Joint replacement surgery is common for patients with arthritis or other joint injury and is usually successful in restoring function.
Data have shown that among the more than 1 million patients who undergo these surgeries annually in the United States, a small percentage will develop a periprosthetic joint infection (PJI) — a serious complication.
“PJI results in protracted hospital stays, additional surgeries, and long-term antibiotic courses,” Angela Hewlett MD, MS, professor of infectious diseases and director of the orthopedic infectious diseases service at the University of Nebraska Medical Center, told Healio | Infectious Disease News. “This translates into significant financial burden for patients as well as the health care system.”
According to Hewlett, PJIs remain uncommon, affecting 1% to 2% of patients who undergo primary arthroplasty. The financial burden of these infections is estimated to grow to $1.85 billion by 2030, according to a 2021 study published in the Journal of Arthroplasty.
“While surgical volumes have decreased as a result of the COVID-19 pandemic, it is still predicted that the volume of total joint arthroplasties performed in the U.S. will continue to increase over the coming years,” Hewlett said.
It is thus crucial that specialists in infectious diseases and orthopedics understand these infections and know how to treat them, experts said.
We spoke with Hewlett and other experts about the basics of identifying and treating PJIs and the importance of having ID physicians on the teams that manage these patients.
‘Most dreaded complication’
According to Hewlett, the mortality rate for PJIs is around 24% 5 years after two-stage revision surgery, which is “on-par with many concerning malignancies and other significant medical conditions.”
“PJI is the most dreaded complication of total joint arthroplasty,” Hewlett said.
Despite this, clinicians are not always sure what to look for. Patients with PJIs may present with a range of symptoms and are not always easy to diagnose unless the clinical suspicion is high, according to Poorani Sekar, MD, clinical assistant professor of internal medicine-infectious diseases at the University of Iowa Health Care.
Although it is not an exact science, some patient populations have been identified as being predisposed to PJIs, including older patients, patients with a prior surgery at the site of the prosthesis, patients who are immunocompromised and patients with rheumatoid arthritis, diabetes, poor nutritional status or obesity.
Much like the diversity observed in the patients themselves, PJIs can present in a variety of ways.
“In terms of generalizations, patients with acute infections within 1 month of surgery or less than 3 weeks of symptoms or hematogenous infections may present with fever, erythema, wound warmth, drainage from the incision, significant swelling of the joint, in addition to pain in the joint,” Sekar said.
Hewlett added that patients may present differently “depending on the chronicity of the infection” and the organism responsible. Typically, she explained, patients may have pain, swelling and erythema over the affected joint or systemic illness that might include fever, chills or other signs of sepsis
“Alternatively, patients with longstanding chronic prosthetic joint infections can present with a gradual onset of pain and swelling, which is sometimes very insidious,” Hewlett said. “If the infection is a very chronic one, a sinus tract overlying the joint may be present. Since systemic illness may not accompany these chronic symptoms, patients — and sometimes their physicians — may not interpret their symptoms as infection related, leading to a delay in diagnosis.”
Clinical presentation is often determined by the pathogen, and Hewlett said some of the most common pathogens responsible for PJIs are Staphylococcus aureus, streptococci and gram-negative pathogens.
“More aggressive bacteria, including MRSA, are becoming more common and are difficult to treat,” Paul Maxwell Courtney, MD, associate professor of orthopedic surgery at the Rothman Institute, said.
Sekar said clinicians should be suspicious if patients show problems with healing after surgery — such as drainage for more than 7 to 10 days, “dehiscence of the incision” or “superficial infection occurring at the site of the artificial joint.”
Additionally, patients who continue to have significant pain after a joint replacement or who experience a recurrence of pain after a period should also be monitored closely, especially if there is a sinus tract or if the patient is experiencing loosening of the prosthetic joint or loss of bone on X-ray, Sekar said.
Two approaches
Because diagnosis of a PJI can sometimes be delayed, developing and starting a treatment plan is crucial.
The American Academy of Orthopaedic Surgeons published guidance on diagnosing and preventing PJIs in 2019, but the most recent Infectious Diseases Society of America guidelines on diagnosing and managing the infections were published in 2012.
