Periprosthetic Joint Infection (PJI) is a serious complication of Total Knee Arthroplasty (TKA), affecting 1%–2% of patients and posing a substantial burden on individuals and the global healthcare system (Nelson et al., 2023; Patel, 2023). The primary objectives of PJI management are eradicating infection, relieving pain, and restoring joint function (Rajput et al., 2022). Treatment choice depends on the Tsukayama classification and the patient’s clinical condition. Key treatment options include antibiotic therapy, debridement with prosthesis retention, one- or two-stage revision after debridement, knee fusion, and amputation (Fiore et al., 2022). Two-stage revision surgery, involving temporary spacer implantation and concurrent antibiotic therapy, is a widely adopted approach for advanced chronic periprosthetic infections, achieving infection control rates of 85%–95% (Charette and Melnic, 2018; Craig et al., 2022). The primary strategy of PJI treatment is the combination of local and systemic antibiotic application with surgical intervention. However, systemic antibiotic therapy is often limited by poor penetration and insufficient blood supply to the infected area (Wiesli et al., 2022). Prolonged high-dose antibiotic use can promote the emergence and dissemination of antibiotic-resistant genes in gut flora, escalating bacterial resistance and triggering severe systemic adverse effects (Barrett et al., 2014; Francino, 2015; Zhang and Chen, 2019).

In contrast, local antibiotic delivery systems (DDS) achieve high antibiotic concentrations at the infection site, effectively reducing or preventing adverse reactions linked to systemic therapy. Therefore, selecting an appropriate antibiotic carrier during two-stage revision is vital (Risitano et al., 2018). Recently, biodegradable calcium sulfate has gained popularity in managing PJI during two-stage revision surgeries. It can fully release antibiotics during degradation, creating an environment unfavorable for bacterial colonization (Moore et al., 2021; Levack et al., 2022). These characteristics make calcium sulfate an optimal carrier for localized antibiotic delivery.

This retrospective study aimed to share our experience with two-stage revision procedures using antibiotic-loaded calcium sulfate beads, emphasizing their efficacy in eradicating infection and enhancing joint mobility.

A total of 103 patients were initially enrolled in the study. Six were excluded due to incomplete data, and three opted out of the second-stage procedure, citing perceived improvement in knee function during the interval period. The final analysis included 47 patients (21 males, 26 females) in the calcium sulfate group, with a median age of 65.6 ± 10.5 years, and 47 patients (19 males, 28 females) in the matched control group, with a median age of 67.1 ± 12.3 years. Twenty patients had undergone primary TKA at our institution, while the remaining 74 were referred from other institutions with a confirmed diagnosis of PJI. No significant differences in demographic characteristics were observed between the two groups (P > 0.05, Table 1).

Treating periprosthetic infections after TKA remains a key area of clinical research. For advanced chronic infections or cases lacking preoperative etiological evidence, two-stage revision surgery with temporary spacer implantation and antibiotic therapy is the widely accepted approach (Chang et al., 2019). This approach provides benefits including early joint mobilization, shorter hospital stays, and reduced postoperative infection recurrence rates (Craig et al., 2022). The articulating spacer replicates the knee joint’s anatomical structure, aiding in the prevention of joint contracture and the maintenance of range of motion (Vasarhelyi et al., 2022). Furthermore, Skwara et al. found no significant difference in infection control outcomes between articulating and static spacers (Skwara et al., 2016). Along with radical surgical debridement, effective treatments may involve long-term suppressive antibiotic therapy and local antibiotic delivery via devices made from biodegradable or non-biodegradable materials. Systemic antibiotic therapy often fails to achieve sufficient antibiotic concentrations at the infection site due to poor local blood supply.

Local antibiotic delivery systems, which form a DDS, are widely utilized as they achieve high local drug concentrations while minimizing systemic exposure, thereby reducing the risk of severe side effects (Hasegawa et al., 2021). Studies have shown that effective antibiotic concentrations in infected bone areas persist in surrounding tissues for up to 6 weeks after the topical application of antibiotic delivery devices. Biodegradable delivery systems (such as calcium sulfate) and non-biodegradable delivery systems (such as bone cement) are common carriers for local DDS, both having a substantial history of clinical application. Since Buchholz et al.'s pioneering attempt in 1970 to use antibiotic-loaded bone cement for managing joint infections, this method has gained widespread recognition as an effective adjunctive therapy for orthopedic infections. Antibiotic-loaded bone cements are frequently used as spacers, serving to elevate local antibiotic concentrations, mitigate soft-tissue contracture, allow partial weight-bearing, and alleviate movement restrictions (Roof et al., 2021). Additionally, these cements can fill intra-articular defects left by removed components, potentially aiding in the recovery of knee joint function.

Initially, bone cement releases antibiotics rapidly, but over time, its release kinetics become sub-therapeutic, resulting in decreasing levels of eluted antibiotics. Studies have reported a reduction to 10% of the initial concentration within 24 h post-implantation (McKee et al., 2010). If the antibiotics released from bone cement fall below the minimum inhibitory concentration, pathogens may colonize the surface of cement spacers, leading to biofilm formation. This bacterial biofilm could impede antibiotic penetration, potentially exacerbating chronic infection and its recurrence (Howlin et al., 2015).

