- Email: [email protected]
Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid
ORIGINAL ARTICLE
10.1111/j.1469-0691.2007.01691.x
Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid C. A. Aboltins1, M. A. Page1, K. L. Buising1, A. W. J. Jenney1, J. R. Daffy1, P. F. M. Choong2 and P. A. Stanley1 1
Department of Infectious Diseases and 2Department of Orthopaedic Surgery, St Vincent’s Hospital, Melbourne, Victoria, Australia
ABSTRACT There is growing evidence of the efficacy of treating early staphylococcal infections of prosthetic joints with surgical debridement and prosthesis retention, combined with oral antibiotic regimens that include rifampicin in combination with a fluoroquinolone. With rising rates of fluoroquinolone-resistant staphylococci, evidence concerning the efficacy of alternative combinations of antibiotics is required. Twenty patients with staphylococcal prosthetic joint infections who had been treated with surgical debridement and prosthesis retention, and a combination of rifampicin and fusidic acid were analysed. The mean duration of symptoms before initial debridement was 16 (range 2–75) days. The median time of follow-up was 32 (range 6–76) months. Treatment failure occurred in two patients. The cumulative risk of treatment failure after 1 year was 11.76% (95% CI 3.08–39.40%). Two patients had their treatment changed because of nausea. Ten of 11 patients with infections involving methicillin-resistant Staphylococcus aureus had successful outcomes. Debridement without prosthesis removal, in combination with rifampicin and fusidic acid treatment, was effective and should be considered for patients with early staphylococcal prosthetic joint infections, including those with infections involving fluoroquinolone-resistant organisms. Keywords
Antibiotic regimens, debridement, fusidic acid, prosthetic joint infection, rifampicin, Staphylococcus spp.
Original Submission: 3 September 2006;
Revised Submission: 26 November 2006;
Accepted: 3 December 2006
Clin Microbiol Infect 2007; 13: 586–591
INTRODUCTION Prosthetic joint infection is an uncommon but serious complication of prosthetic joint implantation, resulting in substantial morbidity, often with pain, immobility, prolonged hospital stay and further surgery, and thus additional costs [1,2]. The approach of two-stage exchange arthroplasty has been preferred for the treatment of prosthetic joint infections in many centres. This has resulted in successful outcomes for >80% of patients with joint replacement infections in various studies [2– 4], but disadvantages include the technical difficulty of the surgery involved and the morbidity and costs of prolonged immobilisation of patients, who are often elderly [5]. Corresponding author and reprint requests: C. Aboltins, Department of Infectious Diseases, St Vincent’s Hospital, Victoria Pde, Fitzroy, Victoria, 3065 Australia E-mail: [email protected]
An alternative approach of debridement with prosthesis retention involves simpler surgery and potentially minimises the problems associated with prolonged immobilisation and hospitalisation. However, cure rates of infection are <40% in many studies. Where reported, such studies mostly included cases in which b-lactam-based antibiotic regimens were used, and a factor that was associated consistently with a higher risk of failure was a longer duration of symptoms before debridement [6–9]. Recent data have demonstrated the efficacy of treating patients with early (symptoms for <21 days) staphylococcal orthopaedic implant infections with retention and debridement of a stable prosthesis, combined with oral rifampicin and a fluoroquinolone [10–12]. However, fluoroquinolone resistance is now at high levels in nosocomial strains of staphylococci [13,14], thereby limiting the usefulness of rifampicin and fluoroquinolone combinations in this setting.
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
Aboltins et al.
These organisms usually remain susceptible to fusidic acid [14], but there are few data available to support the use of fusidic acid in combination with rifampicin for prosthetic joint infections. Accordingly, the aim of the present study was to evaluate the efficacy and safety of treating staphylococcal prosthetic joint infections with debridement, prosthesis retention, and the specific antibiotic combination of rifampicin and fusidic acid.
Treatment of prosthetic joint infections 587
IL, USA) and agar dilution methods were used for isolates from 1998 and 1999, and the Vitek-2 system (bioMe´rieux, Durham, NC, USA) was used for isolates from 2000 until 2003. Isolates with a fusidic acid MIC £1 mg ⁄ L were considered to be susceptible. Statistical analysis The Kaplan–Meier method was used to estimate the 1-year cumulative risk of treatment failure.