“They’re out of date,” said Laura Certain, MD, PhD, a clinical assistant professor of internal medicine and adjunct assistant professor of orthopedics at the University of Utah School of Medicine.
Certain noted two major randomized clinical trials that were completed in recent years: OVIVA, which demonstrated that oral antibiotic therapy is noninferior to IV antibiotic therapy when used in the first 6 weeks of treatment for complex bone and joint infections; and DATIPO, which showed that a 6-week course of antibiotics for PJI did not meet the criterion for noninferiority compared with a 12-week course — “a rare instance where shorter is not better,” she said.
The results of both studies were published in The New England Journal of Medicine. The authors of the OVIVA study, which included more than 1,000 adults being treated for a bone or joint infection in the United Kingdom, said their results “challenge a widely accepted standard of care” that includes a prolonged course of IV antibiotics.
“The preference for intravenous antibiotics reflects a broadly held belief that parenteral therapy is inherently superior to oral therapy, a view supported by an influential 1970 article that suggested that ‘… osteomyelitis is rarely controlled without the combination of careful, complete surgical debridement and prolonged (4 to 6 weeks) parenteral antibiotic therapy … .’ However, intravenous therapy is associated with substantial risks, inconvenience, and higher costs than oral therapy,” the authors wrote.
In the DATIPO study, which enrolled more than 400 participants, patients who received the shorter 6-week course of antibiotic therapy not only had nearly twice the rate of persistent infection as patients who received 12 weeks of therapy, they also experienced a higher rate of unfavorable outcomes.”
“This difference in risk seemed to be less marked among the patients who had undergone one-stage or two-stage implant exchange, but this observation remains to be explored in a specific randomized trial,” the authors wrote.
Certain said the two basic approaches to PJI in the United States involve a regimen of debridement, antibiotics and implant retention known as DAIR and a two-stage exchange that starts with removing the prosthesis and cement and replacing it with an antibiotic spacer — “sort of a temporary prosthetic joint that has antibiotic-loaded bone cement in or around it” — followed by a course of antibiotics. The joint is then reimplanted.
“Broadly speaking,” Certain said, “successful treatment requires a combination of surgery and a prolonged course of antibiotics.”
‘A multidisciplinary effort’
The experts interviewed for this story agreed that ID specialists play an important role in caring for patients with PJIs — “an imperative part of the team,” according to Sekar.
“We work very closely with our ID colleagues to manage these complex patients,” Courtney said. “Infectious disease physicians manage the antibiotics and their side effect profiles. We have multidisciplinary meetings with patients and their families to determine the best treatment course for each patient.”
Certain’s clinic at the University of Utah is housed within orthopedics, so that patients with PJIs can see her and their surgeon on the same day. She said the team works together to develop the best plan for the patient.
“Any orthopedic surgeon who has access to an ID physician is likely to enlist their help in managing these infections,” she said. “Certainly at large medical centers, I would say it is standard for the ID team to be involved in the care.”
According to Hewlett, ID clinicians with a special interest in the management of complicated bone and joint infections have become more prevalent over the past few years, resulting in the formation of orthopedic infectious diseases clinical services at multiple hospitals, particularly at tertiary care facilities where the local surgeons receive frequent referrals to manage bone and joint infections.
“The involvement of ID clinicians, particularly those with experience in managing PJI, can certainly be a major asset,” Hewlett said. “This is particularly important because the management of PJI usually involves prolonged courses of antibiotics, and the monitoring of these patients for evidence of residual infection as well as potential adverse events from the antimicrobial therapy is a multidisciplinary effort.”
Hewlett said the involvement of pharmacists, including in outpatient parenteral antimicrobial therapy programs, “is also an integral part of the care of patients with PJI, in order to closely monitor for adverse drug reactions and modify therapy as necessary.”
Complications
Despite dedicated treatment teams, there are complications that may result in an inability to rid patients of an infection or perform revision arthroplasty. According to Hewlett, these include multidrug-resistant organisms, recurring infections and patients declining further surgeries.
“Unfortunately, some patients may require amputation,” she said, adding that other patients with “recalcitrant infections” or those who do not want to undergo further surgeries are sometimes managed with lengthy oral antibiotic courses, with the intent of suppressing the infection rather than curing it.
