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Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term remission for 6 weeks as compared to 12 weeks

Open AccessPublished:August 10, 2017DOI:https://doi.org/10.1016/j.ijid.2017.08.002

      Highlights

      • A minority of all prosthetic joint infections are treated with the DAIR procedure.
      • In prosthetic joint infections treated with the DAIR procedure, post-surgical duration of systemic antibiotic therapy after DAIR could be reduced to as short as 6 weeks.

      Abstract

      Background

      The required duration of antibiotic treatment for prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR procedure) is unknown.

      Methods

      Multicenter retrospective study emphasizing the duration of antibiotic therapy in patients treated with by DAIR.

      Results

      We included 87 hip or knee PJI episodes in 87 patients from three university hospitals in France and Switzerland. All debridements were performed within 3 weeks of symptom onset. After a mean follow-up of 52.1 months, 60 patients with PJI (69%) remained in remission, with no significant difference between hip and knee cases (73.3% vs. 59.3%, 95% confidence interval (CI), 0.20–1.38), or between patients receiving 6 compared with 12 weeks of antibiotic treatment (70.5% vs.67.4%, 95%CI 0.27–2.10, p = 0.60). Methicillin-resistant Staphylococcus aureus was isolated from 13.8% of infections and this was the only variable associated with a poorer outcome (remission in 41.7% vs. 73.3% for those with other pathogens, 95%CI 0.05–0.77, p = 0.02).

      Conclusions

      In patients undergoing DAIR for hip or knee PJI, the likelihood of long-term remission was not significantly different for those receiving 6 versus 12 weeks of antibiotic therapy. Prospective randomized trials are required to confirm this observation.

      Abbreviations:

      PJI (prosthetic joint infection), DAIR (debridement and implant retention), MRSA (methicillin-resistant Staphylococcus aureus), IDSA (Infectious Diseases Society of America), 95%CI (95% confidence interval)

      Keywords

      Introduction

      PJIs are associated with considerable morbidity. Their treatment is challenging and costly (
      • Zimmerli W.
      • Trampuz A.
      • Ochsner P.E.
      Prosthetic-joint infections.
      ). PJI management requires both surgery and antimicrobial therapy. The surgical options classically include one- or two-stage implant exchange, resection arthroplasty (with or without arthrodesis) or DAIR. IDSA guidelines recommended DAIR only for PJI with a well-fixed prosthesis; absence of a sinus tract; occurring within 30 days of implantation or less than three weeks of symptoms; or for elderly patients for whom alternative surgical strategies are unacceptable or very risky (
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • Lew D.
      • Zimmerli W.
      • Steckelberg J.M.
      • et al.
      Executive summary diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.
      ). Patients undergoing DAIR witness long periods of antibiotic treatment, e.g. three to six months for staphylococcal infections (
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • Lew D.
      • Zimmerli W.
      • Steckelberg J.M.
      • et al.
      Executive summary diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.
      ,
      • Zimmerli W.
      • Widmer A.F.
      • Blatter M.
      • Frei R.
      • Ochsner P.E.
      Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group.
      ).
      However, personal experience in several French tertiary hospitals and Geneva suggests that shorter courses of antibiotic therapy may be appropriate for most PJI or osteomyelitis (
      • Bernard L.
      • Legout L.
      • Zürcher-Pfund L.
      • Stern R.
      • Rohner P.
      • Peter R.
      • et al.
      Six weeks of antibiotic treatment is sufficient following surgery for septic arthroplasty.
      ,
      • Bernard L.
      • Dinh A.
      • Ghout I.
      • Simo D.
      • Zeller V.
      • Issartel B.
      • et al.
      Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.
      ,
      • Farhad R.
      • Roger P.M.
      • Albert C.
      • Pélligri C.
      • Touati C.
      • Dellamonica P.
      • et al.
      Six weeks antibiotic therapy for all bone infections: results of a cohort study.
      ) and associated with a reduced incidence of adverse events and emergence of microbiological resistance (
      • Bernard L.
      • Dinh A.
      • Ghout I.
      • Simo D.
      • Zeller V.
      • Issartel B.
      • et al.
      Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.
      ,
      • Meropol S.B.
      • Chan K.A.
      • Chen Z.
      • Finkelstein J.A.
      • Hennessy S.
      • Lautenbach E.
      • et al.
      Adverse events associated with prolonged antibiotic use.
      ). We therefore undertook a three-center, bi-national study evaluating if a shorter duration of antibiotic treatment in DAIR (6 weeks) is as effective as a longer course (3 months).

