage injected directly into the bubae.  

With results like these, doctors started to take notice. Raiga reported a young woman who presented with puerperal fever after giving birth, a notorious and deadly infection of the vulnerable post-partum uterus, caused usually by streptococcus. She was given the standard of care — septicemine and pyroformine, both toxic anti-infective drugs, and transfusion of serum from patients who had survived streptococcus. But all these failed and she developed the dreaded pyemia — seeding of bacteria across the body. This would have been a death sentence even a few years earlier. However, this time, the desperate attending physician requested Dr. Raiga try phage therapy. He gave an IV infusion of streptococcus bacteriophage, and while she clinically improved, she continued to have fevers, and positive blood cultures. He then directly injected the bacteriophage into her phlegmonous abscesses throughout her body. With this, her fever lowered, her cultures cleared, and within two months she had made a full recovery. 

Drug companies responded in kind, and by the 1930s the biggest drug companies in the world — Parke-Davis, Lilly, Abbott and Squibb in the U.S., and Robert and Carrière in Europe — were producing and marketing not only individual bacteriophages, but blended cocktails for different infections. The could be sprayed directly in the throat or inhaled in the case of pneumonia. They had caught the popular imagination as well. Phage therapy plays a major part in the Pulitzer Award-winning novel Arrowsmith by Sinclair Lewis, where the protagonist uses them to cure the plague on a fictional Caribbean island. And when the actress Elizabeth Taylor was in London filming Cleopatra, she developed a serious pneumonia and required an emergency tracheostomy. At the request of her doctors, staphylococcal bacteriophage was flown directly from Philadelphia to London, and the actress recovered. 

d’Herelle felt vindicated. The high school graduate was awarded an honorary doctorate from the University of Leiden, given a professorship at Yale, and awarded the Leeuwenhoek medal — the same medal that Pasteur himself had received decades before. And he was nominated for the Nobel Prize at total of 28 times, though he never won. And yet, by the early 1950s, phage therapy had pretty much died out in the West. So why don’t I treated MRSA sepsis with a staphylococcal bacteriophage lysate today? There are probably a couple of reasons.

The first — the evidence on the whole wasn’t that great. The American Medical Association performed three systematic reviews on the therapy — the first in 1934, the last in 1945. Randomized controlled trials did not exist yet, and the studies, while many had controls, were small and of varying quality. This review found the evidence mixed at best — with the most convincing evidence in the treatment of staph and strep skin infections, and in urinary tract infections. And the despite popular support, the medical community as a whole still mostly treated d’Herelle as a heretic. Despite the evidence, the first two AMA reviews were hostile to even the idea that bacteriophages might be viruses; it took the first electron microscopy pictures from late 1930s to change their minds.

The second reason was its competition. Sulfa drugs were introduced in the 1930s, and the 1940s saw penicillin and the introduction of effective antibiotics. These medications were incredibly effective, and changed the prognosis of many diseases basically overnight. They were also far easier to manufacture and give — penicillin could be reconstituted and given directly into the muscle. By contrast, a living phage cocktail had to be brewed in an industrial laboratory in vats full of bacteria, filtered, and then maintained with refrigeration. In a world still dominated by the individual practitioner, antibiotics had an obvious allure.  And viruses were, for lack of a better word, creepy. Look at those EM photos of phages, which I’ve posted to my Twitter. They look like some sort of six-legged mechanical killing machine from War of the Worlds, not quite alive, yet not quite non-living. Penicillin, with its chemical promise of swift death for bacteria, was far preferred in the popular imagination. 

And yet, even with the advent of penicillin there was no reason to think that phages couldn’t also work with antibiotics. Resistance to penicillin emerged even before the drug was commercially available, and in 1945 Hemmelweit developed a cross-administration of penicillin and phage that greatly decreased resistant strains. 

No, what likely killed bacteriophage therapy in the West was the politics of the Cold War. While d’Herelle had an almost religious following in some quarters, he had tired of the constant fighting. In the 1920s, he had become friends with a young Georgian doctor named George Eliava, who had started a research institute in Tbilisi. In 1934, he turned down a post at Yale and instead accepted a Soviet offer to start a phage research program. He jumped at the opportunity to work with his old friend again, and he had a natural affinity for communism. He built a cottage of the grounds of the Tbilisi Institute and planned to move his family to Georgia.. The honeymoon period wouldn’t last long. The handsome Eliava ran afoul of the secret police — apparently they were both in love with the same woman. Eliava was executed, d’Herelle was denounced, his book he had published in the Soviet Union was banned, and he returned to France shortly before the beginning of World War II. d’Herelle’s story doesn’t end well either — France soon fell to the Nazis, and he was placed under house arrest by the Vichy government for the remainder of the war, and died a broken and forgotten man in 1949. 

