Treating PJI Biofilms, One Phage at a Time
A comprehensive review of detrimental PJI infections and phage therapy
Picture this: Your family member, a grandparent perhaps, is going into surgery to have a knee replacement, which will finally end their constant knee pain limiting their ability to move and thrive. However after surgery, one that was supposed to allow them to return to their old active life, their knee becomes red and inflamed, and they develop a high fever. After a multitude of tests, it is determined they have PJI, a periprosthetic joint infection, and the only way to possibly treat this infection is through multiple, painful surgical revisions and long-term antibiotics.
This is the painful reality for 2% of patients who have lower extremity arthroplasties (knee + hip replacements), and 4% of those who have revision surgeries.
In this article I will be covering how periprosthetic joint infections are currently being treated and how phage therapy could possibly revolutionize the treatment of these infections.
“Periprosthetic joint infection is the leading cause of failure for knee replacements and the third leading cause for failure in hip replacements, accounting for between 15 and 25% of all revision surgeries” (Kamath et al., 2015)
Periprosthetic Joint Infections + Biofilms
After lower extremity arthroplasties, periprosthetic joint infections (PJI) are one of the most frequent and challenging complications to deal with. Unfortunately, because of our aging society, more of these surgeries are performed every year, resulting in more individuals contracting this hard to treat infection. At this point, many of you may be thinking, “okay this infection can be simply treated with a course of regular antibiotics like most infections”. Unfortunately, this isn’t the case and this is why:
One word: Biofilms. What makes PJI so hard to eradicate is because biofilms form on the surface of the orthopedic implant and surrounding tissue structures which are almost impossible to eradicate with antibiotics. Think of it like a volcano exploding. The lava (PJI bacteria) flows down the volcano and hardens on all surrounding structures around the volcano (the knee joint and prosthetic) making it almost impossible to remove with regular tools (antibiotics).
There are 3 stages to biofilm formation:
- Attachment- When bacteria clumps together forming a community of bacteria heightening their chance for survival. These bacterial clumps excrete an adhesive substance that allows bacterial films (biofilms) to form on any damp structure (in this case, orthopedic implants).
- Growth- Bacteria colonies start producing EPS ( Extracellular Polymeric Substance) which allows them to attach to a surface, trapping nutrients and forming a shield between the biofilm growth and antibiotics. This allows the biofilm to become an impenetrable microcolony.
- Detachment/Dispersal- To further grow the bacterial colonies, the biofilm releases small chunks of bacterial growth to flow through the body and attach to other structures downstream from the original infection site.
Now I am going to expand on why biofilms can’t be treated by a simple round of antibiotics commonly prescribed by your doctor.
Think of biofilm colonies like a mighty fortress that is impenetrable from the outside. No matter the amount of ammunition (antibiotics) you use, this fortress is still standing unaffected by the attempted attack. The main reason biofilms are so resilient is due to EPS (extracellular polymeric substance) which acts as the protector of the biofilm (like a high wall around a fortress) and protects the bacterial colonies inside. It isn’t affected by lack of water, low or high pH, or even antibiotics. Biofilms even produce their own nutrients through organic carbon containing materials, making them almost self-reliant.
This is the scary part of the whole situation… it seems that once you have a biofilm infection, it will never go away. Some patients have even had biofilm infections for a large part of their lives due to how difficult it is to eradicate them even after preventative surgery.
However, there is one last hope for individuals with PJI biofilms: Bacteriophages!
The Bacteriophage- a Short Explanation
Okay so what exactly is a bacteriophage? Well in short, a phage is a virus that replicates within bacteria. Their primary goal is to break down and destroy harmful colonies of bacteria. They are primarily being researched to treat bacterial infections which are antibiotic resistant. Phage cocktails are made to treat specific infections and bacteriophage therapy is considered personalized medicine.
The two main ways phages attack bacteria are through 2 cycles:
The Lytic Cycle: This is when the bacterium is infected by phage DNA, allowing mini phages to grow inside of the cell causing it to explode (lyse) and die. This allows phages to reproduce in large quantities by using the bacteria as a host.
The Lysogenic Cycle: This cycle occurs when a phage infects a bacterium and inserts its DNA into the bacterial chromosome allowing phage DNA (prophage) to be copied and passed down along with the cell’s own DNA.
If you want to learn more about phages, please read my previous article here.
