Rifampin is an antibiotic characterized by its bactericidal activity against microorganisms that form slow-growing biofilms on surfaces. It operates through a distinctive mechanism of action that involves inhibiting RNA polymerase, a crucial enzyme responsible for RNA synthesis in bacteria. By binding to the beta subunit of the enzyme, rifampin disrupts the transcription process, effectively hindering bacterial RNA synthesis. The antibiotic spectrum of rifampin is notably broad, encompassing both Gram-positive and some Gram-negative bacteria [31, 33, 35]. It possesses a high degree of oral bioavailability and demonstrates the ability to penetrate bone and joint tissues [28].
Numerous studies have demonstrated favourable outcomes following the extended administration of combination antibiotic therapy featuring rifampin, particularly in the context of PJI instigated by staphylococci [29, 30]. While the available studies on this subject are notably limited, it is worth noting that rifampin, when employed as an antibiotic in combination therapy, also seems to contribute to a diminished failure rate in the treatment of streptococcal and enterococcal PJIs [31, 32, 33]. The authors hypothesized that rifampin-resistant PJI are associated with worse outcomes. The results of the presenting study confirm the hypothesis especially regarding functional outcome.
In 2021, Beldman et al. conducted a multicentre study, which examined the outcomes of a large cohort comprising 669 patients afflicted by acute staphylococcal PJI. Their research revealed a notable advantage associated with antibiotic regimens that included rifampin. Treatment failure occurred in 32.2% (131 out of 407) of patients who received rifampin, while it was notably higher at 54.2% (142 out of 262) among those who did not receive rifampin (p < 0.001) [28]. Similar results have been demonstrated in numerous studies, underscoring that antibiotic treatment regimes that do not include rifampin exhibit a higher rate of treatment failure [30, 31, 34]. Hence, the emergence of rifampin resistance, especially among pathogens responsible for PJI, is a significant concern requiring careful attention. Rifampin cannot be employed as a standalone agent in the treatment of staphylococcal infections, primarily due to the swift emergence of resistance facilitated by a singular mutation in the RIF region of the rpoB gene within the DNA-dependent RNA polymerase. Therefore, it is imperative to co-administer rifampin with other antibiotics when treating PJIs [28, 35].
Additional research suggests that the timing of rifampin administration plays a pivotal role, with delayed introduction significantly reducing the emergence of rifampin resistance [12, 14]. Belman et al., in their multicentre observational study, demonstrated that the timing of administration had a significant influence on the treatment failure rate. When rifampin was initiated within 5 days following surgical debridement, they observed a treatment failure rate of 40.8% (80 out of 196 cases), in contrast to 20.9% when rifampin was commenced after this time threshold [29].
A study conducted by Lazarinis et al. in 2023, which analysed the outcomes of 238 patients with PJI, found that in cases of PJI caused by rifampin-resistant bacteria, the rates of infection relapse and treatment failure were higher, at 20% (eight cases), compared to PJIs caused by rifampin-sensitive bacteria, where these rates were lower at 9.6% (19 cases). Furthermore, the 2-year infection-free survival rates were estimated at 78.6% for the rifampin-resistant group and 90% for the rifampin-sensitive group, although the difference did not reach statistical significance (p = 0.07) [14].
The results of the present study go in line with the data of the previously mentioned research. The higher rate of treatment failure in patients with rifampin-resistant PJI was not statistically significant. (p = 0.4438). One plausible rationale for this observation could be attributed to the treatment approach employed in this group. In group 2, a higher proportion of patients received antibiotic therapies involving vancomycin (82.1% as opposed to 54%) and flucloxacillin (60.7% compared to 45.7%) in comparison to group 1. Furthermore a considerable number of patients received intravenous antibiotics for longer durations, which differed from the management of rifampin-sensitive cases in group 1.