Even with the execution of Eliava, phage therapy continued unabated in the Soviet Union — penicillin in particular was not immediately available in the USSR, and even when it was, it was in small quantities. In fact, there’s some evidence that the Germans had conquered Georgia for the express purpose of taking over the Tbilisi Institute’s phage production capacities, and vials of Tbilisi phage were standard issue for Rommel’s forces in North Africa. After World War 2, phage therapy in particular became associated with “pink” ideas, and was rejected out of hand in the United States. In the Soviet Union, research into bacteriophages continued unabated, and phage products are used to this day. Tbilisi is still the center of research, since renamed the Eliava Institute since the fall of the Soviet Union. Thousands of articles have been published in Georgian and Russian. Phages from Eliava were even used in a promising randomized-controlled trial in cholera in 1960 in what was then called East Pakistan. But in the West, phage therapy more or less completely died out, barely an afterthought in medical textbooks.

Until, of course, the last few decades. What happened? In brief, antibiotics have stopped working. As I mentioned earlier, penicillin resistance in staphylococcus was noted even before penicillin began to be commercially used, and by the 1950s resistance had become commonplace and there was a panic that antibiotics might no longer work. But new penicillin-derivative antibiotics were developed. Over the next several decades there was a cat and mouse game played between drug companies and antibiotics, and medicine seemed to have the upper hand on our bacterial foes. But since the late 1980s, fewer and fewer new antibiotic classes were developed. The reasons for this are complicated — clearly antibiotics have been overly and inappropriately prescribed, which has fueled resistance. And not only the Z-pak given to people with a cold; up to 30-60% of antibiotics used in ICUs are unnecessary or inappropriate. But that’s just the tip of the iceberg. 80% of antibiotics in the US are given to animals in the food supply. Not only do these antibiotics pass to us, they also wash off and affect resistance in the environmental microbiome. And finally, drug companies have largely abandoned antibiotic development — the drugs are used for short periods of time, and patients are often cured. From the perspective of drug companies, why not invest developing drugs for chronic conditions, which patients will take for the rest of their lives?

With these factors, multidrug organisms have started to pop up pretty much everywhere. There’s methcillin-resistant staph aureus, or MRSA, of course, and vancomycin resistant enterococcus, or VRE. A sobering statistic — 75 years after the introduction of penicillin, MRSA still kills almost 20,000 people in the U.S. a year. But in recent years, we’ve started to see resistant C. diff, pseudomonas, gonorrhea, salmonella, and shigella — and that’s not even mentioning the drug resistant tuberculosis that is again rearing its head in dark corners of the world.

Andy takes the big picture view of antibiotic resistance.

If you step back and look at current state of antibiotics and antibiotic resistance. It has been 70 years since we came out with penicillin. If you look at the arc of human history is nothing. Where are we gonna be in 100 years to antibiotics? The rate of resistance is happening so much faster than the rate of antibiotic discovery. We absolutely need novel ways to treat infection. 

I asked Andy what a modern example of bacteriophage therapy would even look like. 

Scenario? 605

So many examples. One would be where antibiotics frankly don’t work. Certain types of bacteria that are pan-resistnat. Gonorrhea species, acinetobacter spies. Antibiotics are poorly active at best. Pts need alternative therapies.

2) There are a lot scenarios where antibiotics work, but not terribly well. Long therapy, toxic, without a high chance of success. Say MRSA infection. 6 weeks IV, and long course orals. Having adjuvant therapy would be incredible.

What would it look like today? 722  

A bit hard to speculate. In an ideal scenario would be a rpoduct we give like any other drug. Be in the pharmacy and just give it. In some scenarios, adjuvant, others standalone. We need to built the evidence base; it’s premature. 

But just like in the 30s, sometimes terrible individual patient scenarios have driven experimentation with phages before an evidence base has been built. In 2015, a 69 year-old man developed severe abdominal pain, fevers, and vomiting while on a vacation in Egypt. He was medevaced, first to Germany, then to UCSD, and a scan showed necrotizing pancreatitis with a pancreatic pseudocyst. The fluid was drained, and it grew a resistant organism called Acinetobacter baumanii. He was treated with multiple courses of antibiotics, and had multiple attempts to drain the cyst. But he worsened and developed septic shock, and slipped into a coma. He was intubated in the ICU, on three different pressors to maintain his blood pressure with worsening kidney and liver failure. His desperate team had sent isolates of his antibiotic-resistant bacteria to phage libraries across the United States, and they several hits, including one isolated from sewage. The FDA granted  emergency approval to try phage therapy, and the team infused this personalized phage cocktail directly into his blood, and into the cavities filled with acinetobacter pus. And it worked — three days later he awoke from his coma, his pressors were weaned, his kidney and liver improved. Bacteriophages had to be continued for eight weeks — but at the end of all of this, he discharged home, and returned to work. His wife gave an excellent TED Talk, and I’ve linked to this and some articles about this case in the shownotes. It’s an amazing turnaround, and a life saved — but what I find most remarkable about this case is that the story is basically the same as Dr. Raiga’s patient with strep pyemia for puerperal fever 80 years before. 