      Methods

      We performed a retrospective, multicenter study of PJI patients hospitalized in France or Switzerland (involving the orthopaedic units of Tours and Geneva and the infectious diseases division of Garches University Hospital) between 1989 and 2011. Geneva keeps an ongoing prospective cohort of total hip and knee arthroplasties since 1996 (one Number of Ethical Commission 05-041 (NAC 05-017)). Regarding the aforementioned French centers, we reviewed all PJI codes. All investigations involved our own patients and were part of an ongoing quality assessment.

      Setting and definitions

      We defined PJI as the presence of intraarticular pus together with at least one positive microbiological culture of intraoperative tissue sampling. For the main analysis, we included only PJIs treated by DAIR (which includes the removal of any hematoma, fibrous membrane, sinus tract, inlay and devitalized bone and soft tissue) occurring within 3 weeks after the first clinical symptoms, and only if the patient completed systemic postsurgical antibiotic treatment of either exactly 6 or exactly 12 weeks. In a second analysis we were interested if the duration of antibiotic prescription was specific to the DAIR procedure, i.e. if the remission rates were different with and without DAIR. For all analyses, we excluded fungal and mycobacterial infections and cases treated with other durations of antibiotic therapy. PJI was classified as early (infection within three months of arthroplasty), delayed (3–12 months after arthroplasty) or late (more than 12 months after arthroplasty) (
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • Lew D.
      • Zimmerli W.
      • Steckelberg J.M.
      • et al.
      Executive summary diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.
      ). Remission was defined as: 1) the absence of clinical, imaging and biological (i.e., inflammatory markers) signs of infection after a minimum follow-up period of 12 months after surgery; and, 2) no need for continuing antibiotic therapy, e.g. for suppressive treatment. The duration of antibiotic therapy was at the discretion of the treating surgeon or physician. However, the choice of the antibiotic agents must be appropriate according to nationwide Swiss or French recommendations.

      Statistical analyses

      Group comparisons were performed with the Pearson-χ2-test. A uni- and multivariate logistic regression analysis investigated the association of various variables with the outcome parameter “remission at 1 year after DAIR”. Survival curves were computed with the logrank-test and plotted as Kaplan-Meier curves. In a second step, we performed an exploratory analysis by including all cases which were excluded because ‘surgical treatment was not a DAIR’ and ‘DAIR more than 3 weeks after symptoms’. We used the SAS 9.2 statistical program and considered p values ≤0.05 (two-tailed) as significant.

      Results

      We identified 384 PJI episodes. Among them, 88 were ineligible for the following reasons: 28 were lost to follow-up; 23 did not finish the antibiotic course; 9 died during treatment (six related to the PJI); and 28 were treated with antibiotics for fewer than 6 or greater than 12 weeks for various reasons. For the main analysis, we excluded a further 178 PJI cases because the surgical protocol was not consistent with a DAIR procedure and 31 patients because surgery was performed more than 3 weeks after the onset of symptoms (Figure 1). For the explanatory analysis of all PJI (independently of DAIR and the delay of symptoms), we incorporated them into the final model summing 296 PJI.
      Figure 1
      Figure 1Flow chart displaying the inclusion and exclusion criteria of our study.
      Table 1 shows characteristics of the 87 PJIs in 87 individual patients in the DAIR analysis. Their median age was 71 years; 42 episodes (48.3%) occurred in women. There were 60 total hip arthroplasties (16 cemented) and 27 total knee arthroplasties (8 cemented). On admission, 44 PJI patients (50.6%) had fever ≥38 °C, and 51 (58.6%) witnessed pain in the affected joint. Median serum C-reactive protein concentration on admission was 120 mg/l (range, 8–569 mg/l) and the median serum leukocyte count was 7715/mm3 (range, 1240–65300/mm3). We classified 60 (69.0%) PJI as early, 7 (8.1%) as delayed and 20 (23.0%) as late PJI. Most infections were monomicrobial (n = 72, 82.8%). The predominant pathogens were methicillin- susceptible Staphylococcus aureus (n = 34, 39.1%), coagulase-negative staphylococci (25, 28.7%), Streptococcus sp. (12, 13.8%), and MRSA (12, 13.8%).
      Table 1Demographic and clinical comparisons of long-term remission rates of 87 patients with a prosthesis joint infection treated by debridement and implant retention (DAIR), stratified upon the duration of antibiotic treatment.
      VariablesSix weeks