Courtney said that even in the best studies, the success rate for curing a PJI is only 80%, so the best way to manage them “is to prevent them from occurring in the first place [with] careful sterile technique, medical optimization with patients before surgery [and] meticulous wound closure.”
Although data on prolonged suppressive antibiotic treatment are sparse, one large 2006 study published in Clinical Infectious Diseases found a success rate of approximately 60% for infection suppression in both hip and knee replacements after a single-debridement surgical procedure, 4 weeks of IV antibiotics and prolonged oral antimicrobial treatment.
Researchers found a higher likelihood of treatment failure if the patient had symptoms for a longer period or if a cutaneous sinus tract had formed. Additionally, when the pathogen causing the infection was S. aureus, suppression success was reduced to 22%, whereas streptococci and coagulase-negative staphylococci were successfully suppressed in 92% and 82% of patients, respectively.
However, the suppressive treatment approach is not without risks, and experts agreed that additional data are needed to further evaluate this treatment option.
“People are living longer, and it’s hard telling somebody that they have to be on antibiotics for their entire life,” Certain said. “That can be a long time. If they get their knee replaced at 70 and have a periprosthetic joint infection at 72, we could be looking at another 20 years on antibiotics.”
Additionally, during these years, successful suppression can be a crucial aspect of care because patients who have a history of PJI are more likely to experience recurrence.
“Sometimes recurrence manifests as persistence of the initial infection, but it can also be due to a completely different pathogen, signaling an entirely new infection,” Hewlett said. “The reason behind this is likely multifactorial and is not fully understood.”
Certain said physicians need updated data on prolonged suppressive antibiotic treatment for PJIs.
“Guidelines or more and better data about who needs to be on long-term suppression and who does not are definitely needed,” Certain said.
Additional complications are caused by multidrug-resistant organisms, which “are always concerning, since these infections are difficult to manage and can result in catastrophic consequences like amputation,” Hewlett said. This makes antimicrobial resistance a major concern for PJIs, and newer antibiotics are needed, she said.
Need for new guidelines
In terms of managing PJIs, Hewlett said the “paucity of data in the medical literature, particularly in the form of high-quality studies” is partly due to the low incidence of infection.
“Large, multicenter trials to provide an appropriate number of subjects to achieve statistical power are difficult to accomplish, and scant,” she said. “Large, prospective studies are necessary in order to influence our ability to predict which patients are most likely to develop PJI and how best to clinically manage these complex infections when they occur.”
She said some improvements have been made, however, including establishing evidence-based criteria for diagnosing PJIs and the use of bacteriophages to help manage infections.
A study published in Clinical Infectious Diseases in 2020 described the use of bacteriophages for PJI in a 62-year-old man at the Mayo Clinic with a history of obesity and diabetes who was facing potential amputation after failed courses of antibiotics and surgery following a total knee arthroplasty. As a last resort, his doctors began phage therapy for hardware associated Klebsiella pneumoniae, and it worked.
“A lot of these infections can be pretty recalcitrant,” Certain said. “If phage therapy proved more effective than systemic antibiotics, that would be great.”
Experts hope for more innovations like this moving forward. Courtney suggested that an implant with a material or coating that prevents infection would be ideal “but we are still a long way off.”
Experts agreed that updated guidance is needed for several important topics.
“I would like future guidelines to discuss the utility of newer diagnostic tests, including alpha defensin assays, synovial fluid inflammatory markers, the use of next generation sequencing and PCR assays in the diagnosis of PJI,” Sekar said.
Sekar mentioned that future guidelines should also address the management of culture-negative PJIs and the education of clinicians to help them manage antibiotics.
“If a patient with a prosthesis complains of ongoing pain, infections need to be considered as an etiology and a synovial fluid analysis needs to be performed,” she said. “We need to educate colleagues on not starting antibiotics in clinically stable patients with PJI so that we can get the best chance at identifying a pathogen responsible for PJI.”
Overall, though, Courtney said understanding PJIs well enough to prevent them is the key.
“Benjamin Franklin’s quote ‘An ounce of prevention is worth a pound of cure’ certainly is true with infection,” he said.
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