We’re coming up on the 100 year anniversary of bacteriophage therapy, when Felix d’Herelle and his family ingested cholera phage to see if it was safe and then subsequently used it to treat dysentery. But it’s used in only a few countries in the world. That seems to be changing. There are considerable problems to instituting phage therapy. I asked Andy about some of the regulatory challenges: 

10:45: challenges to bringing phage therapy into the 21st century. 

No expert in FDA regulatory approval process. Phages are very selective — not a single s. Aureus, but so a single subtype. Need to make cocktails of phages — 5 or 6, or even dozens. The current FDA approval process requires proof of safety and efficacy of every component.

But we’re at the point that we can start to imagine what 21st century bacteriophage therapy and research would look like. I asked Andy what future studies might look like.

Four avenues I think that phage therapy can be used for.

1 — used for MDR or pan drug resistant bacteria. Horribly resistant gram negative, antibiotics alone versus abx + phage therapy. Pan resistnant gonorrhea that’s going on, that would be an obvious place to try and do a phage therapy.

2 — when antibiotics don’t work well XDR or MDR TB. Even something as simple as an orthopedic hardware infection, where patients are looking if the metal remains in the body. Monts to years of antibiotics. Great to see a trial.

3 — Opportunity to bioengineer phages. Turn genes on or off. Manipulate bacteria in ways that we want.

4 — These viruses iunteract with and kill bacteria in specific ways, and each one does it in its own way. Whcih means there are targets, and these bacterial cellular targets might be ways to make new antibiotics and chemicals, with new enzymes. Use those proteins as biologics that would also be antibacterials. A protein-based antibiotic is nots omething that exists right now, but a potential unlimited source. Probably be easier to approve in the current FDA pathways.

1840 — ask the question again — what attracted both of us to this story is that the science is exciting, but there’s been a 70 year, lag, potentially costing millions of lives. And what lessons do you and I take?>

The years to come will show us what phage therapy can offer. If phage therapy really bears fruit in terms of good therapies for patients, it’s a lesson of humilty and hubris for Western medicine, where phage therapy became a sort of Eastern European, this is not how we do things in the West. Keeping an open mind with nonstandard therapies going forward. With the caveat that we need to robust science.

The science is happening, even if its slowly. But every year bacteria become more and more resistant to our antibiotics. d’Herelle, it seems, was just ahead of his time.

Well, that’s it for the episode! If you’re interested, keep listening after the credits, because Andy and I continue our discussion by talking about the role of bacteriophage in the cholera outbreaks of the nineteenth century, and how humanity might just be collateral damage in a long-running war between cholera and bacteriophages. But first — it’s time for #AdamAnswers!

#AdamAnswers is the section on the show where I answer whatever questions you have about medicine, no matter what they are. But this episode, since Andy was kind enough to be asked random infectious disease questions without having time to prepare, I asked my listeners for contributions to the first ever #AndyAnswers.

Okay, that’s really it for the show! I especially want to thank Andy — this entire episode was his idea. I’d give his Twitter handle, but he’s not really much of a Tweeter. And I want to put a plug in for the course Physiology on the Fly, held at Mount Desert Island Biological Laboratory in Maine. Andy teaches a course there on comparative and evolutionary biology, and he and I got to talking about bacteriophages over beer and lobsters — apparently he has the MDI record for most lobsters eaten in one sitting. So basically I got to spend a week recreating classic physiology experiments, hiking in Acadia National Park, eating delicious food, and hanging out with some amazing people. I can’t recommend the course enough, and the 2019 registration is open if you’re interested. The website is https://mdibl.org/course/physiology-on-the-fly-2019/ (also posted to Twitter so don’t worry), or you can send a message on Twitter to Dan Ricotta @DanRicotta. And just so you know, listeners, this is not a paid advertisement, I really had that good a time, though I also suffer from the bias that the people who run the course are my friends and colleagues. 

If you’re an ACP member, you can get CME or MOC credit for listening to this episode. Just go to www.acponline.org/BedsideRounds, or click the link in the shownotes. The website is www.bedside-rounds.org; I’m also on facebook at /BedsideRounds. You can listen to all the episodes on iTunes, Spotify, Stitcher, or the podcast retrieval method of your choice. Come find me on Twitter @AdamRodmanMD! I Tweet frequently about medical history and evidence-based medicine.

All the sources in the shownotes.

And finally, while I am actually a doctor and I don’t just play one on the internet, this podcast is intended to be purely for entertainment and informational purposes, and should not be construed as medical advice. If you have any medical concerns, please see your primary care provider.