Multidisciplinary teams crucial for joint infection treatment

A significant complication following total joint arthroplasty, the reported incidence of periprosthetic joint infection ranges from 1% to 2% depending on the involved joint, according to the published literature.

Although an uncommon complication, Nemandra A. Sandiford, MRCS, FFSEM (RCSI), FRCS (Tr/Orth), and his colleagues noted in an editorial in the Annals of Joint that PJIs can be challenging for surgeons to manage and a physical and mental burden for patients.

Angela Hewlett, MD, MS, professor of infectious diseases and director of the orthopedic infectious diseases service at University of Nebraska Medical Center, said PJI can become a significant financial burden for patients and the health care system due to protracted hospital stays, additional surgeries and long-term antibiotic courses. 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 told Healio/Orthopedics Today.

It is crucial that specialists in orthopedic surgery and infectious diseases understand PJIs and know how to treat these, experts said.

‘Most dreaded complication’

According to Hewlett, the mortality rate for PJIs is about 24% at about 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,” she 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 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 said patients may present differently “depending on the chronicity of the infection” and the organism responsible. She said typically 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 insidious,” Hewlett said. “If the infection is a chronic one, a sinus tract overlying the joint may be present. Because 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.”

Presentation: Beyond pathogen alone

Sometimes PJIs can have a subtle presentation and some patients may not present with any symptoms, which William A. Jiranek, MD, FACS, professor of orthopedic surgery at Duke University School of Medicine, said could be due to indolent bacteria that coexist within the body.

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,” P. Maxwell Courtney, MD, associate professor of orthopedic surgery at Rothman Orthopaedic Institute, told Healio/Orthopedics Today.

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.”

In addition, patients who continue to have significant pain after a TJA 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 radiographs, Sekar said.

Two approaches

Because diagnosis of a PJI can sometimes be delayed, developing and starting a treatment plan are 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 these 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 University of Utah School of Medicine.

Certain said two major randomized clinical trials were completed in recent years: Oral vs. Intravenous Antibiotics for Bone and Joint Infection (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 Duration of Antibiotic Treatment in Prosthetic Joint Infection (DATIPO), which showed that a 6-week course of antibiotics for PJI was not noninferior compared with a 12-week course — “a rare instance where shorter is not better,” she said.

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.

‘An imperative part of the team’

Experts interviewed for this article agreed that ID specialists — “an imperative part of the team,” according to Sekar — play an important role in caring for patients with PJIs.

At Duke University School of Medicine Ortho-ID clinic, orthopedic surgeons and ID specialists see patients together, creating an environment that allows for different perspectives, standardized protocols by consensus and better patient care, Jiranek said.

“What we have shown in medicine, a lot of times, is you get better results with more standardization of treatment. It follows that the aggregate results of management of PJI across the country improves if there is more communication and development of consensus among all members of the treatment team,” Jiranek told Healio/Orthopedics Today.

According to Hewlett, ID clinicians with a special interest in the management of complicated bone and joint infections have recently become more prevalent, resulting in the formation of orthopedic infectious diseases clinical services at multiple hospitals and 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 possible

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 who decline 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 these “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 study from 2006 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 in the study, respectively.

PJI recurrence

However, a suppressive treatment approach is not without risks. Experts said 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 [years old] and have a periprosthetic joint infection at 72 [years old], 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.”

Suppressive antibiotics

Because infection recurrence is a big worry among orthopedic surgeons, Jiranek said he discusses both the chance of infection and the chance of recurrence with his patients undergoing TJR.

“When doing a treatment for an established infection, we have to tell the patient one in five are not going to have a successful outcome,” Jiranek said. “At best, that gives them four-in-five chances, but it is not the excellent results reported for primary arthroplasty, which is why optimizing patients before doing a primary joint is so important. Prevention is the best management of PJI.”

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,” she said.

Additional complications are caused by multidrug-resistant organisms, which “are always concerning, because 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.