      n = 44 (%)
      Twelve weeks

      n = 43 (%)
      Comparison

      P-value
      Female sex20 (45.45)22 (51.16).59
      Median age (years)7171.96
      Joints
       Hip arthroplasty31 (70.45)29 (67.44).76
       Knee arthroplasty23 (29.55)14 (32.56).76
      Center
       Garches2 (4.55)4 (9.30).67
       Geneva10 (22.73)10 (23.26).67
       Tours32 (72.73)29 (67.44).67
      Indication for arthroplasty
       Arthritis or fracture34 (82.93)38 (92.68).18
      Infection onset
       Early (<3 months26 (59.09)34 (79.07).045
       Delayed (3–12 months)3 (6.82)4 (9.30).045
       Late (>12 months)15 (34.09)5 (11.63).045
      Causative pathogens
       MRSA5 (11.36)7 (16.28).51
       CoNS13 (29.55)12 (27.91).87
      Antibiotic treatment
       Combination treatment32 (72.73)36 (83.72).21
       Rifampin + other30 (68.18)30 (69.77).87
       Fluoroquinolones + other26 (59.09)28 (65.12).56
       Flurooquinolone + Rifampin22 (50.00)22 (51.16).91
       Exclusively intravenous therapy17 (38.64)14 (32.56).55
      Death11 (25.00)13 (30.23).59
      CoNS: coagulase-negative staphylococci; MRSA: methicillin-resistant Staphylococcus aureus.

      Treatment

      DAIR was performed at a median of 6 days after the first symptoms. After surgical debridement and exchange of mobile parts of the prosthesis, the targeted systemic antibiotic was administered for exactly 6 weeks in 44 episodes (50.6%) and for exactly 12 weeks in 43 episodes (49.4%). Overall, durations did not significantly differ among the three centers. Rifampin was the most frequently prescribed agent (69% and always in combination therapy), followed by a fluoroquinolone (62.1%), a glycopeptide (21.8%), amoxicillin (11.6%) and trimethoprim-sulfamethoxazole (5.8%). Combination treatments were administered in 78.2% of cases. For infections caused by staphylococci, rifampin combination therapy was prescribed in 80% of cases, and was combined with a fluoroquinolone in 75% of cases. Antibiotic therapy for PJI was administered intravenously in 31 cases (35.6%) and by a combination of initial intravenous followed by oral therapy in 55 (63.2%) cases. In one case, oral treatment was prescribed from the start. In patients receiving therapy by both routes, the mean duration of initial parenteral therapy was 10 days for the 6-week group (range, 2–45 d) and 13 days for the 12-week group. The median number of surgical debridements was 1 in both groups.

      Outcome

      Overall, 60 PJI (69%) remained in final remission after minimal and median follow-ups of 14 and 52 months: 70.5% in the 6 week treatment group, and 67.4% in the 12 week treatment group. The Kaplan–Meier curves (time-to-treatment-failure) paralleled regarding remission when plotted against the antibiotic duration (Figure 2). Similarly, we found no differences between the 6-and the 12-week groups when performing uni- and multivariate analyses (adjusted odds ratio (OR) 0.76, 95% CI 0.27–2.10) (Table 2).
      Figure 2
      Figure 2Kaplan Meier remission curve for patients treated for 6 or 12 weeks with antibiotics (with treatment failures as events). Line: 6 weeks. Dotted line: 12 weeks.
      Table 2Odds ratios (OR) and 95% confidence intervals (CI) of prosthetic joint infections treated with debridement and implant retention (DAIR).
      Remission

