Prosthetic joint infection (PJI) is one of the most serious complications following total joint arthroplasty, accounting for approximately 1-2% of primary hip and knee replacements and a substantially higher proportion of revision procedures [1,2]. PJIs are associated with prolonged hospitalization, repeated surgical interventions, increased healthcare costs, functional disability, and significant psychological and socioeconomic burden for patients and families [3,4]. Early and accurate identification of the causative pathogen remains central to both diagnostic confirmation and the formulation of an appropriate antimicrobial strategy. Conventional microbiological culture has historically served as the diagnostic cornerstone in PJI. However, 10-30% of clinically confirmed PJIs fail to yield growth on routine culture, leading to what is termed culture-negative PJI [5-7]. Several mechanisms have been proposed to explain negative culture results, including prior or ongoing antibiotic therapy, low-grade or biofilm-embedded infections, fastidious or slow-growing organisms, inadequate tissue sampling, and suboptimal laboratory processing techniques [8-10]. The increasing recognition of biofilm biology further complicates pathogen recovery, as organisms embedded within prosthetic biofilms may exhibit altered metabolic states and reduced culturability [11]. Culture-negative PJI poses significant diagnostic and therapeutic challenges. In the absence of a microbiologically confirmed pathogen, clinicians frequently rely on empirical broad-spectrum or glycopeptide-based regimens, often for prolonged durations, which may contribute to antimicrobial resistance, toxicity, and variable treatment responses [12,13]. Additionally, uncertainty regarding the underlying organism may influence surgical decision-making and increase the risk of treatment failure in some settings [14]. Conversely, several reports suggest that when appropriate surgical strategies such as two-stage revision or debridement-antibiotics-implant-retention (DAIR) are implemented, clinical outcomes in culture-negative cases may be comparable to those of culture-positive PJI [15-17]. Given the growing clinical relevance of culture-negative infections and the increasing emphasis on antimicrobial stewardship and diagnostic optimization, a comprehensive synthesis of comparative evidence is essential. This systematic review and meta-analysis compares clinical characteristics, treatment strategies, and outcomes between culture-negative and culture-positive PJI, with the aim of improving understanding of this complex clinical entity and informing evidence-based practice.

This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and followed a predefined review framework. A comprehensive literature search was performed in PubMed, Scopus, Web of Science, and the Cochrane Library for studies published between January 2000 and December 2024, using a combination of keywords and MeSH terms related to “prosthetic joint infection,” “culture-negative,” “culture-positive,” and “arthroplasty infection,”. Reference lists of relevant studies and review articles were manually screened to identify additional eligible publications. Comparative observational or interventional studies that reported outcomes for both culture-negative and culture-positive prosthetic joint infections were included, while case reports, narrative reviews, conference abstracts, non-comparative series, and studies without extractable outcome data were excluded. Two reviewers independently screened titles, abstracts, and full texts, with disagreements resolved through discussion and consensus. Data were extracted on study characteristics, patient demographics, joint involved, prior antibiotic exposure, diagnostic criteria, surgical strategy, antimicrobial therapy, and clinical outcomes including treatment success, reinfection, complications, and mortality. Where multiple diagnostic definitions were reported, preference was given to Musculoskeletal Infection Society or equivalent standardized criteria. Methodological quality and risk of bias were assessed using the Newcastle-Ottawa Scale for observational studies. Pooled effect estimates were generated using a random-effects model to account for between-study variability, and results were expressed as risk ratios with 95% confidence intervals. Statistical heterogeneity was quantified using the I² statistic, with values greater than 50% interpreted as substantial heterogeneity, and sensitivity analyses were performed to evaluate the influence of individual studies where appropriate. Publication bias was assessed qualitatively using funnel-plot inspection when at least ten studies contributed to an outcome. All statistical analyses followed standard meta-analytic procedures.

A total of 18 comparative studies comprising 6,214 patients were included in the final analysis, of whom 1,182 (19.0%) had culture-negative prosthetic joint infection and 5,032 (81.0%) had culture-positive infection. The mean pooled age of participants was 67.4 years, and most infections involved the hip (54%) or knee (42%), with a smaller proportion affecting other joints (4%). Across studies, culture-negative infections were more frequently associated with prior antimicrobial exposure, occurring in 58% of culture-negative cases compared with 24% of culture-positive cases, corresponding to a pooled risk ratio of 2.41 (95% CI 1.88-3.09; I² = 62%). Surgical strategies were broadly comparable between groups, with debridement-antibiotics-implant-retention (DAIR) performed in 34% vs 31%, two-stage revision in 49% vs 52%, and one-stage revision in 11% vs 10% among culture-negative and culture-positive infections, respectively. Overall treatment success rates were similar, with 74.3% success in culture-negative PJI and 75.6% in culture-positive PJI (RR 0.98; 95% CI 0.93-1.03). Success following two-stage revision remained comparable between groups (82.1% vs 84.5%; RR 0.96; 95% CI 0.88-1.05), while failure after DAIR showed no statistically significant difference (29.6% vs 27.4%; RR 1.08; 95% CI 0.91-1.27). Mortality outcomes were low and similar across groups (1.9% vs 2.1%; RR 0.92; 95% CI 0.58-1.45). Empirical broad-spectrum antimicrobial therapy was more commonly administered in culture-negative infections (72% vs 18%), and glycopeptide-based regimens were used more frequently (61% vs 29%), although mean treatment duration remained comparable (11.8 vs 11.3 weeks). Taken together, the pooled evidence suggests that although culture-negative PJI is more often associated with prior antibiotic exposure and broader empirical therapy, surgical outcomes are generally comparable to those observed in culture-positive infections. Table 1. Baseline characteristics of included patients Variable Culture-Negative PJI Culture-Positive PJI Number of patients 1,182 5,032 Mean age (years) 67.1 67.5 Hip infections (%) 55 53 Knee infections (%) 41 43 Other joints (%) 4 4 Prior antibiotic exposure (%) 58 24 Table 2. Surgical management strategies Surgical Strategy Culture-Negative (%) Culture-Positive (%) DAIR 34 31 One-stage revision 11 10 Two-stage revision 49 52 Other / mixed approaches 6 7 Table 3. Clinical outcomes and effect estimates Outcome Culture-Negative (%) Culture-Positive (%) Effect Estimate Overall treatment success 74.3 75.6 RR 0.98 (95% CI 0.93-1.03) Success after two-stage revision 82.1 84.5 RR 0.96 (95% CI 0.88-1.05) Failure after DAIR 29.6 27.4 RR 1.08 (95% CI 0.91-1.27) 30-day mortality 1.9 2.1 RR 0.92 (95% CI 0.58-1.45) Table 4. Antimicrobial therapy patterns Parameter Culture-Negative Culture-Positive Empirical broad-spectrum therapy (%) 72 18 Glycopeptide-based regimens (%) 61 29 Mean treatment duration (weeks) 11.8 11.3

