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Taking Aim at Prosthetic Joint Infections
ADULT ORTHOPAEDICS
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Taking Aim at Prosthetic Joint Infections

Basic laboratory research sheds light on the causes of a serious surgical complication
Surgeon-scientist Alberto Carli, MD, speaks about PJI areas of focus at the HSS Complex Joint and Reconstruction Center.

To find better ways to fight the devastating effects of prosthetic joint infections (PJIs), surgeons and scientists at HSS are working together to pursue innovative techniques and research that could broadly benefit all patients with the condition.

“The risk of these infections at HSS is less than 1 percent, but when they do occur they’re a serious problem,” says HSS surgeon-scientist Alberto V. Carli, MD, who specializes in research on how to improve joint-replacement surgeries.

The big challenge in attacking these infections is biofilm, the protective, evolutionary adaptation of bacteria. Once biofilm forms on implants, antibiotics are usually not effective — even at very high doses. The extent of surgery to combat these infections gets more involved the longer the biofilm is on the implant.

The risk of these infections at HSS is less than 1 percent, but when they do occur they’re a serious problem.

For infections that have had a longer time to take hold, complete implant replacement is usually required. Fully eliminating the infection is particularly challenging in those who are infected with more virulent bacterial strains or whose immune systems are weaker — including smokers, the obese, and those with kidney disease or uncontrolled diabetes.

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Hss’s complex joint reconstruction center has identified infection as a major emphasis of research within the arthroplasty service.
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An important tool for tackling infections in prosthetic joints has been developed by Dr. Carli and surgeon-scientist Mathias P. Bostrom, MD, Chief of the Adult Reconstruction and Joint Replacement (ARJR) Service. It’s a mouse model for studying PJIs that employs mice fitted with tiny, 3-D-printed knee implants.

The miniature implants are about the thickness of a shirt pin, but when bacteria are introduced around these artificial joints, they form the same biofilms that are observed in human patients. Dr. Bostrom’s lab is using these models to study a completely new approach to attacking biofilms: an enzyme made by bacteriophages. The enzyme works by lysing the cell walls of the bacteria.

The particular enzyme they are studying, called PlySs2, is being developed in collaboration with Vincent Fischetti, a scientist at The Rockefeller University.

In a recent study, the team showed that in a dish PlySs2 treatment reduced 99 percent more colony-forming units (CFUs) and 75 percent more biofilm compared with the antibiotic vancomycin.

In mice with infected prosthetic knee implants, a combination of vancomycin and PlySs2 delivered locally to the site of infection reduced the number of CFUs on the surface of implants by 92 percent and by 88 percent in the periprosthetic tissue.

a combination of antibiotic and enzyme treatment in infected mice showed:
92%reduction in cfus on the surface of implants
88%reduction in cfus in the periprosthetic tissue

At the 2020 meeting of the Hip Society, Dr. Bostrom and his colleagues received the John Charnley Award, one of the society’s highest honors, for this work. Bacteriophage therapies are also being studied as a treatment for sepsis. The researchers plan to wait until these therapies are approved for sepsis before beginning clinical trials for PJIs.

In the meantime, they’re using these mouse models as research tools to develop other potentially game-changing treatments, including those that can harness the immune system to fight PJI. Immunologist Lionel B. Ivashkiv, MD, Chief Scientific Officer at HSS, is one such investigator collaborating with Drs. Bostrom and Carli to develop potential treatments for PJI by exploring how the immune system responds to these infections.

Watch an animation showing how biofilm forms — and how PlySs2 could provide a more effective alternative to treating it.

“Once we fully understand the immune response to PJI, we hope to develop immunotherapies for treating it,” Dr. Ivashkiv says. “In the same way that cancer immunotherapies activate the immune system to destroy tumors, we’d like to find ways to redirect the immune system to more effectively eradicate infectious microbes around prosthetic joints.” This could apply not only to finding new ways to target biofilms, but also to discovering better ways to eliminate bacteria that have developed resistance to antibiotics.

Dr. Ivashkiv's team uses molecular, cellular and genomic approaches to study immune responses in mouse models of PJI as well as in patients with PJI. Dr. Ivashkiv is also part of a large collaborative team that includes scientists and surgeons from the ARJR Service and the Complex Joint Reconstruction Center, which, under the direction of Thomas P. Sculco, MD, HSS Surgeon-in-Chief Emeritus, has established a translational project utilizing patient samples for research.

once we fully understand the immune system response to pji, we hope to develop immunotherapies for treating it.
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“We’re trying to find out if there are immune cell differences between acute and chronic joint infections,” Dr. Ivashkiv says. “We’re also comparing tissue samples taken when patients have the first part of their revision surgery to tissues taken when they have the reimplantation.”

experts note that until better treatments for pji are developed, prevention and early diagnosis are vitally important.

Dr. Carli also plans to use patient samples in the lab to develop personalized treatments. This research will involve culturing bacterial strains isolated from patients with different types of joint implants and studying potential therapeutic approaches.

Until better treatments for PJI are developed, prevention and early diagnosis remain vitally important. On this front, Laura Donlin, PhD, a member of the David Z. Rosensweig Genomics Research Center and Co-Director of the Derfner Foundation Precision Medicine Laboratory, is exploring the potential of next-generation sequencing (NGS) to effectively and rapidly diagnose PJI before the first symptoms develop. Preliminary data has shown that NGS was able to replicate the accurate detection of pathogens 60 percent of the time. Dr. Donlin is working with orthopaedic surgeon Michael B. Cross, MD, to improve the rate of diagnostic accuracy.

Dr. Carli is also developing a more-accurate risk calculator to determine which patients are most likely to develop infections. Current calculators add up factors like obesity and smoking to determine each individual’s risk. “Unfortunately, these calculators are not very good,” Dr. Carli says. “We’re using our database to develop our own risk calculator, which we think will be more accurate.”

Dr. Bostrom credits the wide-ranging expertise at HSS — as well as its location — for enabling him and his colleagues to develop such an innovative research program. “We have something unique here, including a critical mass of people doing great research,” he notes. “We’re able to partner with investigators all over HSS as well as those working at other institutions that share our neighborhood on the Upper East Side of Manhattan.”

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