Summary: Researchers found a positive correlation between glioblastoma cell proliferation and lactate metabolic indicators. Based on this observation, the researchers developed a biomimetic formulation using targeted delivery agents for lactate metabolism-based synergistic therapy against glioblastoma brain cancer.
Source: Chinese Academy of Science
Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. New and effective approaches for GBM treatment are therefore urgently needed.
Based on observation of elevated lactate in resected GBM, researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences and Shenzhen Second People’s Hospital have developed a biomimetic formulation using targeted delivery agents for lactate metabolism-based synergistic therapy against GBM.
The study was published in Nature Communications on July 21.
Targeting lactate metabolism is an attractive tumor therapeutic strategy. However, there are no reports that directly harness lactate metabolism for GBM treatments.
One limitation is the existence of the blood-brain barrier, which prevents most drug molecules (including those interfering with lactate metabolism) from reaching the brain.
Moreover, considering the complexity and infiltrating characteristics of GBM, lactate metabolic monotherapy is very unlikely to effectively eliminate GBM cells. Therefore, it is vital to develop synergistic strategies to enhance the therapeutic efficiency of lactate metabolic therapy.
In this study, the researchers collected glioma samples from a large cohort of patients and quantified the lactate metabolic indicators LDHA and MCT4 and a representative proliferation marker Ki67.
“We observed a positive correlation between lactate metabolic indicators and the extent of glioma proliferation,” said Prof. LI Weiping from Shenzhen Second People’s Hospital. Thus, an efficient metabolism-based synergistic therapy was proposed that would directly harness the elevated lactate in GBM.
The researchers fabricated self-assembly nanoparticles (NPs) composed of hemoglobin (Hb), lactate oxidase (LOX), bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO), and chlorin e6 (Ce6) using a one-pot approach.
They subsequently encapsulated these self-assembled NPs with membrane materials prepared from U251 glioma cells to generate the biomimetic M@HLPC system. This design concept was able to achieve targeted delivery for combination therapy.
“After intravenous injection, the M@HLPC could cross the blood brain barrier via transcytosis sourced from integrin and vascular cell-adhesion-protein-mediated recognition, and then accumulated in GBM through homotypic recognition based on cell-recognition-function-associated proteins,” said Prof. WEI Wei from IPE.
In tumors, LOX in the NPs converted lactate into pyruvic acid and hydrogen peroxide (H2O2). The pyruvic acid inhibited cancer cell growth by blocking histone expression and inducing cell-cycle arrest. In parallel, the H2O2 acted as a local fuel to react with the delivered CPPO to release energy, which could then be used by the co-delivered photosensitizer Ce6 for the generation of cytotoxic singlet oxygen to kill glioma cells.
Preparation of biomimetic formulation and tumor inhibition mechanism. Credit: LU Guihong
Potent therapeutic efficacy was confirmed in both cell-line-derived xenograft and patient-derived xenograft (PDX) tumor models.
“Considering the safety of the formulation and the potent therapeutic effects against the matched PDX model, our personalized biomimetic formulation has the potential to translate to clinical application,” said Prof. MA Guanghui from IPE.
A peer reviewer from Nature Communications said, “The idea of this work is interesting.” Another reviewer emphasized that “a multi-targeting, personalized, smart nanoplatform to tackle glioblastoma multiforme is presented. Rationale is well explained, I indeed appreciate the multi-strategies approach and the biomolecular characterization.”
New research by Georgia State University’s TReNDS Center may lead to early diagnosis of devastating conditions such as Alzheimer’s disease, schizophrenia and autism—in time to help prevent and more easily treat these disorders.
In a new study published in Scientific Reports a team of seven scientists from Georgia State built a sophisticated computer program that was able to comb through massive amounts of brain imaging data and discover novel patterns linked to mental health conditions.
The brain imaging data came from scans using functional magnetic resonance imaging (fMRI), which measures dynamic brain activity by detecting tiny changes in blood flow.
“We built artificial intelligence models to interpret the large amounts of information from fMRI,” said Sergey Plis, associate professor of computer science and neuroscience at Georgia State, and lead author on the study.
He compared this kind of dynamic imaging to a movie—as opposed to a snapshot such as an x-ray or, the more common structural MRI—and noted “the available data is so much larger, so much richer than a blood test or a regular MRI. But that’s the challenge—that huge amount of data is hard to interpret.”