Current Treatment Options for PJI
Let’s explore what treatment options are currently available for this infection and their associated issues.
- Multiple surgical revisions- This revision process usually involves debridement of the joint and removal of the orthopedic prosthetic along with antibiotic treatments. The prosthetic is either replaced during the same surgery, or is replaced after the span of 6 to 12 months depending on the patient’s condition. However, this treatment method can cause a recurrence of infection and definitely isn’t ideal. It can even lead to amputation if the surgery is unsuccessful.
- Long-term anti-microbial treatment- If the infection isn’t as advanced, doctors usually attempt to flush the body with a course of strong, antimicrobial treatments. However, this is usually unsuccessful and surgery is required to attempt to eradicate the infection.
After reading these two options, we can all recognize they definitely aren’t ideal, with both leading to the risk of a recurrence. Surgery is extremely invasive and can cause further damage to surrounding tissues. Antibiotics, if strong enough, can deplete a body of it’s healthy microbiome — which is essential to keep our digestive system healthy — leading to further problems such as permanent digestive issues and infection.
Treating PJI- Bacteriophages Save the Day
So is there a better option? Well we briefly touched upon what a bacteriophage is and how it could possibly be the solution for this significant issue, and now I will expand on the benefits of this future, potential treatment and how bacteriophages can break down biofilms. Clinical trials are currently underway and have shown promise to date.
There are many different routes that phages can take, the main ones include:
- EPS degradation- Bacteriophages have the ability to degrade the extra polymeric substance (EPS) to reach the main bacterial colony that, as mentioned above, is almost impenetrable to antibiotics. They can do this through enzyme production, specifically ones that hydrolyze (break down) the EPS, destroy the capsule of the bacterial cell, and/or destroy the cell wall of the bacteria.
- Amplification- This process involves using a small amount of phages to kill bacteria through lysis replication. Essentially what occurs in this process is that the high number of bacteria relative to the low number of phages causes the phages to increase in quantity within the body. This reduces the bacterial population significantly, and is commonly called active penetration as the phages are penetrating through the biofilms to reach the bacteria inside of the EPS layer. This process allows phages to spread rapidly, attack and eradicate the bacterial colony inside of the EPS.
- Attacking persistent cells- Persistent cells, found in the creation process of biofilm structures, can be targeted by bacteriophages in a way that antibiotics can’t. Although these cells can’t be attacked by prophages (lysogeny), they can be effectively attacked by lytic infection (lysis). When this bacteria changes from a slow to normal growth rate either when they are forming, or re-forming biofilm, phages are able to attack.
Using these routes, bacteriophages can break down biofilms and make the bacteria that still exists on the joint and prosthetic more susceptible to other treatments like antibiotics.
The Actual Process and Potential Future Applications
The process of administering phages is actually quite simple. Once the correct cocktail of bacteriophages is properly prepared, it is administered to the patient either orally through a liquid or powder mixture, or more popularly, injected intravenously into the body.
When phages are injected into the body, studies have shown that they can penetrate deeper into the PJI infection as their numbers are greater than phages that are ingested and have to work their way to the infection site. The two popular methods of intravenous injection are injecting a solution through a vein, or injecting a hydrogel solution directly into an infected joint and implant.
Now you may be thinking, is there a way to use phages as a more preventative measure, rather than a treatment when the infection has already developed? Well this is currently being researched. Since PJI is one of the leading infections associated with joint replacements and biofilms are so common with these infections, scientists and doctors are hoping to coat the prosthetic joint with a phage cocktail before insertion to prevent infection from occurring in the first place. This can either be done through mixing phages with bone cement used during the surgery, or coating the actual joint implant with a thin layer of phages.
Overall, phage therapy could revolutionize the way we treat PJI infections! In an era where we are dealing with an antibiotic resistant bacteria and superbug crisis, this treatment option could save so many from suffering after having joint replacement surgery.
If you are intrigued by this topic, I encourage you to read these medical journals:
The Rationale for Using Bacteriophage to Treat and Prevent Periprosthetic Joint Infections (nih.gov)
Thank you so much for reading and make sure to subscribe to see my future articles! If you want to contact me, feel free to connect with me on Linkedin or email me at: melanieseymour77@gmail.com
I will also be making an in-depth YouTube video on the topic, make sure to subscribe to my channel to get notified when it is released! Melanie Seymour — YouTube