      (%)
      Unadjusted OR (95% CI)P-valueAdjusted OR

      (95% CI)
      P-value
      Sex
       Female28 (66.67)1
       Male32 (71.11)1.23 (.50–3.06).65
      Age (years)
       <6417 (77.27)1
       64–7117 (73.91).83 (.21–3.26).79
       72–7812 (57.14).39 (.11–1.47).16
       >7814 (66.67).59 (.15–2.27).44
      Diabetes
       No52 (71.23)1
       Yes8 (57.14).54 (.17–1.74).30
      Alcohol
       No53 (67.95)1
       Yes7 (77.78)1.65 (.32–8.52).55
      Obesity
       No45 (67.16)1
       Yes15 (75.00)1.47 (.47–4.55).51
      Immune-suppression
       No54 (71.05)1
       Yes6 (54.55).49 (.14–1.77).28
      Joint
       Hip44 (73.33)11
       Knee16 (59.26)0.53 (.20–1.38).19.52 (.18–1.51).23
      Microbiology: CoNS
      SCN: coagulase-negative staphylococci.
       Others43 (69.35)1
       CoNS17 (68.00).94 (.35–2.55).90
      Microbiology: MRSA
      MRSA: methicillin-resistant S. aureus.
       Others55 (73.33)11
       MRSA5 (41.67).26 (.07–.91).04.20 (.05–.77).02
      Infection
       Early (<3 months)44 (73.33)11
       Delayed (3–12 months)5 (71.43).91 (.16–5.16).91.84 (.13–5.24).85
       Late (>12 months)11 (55.00).44 (.16–1.27).13.40 (.12–1.34).14
      Antibiotic agent(s)
       Others26 (60.47)1
       FQ + rifampicin34 (77.27)2.22 (.87–5.65).09
      Antibiotic agent: Rifampin
       Others19 (70.37)1
       Rifampin41 (68.33)0.91 (0.34–2.44)0.85
      Route of treatment
       Oral treatment41 (73.21)1
       Exclusively IV19 (61.29)0.58 (0.23–1.47)0.25
      Duration of antibiotic treatment
       Six weeks31 (70.45)11
       Twelve weeks29 (67.44)0.87 (.35–2.16)0.76.76 (.27–2.10).60
      FQ: Fluoroquinolones.
      a SCN: coagulase-negative staphylococci.
      b MRSA: methicillin-resistant S. aureus.
      In contrast, PJI due to MRSA, as compared to other pathogens, was the only variable significantly associated with reduced remission (adjusted OR 0.20,95% CI 0.05-0.77), while age, sex, the duration of sepsis, the duration of intravenous antibiotic treatment, antibiotic monotherapy, or delay between arthroplasty implantation and infection did not influence outcome. Of note, rifampin, or its combination with a fluoroquinolone, was not associated with remission (OR 0.91, 95%CI 0.34–2.44 for rifampin with any other antibiotic; and OR 2.22; 95%CI 0.87–5.65 for the rifampin/fluoroquinolone combination).

      Additional exploratory analysis with all PJI cases

      We realized an exploratory analysis of all PJI cases treated for 6 or 12 weeks, independently of the surgical approach, DAIR or the delay between symptoms and first surgery. A total of 296 PJI were included. After a mean post treatment follow-up of 59 months, 226 PJI (76.4%) were in remission. Surgical treatments included debridement and retention (DAIR) of the prosthesis (39.9%), one- (6.7%) or two-stage (32.1%) exchange or resection arthroplasty (21.3%). Remission did not differ regarding hip or knee PJI (79% vs. 72%, p = 0.24), proportion of patients with more than two co-morbidities (77% vs. 77%, p = 0.95) or total antibiotic duration. The same remission rate was obtained with 6 weeks of antibiotic treatment as with 12 weeks (78% vs. 74%, P = 0.76). Remission rates stratified upon the surgical treatment were 85.3% in two-stage exchange, 84.1% in resection arthroplasty, 70% in one-stage and 66.1% in DAIR.