RESULTS MATERIALS AND METHODS
Study population
Study design
In total, 29 patients were diagnosed at St Vincent’s Hospital as having a staphylococcal prosthetic hip or knee joint infection during the study period. Five of these patients were excluded from the study population because they underwent prosthesis removal and then either immediate (two patients) or delayed (three patients) joint re-implantation as the primary surgical treatment. Two patients were excluded because there was no initial surgical intervention. Two other patients were excluded because they received rifampicin and ciprofloxacin as oral antibiotic therapy. The medical records did not indicate reasons for the different surgical or medical treatment approaches taken for each patient. The remaining 20 patients formed the study population and met the inclusion criteria of treatment with surgical debridement, prosthesis retention, and rifampicin and fusidic acid. Characteristics of individual patients and their outcomes are summarised in Table 1. The median age of the study population was 76 years. Thirteen patients had hip joint replacements and seven had knee joint replacements. The indication for the original joint replacement surgery was osteoarthritis (15 patients), rheumatoid arthritis (three patients), aseptic loosening of a previous prosthesis (one patient), and reversal of a previous arthrodesis (one patient). Six patients had type 2 diabetes mellitus, and four were receiving immunosuppressive medication. The median duration from insertion of prosthesis until initial debridement (joint age) was 38 (range 12–743) days. The mean duration from onset of symptoms to initial debridement was 16 (range 2–75) days. No patient showed evidence of prosthesis loosening on X-rays or at initial debride-
A retrospective cohort analysis of a prospectively compiled register of all patients with prosthetic hip and knee joint infections at St Vincent’s Hospital, Melbourne, Australia, between 1998 and 2003 was performed. The clinical management of each patient was determined by the responsible clinicians. Surgical and medical therapies were not standardised for the purpose of the study, although it was common practice to treat prosthetic joint infections with a short duration of symptoms with surgical debridement, prosthesis retention and rifampicin in combination with fusidic acid. Prosthetic joint infections of longer duration (>3 months) were typically treated with removal of the prosthesis. Study population The study population consisted of consecutive patients who had undergone treatment with one or more surgical debridements with prosthesis retention for a staphylococcal prosthetic hip or knee joint infection, who then commenced treatment with rifampicin and fusidic acid. A period of intravenous antibiotics perioperatively with either a b-lactam or a glycopeptide was usual. Patients were excluded from the study if they had a joint replacement for a previously infected prosthesis, or if causative organisms other than staphylococci were isolated. Definitions A staphylococcal prosthetic joint infection was defined by the isolation of staphylococci from two or more deep culture specimens, or the isolation of staphylococci from one deep culture specimen together with either purulence surrounding the joint at the time of operation, a sinus tract communicating with the prosthesis, or acute inflammation demonstrated on histopathology of surgical specimens [9]. Treatment failure was defined as persistence or recurrence of symptoms or signs of prosthetic infection, the isolation of the same or different organisms from subsequent surgical samples, or the removal of the prosthesis while antibiotic therapy continued. Susceptibility testing Susceptibility testing of staphylococcal isolates was performed according to CLSI guidelines for agar and broth dilution. The MicroScan WalkAway system (Dade Behring Inc., Deerfield,
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 13, 586–591
588 Clinical Microbiology and Infection, Volume 13 Number 6, June 2007
Table 1. Patient profiles and outcomes
Patient
Age (years)/ gender
Joint
Joint age (days)
Symptom duration (days)
Debridement procedures
Organism
Duration of intravenous antibiotics (days)
Duration of oral antibiotics (months)
Follow-up (months)
Treatment failure
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
75 ⁄ Male 76 ⁄ Female 63 ⁄ Male 58 ⁄ Male 75 ⁄ Female 61 ⁄ Female 63 ⁄ Male 71 ⁄ Male 80 ⁄ Male 80 ⁄ Female 74 ⁄ Male 58 ⁄ Male 81 ⁄ Female 83 ⁄ Male 74 ⁄ Female 73 ⁄ Female 59 ⁄ Male 64 ⁄ Female 72 ⁄ Female 74 ⁄ Female
Hip Hip Knee Hip Knee Hip Hip Hip Knee Hip Hip Knee Knee Hip Knee Hip Hip Hip Hip Knee
22 25 21 91 23 57 743 27 199 41 145 140 34 75 70 19 18 17 55 12
7 17 11 75 7 25 3 8 3 22 6 8 20 14 62 4 4 3 9 2
3 1 1 1 2 1 1 2 2 4 3 3 4 1 3 4 1 1 4 3
MRSA CNS MSSA, CNS MRSA MSSA MRSA MSSAc MRSA MSSAc MRSA MRSA MSSA MRSA MRSA MRSA MSSA MSSA MSSA MRSA, MSSA MRSA
10 3 5 6 18 8 10 29 14 12 18 21 9 5 19 14 12 8 19 14
12 11 12 12 12 6 21 24d 6 22 12 Ongoingd,f 11 28 11 17 24 12 33 12
29 24 65 28 27 31 47 63 6e 34 76 26 28 50 25 32 42 48 70 26
No No Yesa No No Yesb No No No No No No No No No No No No No No
MRSA, methicillin-resistant Staphylococcus aureus; CNS, coagulase-negative staphylococcus; MSSA, methicillin-susceptible S. aureus. a Prosthesis replaced after 12 months because of instability while still receiving antibiotics. No evidence of infection at further surgery. b Ongoing symptoms of infection with rifampicin-resistant CNS and Enterococcus faecalis isolated at change of prosthesis at 7 months. c Clinical features suggest infection possibly acquired by haematogenous seeding. d Antibiotic treatment modified because of nausea. e Patient died from unrelated cause during treatment. f Treatment duration extended because of immunosuppression.
