Bacterial DNA from prosthetic joint infections can be detected in circulating blood and sequenced to identify the bacteria causing the infection, a Hospital for Special Surgery (HSS)-led team of investigators suggests.

The approach has the potential to help doctors treat patients who develop prosthetic joint infections with targeted antibiotics faster than is currently possible with standard lab cultures and monitor infection clearance before conducting revision surgeries, according to their study, published recently in the Journal of Bone & Joint Surgery.

“Our infection rate is significantly below the national average, but prosthetic joint infections are devastating for affected patients. Many do not return to the full potential of their original joint replacement.”

— Mathias P. Bostrom, MD, chief of the Adult Reconstruction and Joint Replacement Service at HSS

Identifying the Bacteria is Essential

It is essential to identify the bacteria causing an infection so that a patient receives the right antibiotic. Since current blood tests only report levels of inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, surgeons typically collect a fluid sample from the joint via needle aspiration. However, standard lab test results take at least 3 days and fail to identify the infectious pathogen in 15% to 20% of cases due to the challenges of growing bacteria in culture. 

When bacterial identification is unknown, surgeons withhold antibiotics until they obtain tissue samples during the implant removal surgery. The removal procedure involves taking out the contaminated implant hardware and infected soft tissue. Surgeons insert a temporary spacer containing high-dose antibiotics, and they may also place antibiotic beads into the joint.

Patients are also treated with high-dose intravenous antibiotics. It takes about 6 weeks to 3 months for an infection to clear before patients can undergo another operation to remove the spacer and receive a new permanent joint implant, a media release from Hospital for Special Surgery explains.

Need to Find a New Way

The idea for finding a new way to improve the diagnostic approach for patients with prosthetic joint infections began with principal investigator Laura Donlin, PhD, co-director of the Derfner Foundation Precision Medicine Laboratory and a member of the arthritis and tissue degeneration program of the HSS Research Institute. She attended a talk by a professor of bioengineering at Stanford University who had analyzed DNA shed from transplanted organs circulating in blood, called cell-free DNA, as an early detection system for transplant rejection. But through genomic sequencing of circulating cell-free DNA, he had also found increased levels of viral cell-free DNA in some patients’ blood indicating they had developed viral infections while taking immunosuppressant medications.

Dr. Donlin wondered if it would be possible to use the same approach to identify bacteria in patients with prosthetic joint infections.

“It was unknown whether bacterial DNA from localized tissue infections around joint implants would be detectable in blood. It’s a challenging environment with many other bits of circulating microbial DNA from skin flora, the gut microbiome and other infections.”

— Laura Donlin, PhD

For their proof-of-concept study, Dr. Donlin together with orthopedic surgeons including Michael P. Cross, MD, and Dr. Bostrom and colleagues at HSS and Weill Cornell Medicine, collected blood samples from 53 patients with known hip or knee prosthetic joint infections beginning in 2018. 

Karius, a genomic insights company based in Redwood City, California, sequenced blood samples collected from patients before treatment for infection and at the time of reimplantation surgery. They compared microbial cell-free DNA in the blood samples to their proprietary database of more than 1,300 known microbial genomes. The HSS investigators compared sequencing findings with results from standard tissue cultures.

Among surgical tissue samples from these 53 patients, traditional lab cultures identified the bacterial species in 35 cases and the bacterial genus in 11 cases, an overall detection rate of 87%. Microbial cell-free DNA sequencing identified the bacterial species in 23 cases in agreement with standard culture results. The new approach also identified the bacterial species in eight cases where cultures identified the bacterial genus only and four cases where cultures failed to determine the presence of bacteria.

On its own, microbial cell-free DNA sequencing pinpointed the bacterial species in 66% of samples. However, as an addition to standard culture results, it increased pathogen detection from 87% to 94% of samples. Microbial cell-free DNA sequencing was 3 days faster reporting the bacterial species for cases where culture results had only identified the bacterial family.

Analyses of follow-up blood samples after joint removal surgery and treatment with antibiotics showed undetectable or reduced bacteria levels, the release continues.

“For most patients, we saw microbial cell-free DNA levels drop below detection, indicating the infections had most likely cleared. But there were some cases with lower yet detectable levels after six weeks of antibiotic treatment. Considering that cell-free DNA lives in the bloodstream for only a few minutes, that meant these patients still had an ongoing infection and might require modification to their antibiotic treatment plan.”

— Laura Donlin, PhD

“An indication that there is an infection, at least to the genus level for samples that fail to show results in standard cultures, will be beneficial for diagnosing and treating patients earlier for improved outcomes. As a monitoring tool, microbial cell-free DNA sequencing has the potential to provide important information on the right time to change or stop antibiotics and for reimplantation surgery.”  

— Mathias P. Bostrom, MD

Donlin and colleagues are improving the sensitivity and specificity of the new diagnostic method in collaboration with Karius and planning a multicenter study to test it on a larger scale.

“In the future, we hope microbial cell-free DNA sequencing will prove to be a useful tool for detecting joint infections more quickly than is currently possible,” Dr. Donlin concludes. “We’re very excited that our innovation may one day translate to improved outcomes for patients.”

[Source(s): Hospital for Special Surgery, PR Newswire]

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