Impact of rifampicin dose in bone and joint prosthetic device infections due to Staphylococcus spp: a retrospective single-center study in France

The disease burden of bone and joint prosthetic device infections (PJI) is high [1‐3], because of a need for intensive care in 6% of cases and an estimated in-hospital lethality of 5% [4], increasing with age. Length of stay is high (between 18 and 21 days) and repeated admission rate is estimated at 19.3%, with increasing costs [1, 5, 6].

For PJI due to sensitive germs, Rifampicin (RIF) is a cornerstone, owing to its high bone and tissue diffusion and its action in biofilm [7, 8]. RIF is always used in combined therapy, most frequently with Fluoroquinolones [9‐11], with an overall recommended antibiotics course duration of 6 to 12 weeks [9].

However, the ideal RIF dose for PJI is not clearly defined, varying from 5 to 20 mg/kg/day depending on the study [12‐15]. The 2009 French guidelines suggested 10 mg/kg of RIF twice a day (i.e. 20 mg/kg/day) [9], whereas American guidelines (2013) did not take patient weight into account and recommended lower doses of 600 to 900 mg daily, taken once or twice (i.e. 8-12 mg/kg/day for a standard 75 kg person) [14].

Without clear data on outcomes according to RIF dose, clinicians are often guided by experiences of poor tolerance of high RIF dose [11, 16]. However, up today all pharmacokinetics studies have failed to demonstrate a correlation between RIF serum concentrations and occurrence of adverse events (AEs) [16, 17]. The rate of AEs linked to RIF in PJI varies between 4.3 and 31.2% depending on the study [12, 18‐20], often attributed to variable inter-individual susceptibilities [21, 22]. Because some studies, although with low sample sizes, suggest that lower-dose RIF could remain effective while improving the drug’s tolerance [12, 20], tendency of low-dose RIF has become common without guidelines changes.

From January 2008 until December 2018, 837 patients were treated for PJI due to Staphylococcus spp. (Fig. 1). A total of 411 patients were included (223 males, 54.25%) with a median age of 64.5 years (IQR [55–76], extremes 18 to 95 years), and a median weight of 82.5 kg (IQR [68–95]). (The flow chart is detailed in Fig. 1). However only 321 patients (78%) received RIF for the full length of treatment, while in 90 patients (22%) it was discontinued early because of AEs. The characteristics of the patients are detailed in Table 1.

Recovery rate was not statistically different between different groups of RIF dose: 55,6%, 76,2 and 67.3% in low-dose, intermediate-dose and high-dose groups respectively (p = 0.083) (Table 2). Results were similar while grouping low and intermediate dose-groups: the recovery rate was 74.8% in the < 20 mg/kg/day group and 67.3% in the > 20 mg/kg/day group. This was true when including patients who discontinued RIF before the end of treatment: 62.6% of recovery rate in the < 20 mg/kg/day group, and 62.9% in the > 20 mg/kg/day group (p = 0.310).

In a univariate analysis, being a female was the only variable associated with a lower recovery rate (p = 0.012), no association was found between recovery and RIF dosage or Staphylococcus phenotype (SA or CNS) or the number of germs on intraoperative sampling (Table 3). In a multivariate analysis, older age (p = 0.01) and shorter treatment duration (< 60 days, p <  0.01) were significantly associated with treatment failure (Table 4).

Seventy percent of PJI were due to SA (n = 289) with 82.4% of Meticillin-sensitive SA (MSSA), while only 54.9% (n = 67) of CNS were Meticillin-sensitive. The most frequently identified CNS species was Staphylococcus epidermidis (67.8%). Infections were polymicrobial in 26% of cases (n = 107). Recovery rate was not statistically different according to staphylococcal resistance profile or in polymicrobial infections.

Median RIF dosage was 15.7 mg/kg/day (IQR [8–18], extremes 5.8–41 mg/kg/day) and only 27 patients (6.6%) received low-dose RIF (< 10 mg/kg/day). The median duration of the antibiotic course was 39 days (IQR [9–60]). RIF was mainly combined with fluoroquinolones (67.6%), clindamycin (15.6%) or glycopeptides (8.7%).