ment. No patient had a definite sinus tract communicating with the joint. Microbiology The organism involved was methicillin-resistant Staphylococcus aureus (MRSA) in ten patients, methicillin-susceptible S. aureus (MSSA) in seven patients, a coagulase-negative staphylococcus (CNS) that was resistant to methicillin in one patient, MRSA mixed with MSSA in one patient, and MSSA mixed with methicillin-susceptible CNS in one patient. All isolates were susceptible to rifampicin and fusidic acid. All MRSA isolates were resistant to ciprofloxacin. All MSSA and CNS isolates were susceptible to ciprofloxacin. Surgical treatment The mean number of surgical debridements was 2.2 (range 1–4). All debridements were performed by open arthrotomy, and involved changing polyethylene liners where possible, removal of infected soft-tissue, and wash-out of the joint with high-pressure pulsatile lavage. Typically, the responsible physicians considered factors such as duration of symptoms, significant purulence of the joint at initial debridement, ongoing fever or ongoing wound discharge to assess whether repeated debridements were required.
Medical treatment The median duration of intravenous antibiotic treatment was 12 (range 3–29) days, and the median duration of hospitalisation for treatment of the infection was 20 (range 5–81) days. The median duration of oral antibiotic treatment was 12 (range 6–33) months. Typically, the duration of treatment was extended if symptom resolution was initially delayed or if patients were immunosuppressed. Doses administered were exclusively rifampicin 300 mg orally twice-daily and fusidic acid 500 mg orally three-times-daily. Patients were informed about the importance of compliance with the antibiotic regimen, and this information was reinforced with written patient information sheets. Two of the 20 patients reported nausea associated with rifampicin and fusidic acid treatment that was sufficiently severe to require a change of treatment. For patient 8, treatment was changed after 4 days to rifampicin plus ciprofloxacin, and for patient 12, after 2 weeks, to fusidic acid plus ciprofloxacin, both with subsequent improvement in nausea. These two patients were censored from the Kaplan–Meier estimation, but continued follow-up (Table 1). A further two patients experienced transient nausea, but were able to continue treatment. Two patients had transient mild rashes and
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 13, 586–591
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pruritus early in treatment, which improved without discontinuation of treatment. Two patients had a perioperative thromboembolic episode, and one male patient had traumatic urinary bladder catheterisation during admission. There were no episodes of hepatoxicity. Follow-up Patients were followed closely as outpatients, with review initially on a monthly basis. The median duration of follow-up was 32 (range 6–76) months from the time of infection. The median time of follow-up after discontinuing antibiotics was 16 months. Outcomes There was no evidence of treatment failure for 18 patients. Sixteen of these patients retained their original prosthesis and were followed for >12 months after discontinuing antibiotics. One patient (patient 12) had no evidence of infection after 26 months of follow-up, but the responsible physicians chose to undertake a course of suppressive antibiotic therapy because of significant immunosuppression. One patient (patient 9) died 6 months after initial debridement from unrelated causes. There was evidence of treatment failure in two patients. In one of these patients (patient 6), who initially had an infection with MRSA, signs of infection were ongoing and further surgery was required 6 months after initial debridement. Intra-operative cultures yielded different organisms (a rifampicin-resistant CNS and an Enterococcus faecalis). In the other patient (patient 3), there was evidence of prosthetic loosening, with pain, after treatment for 12 months, and exchange arthroplasty was therefore undertaken. Histology of tissue taken during further surgery showed a foreign body-type reaction. There was no other clinical, biochemical or microbiological evidence of infection, and the patient remained free of signs of infection after a further 65 months. The cumulative risk of treatment failure at 1 year was 11.76% (95% CI 3.08–39.40%). Ten of 11 infections involving MRSA, eight of nine infections involving MSSA, and one of two infections with CNS were resolved.
