by Elizabeth Hofheinz, M.P.H., M.Ed., January 16, 2020
Kenneth Urish, MD, PhD is Associate Medical Director of the Magee Bone and Joint Center and Director of the Arthritis and Arthroplasty Design Laboratory at the University of Pittsburgh.
As an adult reconstructive and arthroplasty orthopedic surgeon, Dr. Urish has married his engineering background with his clinical practice in order to solve real-world problems. He told OSN, “The most intractable problem facing joint replacement surgeons is infection. And the largest surgical procedure by volume is hip and knee replacement…alas, the biggest reason they fail is infection.”
“To tackle this scourge, we divide our work between clinical studies, translational research, and examining how we can improve treatment paradigms.”
In his efforts, Dr. Urish works up against an unavoidable reality: antibiotics are virtually powerless when it comes to removing biofilms from surgical implants.
“While the general notion is that bacteria floats, in fact it binds together and establishes a 3D community of biofilm. Most people think that when you give someone an antibiotic that it kills all of the bacteria. It does not. When I first started my lab, I was blown away that high doses of prolonged antibiotics for more than a day were unable to destroy biofilm. When the bacteria are floating in solution, they are relatively sensitive to antibiotics (99.9%) but when they adhere together and form a community, they become tolerant to antibiotics. You can give an atomic dose of antibiotics for 24 hours and still have 10% of the bacteria remain alive. The fact is that in Gram-positive bacteria, much of the behind-the-scenes workings behind biofilm antibiotic tolerance and infections remain poorly understood.”
For example, says Dr. Urish, penicillin disrupts cell wall synthesis. “If a bacteria is dividing and cefazolin shows up and disrupts the cell walls synthesis then there is no more cell wall—it falls apart. One of the concepts we have been working on is that bacteria inhibit their metabolism as a strategy to protect themselves from antibiotics.”
A new mechanism the his has identified to accomplish this in biofilms are toxin-antitoxin systems. A toxin antitoxin system is a toxin that can stop bacteria metabolism, such as mRNAse, that is locked up by an antitoxin. Dr. Urish: “mRNA is necessary for protein transcription and controlling the entire metabolism of the bacteria. If the bacteria senses stress, then the antitoxin falls off and you have the toxin, here mRNAse, floating around. This enzyme destroys the mRNA, protein translation stops, and the bacteria shuts down. Now it does not matter how much cefazolin is around, there is no metabolic pathway to disrupt. When the cefazolin is cleared, the bacteria can ‘turn back on.’ Although the bacteria do not have any genetic resistance to the antibiotic, a population in the bacteria’s community have effectively created a temporary solution to protect themselves. This behavior is primarily intact only when the bacteria are organized as a biofilm. In contrast, genetic resistance, such as MRSA, have a hard-wired approach that make them completely resistant at all times to cefazolin.”
As for his lab’s translational studies, Dr. Urish explains, “Recently, there have been an absence of new antibiotic classes that have been developed. Most new antibiotics are derivatives of an already-established class. For example, Daptomycin, was the last major new class of antibiotics for gram-positive organisms and was developed in the early 2000s. In our lab, we have shown that a new class of antimicrobials, WLBU2, does an incredible job of eliminating biofilm. I can take a biofilm from an implant and expose it to this compound and in five minutes the implant will be completely sterilized. This is the only non-toxic antimicrobial that can accomplish this as a solitary treatment. Currently, this compound is finishing up Phase I clinical studies.”
Regarding their work on the big picture issue of improving treatment paradigms, Dr. Urish told OSN, “We are taking a hard look at what we are doing now and how can we make improvements, particularly in the realm of antibiotic stewardship. Simplified, there are currently two common ways to treat a joint infection. You can do an irrigation and debridement and save the implant which has a success rate of about 50%. The gold standard treatment is a two-stage exchange where the implants are removed and after roughly three months of treatment the patient undergoes a second surgery to place the new implants. Usually, I do a two-stage exchange, but with the right circumstances I am doing an irrigation and debridement.”
“There is an ongoing debate as to when antibiotics should be terminated and if extended period of antibiotics should be used. Should we do just at six weeks of IV antibiotics or keep the patient on an oral antibiotic for longer periods? My colleague, Neel Shah, and I have done a series of clinical studies asking, ‘Does putting someone on oral antibiotics for an extended period of time result in improved outcomes?’ We found that it does. We also sought to determine if there were differences in side effects from being on antibiotics for longer—it did not. Third, we wanted to know when might be an appropriate time to stop antibiotics. We found that at one year there was no further benefit from these drugs. This improves antibiotic stewardship. Of course, more studies need to be done.”
“The bottom line is that when a physician is with a patient, he or she is thinking solely of that one person.”