Biodegradable calcium sulfate beads provide an alternative method for localized antibiotic delivery in infected areas. The application of calcium sulfate for osteomyelitis treatment dates back to 1892 (Laycock et al., 2018). This delivery device features a porous structure that allows effective local antibiotic delivery and complete in vivo absorption. Antibiotics released from calcium sulfate beads exhibit zero-order kinetics, which effectively mitigates biofilm formation and potentially inhibits bacterial colonization. Their exceptional elution properties maintain high local antibiotic concentrations continuously for 4–6 weeks. This enables antibiotics to reach the minimal bactericidal concentration within biofilms at infected sites, ensuring low systemic and local toxicity. This is crucial for effectively controlling infection during the interval period (Cooper et al., 2016; Smolle et al., 2023). The study by Howlin et al. demonstrated that antibiotic-loaded calcium sulfate beads can eradicate 10^6 CFU/mL planktonic cultures, inhibit bacterial colonization, and significantly reduce biofilm formation within days (Howlin et al., 2015). The synergistic effect between antibiotics and calcium sulfate enhances porosity, facilitating increased antibiotic release and broadening the antibacterial spectrum. Studies have shown that the combination of multiple antibiotics with calcium sulfate increases and prolongs antibiotic release compared to a single antibiotic (Levack et al., 2022).

This study demonstrated effective infection control in both groups following standardized treatment, with the calcium sulfate group exhibiting a higher infection control rate than the matched control group (95.7% vs. 80.9%). A review by Pangaud et al. (2019), which included 18 studies from 2000 to 2018, reported a mean infection control rate of 85% for chronic PJI of the knee treated with two-stage revision. Similarly, a multicenter retrospective study by Kildow et al. (Kildow et al., 2022) on two-stage revision for chronic knee PJI found an overall infection control rate of 88.98%. Kallala and Haddad (2015) reported a 93.3% infection control rate in PJI revision using antibiotic-loaded calcium sulfate. Lum and Pereira (2018) also reported a high infection control rate, achieving 100% in a study of 14 patients with PJI using antibiotic-loaded calcium sulfate. In this study, the calcium sulfate group achieved an infection control rate superior to that in earlier studies, while remaining consistent with recent findings. This superior infection control rate can be attributed to several key factors, including thorough debridement of infected tissues, excellent intraoperative visualization, an expanded scope of debridement, and the use of local antibiotic carriers. For patients with periprosthetic joint infection, bacteria are primarily located at the prosthesis-tissue interface, where they secrete a polysaccharide-protein complex and adhere to form bacterial biofilms. These biofilms effectively isolate bacteria from antibiotics, making their eradication challenging. To address this, our approach in the first-stage procedure involved the implantation of a new femoral prosthesis rather than reimplanting the original prosthesis sterilized by high-pressure techniques, as traditionally performed. This strategy, combined with the effective local antibiotic release provided by calcium sulfate beads, was pivotal in achieving the high infection control rate observed in our study.

The two patients in the calcium sulfate group who failed infection control were found to have methicillin-resistant Staphylococcus aureus (MRSA) in both pre- and post-treatment cultures. The risk of reinfection following revision surgery for MRSA-induced PJI was 20.5 times higher compared to PJI caused by sensitive or unidentified bacteria, with the reinfection rate increasing from 19% to 52% (Vasso et al., 2016). Lim et al. (2009) found that in a study comparing two-stage revision outcomes, 33% of patients with PJI caused by resistant bacteria experienced infection recurrence, while no recurrence was observed in those with non-resistant infections. Given the high virulence and recurrence risk associated with pathogens such as fungi, drug-resistant bacteria, and coagulase-negative staphylococci, we recommend thorough debridement, strict antimicrobial strategies, and comprehensive patient education to enhance treatment compliance.

In a retrospective analysis of the use of antibiotic-loaded calcium sulfate beads in infection-related revision arthroplasty, Kallala et al. reported three instances of hypercalcemia among 15 patients, with an average follow-up period of 16 months (Kallala and Haddad, 2015). Although hypercalcemia is considered a potential complication following the use of calcium sulfate, it was not observed in the present study. However, five cases of asymptomatic HO occurred after the first-stage surgery. While the exact reasons for HO remain unclear, it is plausible that the excessive aggregation of calcium sulfate beads may elevate local calcium concentrations, thereby increasing the risk of HO (Kallala et al., 2018).

This retrospective analysis highlights the importance of thorough removal of infected tissue, optimal intraoperative visualization, a broader debridement area, and careful selection of local antibiotic delivery systems to improve surgical success rates. In periprosthetic infections, bacteria primarily colonize the active interface of the prosthesis, secreting polysaccharide-protein complexes to form protective biofilms. As biofilms protect bacteria from antibiotics, replacing the femoral prosthesis is crucial for ensuring effective debridement.

This study has several limitations, including its retrospective design and the lack of prior sample size calculation. The retrospective nature of the study prevented the assessment of additional potential risk factors for recurrence or persistent infection, such as alcoholism, prior intra-articular corticosteroid injections, cutaneous ulcers, and diabetes. Additionally, the study had relatively low detection rates for bacterial cultures and histopathological examinations, which may have increased the likelihood of false-negative results. Future research should explore alternative detection methods, such as metagenomic sequencing, to improve detection rates, especially in false-negative cases. Therefore, a large-scale randomized controlled trial is necessary to thoroughly evaluate the effectiveness of antibiotic-loaded calcium sulfate beads in treating TKA infections during two-stage revision.

The use of antibiotic-loaded calcium sulfate in two-stage revision surgery for chronic knee PJI ensures sustained local antibiotic release at high concentrations, leading to rapid reduction in inflammatory markers, effective infection control, and a low complication rate. This approach is a safe and effective treatment for chronic knee PJI.