Improvements in PJI research

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 use of bacteriophages for PJI in a 62-year-old man with a history of obesity and diabetes who faced 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. It worked.

“A lot of these infections can be recalcitrant,” Certain said. “If phage therapy proved more effective than systemic antibiotics, that would be great.”

Optimization of patient, OR

Experts want more innovations like this. Courtney said use of an implant made of a material or with a coating that prevents infection would be ideal, “but we are still a long way off.”

Jiranek said the ability to cure an infection without having to remove the implant needs to be developed. In the meantime, he said surgeons must not only optimize their patients, but also optimize the operating environment to reduce the risk of infection.

“It follows that decreasing the amount of floating bacteria and decreasing the chance of contamination in the surgical instruments and among the surgical personnel will decrease the chance of nosocomial infections,” Jiranek said.

Need for new guidelines

Sources said 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 said future guidelines should also address the management of culture-negative PJIs , as well as the education of clinicians to help them better 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, understanding PJIs well enough to prevent these is the key, Courtney said. “Benjamin Franklin’s quote ‘An ounce of prevention is worth a pound of cure’ certainly is true with infection,” he said.

Editor's note: On Oct. 19, 2022, a sentence under the subhead “Two approaches” in the above article was corrected to clarify data that researchers found were not noninferior. The editors regret the error.

• References:
• Ahmed SS, et al. Bone Joint Res. 2019;doi:10.1302/2046-3758.812.BJR-2019-0340.
• American Academy of Orthopaedic Surgeons. Diagnosis and prevention of periprosthetic joint infections. https://aaos.org/globalassets/quality-and-practice-resources/pji/diagnosisandpreventionofperiprostheticjointinfections-7-24-19.pdf. Published March 11, 2019. Accessed Aug. 18, 2022.
• Barton CB, et al. J Arthroplasty. 2021;doi:10.1016/j.arth.2019.12.005.
• Bernard L, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa202019.
• Cano EJ, et al. Clin Infect Dis. 2020;doi:10.1093/cid/ciaa705.
• Gausden EB, et al. J Arthroplasty. 2021;doi:10.1016/j.arth.2021.05.010.
• Kim HS, et al. J Korean Med Sci. 2020;doi:10.3346/jkms.2020.35.e410.
• Kremers HM, et al. J Bone Joint Surg Am. 2015;doi:10.2106/JBJS.N.01141.
• Li HK, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1710926.
• Marculescu CE, et al. Clin Infect Dis. 2006;doi:10.1086/499234.
• Phage therapy shows potential for treating prosthetic joint infections. https://newsnetwork.mayoclinic.org/discussion/phage-therapy-shows-potential-for-treating-prosthetic-joint-infections/. Published July 23, 2020. Accessed Aug. 18, 2022.
• Osmon DR, et al. Clin Infect Dis. 2012;doi:10.1093/cid/cis803.
• Premkumar A, et al. J Arthroplasty. 2020;doi:10.1016/j.arth.2020.12.005.
• Sandiford NA, et al. Ann Joint. 2021;doi:10.21037/aoj-2020-pji-11.
• Zardi EM, et al. J Infect Public Health. 2020;doi:10.1016/j.jiph.2020.09.006.

• For more information:
• Laura Certain, MD, PhD, can be reached at 50 North Medical Dr., Salt Lake City, UT 84132; email: laura.certain@hsc.utah.edu.
• P. Maxwell Courtney, MD, can be reached at 925 Chestnut St., Philadelphia, PA 19107; email: paul.courtney@rothmanortho.com.
• Angela Hewlett, MD, MS, can be reached at 985400 Nebraska Medical Center, Omaha, NE 68198; email: alhewlett@unmc.edu.
• William A. Jiranek, MD, FACS, can be reached at 311 Trent Dr., Durham, NC 27710; email: wjiranek@gmail.com.
• Poorani Sekar, MD, can be reached at 200 Hawkins Dr., Iowa City, IA 52242; email: poorani-sekar@uiowa.edu.

Click here to read the Point/Counter to this Cover Story.