AEs attributable to RIF were reported in 106 patients (26%), leading to treatment suspension in 65 (61.3% of AEs), with a median treatment duration of 12.5 days at occurrence (IQR [5–21]). Dosage was discreased in 2 patients, and galenic was changed in 6 patients In 31 cases (29.2% of AEs), no modification was done despite middle AEs. The most frequent AEs were digestive (n = 51), hepatic (n = 12) and cutaneous (n = 11), usually benign with grades I – II in 75 cases (70.8% of AEs). Fifteen patients presented with grade III – IV, mainly digestive (n = 10) AEs. AE occurrence rate was 20.9% in the medium-dose group versus 5.2% in the high-dose group (p = 0.640), and 1.3% in the low-dose group (Table 5). Neither obesity (BMI > 30) nor comorbidities were a risk factor of AEs.

In our study, there was no difference in recovery rate between low-dose and high-dose RIF containing regimens for PJI due to Staphylococcus spp., both in patients who continued treatment for the recommended duration (p = 0.083) and in those who discontinued RIF early (p = 0.31). These findings are in line with previously published data in favor of using lower doses of RIF, without risking treatment failure [12, 20]. However, the absence of statistical difference could be attributed to the low power of our study (1-β = 0.221, α risk = 0.05), despite our relatively large sample size.

Treatment failure was significantly associated with duration of RIF treatment (< 60 days), but not with the dose. This finding is consistent with DATIPO study results, which found a higher risk of treatment failure with shorter courses of antibiotics (< 45 days) [24]. Another randomized multi-center clinical trial also demonstrated the non-inferiority of a combined 8-week fluoroquinolone-RIF regimen, versus 3 or 6 months for hip or knee prostheses respectively, using debridement and implant retention [25].

The rate of AEs attributable to RIF was higher in our study population compared to previously published series, in which the percentage varies from 2 to 15% [10, 13, 26, 27]. One could blame our relatively high RIF dose compared to these studies where doses ranged from 600 mg [28‐30] to 900 mg daily [26, 31] regardless of patient weight. However AE occurrence was the highest in the 10–20 mg/kg/day group and the lowest in the > 20 mg/kg/day (5.2%).Several studies have similarly reported that high dose of RIF (> 30/mg/kg/day) could be used safely over a long period for the treatment of tuberculosis [32, 33]. Conversely, Hagihara et al. suggested that the toxicity associated with prolonged combined antibiotics therapy could be limited by lowering RIF dose [34] Valour et al. found a 6.5% AE rate for a median RIF dose of 18.8 mg/kg/day, with a smaller study population (n = 107) [18]. On the other hand, Randuineau et al. more recently suggested a two-fold increase in AEs in patients treated with RIF at > 12 versus < 12 mg/kg/day, leading to more frequent treatment discontinuation but without any significant reduction in recovery [20].

The poor tolerance of RIF could thus be solely attributable to inter-individual susceptibilities. Yet, multiple studies failed to show any influence of sex, age, height or weight on pharmacokinetic parameters of RIF [22, 35, 36]. Furthermore, studies by Roblot et al. and Dupouey et al. did not demonstrate any association between RIF serum concentrations and the occurrence of AEs neither digestive nor else [16, 17]. Besides, RIF usage should not be limited to non-comorbid patients, given the safety data of this study and previous ones [37]. While the value of pharmacological monitoring during RIF containing regimen remains unproven pharmacogenetics studies could be of help in the future [17]. Biological and clinical surveillance remain the pillar of PJI follow-up to prevent a potential harmful RIF discontinuation due to the use of less powerful antibiotics [11, 19, 27, 38‐40].

In addition, we did not find lower recovery rates in patients with methicillin-resistant Staphylococci, in line with previous studies [28, 41, 42], or in patients with polymicrobial infections, in contrast to a study by Senneville et al. [19].

This study has some limitations. Missing data are inherent to the retrospective nature of our work, cutting off 102 patients from our initial sample. The low number of patients receiving low-dose RIF has probably contributed to our low study power.

In conclusion, our data show the feasibility of using lower doses of RIF than these currently advised by national guidelines, which is consistent with the results of several observational studies [12, 20, 28, 29, 31]. A national French randomized controlled trial (PHRC EVRIOS – NTC 02599493), programmed for 2021, aims to include 460 patients, with the goal of determining optimal RIF dosage (< 10 or > 20 mg/kg/day) in PJI due to Staphylococcus spp., and will probably definitely answer this question.