Total joint arthroplasty (TJA) is one of the most commonly performed orthopedic procedures worldwide (Sloan et al., 2018). Although rare, periprosthetic joint infection (PJI) remains a serious and uniquely challenging complication compared with infections of native bone or joint tissue (Patel, 2023). PJI occurs in approximately 2 % of total joint arthroplasties, and culture-negative infections account for approximately 5 %–42 % of all PJIs (Nelson et al., 2023; Reisener and Perka, 2018; van Sloten et al., 2022). Despite synovial fluid analysis, adjunctive methods such as implant sonication and molecular assays that improve pathogen detection, and advanced techniques including next-generation sequencing (NGS), the causative organism remains unidentified in a subset of culture-negative (CN) cases (Goh and Parvizi, 2022; Goswami et al., 2022). Because the causative pathogen remains unknown in these cases, both antibiotic selection and surgical decision-making are often empirical, and clinical outcomes remain uncertain.

The literature outlines several treatment strategies for managing CN-PJI, including debridement, antimicrobials, and implant retention (DAIR), as well as one-stage and two-stage exchange arthroplasty procedures (Tirumala et al., 2021; van Den Kieboom et al., 2021). For antimicrobial management, there is currently no consensus regarding the optimal empirical antimicrobial regimen for CN-PJI (Zhou et al., 2024). Previous studies have reported that there is no statistically significant difference in terms of outcome between CN and culture-positive PJIs (Lu et al., 2024; Reisener and Perka, 2018; Ronan et al., 2024). However, Paz et al. (2021) observed that CN-PJI may present with less severe disease and may be associated with better outcomes (Paz et al., 2021).

A 2018 systematic review of CN-PJI included a limited number of studies and provided only restricted quantitative analysis of treatment strategies and outcomes. Since then, additional studies and larger cohorts have been published. The present systematic review and meta-analysis aimed to evaluate treatment strategies and outcomes of CN-PJI, with a focus on surgical approaches and antimicrobial regimens, and to provide an updated quantitative synthesis of treatment success, failure, and mortality across available studies.

This systematic review and meta-analysis was designed and conducted in accordance with the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study followed a predefined protocol, which is available from the first or corresponding author upon reasonable request (Page et al., 2021). The full inclusion and exclusion criteria are detailed in the Appendix.

This systematic review and meta-analysis showed that CN-PJI is generally associated with favorable outcomes, with pooled treatment success, failure, and mortality proportions of 83.6 %, 17.2 %, and 2.4 %, respectively. Sensitivity analyses supported the stability of these findings despite several influential studies contributing to heterogeneity. Subgroup analyses showed significant differences by treatment strategy and joint type: DAIR was associated with lower success and higher failure, whereas one-stage and two-stage exchange arthroplasty showed better outcomes. Hip CN-PJI also showed higher treatment success than knee CN-PJI. Although funnel plot asymmetry and Egger's test suggested possible publication bias for success and failure, the overall evidence suggests that CN-PJI does not necessarily confer a poor prognosis, particularly when managed with exchange arthroplasty.

Surgical management of CN-PJI generally follows the same principles as culture-positive PJI. Previous studies have shown that two-stage exchange is the most used approach and is often considered to be the standard treatment, whereas DAIR is usually reserved for selected acute cases with short symptom duration, a stable prosthesis, and no sinus tract (Patel, 2023). In our systematic review, two-stage exchange was also performed more often than one-stage exchange, which is consistent with prior reports (Patel, 2023). Although our subgroup analysis showed similar success rates for one-stage and two-stage exchange, this finding should be interpreted with caution.

This cautious interpretation is also supported by recent literature on culture-positive and joint-specific PJI populations. Similarly, previous studies comparing one-stage and two-stage exchange in knee, hip, and shoulder PJI have reported comparable outcomes while emphasizing the influence of selection bias (Lazic et al., 2021; Kunutsor et al., 2018; Belay et al., 2020). Similarly, Thakrar et al. (2019) reported that favorable outcomes with one-stage exchange are mainly observed in carefully selected patients without significant host compromise, severe soft-tissue or bone defects, or resistant or atypical organisms while also acknowledging the inherent selection bias in observational studies. Taken together, these findings suggest that comparable results with one-stage exchange should not be interpreted as being equivalent to those with two-stage exchange but rather should be interpreted as evidence that one-stage exchange can achieve good outcomes in appropriately selected patients.