      Discussion

      We considered eligible 87 DAIR procedures for hip or knee PJI and included them in the analyses. Minimum follow up was 14 months. The primary outcome measure was remission of infection (without suppressive antimicrobial therapy) for 12 months following surgery. Overall, remission rate was 69% and there was no significant difference between 6 and 12 weeks of antimicrobial therapy, independently of rifampin combination for staphylococcal PJI, or duration of the initial parenteral antibiotic administration, the DAIR procedure or the delay of symptoms prior to first surgery for infection. The overall DAIR success in both duration groups was roughly 70%, a percentage which is largely reproduced in the DAIR literature, which indicates success rates around 70% (
      • Byren I.
      • Bejon P.
      • Atkins B.L.
      • Angus B.
      • Masters S.
      • McLardy-Smith P.
      • et al.
      One hundred and twelve infected arthroplasties treated with ‘DAIR’ (debridement, antibiotics and implant retention): antibiotic duration and outcome.
      ,
      • Martínez-Pastor J.C.
      • Muñoz-Mahamud E.
      • Vilchez F.
      • García-Ramiro S.
      • Bori G.
      • Sierra J.
      • et al.
      Outcome of acute prosthetic joint infections due to gram-negative bacilli treated with open debridement and retention of the prosthesis.
      ,
      • Kuiper J.W.
      • Vos S.J.
      • Saouti R.
      • Vergroesen D.A.
      • Graat H.C.
      • Debets-Ossenkopp Y.J.
      • et al.
      Prosthetic joint-associated infections treated with DAIR (debridement, antibiotics, irrigation, and retention): analysis of risk factors and local antibiotic carriers in 91 patients.
      ), albeit with much longer antibiotic therapies.
      DAIR is different from what is often called “suppressive therapy,” i.e., the planned life-long treatment for very elderly and bedridden patients. Remission with DAIR is common, despite the fact that the joint implant is left in place. With DAIR, after the initial surgical debridement(s) and exchange of all mobile parts, the therapeutic activity relies on the antibiotic treatment (
      • Zimmerli W.
      • Trampuz A.
      • Ochsner P.E.
      Prosthetic-joint infections.
      ,
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • Lew D.
      • Zimmerli W.
      • Steckelberg J.M.
      • et al.
      Executive summary diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.
      ). However, the optimal duration of this treatment remains unclear. Recommendations are only based on expert opinion, which usually suggests that staphylococcal infections should be treated for three months in cases of hip PJI and six months in cases of knee PJI, whereas non-staphylococcal infections should be treated for at least six weeks (
      • Zimmerli W.
      • Trampuz A.
      • Ochsner P.E.
      Prosthetic-joint infections.
      ,
      • Osmon D.R.
      • Berbari E.F.
      • Berendt A.R.
      • Lew D.
      • Zimmerli W.
      • Steckelberg J.M.
      • et al.
      Executive summary diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America.
      ). For non-implant-related orthopaedic infections, six weeks seems to be largely sufficient. We have previously demonstrated that 6 weeks of antibiotic treatment is not inferior to 12 weeks for patients with vertebral osteomyelitis and spodylodiscitis, including S. aureus (
      • Bernard L.
      • Dinh A.
      • Ghout I.
      • Simo D.
      • Zeller V.
      • Issartel B.
      • et al.
      Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.
      ). Similarly, another study revealed that there was no significant difference in remission rates for non-amputated diabetic foot osteomyelitis treated for 6 weeks versus 12 weeks (
      • Tone A.
      • Nguyen S.
      • Devemy F.
      • Topolinski H.
      • Valette M.
      • Cazaubiel M.
      • et al.
      Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study.
      ). Moreover, non-randomized studies of PJI patients failed to reveal differences in treatment outcomes between those receiving antibiotics for six weeks compared to longer periods (
      • Bernard L.
      • Legout L.
      • Zürcher-Pfund L.
      • Stern R.
      • Rohner P.
      • Peter R.
      • et al.
      Six weeks of antibiotic treatment is sufficient following surgery for septic arthroplasty.
      ,
      • Farhad R.
      • Roger P.M.
      • Albert C.
      • Pélligri C.