In addition, fMRI’s on these specific conditions are expensive, and not easy to obtain. Using an artificial intelligence model, however, regular fMRI’s can be data mined. And those are available in large numbers.
“There are large datasets available in individuals without a known clinical disorder,” explains Vince Calhoun, Founding Director of the TReNDS Center, and one of the study’s authors. Using these large but unrelated available datasets improved the model’s performance on smaller specific datasets.
“New patterns emerged that we could definitively link to each of the three brain disorders,” Calhoun said.
The AI models were first trained on a dataset including over 10,000 individuals to learn to understand basic fMRI imaging and brain function. The researchers then used multi-site data sets of over 1200 individuals including those with autism spectrum disorder, schizophrenia, and Alzheimer’s disease.
How does it work? It’s a bit like Facebook, YouTube or Amazon learning about you from your online behavior, and beginning to be able to predict future behavior, likes and dislikes. The computer software was even able to home in on the “moment” when the brain imaging data was most likely linked to the mental disorder in question.
To make these findings clinically useful, they will need to be applied before a disorder manifests.
“If we can find markers for and predict Alzheimer’s risk in a 40-year-old,” Calhoun said, “we might be able to do something about it.”
Similarly, if schizophrenia risks can be predicted before there are actual changes in brain structure, there may be ways to offer better or more effective treatments.
“Even if we know from other testing or family history that someone is at risk of a disorder such as Alzheimer’s, we are still unable to predict when exactly it will occur,” Calhoun said.
Similarly, if schizophrenia risks can be predicted before there are actual changes in brain structure, there may be ways to offer better or more effective treatments. Image is in the public domain
“Brain imaging could narrow down that time window, by catching the relevant patterns when they do show up before clinical disease is apparent.”
“The vision is that we collect a large imaging dataset, our AI models pore over it, and show us what they learned about certain disorders,” Plis said. “We are building systems to discover new knowledge we could not discover on our own.”
“Our goal,” said Md Mahfuzur Rahman, first author on the study and a doctoral student in computer science at Georgia State, “is to bridge big worlds and big datasets with small worlds and disease-specific datasets and move towards markers relevant for clinical decisions.”
After an 18-year-old shooter murdered 19 elementary school students and two teachers in Uvalde, Texas, distraught parents directed their rage at the multiple police officers who failed to enter the classroom where children were being shot. A teacher who survived his wounds derided the officers as “cowards.”
It’s possible that a broken chain of command was more consequential than a lack of courage. But the actions – or inaction – of these officers stand in stark contrast to the heroism displayed by others under similar circumstances.
For example, in August 2015, three young American men were on a crowded train heading from Paris to Amsterdam when they encountered a heavily armed terrorist. With little regard for their personal safety, they rushed the terrorist and subdued him. No one disputes that these men deserve to be called heroes.
Only some people seem capable of this split-second form of heroism. What separates them from everyone else?
Psychology researchers like myself have explored this question through the lens of evolutionary and personality psychology. Study after study has shown that men tend to be more willing to put themselves at physical risk to help others.
Why some men rise to the occasion – and others don’t – has been a bit trickier to pin down.
A ‘guy thing’?
The Carnegie Medal is an award given to individuals in the United States or Canada who have valiantly risked their lives in attempts to save others. In 2022, 15 of the 16 Carnegie Medal winners were men.
In my view, this is no coincidence.
Of course, heroism and courage can appear in many forms, and men and women alike risk their reputations, health and social standing to do what they think is right. There is no shortage of courageous women. Meta whistleblower Frances Haugen and the testimony by 26-year-old Cassidy Hutchinson before the House Select Committee to Investigate the January 6 Attack on the United States Capitol are just two recent profiles in female courage.
Throughout human history, attaining a position of high status or dominance among one’s peers has been the ticket that needs to get punched for men to attract mates and father children. Establishing a reputation as a hero isn’t a bad way to quickly elevate your status and desirability.
I am not suggesting that heroes consciously calculate all of the great stuff that will come their way if they risk their lives; they aren’t thinking, “Nothing impresses the ladies like a Legion of Honor Medal!” In fact, interviews with men who have won the Carnegie Medal reveal that their heroic actions were intuitive – even impulsive – rather than a product of thoughtful deliberation.