Treatment of prosthetic joint infections 589
DISCUSSION The approach of debridement with prosthesis retention, combined with treatment with oral rifampicin and fusidic acid, was successful in this study, with only two of 20 patients failing treatment with this regimen after a median follow-up period of 32 months. The two patients who failed treatment did not show evidence of persistence of the original infecting organisms. The 1-year cumulative risk of treatment failure of 11.76% compares favourably with those in other studies examining treatment with debridement, prosthesis retention, and a combination of rifampicin and fluoroquinolones [10–12], in which up to 100% of patients who were able to complete the treatment had a successful outcome. Among a subgroup of 11 patients in the present study cohort who had MRSA infections, for whom fluoroquinolones were not a treatment option because of primary resistance, ten had a successful outcome. This was notably more successful than outcomes published previously concerning treatment of MRSA infections with prosthesis retention and other antibiotics [11,12]. It is important to note that the results of the present study cannot be generalised to all prosthetic joint infections. Each patient in the study exhibited several features that have been shown previously to be associated with good success rates, namely a short period of time from onset of symptoms until initial debridement, with a mean of 16 (range 2–75) days, a stable prosthesis, and the absence of a definite sinus tract [6–10]. The utility of the study treatment regimen in patients without these good prognostic factors is unknown. Rifampicin and fusidic acid have good activity against most staphylococci, and have retained activity against the majority of methicillin-resistant and fluoroquinolone-resistant staphylococci isolated in most parts of the world [14,15]. These antimicrobial agents are well-absorbed after oral administration, and demonstrate excellent penetration into tissues and the intracellular space [16]. Rifampicin has demonstrated excellent efficacy against slow-growing organisms and organisms associated with biofilms, both of which are important in the pathogenesis of infections involving prosthetic material [17–19]. Resistance develops quickly in staphylococcal infections when either of these antibiotics is used
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 13, 586–591
590 Clinical Microbiology and Infection, Volume 13 Number 6, June 2007
alone. However, the risk of emergence of resistance is considerably reduced when the agents are used in combination [15,16,19]. Patients in the present study received extensive verbal and written instructions concerning the importance of compliance, and were carefully monitored as outpatients. This close attention to optimising compliance was probably an important factor in the good success rate seen in this patient group. Rifampicin and fusidic acid are generally welltolerated, as was the case in this study. Important known side-effects are nausea, allergic reactions and abnormalities in liver function test results [16]. Two patients in this study with MSSA infections developed nausea that was sufficiently severe to require a change in the antibiotic regimen. Nausea has been a limiting factor when these antibiotics have been used previously to treat orthopaedic implant infections [10,20]. A previous study evaluated the treatment of patients with staphylococcal orthopaedic implant infections with retention of the implant and a combination of rifampicin 900 mg ⁄ day with either fusidic acid 500 mg twice-daily or ofloxacin [20]. Cure rates for prosthetic joint infections were low (33% for knee prostheses and 41% for hip prostheses). Infected prostheses did not necessarily undergo early surgical debridement. Rifampicin-resistant staphylococci were responsible for most of the treatment failures in the fusidic acid group, resulting in the conclusion that fusidic acid 500 mg three-times-daily may have been more appropriate to prevent the emergence of rifampicin resistance. There was no significant difference in outcomes between the fusidic acid and ofloxacin groups. In the present study, patients generally underwent debridement via open arthrotomy, and debridements were repeated if necessary. Polyethylene liners of prostheses were changed, if possible, to enable greater access to infected tissues. There is already evidence that an approach involving more extensive surgical debridement results in better outcomes than less extensive or arthroscopic debridement [4]. Recommendations published recently include rifampicin in combination with fusidic acid as an option after debridement and prosthesis retention for the management of early prosthetic joint infections [21,22]. This option is particularly useful in the case of MRSA infections, where fluoroquinolone resistance is common, or where
the patient shows intolerance to fluoroquinolones. To our knowledge, the present study is the first to examine the efficacy of this treatment protocol. Although further controlled and prospective studies that include functional outcomes and shorter treatment durations are required, the present study suggests that debridement without prosthesis removal, combined with oral rifampicin and fusidic acid, is a good alternative for the treatment of early staphylococcal prosthetic joint infections. ACKNOWLEDGEMENTS We thank L. MacGregor for assistance with statistical analysis.
REFERENCES 1. Hebert CK, Williams RE, Levy RS, Barrack RL. Cost of treating an infected total knee replacement. Clin Orthop Relat Res 1996; 331: 140–145. 2. Steckelberg JM, Osmon DR. Prosthetic joint infections. In: Bisno AL, Waldvogel FA, eds, Infections associated with indwelling devices, 3rd edn. Washington, DC: American Society for Microbiology, 2000; 173–209. 3. Fitzgerald RH, Jones DR. Hip implant infection: treatment with resection arthroplasty and late total hip arthroplasty. Am J Med 1985; 78 (suppl 6B): 225–228. 4. Tsukayama DT, Estrada R, Gustilo RB. Infection after total hip arthroplasty: a study of the treatment of one hundred and six infections. J Bone Joint Surg 1996; 78: 512–523. 5. Lieberman JR, Callaway GH, Salvati EA, Pellicci PM, Brause BD. Treatment of the infected total hip arthroplasty with a two-stage reimplantation protocol. Clin Orthop Rel Res 1994; 301: 205–212. 6. Marculescu CE, Berbar EF, Hanssen AD et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis 2006; 42: 471–478. 7. Tattevin P, Cre´mieux A, Pottier P, Huten D, Carbon C. Prosthetic joint infection: when can prosthesis salvage be considered? Clin Infect Dis 1999; 29: 292–295. 8. Crockarell JR, Hanssen AD, Osmon DR, Morrey BF. Treatment of infection with debridement and retention of the components following hip arthroplasty. J Bone Joint Surg Am 1998; 80: 1306–1313. 9. Brandt CM, Sistrunk WW, Duffy MC et al. Staphylococcus aureus prosthetic joint infection treated with debridement and prosthesis retention. Clin Infect Dis 1997; 24: 914–919. 10. Zimmerli W, Widmer AF, Blatter M, Frei R, Oohsner PE. Role of rifampin for treatment of orthopedic implantrelated staphylococcal infections: a randomised controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998; 279: 1537–1541. 11. Barberan J, Aguilar L, Carroquino G et al. Conservative treatment of staphylococcal prosthetic joint infections in elderly patients. Am J Med 2006; 119: 993.e7–e10.
