In order to explain phage therapy for recurrent UTIs, and why it may be helpful, it’s best if we start with a question: What are bacteriophages?
Though it may be a creepy thought, our bodies are not just made up of human cells. Our bodies are a world of their own, composed of viruses and an estimated 10,000 species of bacteria.
Our microbiomes help us digest food and absorb nutrients, they produce vitamins and anti-inflammatories, and they are absolutely necessary for our survival. But, like any world, our microbiomes need checks and balances, and this is where bacteriophages come in.
Jump To Section:
- What Is A Bacteriophage? >>>>
- What Is Bacteriophage Therapy? >>>>
- Is Phage Therapy An Alternative to Antibiotics? >>>>
- A Phage Therapy Success – Patti’s Story. >>>>
- How Much Does Phage Therapy Cost? >>>>
- Where Can I Access Phage Therapy For UTI? >>>>
What Is A Bacteriophage?
Bacteriophages, also known as phages, are viruses that infect and destroy specific bacteria. For example, phage VB_EcoS-Golestan has been shown to target E. Coli, one of the most common UTI causing bacteria.
While phages and their fascinatingly sci-fi appearance may be new to many of us, they are actually thought to be the most abundant organism on the planet. They occur naturally throughout the human body, but those in the urinary tract aren’t well understood.
One thing that has been established – bacteriophages do occur in the bladder. How do we know? Well, when a bacterium comes in close contact with their specialized phage, the phage inserts some of its own genome into the bacteria.
When researchers looked at bacteria in the bladder, they found that 86% of bladder bacteria contain some phage genome. This indicates that phages are present in the same environment as their bacterial counterparts – in this case, the bladder.
What Is Bacteriophage Therapy?
Bacteriophage therapy dates way back to 1919, when phages were first used in birds to protect against Salmonella gallinarum. And though discovered almost a century ago, the western research into phage therapy was largely abandoned after penicillin was proven to be an effective antibiotic.
Now, with the rise of antibiotic and multidrug resistance, phage therapy has once again become more popular in western research. In fact, some studies have predicted that all pathogens will have 100% antibiotic resistance in the coming years.
It’s clear that finding alternatives to antibiotics is urgent and necessary, and bacteriophage therapy is a promising prospect.
Phage therapy utilizes the fact that bacteriophages only attack specific species or strains of bacteria. The phages must be isolated from their environment before being given to humans.
One study suggested that the best way to attain clinically relevant phages may be from hospital sewage and wastewater, where there are high concentrations of resistant bacteria. This could provide the best chance of identifying and using phages that are already successfully attacking resistant bacteria.
Watch our interview with a team of US-based phage therapy specialists, to learn more:
How Does Phage Therapy Work?
There are two types of phages: virulent and temperate phages. Phage type is determined by the life cycle phase. Only virulent phages are used in phage therapy and these are in what is known as the lytic cycle.
In the lytic cycle, the phage attaches to the bacteria and inserts its genome. This allows the phage to hijack the bacterial cell, using the cell’s own machinery to create more phages. The produced phages then break out of, or lyse, the cell, killing the bacteria.
The way phages work is pretty spectacular, really. They use the bacterial cell’s own mechanisms to create more phages from inside the bacterial cell, then they break free of the cell, killing it in the process.
The newly produced phages can then go on to infect more of this species of bacteria. The phages will continue to repeat this cycle until there are no further bacteria of this species left to infect, and they will then die out themselves. A particular phage cannot infect other species of bacteria, so the healthy bacteria that make up the microbiome remain untouched.
The other type of phage, temperate phages, use the lysogenic cycle. In the lysogenic cycle, the phage also attaches to the bacteria and inserts its genome. But in the lysogenic cycle, the phage genome remains dormant within the bacterial cell and only creates phages when the right trigger occurs.
In this case, the phage genome becomes incorporated in the bacterial DNA. Some temperate phage genomes may actually offer the bacteria antibiotic resistance. Obviously, this is exactly what treatment is aiming to avoid. For this reason, temperate or lysogenic phages are not used in bacteriophage therapy.
Can Phage Therapy Be Used To Treat UTIs?
Short answer: It seems likely! But it’s important to note that phage therapy is still under research in the U.S. and is not clinically validated. This is primarily due to a lack of randomized control trials.
|“We need modern science to help us understand what the role of phage therapy is, when it’s needed, when it’s safe, how it should be applied. And although we know there are pockets of the world where therapy is being administered, we just don’t have the scientific rigor to understand what’s going on there.”