Conspicuously displaying courage and strength by taking and surviving great risks seems to signal to others that a man has special qualities, so these impulses have been selected for through evolution because heroic action has reliably provided mating advantages for men.
Bravery as a mating strategy
The notion that bravery is intimately linked with mating motives has been around for quite some time. The Sioux warrior Rain in the Face described the effect that the presence of women in a war party had on male warriors: “When there is a woman in the charge, it causes the warriors to vie with one another in displaying their valor.”
I’ve conducted a series of laboratory studies demonstrating that men are most likely to endure pain so that others can benefit when females are present and another male is also present as a competitor.
A team of European psychologists explored the proposition that war provides an arena for men, but not for women, to burnish their heroic credentials and impress both their male rivals and females who might be potential mates.
In their first study, they found that 464 American men who had won the Medal of Honor during World War II eventually had more children than other U.S. servicemen. This is consistent with the hypothesis that heroism gets rewarded with greater reproductive success.
Heroic actions are often intuitive – even impulsive – rather than a product of thoughtful deliberation. Image is in the public domain
In their second study, women rated the sexual attractiveness of men who behaved heroically in war higher than that of other soldiers. Tellingly, women did not find men who had behaved heroically in sports or business to be more attractive. A third study revealed that when female soldiers behaved heroically in war, it didn’t increase their attractiveness to men.
The hero and the … psychopath?
Of course, not everyone will rise to the occasion upon encountering someone in dire need.
Is there such a thing as a heroic personality type?
People tend to have an idea of what heroes are like. In one study, when rating the personalities of movie heroes, participants expected them to be more conscientious, open to experience, extroverted, agreeable and emotionally secure than the average person.
Studies of real-life heroes tell a different story.
However, the study of the relationship between personality and heroism is in its infancy. Psychologists are still at a loss to predict in advance who will heroically step up when needed.
Often, the hero is an otherwise ordinary person who finds himself in extraordinary circumstances, while some individuals who have trained to behave heroically might dither during a crisis, like the armed school resource officer who stayed outside of the high school in Parkland, Florida, while a gunman was on a rampage inside.
Unfortunately, there will be future calamities that cry out for acts of true heroism. Hopefully the right mix of circumstances and personalities enable courage, rather than cowardice, to carry the day.
Personalised medicine seeks to identify individuals who will benefit most (maximal effects and/or minimal risk) from a particular treatment. The use of aspirin in women at high-risk of preterm pre-eclampsia is an excellent example of personalised pre-eclampsia prevention (Rolnik et al. NEJM. 2017;377:613–22). What do we know about other preventative strategies, such as calcium supplementation?
In this issue, Kinshella et al. compared high- (≥1 g/day) and low-dose (<1 g/day) calcium supplementation for pre-eclampsia prevention through a systematic review of 30 randomised controlled trials (RCTs; 20 445 women) and a subsequent network meta-analysis (Kinshella et al. BJOG. 2022). They also extensively explored subgroup effects on baseline calcium intake, pre-eclampsia risk, co-interventions and intervention timing. They found that calcium supplementation, either high- or low-dose, was effective in pre-eclampsia risk reduction (elative risk [RR] 0.49, 95% confidence interval [CI] 0.39–0.61) when baseline calcium intake was low. There was a concern that the risk of HELLP syndrome with calcium supplementation doubled from an absolute risk of 0.2% to 0.4% (RR 2.09, 95% CI 1.09–4.02), highlighting possible adverse effects in pregnancy. Theoretically, excessive calcium causing hypercalcaemia may induce endothelial dysfunction and cardiovascular complications (Reid et al. Endocrinol Metab 2017;32:339–49).
Does this review bring us further towards personalised pre-eclampsia prevention? We need to evaluate the evidence supporting effectiveness, safety as well as personalisation. Effectiveness may be overestimated in view of the presence of small study effects (potential publication bias) and risk of bias arising from 70% of included trials. On the issue of safety, although there was an increased risk of HELLP syndrome, the absolute risk remained low and there was a reduction in severe maternal morbidity (from 6.1% to 5.1%); the authors correctly highlight the lack of evidence on long-term follow-up of pregnant patients. Personalisation centres on baseline calcium intake: to determine an individual’s baseline calcium intake requires tools such as food diaries or recall surveys, and should account for additional therapies, which may alter absorption/bioavailability. Low calcium intake (<900 mg/day) wasn’t always measured in trial participants, with some baseline intakes inferred from other sources, including national averages (Balk et al. Osteoporos Int 2017;28:3315–3324). As a result, differences in treatment effects between low and adequate calcium intake subgroups may reflect systematic differences between settings, instead of true differences in the effectiveness of calcium supplementation.