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12. Soriano A, Garcı´a S, Bori G et al. Treatment of acute postsurgical infection of joint arthroplasty. Clin Microbiol Infect 2006; 12: 930–933. 13. Diekema DJ, Pfaller MA, Schmitz FJ. Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY antimicrobial surveillance program, 1997–99. Clin Infect Dis 2001; 32 (suppl 2): S114–S132. 14. Nimmo GR, Bell JM, Mitchell D, Gosbell IB, Pearman JW, Turnidge JD. Antimicrobial resistance in Staphylococcus aureus in Australian teaching hospitals, 1989–1999. Microb Drug Resist 2003; 9: 155–160. 15. Turnidge J, Collignon P. Resistance to fusidic acid. Int J Antimicrob Agents 1999; 12 (suppl 2): S35–S44. 16. Kucers A, Crowe SM, Grayson ML, Hoy JF. The use of antibiotics: a clinical review of antibacterial, antifungal and antiviral drugs, 5th edn. Oxford: Butterworth-Heinemann, 1997.
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17. Gristina AG, Costerton JW. Bacterial adherence to biomaterials and tissue. J Bone Joint Surg 1985; 67A: 264–273. 18. Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G. Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clin Infect Dis 1998; 27 (suppl 1): S68–S74. 19. Widmer AF, Frei R, Rajacic Z, Zimmerli W. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis 1990; 162: 96–102. 20. Drancourt M, Stein A, Argenson JN, Roiron R, Groulier P, Raoult D. Oral treatment of Staphylococcus spp. infected orthopaedic implants with fusidic acid or ofloxacin in combination with rifampicin. J Antimicrob Chemother 1997; 39: 235–240. 21. Zimmerli W, Trampuz A, Oschner PE. Prosthetic-joint infections. N Engl J Med 2004; 351: 1645–1654. 22. Barberan J. Management of infections of osteoarticular prosthesis. Clin Microbiol Infect 2006; 12 (suppl 3): 93–101.
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 13, 586–591
10.1111/j.1469-0691.2007.01691.x
Treatment of staphylococcal prosthetic joint infections with debridement, prosthesis retention and oral rifampicin and fusidic acid C. A. Aboltins1, M. A. Page1, K. L. Buising1, A. W. J. Jenney1, J. R. Daffy1, P. F. M. Choong2 and P. A. Stanley1 1
Department of Infectious Diseases and 2Department of Orthopaedic Surgery, St Vincent’s Hospital, Melbourne, Victoria, Australia
ABSTRACT There is growing evidence of the efficacy of treating early staphylococcal infections of prosthetic joints with surgical debridement and prosthesis retention, combined with oral antibiotic regimens that include rifampicin in combination with a fluoroquinolone. With rising rates of fluoroquinolone-resistant staphylococci, evidence concerning the efficacy of alternative combinations of antibiotics is required. Twenty patients with staphylococcal prosthetic joint infections who had been treated with surgical debridement and prosthesis retention, and a combination of rifampicin and fusidic acid were analysed. The mean duration of symptoms before initial debridement was 16 (range 2–75) days. The median time of follow-up was 32 (range 6–76) months. Treatment failure occurred in two patients. The cumulative risk of treatment failure after 1 year was 11.76% (95% CI 3.08–39.40%). Two patients had their treatment changed because of nausea. Ten of 11 patients with infections involving methicillin-resistant Staphylococcus aureus had successful outcomes. Debridement without prosthesis removal, in combination with rifampicin and fusidic acid treatment, was effective and should be considered for patients with early staphylococcal prosthetic joint infections, including those with infections involving fluoroquinolone-resistant organisms. Keywords
Antibiotic regimens, debridement, fusidic acid, prosthetic joint infection, rifampicin, Staphylococcus spp.
Original Submission: 3 September 2006;
Revised Submission: 26 November 2006;
Accepted: 3 December 2006
Clin Microbiol Infect 2007; 13: 586–591
INTRODUCTION Prosthetic joint infection is an uncommon but serious complication of prosthetic joint implantation, resulting in substantial morbidity, often with pain, immobility, prolonged hospital stay and further surgery, and thus additional costs [1,2]. The approach of two-stage exchange arthroplasty has been preferred for the treatment of prosthetic joint infections in many centres. This has resulted in successful outcomes for >80% of patients with joint replacement infections in various studies [2– 4], but disadvantages include the technical difficulty of the surgery involved and the morbidity and costs of prolonged immobilisation of patients, who are often elderly [5]. Corresponding author and reprint requests: C. Aboltins, Department of Infectious Diseases, St Vincent’s Hospital, Victoria Pde, Fitzroy, Victoria, 3065 Australia E-mail: [email protected]
An alternative approach of debridement with prosthesis retention involves simpler surgery and potentially minimises the problems associated with prolonged immobilisation and hospitalisation. However, cure rates of infection are <40% in many studies. Where reported, such studies mostly included cases in which b-lactam-based antibiotic regimens were used, and a factor that was associated consistently with a higher risk of failure was a longer duration of symptoms before debridement [6–9]. Recent data have demonstrated the efficacy of treating patients with early (symptoms for <21 days) staphylococcal orthopaedic implant infections with retention and debridement of a stable prosthesis, combined with oral rifampicin and a fluoroquinolone [10–12]. However, fluoroquinolone resistance is now at high levels in nosocomial strains of staphylococci [13,14], thereby limiting the usefulness of rifampicin and fluoroquinolone combinations in this setting.
