1 University Department of Orthopaedics, 2 Department of Microbiology and 3 Department of Infectious Diseases, Western Infirmary and Gartnavel General Hospital, Dumbarton Road, Glasgow G11 6NT, UK; 4 Bristol Centre for Antimicrobial Research and Evaluation, Department of Microbiology, Southmead Hospital, Bristol BS10 5NB, UK
Received 8 November 2001; returned 26 June 2002; revised 29 July 2002; accepted 19 August 2002
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Abstract |
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Keywords: linezolid, oxazolidinone, bone and joint infection, osteomyelitis, osteo-articular tissue, pharmacokinetics
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Introduction |
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Linezolid is the first of the oxazolidinone group of synthetic antibiotics.1 It has excellent oral bioavailability and activity against clinical isolates of staphylococci and enterococci, including strains resistant to ß-lactams and glycopeptides,2 suggesting a potential role in the management of bone and joint infections.
To date, linezolid has been shown to be effective in a variety of infections caused by Gram-positive cocci, including those where the use of glycopeptide antibiotics was not tolerated.3 Currently there are no published data regarding the penetration of linezolid at steady state into osteo-articular tissues. Herein we describe the distribution of linezolid into such tissues in volunteers undergoing primary total knee arthroplasty.
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Materials and methods |
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Approval for the study was granted by the West Ethics Committee (Greater Glasgow Health Board). Ten patients (five male, five female) with a mean age of 78 years (range 7188 years) undergoing primary total knee arthroplasty for osteoarthritis (nine) and rheumatoid arthritis (one) were recruited. All gave informed written consent. Their mean weight was 67.6 kg (range 44.593 kg) and mean serum creatinine was 105 µmol/L (range 73161 µmol/L). The exclusion criteria were linezolid hypersensitivity, uncontrolled hypertension, severe hepatic or renal impairment, psychiatric disorder, haematological malignancy or myelosuppression, concomitant use of monoamine oxidase (MAO) inhibitors, cold remedy, adrenergic bronchodilators, pethidine and buspirone therapy.
Drug administration
Patients were given linezolid 600 mg orally 12 hourly for 48 h before surgery. The final 600 mg dose was given intravenously 1 h before induction of anaesthesia. Routine antibiotic prophylaxis with intravenous cefuroxime (1.5 g) was given 20 min before inflation of the tourniquet.
Sampling
Total knee replacement was carried out in all patients with a tourniquet applied immediately after induction of anaesthesia. Samples of serum, synovial fluid, synovium, muscle and cancellous bone were collected 30 min after induction. Samples were frozen at 70°C prior to assay.
Drug assay
Linezolid was extracted from tissue samples using the method described by Andrews.4 Briefly, tissue samples were ground, weighed, mixed with twice the volume of phosphate-buffered saline and placed at 4°C for 5 h, for drug extraction. After centrifugation (2000 rpm for 10 min), the supernatant was removed, mixed with acetonitrile (50:50) and centrifuged for a further 5 min. Serum samples were also prepared for assay in this way.
Linezolid was quantified in serum and tissue by HPLC.5 A 20 µL injection volume was used. The stationary phase was Hypersil 5ODS, 10 cm x 4.6 mm (HPLC Technology Ltd, Macclesfield, UK). The mobile phase was 1% ortho-phosphoric acid, 30% methanol, 2 g/L 1-heptane sulphonic acid, adjusted to pH 5 by the addition of 10 M sodium hydroxide. The pump flow rate was 1.0 mL/min. Detection was by UV absorbance (max 254 nm). Linezolid recovery from tissue samples was 100% in an evaluation study.6 The linezolid retention time was
6 min and cefuroxime caused no chromatographic interference.5 The intra-day reproducibility, expressed as the standard deviation/mean x 100, was <6% for quality-control samples containing 5, 15 or 30 mg/L linezolid. The inter-day reproducibility was <12.5%.