Antimicrobial management in CN-PJI was highly heterogeneous and often incompletely reported. When available, regimens were largely individualized rather than protocol-driven. Vancomycin-based therapy was most common, with frequent use of cephalosporins and fluoroquinolones, including oral step-down treatment. This variability likely reflects limited evidence guiding empirical therapy. Broad-spectrum use may also increase toxicity and other adverse events, highlighting the need for better diagnostics and antimicrobial stewardship. Prior evidence suggests that empirical regimens should primarily cover gram-positive organisms, especially staphylococci, with additional gram-negative coverage (Kalbian et al., 2020). This approach is reasonable because staphylococci are common causes of PJI, and resistant or polymicrobial infections may also occur, particularly in acute cases (Kim et al., 2022). Previous studies have suggested that vancomycin plus gram-negative coverage may be preferred for early PJI, whereas beta-lactams or trimethoprim-sulfamethoxazole may be sufficient for late or chronic PJI. However, treatment should be adjusted if a pathogen is subsequently identified by culture or molecular testing (Guo et al., 2026; Kim et al., 2022). In our review, vancomycin, cephalosporins, fluoroquinolones, rifampin, and other broad-spectrum combination regimens were commonly reported, but no standard antibiotic regimen was identified across studies. Prior literature suggests that treatment is often prolonged, with 12 weeks generally being preferred over 6 weeks, particularly in DAIR-managed cases, and that oral agents with good bioavailability are frequently used after an initial intravenous phase. Overall, antibiotic therapy for CN-PJI remains largely individualized. The substantial heterogeneity across studies likely reflects limited high-quality evidence, variability in patient and infection characteristics, and the lack of clear guideline-based recommendations.

From a clinical perspective, the most important finding of this review is that culture-negative PJI was associated with a relatively high pooled treatment success rate despite the absence of pathogen identification. This observation suggests that favorable outcomes remain achievable when treatment decisions are guided by established surgical principles and empiric antimicrobial therapy. While exchange arthroplasty demonstrated higher pooled success rates than DAIR, these findings should not be interpreted as evidence that culture status alone should determine surgical management as treatment selection is strongly influenced by infection chronicity, implant stability, host factors, and other clinical considerations. Instead, our findings highlight the need for future studies aimed at identifying which patients with culture-negative PJI are most likely to benefit from specific surgical approaches and empiric antimicrobial strategies.

This study has several strengths. It provides an updated and comprehensive synthesis of the available evidence on CN-PJI and includes more studies and patients than prior reviews. The meta-analysis allowed pooled estimates of treatment success, failure, and mortality, and sensitivity, influence, and subgroup analyses supported a more detailed interpretation of outcomes by treatment strategy and joint type.

However, several limitations should be noted. Most included studies were retrospective, with inherent risks of selection bias, confounding, and incomplete reporting. There was considerable clinical and methodological heterogeneity, including differences in patient selection, diagnostic approaches, surgical strategies, antimicrobial regimens, and follow-up duration. Inconsistent definitions of treatment success, failure, and reinfection further limited comparability. Despite efforts by Diaz-Ledezma et al. (2013), the Musculoskeletal Infection Society (MSIS) (2019) (Fillingham et al., 2019), and Johns et al. (2022) to establish standardized definitions of success and failure in periprosthetic joint infection (PJI) management, considerable variability remains across the literature. Many studies continue to use institution-specific or study-specific outcome definitions, contributing to substantial heterogeneity among reported results. Although this heterogeneity is an important limitation, it cannot be fully addressed at the current stage due to the lack of uniform outcome reporting across the included studies. We have previously recognized the challenges posed by this variability and, in our earlier work, proposed a definition of treatment success and failure based on the most clinically relevant and widely accepted criteria. Nevertheless, the absence of a universal adoption of standardized outcome measures continues to contribute to residual heterogeneity across studies (Alavi et al., 2026). Variability in diagnostic methods may also have affected CN case classification. In addition, potential publication bias in reported success and failure rates warrants cautious interpretation of pooled results.

Our findings underscore the need for prospective, multi-center studies with standardized definitions of CN-PJI, treatment success, failure, and reinfection, as well as clearer reporting of antimicrobial regimens and surgical selection criteria. Such studies are essential to better define optimal management and to reduce uncertainty arising from heterogeneity and selection bias in the current literature.

In conclusion, this systematic review and meta-analysis suggests that CN-PJI is generally associated with favorable outcomes, particularly when managed with exchange arthroplasty. DAIR was associated with lower success and higher failure, and outcomes appeared to be better in hip than in knee PJI. However, interpretation remains limited by heterogeneity in diagnostic methods, outcome definitions, and study design. Further prospective studies with standardized definitions and reporting are needed to better guide management.