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases
Aboltins et al.
These organisms usually remain susceptible to fusidic acid [14], but there are few data available to support the use of fusidic acid in combination with rifampicin for prosthetic joint infections. Accordingly, the aim of the present study was to evaluate the efficacy and safety of treating staphylococcal prosthetic joint infections with debridement, prosthesis retention, and the specific antibiotic combination of rifampicin and fusidic acid.
Treatment of prosthetic joint infections 587
IL, USA) and agar dilution methods were used for isolates from 1998 and 1999, and the Vitek-2 system (bioMe´rieux, Durham, NC, USA) was used for isolates from 2000 until 2003. Isolates with a fusidic acid MIC £1 mg ⁄ L were considered to be susceptible. Statistical analysis The Kaplan–Meier method was used to estimate the 1-year cumulative risk of treatment failure.
RESULTS MATERIALS AND METHODS
Study population
Study design
In total, 29 patients were diagnosed at St Vincent’s Hospital as having a staphylococcal prosthetic hip or knee joint infection during the study period. Five of these patients were excluded from the study population because they underwent prosthesis removal and then either immediate (two patients) or delayed (three patients) joint re-implantation as the primary surgical treatment. Two patients were excluded because there was no initial surgical intervention. Two other patients were excluded because they received rifampicin and ciprofloxacin as oral antibiotic therapy. The medical records did not indicate reasons for the different surgical or medical treatment approaches taken for each patient. The remaining 20 patients formed the study population and met the inclusion criteria of treatment with surgical debridement, prosthesis retention, and rifampicin and fusidic acid. Characteristics of individual patients and their outcomes are summarised in Table 1. The median age of the study population was 76 years. Thirteen patients had hip joint replacements and seven had knee joint replacements. The indication for the original joint replacement surgery was osteoarthritis (15 patients), rheumatoid arthritis (three patients), aseptic loosening of a previous prosthesis (one patient), and reversal of a previous arthrodesis (one patient). Six patients had type 2 diabetes mellitus, and four were receiving immunosuppressive medication. The median duration from insertion of prosthesis until initial debridement (joint age) was 38 (range 12–743) days. The mean duration from onset of symptoms to initial debridement was 16 (range 2–75) days. No patient showed evidence of prosthesis loosening on X-rays or at initial debride-
A retrospective cohort analysis of a prospectively compiled register of all patients with prosthetic hip and knee joint infections at St Vincent’s Hospital, Melbourne, Australia, between 1998 and 2003 was performed. The clinical management of each patient was determined by the responsible clinicians. Surgical and medical therapies were not standardised for the purpose of the study, although it was common practice to treat prosthetic joint infections with a short duration of symptoms with surgical debridement, prosthesis retention and rifampicin in combination with fusidic acid. Prosthetic joint infections of longer duration (>3 months) were typically treated with removal of the prosthesis. Study population The study population consisted of consecutive patients who had undergone treatment with one or more surgical debridements with prosthesis retention for a staphylococcal prosthetic hip or knee joint infection, who then commenced treatment with rifampicin and fusidic acid. A period of intravenous antibiotics perioperatively with either a b-lactam or a glycopeptide was usual. Patients were excluded from the study if they had a joint replacement for a previously infected prosthesis, or if causative organisms other than staphylococci were isolated. Definitions A staphylococcal prosthetic joint infection was defined by the isolation of staphylococci from two or more deep culture specimens, or the isolation of staphylococci from one deep culture specimen together with either purulence surrounding the joint at the time of operation, a sinus tract communicating with the prosthesis, or acute inflammation demonstrated on histopathology of surgical specimens [9]. Treatment failure was defined as persistence or recurrence of symptoms or signs of prosthetic infection, the isolation of the same or different organisms from subsequent surgical samples, or the removal of the prosthesis while antibiotic therapy continued. Susceptibility testing Susceptibility testing of staphylococcal isolates was performed according to CLSI guidelines for agar and broth dilution. The MicroScan WalkAway system (Dade Behring Inc., Deerfield,
2007 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 13, 586–591
588 Clinical Microbiology and Infection, Volume 13 Number 6, June 2007
Table 1. Patient profiles and outcomes
Patient
Age (years)/ gender
Joint
Joint age (days)
Symptom duration (days)
Debridement procedures
Organism
Duration of intravenous antibiotics (days)
Duration of oral antibiotics (months)
Follow-up (months)
Treatment failure
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
75 ⁄ Male 76 ⁄ Female 63 ⁄ Male 58 ⁄ Male 75 ⁄ Female 61 ⁄ Female 63 ⁄ Male 71 ⁄ Male 80 ⁄ Male 80 ⁄ Female 74 ⁄ Male 58 ⁄ Male 81 ⁄ Female 83 ⁄ Male 74 ⁄ Female 73 ⁄ Female 59 ⁄ Male 64 ⁄ Female 72 ⁄ Female 74 ⁄ Female
Hip Hip Knee Hip Knee Hip Hip Hip Knee Hip Hip Knee Knee Hip Knee Hip Hip Hip Hip Knee
