JAC Advance Access originally published online on October 22, 2002
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Journal of Antimicrobial Chemotherapy (2002) 50, 747-750
© 2002 The British Society for Antimicrobial Chemotherapy
Linezolid penetration into osteo-articular tissues
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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Penetration of linezolid into osteo-articular tissue and fluid was studied in 10 patients undergoing primary total knee replacement. Linezolid 600 mg 12 hourly was given orally over the 48 h before operation and intravenously 1 h before induction of anaesthesia. Mean concentrations of linezolid at 90 min after the final dose, in serum, synovial fluid, synovium, muscle and cancellous bone, assayed by HPLC, were at least twice the MIC90 for staphylococci and streptococci. The concentrations obtained indicate good penetration of this antibiotic and support its use in the management of multidrug-resistant Gram-positive bone, joint and deep-seated soft-tissue infections.
Keywords: linezolid, oxazolidinone, bone and joint infection, osteomyelitis, osteo-articular tissue, pharmacokinetics
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Introduction |
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Osteomyelitis and septic arthritis continue to be major problems in orthopaedic surgery. Prosthetic joint replacement has compounded the difficulties, allowing bacteria of low virulence with multiple antibiotic resistances to cause infection and often joint failure. Infections with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) or vancomycin-resistant enterococci (VRE) are real clinical challenges and result in significant morbidity and sometimes mortality. Management of these infections involves aggressive surgical debridement and combination antibiotic therapy. Treatment is usually prolonged, with few opportunities for effective oral therapy and early hospital discharge. In addition, there are increasing concerns over the emergence of glycopeptide resistance in Gram-positive organisms, as well as the difficulties of managing patients intolerant to these agents.
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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Subjects
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 71–88 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 44.5–93 kg) and mean serum creatinine was 105 µmol/L (range 73–161 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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Linezolid was well tolerated by all patients. The linezolid concentrations in the different tissues and fluid at 90 min following the final dose are shown in Table 1. Linezolid penetrated well into all compartments, achieving concentrations of >4 mg/L (the MIC90 for susceptible Gram-positive organisms7) in all but one of the specimens. The mean synovial fluid, synovium, muscle and bone penetration was 91.9%, 82.2%, 83.5% and 40.1% of the corresponding serum concentration, respectively (Table 2). There were no significant differences in the inflammatory indices of all but one patient with rheumatoid arthritis [erythrocyte sedimentation rate (ESR) 54, range 2–26; C-reactive protein (CRP) 32, range
10]. Overall, there was no correlation between patient weight or renal function and the linezolid concentration in serum, synovial fluid or muscle. However, the single patient with a linezolid concentration in bone of <4 mg/kg (3.3 mg/kg) was significantly heavier (93 kg) than the others (weight range 44.5–82 kg). This patient also had a lower concentration of linezolid in synovium (9 mg/kg, range for the other patients 12.3–25.5 mg/kg). However, for this patient, the linezolid concentrations in other compartments, including serum, were similar to those of the other patients (serum 18.6 mg/L, range for others 15.9–34.9 mg/L).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Linezolid is a recently licensed synthetic antimicrobial agent with excellent oral bioavailability and activity against many multidrug-resistant Gram-positive organisms, including MRSA, MRSE, penicillin-resistant pneumococci and VRE. Its high bioavailability has contributed to a reduction in the requirement for parenteral therapy (and hence the length of hospital stay) in patients with suspected or proven MRSA infection.8 Recent reports have described the successful use of linezolid in patients with complex multidrug-resistant Gram-positive infections, including orthopaedic infections.9 Longer-term outcome data on such patients are awaited with interest. Since most clinical studies of linezolid have been over less than 2 weeks of therapy, little is known about long-term toxicity. Recently, a small number of cases of reversible myelosuppression has been recorded in patients receiving prolonged therapy.10
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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This work was supported by a grant from Pharmacia.
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Footnotes |
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* Corresponding author. Tel: +44-141-211-2000; Fax: +44-141-339-0462
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References |
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1 . Shinabarger, D. L., Marotti, K. R., Murray, R. W., Lin, A. H., Melchior, E. P., Swaney, S. M. et al. (1997). Mechanisms of actions of oxazlidinones: effects of linezolid and eperezolid on translation reactions. Antimicrobial Agents and Chemotherapy 41, 2132–6.
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Rybak, M. J., Hershberger, E., Moldovan, T. & Grucz, R. G. (2000). In vitro activities of daptomycin, vancomycin, linezolid and quinupristin–dalfopristin against staphylococci and enterococci, including vancomycin-intermediate and -resistant strains. Antimicrobial Agents and Chemotherapy 44, 1062–6.
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. 65–75. Oxford University Press, Oxford, UK.
5
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Tobin, C. M., Sunderland, J., White, L. O. & MacGowan, A. (2001). A simple, isocratic high performance liquid chromatography (HPLC) assay for linezolid in human serum. Journal of Antimicrobial Chemotherapy 48, 605–8.
6
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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, 73–7.
7
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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, 225–30.
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, 263–74.[Web of Science][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.
10
.
Green, S., Maddox, J. C. & Huttenbach, E. D. (2001). Linezolid and reversible myelosuppression. Journal of the American Medical Association 285, 1291.
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