Though it is not currently a clinically viable option in the U.S., research has demonstrated the effectiveness of various forms of bacteriophage therapy:
1. Monophage Therapy
Monophage therapy refers to the use of a single phage type which attacks a single species of bacteria. This form of therapy may lead to resistance as the bacteria can learn to protect against this one type of phage.
2. Polyphage or Phage Cocktail Therapy
Polyphage or phage cocktail therapy refers to the use of two or more phage types that attack multiple species of bacteria. These have been found to be effective in treating biofilms.
3. Engineered or Genetically Modified Phage Therapy
Engineered or genetically modified phages are phages that are specifically coded to combat multiple drug resistance and biofilms.
4. Phage Therapy Combined with Antibiotic Therapy
Phage therapy in combination with antibiotics may be the most effective use of phages. By breaking up biofilms, phages allow for the deeper penetration of antibiotics.
Is Phage Therapy An Alternative to Antibiotics?
With the growing number of antimicrobial resistant bacterial strains, it is imperative that we find alternatives to antibiotics. According to the World Health Organization, already 60% of pathogenic bacteria are resistant to antibiotics.
Many antibiotics commonly used for UTIs, such as ampicillin, cotrimoxazole, cephalosporins, and amoxicillin, already have strains of bacteria that are resistant to them.
As mentioned above, phage therapy is thought to be most effective when used in combination with antibiotics. However, some studies have looked at the use of phage therapy alone. The most beneficial approach is likely to depend on the specific situation.
Phages, unlike antibiotics, do not destabilize the microbiome. Antibiotics wipe out large swaths of bacteria, leaving vacancies that allow other harmful bacteria to grow disproportionately. This can lead to an imbalance in the microbiome.
On the other hand, with phage therapy, once the bacteria that the phage targets have been killed, the phages have nothing left to attack and will leave the body in the urine or feces. Research has also shown that phages may be able to help stabilize the bacterial metabolism and community structure.
Our interview with a team of US-based phage specialists goes into more detail on phage therapy for recurrent UTI:
How Are Bacteriophages Delivered To The Bladder?
Phage cocktails may be delivered through an IV, and research is even looking into direct application to the bladder. Some studies tested delivering phages orally, however, this method may only be effective with higher dosages.
Phage therapy may be used to offer relief from a number of bacterial infections, but is most commonly used for chronic or recurrent infections of antibiotic resistant bacteria. For example, there has been a recent focus on phage therapy for Pseudomonas aeruginosa infections in those with cystic fibrosis.
How Can Phage Therapy Help Against Persistent Infection?
Persistent or recurrent infections can occur when the antibiotics given to treat a UTI do not wipe out the pathogenic bacteria, allowing it to repopulate once again. In fact, 68% of recurrent UTIs are caused by bacteria identical to the strain that caused the primary infection.
Persistent bacteria can create biofilms which adhere to and invade the bladder lining. After invasion of the bladder lining, some species of bacteria can create reservoirs, which are isolated colonies deeper in the bladder cell layers. These reservoirs are also called Intracellular Bacterial Communities (IBCs).
Once hidden under the surface in biofilms or IBCs, the bacteria are protected from both our immune system and antibiotics. Biofilm structures are 1000 times more resistant to antibiotics than free floating bacteria.
What Can We Do When Biofilms Are Involved?
Phages have been shown to infiltrate biofilms, and when paired with antibiotics, may have a synergistic effect in deconstructing these protected colonies.
Another angle to consider here, is limiting access to the nutrients needed for the construction of biofilms. For example, iron is essential for the processes bacteria use to create biofilms. Limiting access to iron or introducing ions that attract iron and reduce its bioavailability may help in the reduction of biofilms.
A Phage Therapy Success – Patti’s Story
By 2018, Patti’s Klebsiella UTIs had gotten so bad that she had to be on continuous IV antibiotics.
|“None of the antibiotics were killing the bacteria, all they were doing was suppressing it. But, eventually, I got to the point where I felt the antibiotics themselves were killing me.” Patti Swearingen, US, Patient
With her health quickly declining, her family desperately searched for other answers to her seemingly unsolvable UTIs. It was her son who stumbled upon phage therapy.
Although at first reluctant, desperation prompted Patti to seek out help in Tbilisi, Georgia at the Phage Therapy Center. It took 5-6 weeks to make the custom phage cocktail, but once finished, Patti got on a flight from the United States to Georgia (while still on IV antibiotics).
Within 24 hours of arrival, Patti started her two-week phage therapy treatment and began feeling better immediately. Subsequent E. Coli infections that arose in her newly vacated urethra were easily treated with antibiotics. After the E. coli infections were eradicated, she was symptom free for 11 months. Her life, which had been struck into disarray by her deteriorating health, was restored.