      • Touati C.
      • Dellamonica P.
      • et al.
      Six weeks antibiotic therapy for all bone infections: results of a cohort study.
      ) or between episodes treated for three months compared to longer periods (
      • Puhto A.P.
      • Puhto T.
      • Syrjala H.
      Short-course antibiotics for prosthetic joint infections treated with prosthesis retention.
      ,
      • Vilchez F.
      • Martínez-Pastor J.C.
      • García-Ramiro S.
      • Bori G.
      • Maculé F.
      • Sierra J.
      • et al.
      Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement.
      ). Likewise, a prospective observational non-randomized study on 144 PJI cases by Bernard et al. found similar remission rates (80%) for 6 and 12 weeks of therapy, regardless of the type of surgical treatment (
      • Bernard L.
      • Legout L.
      • Zürcher-Pfund L.
      • Stern R.
      • Rohner P.
      • Peter R.
      • et al.
      Six weeks of antibiotic treatment is sufficient following surgery for septic arthroplasty.
      ). In the present study, we confirm these associations.
      French recommendations suggest that the duration of antibiotic therapy for PJI could be reduced to six weeks (
      • Recommendations for Clinical Practice
      Osteo-articular infection therapy according to materials used (prosthesis, implants, osteosynthesis).
      ,
      • Aboltins C.
      • Daffy J.
      • Choong P.
      • Stanley P.
      Current concepts in the management of prosthetic joint infection.
      ). Certain highly bioavailable oral antibiotics, such as fluoroquinolones, rifampin, linezolid, and co-trimoxazole, reach levels in bone that exceed the minimal inhibitory concentrations (MICs) for most organisms (
      • Spellberg B.
      • Lipsky B.A.
      Systemic antibiotic therapy for chronic osteomyelitis in adults.
      ). There are several lines of evidence suggesting that an early switch to oral antibiotics is as effective as prolonged parenteral regimens for patients with PJI (
      • Soriano A.
      • García S.
      • Bori G.
      • Almela M.
      • Gallart X.
      • Macule F.
      • et al.
      Treatment of acute post-surgical infection of joint arthroplasty.
      ,
      • Berdal J.E.
      • Skråmm I.
      • Mowinckel P.
      • Gulbrandsen P.
      • Bjørnholt J.V.
      Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections.
      ), S. aureus osteomyelitis (
      • Daver N.G.
      • Shelburne S.A.
      • Atmar R.L.
      • Giordano T.P.
      • Stager C.E.
      • Reitman C.A.
      • et al.
      Oral step-down therapy is comparable to intravenous therapy for Staphylococcus aureus osteomyelitis.
      ), and vertebral osteomyelitis (
      • Bernard L.
      • Dinh A.
      • Ghout I.
      • Simo D.
      • Zeller V.
      • Issartel B.
      • et al.
      Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial.
      ). In our study, the use of intravenous antibiotics did not achieve higher remission than oral medication or early switch to oral medication. As oral therapy is less complicated and less expensive than intravenous, making an early switch is beneficial to both patients and the health care system.
      Many retrospective studies suggest that rifampin combinations may increase remission rates for staphylococcal PJI (
      • Aboltins C.
      • Daffy J.
      • Choong P.
      • Stanley P.
      Current concepts in the management of prosthetic joint infection.
      ,
      • Berdal J.E.
      • Skråmm I.
      • Mowinckel P.
      • Gulbrandsen P.
      • Bjørnholt J.V.
      Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections.
      ,
      • Drancourt M.
      • Stein A.
      • Argenson J.N.
      • Zannier A.
      • Curvale G.
      • Raoult D.
      Oral rifampin plus ofloxacin for treatment of Staphylococcus-infected orthopedic implants.
      ,
      • Senneville E.
      • Joulie D.
      • Legout L.
      • Valette M.
      • Dezèque H.
      • Beltrand E.
      • et al.
      Outcome and predictors of treatment failure in total hip/knee prosthetic joint infections due to Staphylococcus aureus.
      ,
      • Lora-Tamayo J.
      • Murillo O.
      • Iribarren J.A.
      • Soriano A.
      • Sánchez-Somolinos M.
      • Baraia-Etxaburu J.M.
      • et al.
      A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention.
      ,
      • Wieland B.W.
      • Marcantoni J.R.
      • Bommarito K.M.
      • Warren D.K.
      • Marschall J.