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Results |
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Discussion |
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Lovering et al.,6 in a recently published study, found that linezolid penetrates rapidly into bone, fat and muscle of patients undergoing hip arthroplasty. The linezolid concentrations achieved were in excess of its MIC90 for susceptible organisms (4 mg/L) following administration of a single pre-operative intravenous 600 mg dose. However, we are unaware of any data describing the steady-state distribution of linezolid into osteo-articular tissues in humans. Our study in healthy, but elderly, patients has demonstrated that at steady state, linezolid penetrates osteo-articular tissues well. Synovial fluid, synovium, muscle and bone penetration was 91.9%, 82.1%, 83.5% and 40.1%, respectively. In all but one patient, concentrations above the MIC90 for Gram-positive organisms were achieved in bone. This particular patient attained a high concentration of linezolid in all tissues except bone and synovium. This may have been due to his significantly heavier body mass compared with other patients.
It would seem prudent that linezolid should be reserved for treatment of multidrug-resistant Gram-positive bone and joint infections, such as MRSA, coagulase-negative staphylococci and resistant enterococci, when patients are intolerant of glyopeptide agents. Factors likely to encourage the development of linezolid resistance in established VRE and MRSA infections are prolonged therapy, failure to remove an infected device and, probably, suboptimal concentrations of linezolid in target sites. Clearly, these risk factors are relevant for patients with bone and prosthetic joint infections and should be considered when prescribing any antibiotic or combination of antibiotics.
In conclusion, our data suggest adequate penetration of linezolid into osteo-articular tissues and fluid. Linezolid may be a useful agent in the management of multidrug-resistant Gram-positive bone and joint infections as well as deep-seated soft-tissue infections; however, further clinical studies are required to prove its efficacy in such cases.
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Acknowledgements |
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Footnotes |
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References |
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2
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Rybak, M. J., Hershberger, E., Moldovan, T. & Grucz, R. G. (2000). In vitro activities of daptomycin, vancomycin, linezolid and quinupristindalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrobial Agents and Chemotherapy 44, 10626.
3 . Moise, P. A., Birmingham, M. C., Forrest, A. & Schentag, J. J. (2000). Linezolid use in patients who are intolerant to or fail vancomycin. In Proceedings of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 16 September 2000. Abstract 2233, p. 487. American Society for Microbiology, Washington, DC, USA.
4 . Andrews, J. M. (1999). The assay of antimicrobials in tissues and fluids. In Clinical Antimicrobial Assays (Reeves, D. S., Wise, R., Andrews, J. M. & White, L. O., Eds), pp. 6575. Oxford University Press, Oxford, UK.
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Lovering, A. M., Zhang, G., Bannister, G. C., Lankester, B. J. A., Brown, J. H. M., Narendra, G. et al. (2002). Linezolid penetration into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. Journal of Antimicrobial Chemotherapy 50, 737.
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Johnson, A. P., Warner, M. & Livermore, D. M. (2000). Activity of linezolid against multi-resistant Gram-positive bacteria from diverse hospitals in the United Kingdom. Journal of Antimicrobial Chemotherapy 45, 22530.
8 . Li, Z., Willke, R. J., Pinto, L. A., Rittenhouse, B. E., Rybak, M. J., Pleil, A. M. et al. (2001). Comparison of length hospital stay for patients with known or suspected methicillin resistant Staphylococcus species infections treated with linezolid or vancomycin: a randomised, multicenter trial. Pharmacotherapy 21, 26374.[ISI][Medline]
9 . Bassetti, M., Cenderello, G., Di Biagio, A., Del Bono, V., Rosso, R., Gatti, G. et al. (2000). Linezolid treatment for prosthetic hip infections due to methicillin-resistant Staphylococcus aureus (MRSA). In Proceedings of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 16 September 2000. Abstract 2231, p. 487. American Society for Microbiology, Washington, DC, USA.
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