Among patients in group 2, those with rifampin-resistant pathogens underwent more extended durations of oral antibiotic treatment (98.2 ± 98.5 days compared to 40 ± 49.4 days among those with rifampin-sensitive pathogens (p = 0.0035)). Additionally, patients in group 2 received a longer period of intravenous antibiotic therapy (205.39 ± 295 days in group 2 versus 111.4 ± 325.6 days in group 1, p = 0.0153). These are two factors that may have contributed to the lower rate of treatment failure despite rifampin resistance.
The study conducted by Krizsan and colleagues in 2022 shows comparable results on the recovery rates of patients undergoing two-stage revision for PJI. Notably, the recovery rate varied significantly based on the rifampin sensitivity of the pathogens causing the PJI. Patients in the rifampin-sensitive group exhibited a notably higher recovery rate of 92.5%, while those in the rifampin-resistant group had a considerably lower recovery rate of 60% (p = 0.0109) [13]. Another study conducted by Krizsan et al. in 2023 involving a cohort of 73 patients presents results that diverge from our observations. The overall recovery rate in the group of patients with rifampin-sensitive organisms (Staphylococcus aureus and coagulase-negative Staphylococci) was 72.3%, and it slightly increased to 76.9% in cases involving rifampin-resistant organisms. It is essential to note that the relatively low number of resistant isolates in their study population, comprising only 13 cases (19.4%), might contribute to this unanticipated trend. Consequently, a larger-scale investigation encompassing a more extensive and diverse patient cohort is necessary to validate those findings [36].
Despite the emphasis placed on treatment failure and recovery rates in these studies, they overlooked the critical aspect of assessing the clinical outcomes of patients. Specifically, there was a dearth of information pertaining to key domains such as activities of daily living, functional mobility, and overall quality of life. In our study, spanning an average follow-up period of 37 months, we evaluated the musculoskeletal condition of our patients using the WOMAC score and the OSS. Our findings revealed a pronounced discrepancy in various domains between patients with PJI caused by rifampin-resistant pathogens and those with PJI triggered by rifampin-sensitive organisms. Notably, patients in the rifampin-resistant group exhibited significantly lower scores in the "Function" domain of the WOMAC score when compared to patients in the rifampin-sensitive group (16.3 ± 10.7 versus 54.6 ± 11.6, p < 0.01). Furthermore, their reported pain levels were notably higher (group 1: 30.3 ± 11.6, group 2: 14.5 ± 6.4, p < 0.01). One plausible explanation for these findings may be attributed to a significant higher frequency of surgical revisions. Patients in group 1 had an average revision count of 3.59 ± 3.39, whereas group 2 exhibited a significantly higher average of revisions with 6.9 ± 5.1 revisions (p = 0.0011). Repetitive surgical procedures may lead to scar tissue formation, which can limit joint and muscle flexibility, consequently impeding mobility in the long term. Additionally, the psychological and emotional stress associated with recurrent surgeries can also influence physical mobility, as it may lead to decreased motivation and physical activity. [7, 37]]
To counteract potential bias resulting from the heterogeneity of the groups regarding the uneven distribution of PJI entities (acute vs. chronic), we conducted a subgroup analysis and further subdivided the two main groups based on acute and chronic PJI entities. Here as well, significant results were observed.
In the acute subgroup, patients who did not test positive for rifampicin-resistant strains exhibited a better clinical outcome in all WOMAC domains (WOMAC Pain p = 0.0007, WOMAC Function p = < 0.001, WOMAC Stiffness p = 0.0031). A functionally better outcome was also observed in chronic infections (Table 6).In their matched case-control study with 48 patients, Achermann et al. provided substantial insights into the factors associated with rifampin resistance in staphylococcal PJI. The utilization of a multivariate model allowed for the identification of several independent risk factors. Notably, their results unveiled male sex, a history of three or more surgical revisions, previous PJI treatment with rifampin in an inadequate manner, and a presumed high bacterial load at the onset of antibiotic treatment as significant risk factors for rifampin resistance. However, it is essential to consider the limitation arising from the small size of the study cohort [38]. Contrasting findings have emerged in larger-scale studies. Beldman et al., with a study cohort comprising 669 patients, and Lazarinis et al., who enrolled 238 patients, did not identify statistically significant disparities in baseline characteristics between the rifampin-sensitive and rifampin-resistant groups. These results align with the outcomes of our investigation. No significant differences were observed in terms of age, gender, BMI, or preoperative ASA score [14, 29].
