By Dr Kyle H. Cichos and Dr Wilhelm Paulander

This review examines periprosthetic joint infection (PJI) detection, highlighting the limitations of traditional methods and introducing isothermal microcalorimetry (IMC) as an innovative tool. IMC offers rapid, sensitive PJI detection, overcoming the challenges of culture-based and molecular diagnostics. Its potential applications in real-time monitoring, treatment efficacy, and research signify a potentially significant advancement in PJI management.

Introduction

Periprosthetic joint infection (PJI) represents one of the more challenging complications in orthopedic surgery, with profound implications for patient health and the health-care system. PJI occurs when bacteria or fungi infect the space around a joint prosthesis, leading to severe complications that often require complex and costly treatment strategies.

The diagnosis of PJI is particularly challenging owing to its varied and often ambiguous clinical presentation that at times can be misidentified with aseptic implant loosening. Symptoms can range from acute inflammation to chronic pain and joint stiffness, making early detection difficult [1]. This diagnostic challenge is compounded by the diverse range of microorganisms that can cause PJI, including antibiotic-resistant strains, and the presence of biofilms that shield bacteria from detection, treatment and an effective immune response aimed at eradicating the infection.

Moreover, the treatment of PJI is complex and multifaceted, often requiring a combination of surgical intervention and prolonged antimicrobial therapy [2]. The choice of treatment depends on several factors, including the type of pathogen, chronicity of detection (acute versus chronic), the duration of infection and prior interventions, and the patient’s overall health status. In cases where the implant must be removed, patients face a significant burden, including potentially multiple surgeries, prolonged hospital stays, and a lengthy recovery period [2].

PJI also poses a significant financial burden on health-care systems owing to the high cost of treatment, including expensive surgical procedures and long-term antibiotic therapy making the mean cost of PJI treatment over USD17 000 per case [3].

The rise of antibiotic resistance further compounds the challenges of PJI. The frequent use of antibiotics in these infections likely contributes to the development of resistant bacterial strains, complicating treatment and potentially  leading to poorer outcomes.

PJIs pose significant challenges for diagnosis, treatment, patient care, and health-care economics. Addressing these challenges requires a multidisciplinary approach, integrating advances in diagnostic techniques, surgical methods, antimicrobial therapies, and antibiotic stewardship. Current methods for PJI diagnosis  and detection

The current gold standard for diagnosis of PJI is multifaceted based on multiple diagnostic criteria [4,5,6], all of which centre around culture-based phenotypic detection of the microorganisms causing the infection. Additionally, many include molecularbased methods using serum and synovial biomarkers, although DNA-based methods targeting the infecting microorganism can complement detection in the cases of culture-negative PJI.

Prosthetic knee replacement (Shutterstock.com)

Culture-based methods

Culturing synovial fluid joint aspirate or periprosthetic tissue samples is the current method of choice to isolate, speciate and test antibiotic susceptibility of microorganisms causing PJI. However, culture-based methods can be limited by long incubation duration (up to 5 days for aerobic incubation and up to 14 days’ incubation for anaerobic cultures) and up to 20% culture-negative results [7,8], potentially due to sensitivity for growth inhibitory effects from prior antibiotic exposure, sampling inadequacies, and difficult-to-culture organisms. Despite these limitations, conventional culture methods remain a fundamental diagnostic tool for identifying the causative micro-organisms and determining their antibiotic susceptibility [9,10].

Molecular methods

Molecular techniques are based on the detection and identification of the infecting microorganism’s DNA. The DNA-based methods [such as 16S rRNA sequencing assays, multiplex PCR and next-generation sequencing (NGS)] have emerged as valuable tools for rapid diagnosis of PJI, currently with a specific application in helping resolve culture-negative cases. 16S rRNA and multiplex PCR can detect and identify bacterial DNA directly from clinical samples, offering a rapid  and highly sensitive alternative to culture-based methods. It is particularly useful for identifying slow-growing, difficult-to-culture, or previously antibiotic-treated organisms. NGS, on the other hand, provides more comprehensive data on the microbial community within a sample, including rare and novel pathogens, and can add information on identified antibiotic resistance markers. These methods offer enhanced sensitivity, reducing the rate of false negatives associated with traditional culture methods. However, a large problem with the amplification of very low levels of DNA is poor specificity, causing them to detect contaminating or colonizing organisms, leading to – in some cases – false-positive results while not fully resolving the culture-negative issue [11,12].