      A retrospective comparison of ceftriaxone versus oxacillin for osteoarticular infections due to methicillin-susceptible Staphylococcus aureus.
      ,
      • San Juan R.
      • Garcia-Reyne A.
      • Caba P.
      • Chaves F.
      • Resines C.
      • Llanos F.
      • et al.
      Safety and efficacy of moxifloxacin monotherapy for treatment of orthopedic implant-related staphylococcal infections.
      ), but its benefit in the DAIR procedure has not yet been formally elucidated. In our patients, the inclusion of rifampin in the antibiotic regimen for the subset of patients with S. aureus infection appeared to confer no statistically significant advantage although the numbers analysed were small. As rifampin may have adverse effects and is known to interact with many other drugs, it is important to determine whether or not it has a role in combination therapy for pure staphylococcal PJIs treated with DAIR. For example, in another previously published experience at the Geneva site, 393 patients with osteoarticular infections received antibiotic treatment for a median of 8 weeks, including 2 weeks intravenously. Among them, 115 (29%) reported various adverse events (e.g., diarrhea, nausea, cholestasis, gastric distress, rash, and mycosis), of which most were due to rifampin. By multivariate Cox regression analysis, the total duration of antibiotic therapy and duration of intravenous administration were significantly associated with adverse events (all p< 0.01) (
      • Schindler M.
      • Bernard L.
      • Belaieff W.
      • Gamulin A.
      • Racloz G.
      • Emonet S.
      • et al.
      Epidemiology of adverse events and Clostridium difficile-associated diarrhea during long-term antibiotic therapy for osteoarticular infections.
      ). Finally, poorer outcomes have been reported for PJIs caused by MRSA than with other pathogens (
      • Peel T.N.
      • Buising K.L.
      • Dowsey M.M.
      • Aboltins C.A.
      • Daffy J.R.
      • Stanley P.A.
      • et al.
      Outcome of debridement and retention in prosthetic joint infections by methicillin-resistant staphylococci, with special reference to rifampin and fusidic acid combination therapy.
      ,
      • Salgado C.D.
      • Dash S.
      • Cantey J.R.
      • Marculescu C.E.
      Higher risk of failure of methicillin-resistant Staphylococcus aureus prosthetic joint infections.
      ). We also confirm this association which is widely believed in the literature, although a large retrospective study of 345 cases of PJI due to MRSA (n = 81) or MSSA (n = 264) treated by DAIR reported similar treatment failure rates for these two pathogens (
      • Lora-Tamayo J.
      • Murillo O.
      • Iribarren J.A.
      • Soriano A.
      • Sánchez-Somolinos M.
      • Baraia-Etxaburu J.M.
      • et al.
      A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention.
      ).
      In conclusion, with rising concerns about adverse effects of prolonged treatment in the elderly population (
      • Schindler M.
      • Bernard L.
      • Belaieff W.
      • Gamulin A.
      • Racloz G.
      • Emonet S.
      • et al.
      Epidemiology of adverse events and Clostridium difficile-associated diarrhea during long-term antibiotic therapy for osteoarticular infections.
      ), it is important to define the optimal duration of antibiotic treatment for PJIs that are treated with DAIR. We conclude that extending the treatment duration following DAIR for hip or knee PJI may offer no clinical advantage but is likely to be associated with an increased risk of adverse events. Prospective trials are welcome to confirm these findings, to determine the optimal duration of antibiotic therapy and to define the place of rifampin in the DAIR procedure.

      Conflict of interest

      There was no funding for the preparation of this manuscript. BAL has served as a consultant to KCI/Acelity, Innocoll, Dipexium. IU has received research funding from Innocoll. However, the content of this paper has no relation with any consultancy.

      Ethics statement

      Number of local Ethical Commission for arthroplasty cohort 05-041.

      Author contribution

      All authors contributed to the writing and reviewing of the manuscript.

      Acknowledgements

      We are indebted to Alice Rivière for her invaluable help for data collection. We thank the teams of the orthopaedic services and microbiology laboratories.

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