Calcium absorption is a complex process dependent on dietary protein, fortified foods, oxalates, vitamin D and other micronutrients, including oral iron supplementation. This systematic review is an important step towards individualised patient assessment to tackle this complex clinical problem. Individualised risk assessment to guide aspirin use for pre-eclampsia prevention considers the individual patient compared with a more generalised population. However, baseline dietary calcium intake of the individual is not straightforward, and population measures of calcium intake have significant limitations. Given the significant reduction in pre-eclampsia risk calcium supplementation achieves, the development of clear clinical recommendations accurately to identify those with low baseline calcium intake to support individualised care is imperative for the successful and safe clinical implementation of these findings, given the rare but real concerns of excessive calcium supplementation.
Surgery for bone metastasis has two primary goals—palliative care to relieve pain, instability and paralysis, and tumor resection for curing the disease. Oncologically en bloc resection, followed by a reconstruction of the bone defect is the treatment of choice in single bone metastasis from renal cell carcinoma or thyroid cancer. Bone metastases may occur in the extremities, pelvis, or spine, and different resection and reconstruction methods depend on the regional anatomy. For instance, multiple options are available for reconstruction of the pelvis, especially for the acetabulum, including anatomical reconstruction using custom-made implants or recycled autologous bone grafting when a long-term prognosis is expected. Recently, for the spine, total en bloc spondylectomy is extensively performed despite the initial limitations of surgical invasiveness, such as blood loss. Principally, palliative surgery aims to maintain lasting bony stability with minimal surgical invasiveness. Intramedullary nails and plate fixation are frequently used in the extremities but the postoperative failure rate is relatively high. Therefore, surgeons should consider the use of long intramedullary nails and long-type stems for endoprosthesis reconstruction along with cement fixation to reduce the failure rate. Although short-term complications, such as dislocation, have been observed with endoprosthesis reconstruction, it is stable in the long-term follow-up. Percutaneous bone cement injection into the spine and pelvis is also effective and less invasive.
Atopic dermatitis disease burden is affected by severity and time spent managing the disease, according to a study.
“Our findings highlight that AD is much more than a rash, and has a myriad of negative impacts on patients’ lives, especially those with moderate to severe disease,” Wendy Smith Begolka, MBS, senior vice president of scientific and clinical affairs at the National Eczema Association (NEA) and one of the study’s authors, told Healio. “Second, each individual affected by AD has a unique lived experience. Physical, emotional, social and other elements can variably contribute over time to the patient’s perspective of disease burden.”
Atopic dermatitis disease burden is affected by severity and time spent managing the disease.
Begolka and colleagues conducted an analysis of data collected from a 32-item survey sent through patient advocacy groups, social media and clinicians. More than 1,000 patients with AD responded to the survey, which asked for a rating of overall impact of AD and specific elements of disease burden on an ordinal scale of 1 (no impact) to 5 (significant impact).
Of 1,065 patients, the majority reported having moderate AD (n = 467; 45%) or severe AD (n = 198; 28%), with 845 (80%) reporting their disease was severe when at its worse.
Thirty-two (3%) respondents said their AD had no overall disease burden in the preceding month, while 194 (18%) reported a low impact, 295 (28%) reported a moderate impact and 228 (21%) reported a high impact. Also, 316 (30%) said their AD had a significant impact on their lives.
Higher AD severity was subsequently associated with more disease burden compared with those with mild disease, according to a multivariable proportional odds model.
Additionally, mood changes were also associated with AD severity.
“Overall AD disease burden is not driven by any single disease or quality of life impact, underscoring its complex heterogeneity,” Smith Begolka said. “There is a significant negative effect of AD on the lives of adult patients. … The burden of AD is multidimensional and can be uniquely experienced by affected individuals.”
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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