Despite advances in molecular diagnostics, culture-based methods continue to play a crucial role in the standard diagnostic algorithm for PJI. The combination of both approaches provides a more comprehensive understanding of the infecting organisms and their antibiotic susceptibilities, which is critical for effective treatment.

Challenges with current methods

Detecting PJIs presents several challenges, both for culture-based and molecular methods.

Culture-based methods

Culture-based methods are time consuming, requiring several days to weeks for bacteria to grow leading to delays in diagnosis and appropriate antibiotic treatment. The sensitivity of culture-based methods is also lower than molecular methods, causing up to 20% false-negative cultures, while also being prone to contamination resulting in false positives [7,8].

Molecular methods

PJIs can be caused by a wide variety of microorganisms including bacteria and fungi. Molecular methods need to be broad enough to capture the diversity of potential causes. However, most molecular methods require specific probes to increase sensitivity, meaning that true broad detection cannot be achieved. That said, multiplexing molecular methods can alleviate this to some extent [11].

Molecular methods detect molecular components of microbes that may not be alive and able to cause harm to the patient. Detecting nucleic acids from dead or contaminating commensal bacteria would lead to a false-positive test result, leading to interventions and treatments that are unnecessary. Molecular methods are also so diverse that standardization between methods and labs is not trivial [13].

Prosthetic hip joint (Shutterstock.com)

Most molecular methods are either quite costly or require significant technical expertise to run. This can limit access to these molecular methods in some health-care settings. A high level of technical expertise is also often needed to interpret the results – distinguishing colonization from infection – that can be very difficult with commensal organisms also capable of being pathogens, such as Cutibacterium acnes and Staphylococcus epidermidis. Furthermore, advances in our understanding of the microbiome continue daily, but we do not currently have enough data to comment on the native microbiome of the joint space – to whatever extent it exists – and how that may impact interpretation of molecular test results [14,15].

Both culture-based and molecular methods have their respective strengths and limitations. Culture methods are time-tested and provide information on antibiotic susceptibility but are slow and may miss some pathogens. Molecular methods are faster and more sensitive but can be expensive and require careful interpretation to distinguish between colonization versus true infection and will not give an antibiotic susceptibility answer, only resistance marker identification. Addressing these challenges is crucial for improving the accuracy and timeliness of PJI diagnosis.

Isothermal microcalorimetry:

a new technique for PJI diagnosis Isothermal microcalorimetry (IMC) is an emerging technique for the detection of PJIs, offering a novel approach to overcome some of the limitations associated with traditional culture-based and molecular methods [16,17].

IMC measures the heat produced by chemical processes in real time. In the context of PJI, it detects the metabolic activity of microorganisms present in joint fluid or tissue samples (Fig. 1). One of the key advantages of IMC is its ability to provide results within a few hours to a couple of days, significantly faster than conventional culture methods. The technique can detect low levels of bacterial metabolic activity, which also makes it highly sensitive. This is particularly beneficial in detecting infections caused by slow-growing or fastidious organisms [17].

There are several features of IMC that make it well suited for the detection of PJI. First, the rapid time-to-detection results in earlier detection of PJI, allowing timely intervention and treatment (Fig. 1). IMC can also detect the metabolic activity of bacteria within biofilms, which are often resistant to traditional culture methods and are present in PJIs as bacteria colonize implanted materials. IMC can further be used alongside other diagnostic methods, adding a valuable dimension to the diagnostic toolkit for PJIs. IMC is a relatively simple method that can detect metabolism in complex samples. No prior information needed, meaning that designing specific probes is not required which reduces the bias during the detection process. However, if molecular techniques also need to be used, the non-destructive nature of IMC allows for many other diagnostic tests to be performed on the same sample [17].