22 25 21 91 23 57 743 27 199 41 145 140 34 75 70 19 18 17 55 12
7 17 11 75 7 25 3 8 3 22 6 8 20 14 62 4 4 3 9 2
3 1 1 1 2 1 1 2 2 4 3 3 4 1 3 4 1 1 4 3
MRSA CNS MSSA, CNS MRSA MSSA MRSA MSSAc MRSA MSSAc MRSA MRSA MSSA MRSA MRSA MRSA MSSA MSSA MSSA MRSA, MSSA MRSA
10 3 5 6 18 8 10 29 14 12 18 21 9 5 19 14 12 8 19 14
12 11 12 12 12 6 21 24d 6 22 12 Ongoingd,f 11 28 11 17 24 12 33 12
29 24 65 28 27 31 47 63 6e 34 76 26 28 50 25 32 42 48 70 26
No No Yesa No No Yesb No No No No No No No No No No No No No No
MRSA, methicillin-resistant Staphylococcus aureus; CNS, coagulase-negative staphylococcus; MSSA, methicillin-susceptible S. aureus. a Prosthesis replaced after 12 months because of instability while still receiving antibiotics. No evidence of infection at further surgery. b Ongoing symptoms of infection with rifampicin-resistant CNS and Enterococcus faecalis isolated at change of prosthesis at 7 months. c Clinical features suggest infection possibly acquired by haematogenous seeding. d Antibiotic treatment modified because of nausea. e Patient died from unrelated cause during treatment. f Treatment duration extended because of immunosuppression.
ment. No patient had a definite sinus tract communicating with the joint. Microbiology The organism involved was methicillin-resistant Staphylococcus aureus (MRSA) in ten patients, methicillin-susceptible S. aureus (MSSA) in seven patients, a coagulase-negative staphylococcus (CNS) that was resistant to methicillin in one patient, MRSA mixed with MSSA in one patient, and MSSA mixed with methicillin-susceptible CNS in one patient. All isolates were susceptible to rifampicin and fusidic acid. All MRSA isolates were resistant to ciprofloxacin. All MSSA and CNS isolates were susceptible to ciprofloxacin. Surgical treatment The mean number of surgical debridements was 2.2 (range 1–4). All debridements were performed by open arthrotomy, and involved changing polyethylene liners where possible, removal of infected soft-tissue, and wash-out of the joint with high-pressure pulsatile lavage. Typically, the responsible physicians considered factors such as duration of symptoms, significant purulence of the joint at initial debridement, ongoing fever or ongoing wound discharge to assess whether repeated debridements were required.
Medical treatment The median duration of intravenous antibiotic treatment was 12 (range 3–29) days, and the median duration of hospitalisation for treatment of the infection was 20 (range 5–81) days. The median duration of oral antibiotic treatment was 12 (range 6–33) months. Typically, the duration of treatment was extended if symptom resolution was initially delayed or if patients were immunosuppressed. Doses administered were exclusively rifampicin 300 mg orally twice-daily and fusidic acid 500 mg orally three-times-daily. Patients were informed about the importance of compliance with the antibiotic regimen, and this information was reinforced with written patient information sheets. Two of the 20 patients reported nausea associated with rifampicin and fusidic acid treatment that was sufficiently severe to require a change of treatment. For patient 8, treatment was changed after 4 days to rifampicin plus ciprofloxacin, and for patient 12, after 2 weeks, to fusidic acid plus ciprofloxacin, both with subsequent improvement in nausea. These two patients were censored from the Kaplan–Meier estimation, but continued follow-up (Table 1). A further two patients experienced transient nausea, but were able to continue treatment. Two patients had transient mild rashes and
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pruritus early in treatment, which improved without discontinuation of treatment. Two patients had a perioperative thromboembolic episode, and one male patient had traumatic urinary bladder catheterisation during admission. There were no episodes of hepatoxicity. Follow-up Patients were followed closely as outpatients, with review initially on a monthly basis. The median duration of follow-up was 32 (range 6–76) months from the time of infection. The median time of follow-up after discontinuing antibiotics was 16 months. Outcomes There was no evidence of treatment failure for 18 patients. Sixteen of these patients retained their original prosthesis and were followed for >12 months after discontinuing antibiotics. One patient (patient 12) had no evidence of infection after 26 months of follow-up, but the responsible physicians chose to undertake a course of suppressive antibiotic therapy because of significant immunosuppression. One patient (patient 9) died 6 months after initial debridement from unrelated causes. There was evidence of treatment failure in two patients. In one of these patients (patient 6), who initially had an infection with MRSA, signs of infection were ongoing and further surgery was required 6 months after initial debridement. Intra-operative cultures yielded different organisms (a rifampicin-resistant CNS and an Enterococcus faecalis). In the other patient (patient 3), there was evidence of prosthetic loosening, with pain, after treatment for 12 months, and exchange arthroplasty was therefore undertaken. Histology of tissue taken during further surgery showed a foreign body-type reaction. There was no other clinical, biochemical or microbiological evidence of infection, and the patient remained free of signs of infection after a further 65 months. The cumulative risk of treatment failure at 1 year was 11.76% (95% CI 3.08–39.40%). Ten of 11 infections involving MRSA, eight of nine infections involving MSSA, and one of two infections with CNS were resolved.
