1 Infectious Diseases Department, University of Genoa School of Medicine, San Martino Hospital; 2 Orthopaedic Department, University of Genoa School of Medicine, Genoa, Italy
Received 16 July 2004; returned 28 September 2004; revised 24 November 2004; accepted 9 December 2004
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Abstract |
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Materials and methods: A retrospective evaluation of patients hospitalized in the Department of Infectious Diseases of San Martino Hospital in Genoa with the diagnosis of Gram-positive prosthetic joint infection and treated with intravenous and/or oral linezolid. Primary end points were the patient clinical outcome at the end of treatment and at long-term follow-up (up to 12 months after the end of treatment).
Results: Between May 1999 and September 2003, 20 patients with prosthetic joint infection were treated with linezolid. Pathogens isolated were: methicillin-resistant Staphylococcus aureus (MRSA), 14 strains; methicillin-resistant coagulase-negative staphylococci, five strains; and Enterococcus spp., one strain. The overall duration of treatment was 7.2 ± 2 weeks (range 610 weeks). Patients were given intravenous therapy for 37 days as inpatients, then were changed as outpatients to oral therapy under weekly laboratory testing. At long-term follow-up (1 year), we observed four cases of failure due to relapsing infections. The other 16 patients treated with linezolid did not need further surgical substitution of prosthesis or surgical joint revision. Linezolid was well tolerated, and no drug-related events leading to discontinuation of treatment were recorded.
Conclusions: Our data indicate that linezolid may be an effective alternative therapy for orthopaedic infections caused by Gram-positive resistant pathogens and that a prospective and comparative evaluation of linezolid in this setting is necessary.
Keywords: Staphylococcus aureus , Staphylococcus epidermidis , safety , efficacy , hips , knees
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Introduction |
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The treatment of infections following total joint arthroplasty involves surgery and antimicrobial treatment. Complete removal of all foreign materials is essential, while simple surgical drainage coupled with a finite course of antibiotics is characterized by a high failure rate.2 A two-stage re-implantation is considered the standard surgical procedure in the treatment of septic prosthetic joints. However, when prosthetic removal is not possible or contraindicated, suppressive antibiotic therapy with retention of the functioning joint arthroplasty may be considered.
Linezolid is a recently introduced oxazolidinone compound for the treatment of serious Gram-positive infections. Oral and intravenous administrations of linezolid are completely bioequivalent. The drug has a favourable pharmacokinetic profile and penetrates in high concentrations into osteo-articular tissue.35 However, clinical experience with linezolid in the treatment of bone and joint infections is limited.6,7
Herein we report on the results of a retrospective study of oral/parenteral linezolid treatment of 20 patients with Gram-positive prosthetic hip and knee infections.
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Patients and methods |
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Data on risk factors for primary prosthetic joint infection (rheumatoid arthritis, diabetes mellitus, poor nutritional status, obesity, concurrent urinary tract infection, steroid therapy, malignancy and post-operative surgical site infection) or for revision procedures (prior joint surgery, preoperative infection of teeth, skin or urinary tract) were recorded.
Linezolid was given at the start of treatment intravenously on an inpatient basis, and then orally on an outpatient basis. We also included patients pre-treated with other antibiotic therapies.
Patients were monitored at the end of treatment (within 72 h after the last dose of study medication), and returned for follow-up visits when deemed necessary on clinical grounds and/or every 3 months (up to 12 months after the end of treatment). Clinical outcomes were categorized as follows: cure and improvement, resolution of clinical signs and symptoms of infection, eradication of Gram-positive infection, a CRP level below 5 mg/L, reduction in ESR when compared with baseline, and the absence of radiological signs of loosening, pseudarthrosis or dislocation of the artificial joint at follow-up visits; and failure, persistence or progression of baseline clinical signs and symptoms of infection, persistence or relapse of positive microbiological culture, progression of baseline infection-related radiographic abnormalities, increase in ESR and CRP, and development of new clinical findings consistent with active infection.
The isolates were identified by standard techniques. MICs of linezolid were determined by Etest (AB Biodisk, Solna, Sweden). Biochemical and haematological analyses were carried out weekly throughout the treatment period.
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Results |
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Patients received linezolid 600 mg twice daily intravenously for the first 37 days, then orally. The overall duration of treatment was 7.2 ± 2 (range 610 weeks).
Assessment of efficacy at the end of treatment showed that all the 20 treated patients achieved clinical and microbiological cure. At long-term follow-up, we observed four cases of failure due to relapsing infections (three strains of MRSA, and one strain of methicillin-resistant coagulase-negative Staphylococcus). MICs of linezolid for relapsing isolates were the same as those for initial isolates. The other 16 patients (80%) treated with linezolid did not need further surgical substitution of prosthesis or surgical joint revision.
Linezolid was well tolerated, and no drug-related events leading to discontinuation of treatment were recorded. In particular, we did not observe relevant haematological abnormalities, such as anaemia, leucopenia and thrombocytopenia. Only mild to moderate untoward events were observed in three patients, which included diarrhoea, vomiting and decreased appetite.
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Discussion |
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In this study, linezolid was found to be effective and well tolerated in the treatment of Gram-positive prosthetic joint infections.
Long-term antibiotic therapy without any adjunctive surgical intervention is frequently unsuccessful in the treatment of prosthetic joint infections. However, chronic antimicrobial suppression without surgery might be taken into consideration when removal of the prosthesis is not feasible, there are no signs of systemic infection, the prosthesis is not already loose, and when the patient is able to adhere to long-term antibiotic treatment.
To our knowledge, the clinical experience with linezolid for conservative treatment of prosthetic joint infection is extremely limited. In our department, we have already successfully used linezolid in two patients with MRSA prosthetic joint infections.6 The efficacy of linezolid in the long-term treatment of a case of methicillin-resistant S. epidermidis prosthetic hip infection has also emerged from another report.7
Therapeutic options for the treatment of methicillin-resistant staphylococcal infections are limited, and new antimicrobial agents are needed. Linezolid is a recently approved agent for the treatment of these infections. An important advantage of linezolid over glycopeptides is the oral administration that reduces time of hospitalization and increases the compliance, especially when the duration of therapy is considerable, as in the treatment of prosthetic joint infections.
Various adverse events have been associated with linezolid therapy, the most serious of these are bone marrow suppression leading to anaemia, leucopenia and thrombocytopenia, and toxic optic neuropathy resulting in rapid visual loss.15,16 Myelosuppression has been reported in patients receiving linezolid for > 2 weeks, and the drug at present is not recommended for more than 28 days.10 However, in a comparative evaluation, linezolid has been used for a longer period in 20 patients with orthopaedic infections.17 As the haematological effects were detectable through weekly monitoring and were reversible, the authors conclude that concerns about myelosuppression do not preclude linezolid use for orthopaedic infections requiring long-term therapy. Likewise, we did not observe any serious adverse event related to linezolid use in our patients, where the median duration of linezolid treatment was 7.2 weeks.
Within the limitations of the study design, the data presented here provide a further basis for the clinical use of linezolid in the treatment of prosthetic joint infections. Our data indicate that linezolid may be an effective alternative therapy for orthopaedic infections caused by Gram-positive resistant pathogens and that a prospective and comparative evaluation of linezolid in this setting is necessary.
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References |
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