As with other growth-based assays, IMC can also be used for rapid antimicrobial susceptibility testing which is crucial for effective treatment of PJI.

Figure 1. Thermogram from Staphylococcus aureus The dashed line indicates when early detection is possible. The unique shape of the curve allows for speciation of the pathogen in many cases.

Applications for IMC in PJI diagnosis

IMC has several promising applications in the detection of PJI, which could revolutionize the approach to diagnosing and managing these infections in several key areas.

Evaluation of treatment efficacy

By measuring the heat flow changes in response to antibiotic treatments, IMC can be used to evaluate the effectiveness of antimicrobial therapies in real time. This would help to tailor patient-specific treatment plans and in making decisions about changing or discontinuing antibiotics [17].

Studying biofilm formation

The ability of IMC to detect biofilm formation offers significant research opportunities in understanding the pathogenesis of PJIs, particularly for biofilm-forming bacteria, which are notoriously difficult to treat [13].

Clinical trials for new therapeutics

IMC can serve as a valuable tool in clinical trials for new antimicrobial agents or therapeutic strategies targeting PJIs. Its rapid and sensitive detection capabilities make it suitable for assessing the efficacy of new treatments on both planktonic cells and those growing in a biofilm [18].

Customized antimicrobial therapies

By providing rapid feedback on the effectiveness of specific antibiotics against the causative organisms of PJI in a particular patient [17], IMC can guide the customization of antibiotic therapy, moving towards a more personalized medicine approach.

Antibiotic stewardship

The information provided by IMC could contribute to antibiotic stewardship programmes by ensuring appropriate antibiotic use, thereby reducing the risk of antibiotic resistance development.

In conclusion, the applications of IMC in PJI detection extend beyond mere diagnosis and antibiotic susceptibility to the evaluation of treatment efficacy, complementing traditional diagnostic methods, and clinical trial research, making it an invaluable tool in the comprehensive management of PJIs. The technique’s contribution to personalized patient care and antibiotic stewardship further underscores its significance in modern health care.

Summary

In conclusion, this article has explored various facets of PJI detection, focusing on the challenges of traditional culture-based and molecular methods, the introduction and benefits of IMC, and its practical applications in PJI detection.

The challenges of conventional culture-based methods in PJI detection, such as time-consuming processes, false negatives, limited sensitivity, and contamination risks, highlight the need for more efficient and reliable diagnostic techniques. Molecular methods, despite offering rapid and sensitive detection, face issues such as detection of non-viable organisms, lack of standardization, high costs, and interpretation challenges.

IMC emerges as a promising alternative, offering rapid detection, high sensitivity, non-specific growth requirement, and versatility in detecting a wide range of pathogens. Its benefits extend to early detection, biofilm detection, and potential in antimicrobial susceptibility testing. This technique presents a potential paradigm shift in PJI diagnosis, addressing several limitations of traditional methods. Moreover, its role in research, particularly in understanding biofilm formation and in clinical trials for new therapeutics, is invaluable. IMC also aids in customizing antimicrobial therapies, contributing to personalized medicine and antibiotic stewardship.

In essence, the incorporation of IMC in the diagnostic arsenal for PJIs represents a potentially significant advancement. It provides a more comprehensive, rapid, and accurate approach to diagnosing and managing these complex infections. The integration of IMC alongside conventional methods may lead to improved patient outcomes, optimized treatment strategies, and a deeper understanding of PJI pathogenesis.

The authors

Kyle H. Cichos*1,2 PhD, Wilhelm Paulander3 PhD

1 Hughston Clinic, Columbus, GA, USA
2 Hughston Foundation, Columbus, GA, USA
3 Symcel, Stockholm, Sweden
* Corresponding author
Email: kcichos@hughston.com

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