Triggered by a traumatic family event, the Klebsiella returned. Between COVID restrictions and the FDA ban on imported phages, Patti has been unable to pursue further phage therapy.
Current phage therapy studies have offered similar success stories for recurrent UTI patients. Access in the U.S. is limited, and if you do manage to be enrolled in a phage therapy study, it will likely take over a year to be administered the phages.
Though phage therapy is a promising treatment option, it requires time, money, and dedication to pursue. Even more importantly, it must be administered correctly. Like any other medical technology, it’s unlikely to be an end all be all treatment. And as with all recurrent UTI treatment options, phage therapy cannot guarantee prolonged health.
How Much Does Phage Therapy Cost?
Although phage therapy is not clinically available in the United States, it may be possible to access on compassionate use terms. Learn more about this in our interview with a US-based phage therapy team:
Some patients opt to travel internationally for phage therapy. The Phage Therapy Center in Georgia offers treatment to patients all around the world for about $3,000-$5,000, depending on the treatment. This cost, however, does not include travel, lodging, or additional expenses for tests on bacterial samples. In Patti’s experience, the total cost for the treatment was $7,000.
Where Can I Access Phage Therapy For UTI?
In our interview with a US-based phage therapy research team, they provided the below lists of phage centers. You can also visit the Phage Directory for information on phage laboratories around the world.
US Phage Centers
- Tailor in Houston, Texas
- CPT in Texas (center for phage technology)
- IPATH – Innovative Phage Applications and Therapeutics (IPATH) at the University of California San Diego School of Medicine
- Mayo Clinic is treating phage patients
- Yale Phage, run by Dr. Paul Turner (focus on Cystic Fibrosis)
Worldwide Phage Centers
- Eliava Institute in Tblisi, Georgia
- Queen Astrid Military Hospital in Brussels, Belgium (provides phage all over Europe and around the world)
- Ludwik Hirszfeld Institute of Immunology and Experimental Therapy in Poland
- Phage Australia (large multicenter phage group associated with Dr. Jon Iredell)
- University of Helsinki (has a large library of phages for therapeutic use)
- Universite de Lyon, France, with Dr. Tristan Ferry
Effective phage therapy treatment requires the specific phage for the infection and, in many cases, infections may be caused by more than one organism.
In order to be treated at the Phage Therapy Center in Tbilisi, Georgia, patients ship bacterial samples to the lab so it can be determined which phage cocktail will be appropriate to treat the infection. Once determined, scientists in the lab create a personalized phage cocktail for the patient.
“Bacterial strains’ sensitivities to antibiotics and phages vary by region. They create the preparations in Georgia for the local region, because they have the most strains there, but if someone from America comes in, there’s about a 60:40 chance their infection is sensitive to these phages, and otherwise they have to make a custom cocktail for them.” Chris Smith, CEO of Phage International Inc.
Ordering phages online may be tempting but should be advised against, particularly if the specific bacterial strain or set of bacteria causing the infection is unknown. Regulations do not allow the shipment of phages into the U.S. once ordered, so it’s best to avoid this practice.
Clinical Trials For Phage Therapy
Another route to phage therapy treatment may be to enroll in a study. The Center for Innovative Phage Applications and Therapeutics (IPATH) at the University of California, San Diego is currently conducting phage therapy trials and research. However, these studies are very exclusive. Participants must pass through rounds of qualifications before acceptance.
In a recent study about IV bacteriophage therapy out of IPATH, each participant needed FDA approval under a single-use IND (Investigational New Drug) application. A successful application required evidence of clinical need, proof of bacterial susceptibility to phages, genetic characterization of phages, lack of lysogenic phage activity, and sterility of the final phage product.
This process is long for both the patient and the researcher, but it is also symbolic of the larger struggle against chronic bacterial infections. Unfortunately, we don’t yet have a quick fix for chronic UTIs, but the research into phage therapy offers hope for non-antibiotic treatment and a respite from those long nights glued to the toilet wishing the pain away.
Other Recurrent UTI Treatment Approaches
Given the complicated nature of recurrent and chronic UTI, there is no single treatment approach that will work for every individual. For this reason, we’ve covered various approaches to recurrent UTI treatment.
Before pursuing a particular treatment path, it’s crucial to identify the root cause of the issue. Lower urinary tract symptoms can be caused by many different conditions that may contribute to infection, or result in infection-like symptoms.
Consulting with a specialist who is familiar with recurrent UTI and the possible causes is often the best place to start. Such a practitioner may recommend more accurate UTI testing or other investigations, depending on the patient’s history and symptoms.