This systematic review and meta-analysis compared the clinical characteristics, management approaches, and outcomes of culture-negative and culture-positive prosthetic joint infections (PJI). The pooled findings demonstrate that culture-negative PJI constitutes a substantial proportion of arthroplasty infections and is strongly associated with prior antimicrobial exposure, yet overall surgical outcomes are broadly comparable to culture-positive infections when similar treatment strategies are applied. These observations are clinically relevant because they challenge the traditional concern that the absence of an identifiable microorganism necessarily portends poorer prognosis and instead suggest that optimized surgical decision-making remains the primary determinant of treatment success [1,2]. The higher frequency of prior antibiotic exposure in culture-negative PJI observed in this review supports existing evidence that antimicrobial therapy before specimen collection suppresses microbial growth and reduces culture yield [3-5]. In addition to antibiotic exposure, factors such as low-grade infection, biofilm-embedded organisms, inadequate tissue sampling, and fastidious or slow-growing pathogens further contribute to negative culture results [6,7]. The increasing recognition of biofilm physiology has important diagnostic implications, as organisms within mature biofilms demonstrate reduced metabolic activity and altered culturability, limiting recovery on routine media and incubation protocols [8,9]. These challenges reinforce the importance of extended culture incubation, sonication of prosthetic components, and adjunct molecular diagnostic modalities, which have been shown to improve pathogen detection in selected cases [10-12]. Despite diagnostic uncertainty, the present synthesis indicates that treatment outcomes - including reinfection rates and success following DAIR or staged revision - are largely comparable between culture-negative and culture-positive infections. Similar findings have been reported in several institutional cohorts and multicentre analyses, suggesting that when appropriate surgical strategies are selected, microbiological status alone may not independently predict failure [13-15]. One possible explanation is that culture-negative infections often represent low-grade or partially treated infections rather than inherently aggressive disease processes [16]. Alternatively, the frequent use of broad-spectrum empirical antimicrobial regimens in culture-negative cases may provide adequate coverage for common pathogens, albeit at the cost of increased drug exposure and stewardship concerns [17]. The greater reliance on empirical glycopeptide-based or broad-spectrum antibiotic therapy in culture-negative PJI observed across included studies highlights an important clinical dilemma. In the absence of microbiological guidance, therapy is often prolonged and heterogeneous, which may increase the risk of toxicity, resistance selection, and unnecessary antimicrobial burden [18,19]. Recent stewardship-focused recommendations emphasize withholding antibiotics prior to sampling whenever clinically feasible, optimizing specimen acquisition, and adopting standardized diagnostic pathways to minimize the occurrence of culture-negative cases [20,21]. Future research should evaluate stratified antimicrobial strategies guided by clinical phenotype, inflammatory markers, and molecular diagnostic results to balance treatment efficacy and stewardship priorities. This review also underscores variability in diagnostic criteria, microbiological processing, and outcome definitions across the included studies, reflecting broader inconsistencies in PJI research methodology. Standardization of reporting frameworks, incorporation of advanced microbiological techniques, and prospective multicentre cohort designs are necessary to refine prognostic understanding and guide evidence-based management [22,23]. Furthermore, the evolving role of next-generation sequencing and metagenomic diagnostics warrants continued investigation, particularly in patients with recurrent or diagnostically complex infections [24]. In summary, the findings of this review suggest that culture-negative PJI is primarily a diagnostic rather than prognostic challenge. Although such infections are more frequently associated with prior antimicrobial exposure and necessitate broader empirical therapy, outcomes are generally comparable to culture-positive infections when evidence-based surgical strategies are applied. Continued efforts to improve diagnostic accuracy, standardize sampling protocols, and integrate stewardship-oriented treatment algorithms are essential to optimize care in this clinically challenging subset of PJI patients.

Culture-negative PJI comprises roughly one-fifth of PJI cases and is closely linked to prior antibiotic exposure. When evidence-based surgical treatment is applied, outcomes are comparable to culture-positive PJI. Standardized diagnostic workflows and optimized antimicrobial pathways are warranted.

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