A further examination of the patient cohort revealed that individuals with rifampin resistance underwent a significantly higher number of surgical revisions in comparison to those without rifampin resistance (group 1: 3.6 ± 3.4 vs 6.9 ± 5.1 revisions, p = 0.0011). The variation may arise from the fact that 75% of PJIs in the rifampin-resistant group were identified as chronic infections, in contrast to only 34.3% in the rifampin-sensitive group. (p = 0.0013). Given that a two/multi-stage exchange regimen was used for managing chronic PJIs, this factor may contribute to the higher number of revisions [4, 39].
Larzarinis et al. support this finding as their study shows that two-stage revision is more effective than a DAIR regime in the initial management of rifampin-sensitive PJI [14].
Data from national surveillance in England revealed that 44% of microbiologically confirmed surgical site infections of hip or knee arthroplasty were attributed to Staphylococcus aureus infection. This finding aligns with Pulido et al., who documented an incidence of 38%. The lower percentage (23.8%) in our study can be attributed to the internal hospital hygiene protocol and standardized hygienic measures taken by our staff such as preoperative nasal and whole-body decolonization, as well as preoperative screening. Ribau et al. came to same conclusion as they did a meta-analysis involving 32 publications, concluding that such measures reduce the risk of Staphylococcus aureus infection [40, 41, 42].
Staphylococcus epidermidis, classified as a coagulase-negative pathogen, is one of the most frequently encountered pathogens associated with PJI [8]. This study found it to be present in 79.4% of all cases. One explanation for this elevated count may be the fact that it could be misidentified as a contaminant, and therefore, not definitely the source of the periprosthetic infection. Nonetheless, Flurin et al. align with our findings, as they reported that both monomicrobial and polymicrobial PJI in the hip and knee were primarily attributed to Staphylococcus epidermidis, although not to the same extent (Monomicrobial PJI in 35% and polymicrobial PJI in 59%) [40, 43].
This study has several limitations. One such limitation arises from the relatively modest sample size within each study group, thereby presenting challenges in conducting statistical analyses and establishing statistical significance in specific instances. This particularly concerns the subgroup analysis in Table 6.
Conducting a multifactorial analysis was impractical given the groups´ sizes. An additional constraint of this study pertains to its limited level of evidence, stemming from its retrospective design. Consequently, constraints must be acknowledged in terms of potential inaccuracies or misinterpretations in the data extracted from medical records especially the suboptimal and partially incomplete documentation of performed therapies in referred patients prior to hospitalization in our institute. It could not be determined exactly and with all certainty to what extent patients had already received antibiotic therapy especially involving rifampin prior to their inpatient stay. Table 4 serve as a summary of the antibiotic partners used to target the different pathogens. Performing a subgroup analysis was not viable due to the restricted number of cases. Our study cohort consisted of individuals with PJI affecting various joint locations, which may introduce an element of interference with our findings. Nevertheless, it is worth noting that uniform therapeutic protocols were adhered to in all instances. Thus, in our assessment, this factor is likely to exert only a moderate influence on the ultimate conclusion drawn from this study. Another limitation of our study pertains to the involvement of different surgeons in the surgical management of the enrolled patients. Although the selection of the most suitable treatment approach adhered to a predefined internal algorithm, some technical decisions were made based on the surgeon's judgment. These individualized choices might have had a minor impact on the progression of the infection.