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DISCUSSION The approach of debridement with prosthesis retention, combined with treatment with oral rifampicin and fusidic acid, was successful in this study, with only two of 20 patients failing treatment with this regimen after a median follow-up period of 32 months. The two patients who failed treatment did not show evidence of persistence of the original infecting organisms. The 1-year cumulative risk of treatment failure of 11.76% compares favourably with those in other studies examining treatment with debridement, prosthesis retention, and a combination of rifampicin and fluoroquinolones [10–12], in which up to 100% of patients who were able to complete the treatment had a successful outcome. Among a subgroup of 11 patients in the present study cohort who had MRSA infections, for whom fluoroquinolones were not a treatment option because of primary resistance, ten had a successful outcome. This was notably more successful than outcomes published previously concerning treatment of MRSA infections with prosthesis retention and other antibiotics [11,12]. It is important to note that the results of the present study cannot be generalised to all prosthetic joint infections. Each patient in the study exhibited several features that have been shown previously to be associated with good success rates, namely a short period of time from onset of symptoms until initial debridement, with a mean of 16 (range 2–75) days, a stable prosthesis, and the absence of a definite sinus tract [6–10]. The utility of the study treatment regimen in patients without these good prognostic factors is unknown. Rifampicin and fusidic acid have good activity against most staphylococci, and have retained activity against the majority of methicillin-resistant and fluoroquinolone-resistant staphylococci isolated in most parts of the world [14,15]. These antimicrobial agents are well-absorbed after oral administration, and demonstrate excellent penetration into tissues and the intracellular space [16]. Rifampicin has demonstrated excellent efficacy against slow-growing organisms and organisms associated with biofilms, both of which are important in the pathogenesis of infections involving prosthetic material [17–19]. Resistance develops quickly in staphylococcal infections when either of these antibiotics is used
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590 Clinical Microbiology and Infection, Volume 13 Number 6, June 2007
alone. However, the risk of emergence of resistance is considerably reduced when the agents are used in combination [15,16,19]. Patients in the present study received extensive verbal and written instructions concerning the importance of compliance, and were carefully monitored as outpatients. This close attention to optimising compliance was probably an important factor in the good success rate seen in this patient group. Rifampicin and fusidic acid are generally welltolerated, as was the case in this study. Important known side-effects are nausea, allergic reactions and abnormalities in liver function test results [16]. Two patients in this study with MSSA infections developed nausea that was sufficiently severe to require a change in the antibiotic regimen. Nausea has been a limiting factor when these antibiotics have been used previously to treat orthopaedic implant infections [10,20]. A previous study evaluated the treatment of patients with staphylococcal orthopaedic implant infections with retention of the implant and a combination of rifampicin 900 mg ⁄ day with either fusidic acid 500 mg twice-daily or ofloxacin [20]. Cure rates for prosthetic joint infections were low (33% for knee prostheses and 41% for hip prostheses). Infected prostheses did not necessarily undergo early surgical debridement. Rifampicin-resistant staphylococci were responsible for most of the treatment failures in the fusidic acid group, resulting in the conclusion that fusidic acid 500 mg three-times-daily may have been more appropriate to prevent the emergence of rifampicin resistance. There was no significant difference in outcomes between the fusidic acid and ofloxacin groups. In the present study, patients generally underwent debridement via open arthrotomy, and debridements were repeated if necessary. Polyethylene liners of prostheses were changed, if possible, to enable greater access to infected tissues. There is already evidence that an approach involving more extensive surgical debridement results in better outcomes than less extensive or arthroscopic debridement [4]. Recommendations published recently include rifampicin in combination with fusidic acid as an option after debridement and prosthesis retention for the management of early prosthetic joint infections [21,22]. This option is particularly useful in the case of MRSA infections, where fluoroquinolone resistance is common, or where
the patient shows intolerance to fluoroquinolones. To our knowledge, the present study is the first to examine the efficacy of this treatment protocol. Although further controlled and prospective studies that include functional outcomes and shorter treatment durations are required, the present study suggests that debridement without prosthesis removal, combined with oral rifampicin and fusidic acid, is a good alternative for the treatment of early staphylococcal prosthetic joint infections. ACKNOWLEDGEMENTS We thank L. MacGregor for assistance with statistical analysis.
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