1 Bristol Centre for Antimicrobial Research & Evaluation and 3 Department of Orthopaedics, Southmead Hospital, Bristol BS10 5NB, UK; 2 Institute of Antibiotics, Huashan Hospital, Fu Dan University, Shanghai 200040, Peoples Republic of China
Received 22 October 2001; returned 22 February 2002; revised 4 March 2002; accepted 21 March 2002
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Abstract |
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Introduction |
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Linezolid is rapidly absorbed following an oral dose to give concentrations similar to those following parenteral administration, with bioavailability c. 100%.47 Linezolid has a relatively high volume of distribution (c. 50 L in adults), and achieves levels in inflammatory fluid similar to those in blood, suggesting good penetration into extra-vascular sites and a possible role in the treatment of infections involving a wide range of soft tissue sites.8 Linezolid is cleared primarily through the renal route with a half-life of c. 5 h, which permits a twice daily dosing regimen.46
MRSA is an established problem in many hospitals across the world, causing problems of both colonization and nosocomial infection.9 When these infections involve either bone or joint prostheses they present a particularly difficult problem in patient management, frequently resulting in prolonged periods of hospitalization for parenteral therapy, and often only modest therapeutic success. As linezolid has both a microbiological and pharmacokinetic profile, which suggests a potential use in the treatment of such infections, we have evaluated the penetration of linezolid, after a single 600 mg iv dose, into the bone and associated fat and muscle of 12 patients undergoing routine total hip replacement and receiving standard prophylaxis with cefamandole.
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Materials and methods |
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This was approved by the local medical research ethics committee and all patients gave written informed consent. Twelve patients who had not received antimicrobials in the preceding 72 h and were to undergo routine hip replacement were enrolled into the study. Immediately before the induction of anaesthesia a 20 min infusion of 600 mg of linezolid followed by a single bolus of 1 g of cefamandole were administered through a forearm vein. The operation began immediately at the end of the infusion and all timings are expressed relative to this time point. Further doses of cefamandole were administered 8 and 16 h after the start of the operation and a further dose of linezolid was given 12 h after the start of the operation. Routine total hip replacement was carried out on all patients, and samples of bone, fat, muscle and blood were collected 10, 20 and 30 min after the start of the operation. Samples of the haematoma fluid draining from the operation site were collected over the periods 68, 1012 and 1416 h after the start of the operation, and samples of blood were collected at 8, 12 and 16 h immediately before the administration of further doses of cefamandole or linezolid. Blood and haematoma samples were centrifuged, and the supernatant removed and stored at 70°C along with the bone, fat and muscle samples until assayed.
HPLC assay procedures
Samples were assayed for the presence of cefamandole and linezolid by a high-performance liquid chromatography (HPLC) method that permitted the simultaneous assay of both agents, adapted from Tobin et al.10 Chromatography was performed on a Hypersil 5ODS column (HPLC Technology Ltd, Macclesfield, UK) using a mobile phase of methanol/water/phosphoric acid (30:69:1) with the addition of 2 g/L heptane sulphonic acid (Sigma Chemical Co.) and the pH adjusted to 4.5. Detection of both compounds was by UV absorbance at 254 nm with quantification by the external standard method. Serum and haematoma samples were diluted with an equal volume of acetonitrile, centrifuged at 5000g and 10 µL of the supernatant was injected into the chromatograph. Bone, fat and muscle samples were processed as previously described and the two antibiotics were extracted in phosphate-buffered saline (PBS) at 4°C for 5 h.11,12 In brief, bone samples (c. 0.5 g) were crushed, a volume of PBS equal to twice the weight of bone added (1 g 1 mL) and the antimicrobial agents extracted at 4°C for 5 h. Any samples with visible evidence of blood contamination were discarded and, where possible, the total sample collected was processed. After extraction the samples were centrifuged at 5000g and an aliquot of the aqueous layer was treated with acetonitrile, as described for serum samples. Samples of fat and muscle were treated as described for bone, but were finely sliced rather than crushed.
The assay response was linear over the concentration range 0.5100 mg/L, with a lower limit of detection of 0.1 mg/L for linezolid and 0.5 mg/L for cefamandole. Recovery of the two agents from spiked bone and fat samples was in the range 95110%, depending on drug, concentration and tissue, and for the purposes of this study was taken as 100%. Intra- and inter-day accuracy and precision were assessed by the use of quality control standards with limits for accuracy of 10% and coefficient of variability for precision of 5% used.
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Results |
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For all tissue samples the concentrations of cefamandole were significantly higher (Welchs t-test, P < 0.01) than those of linezolid, but when corrected for the simultaneous blood concentrations the penetration of linezolid into these tissues was significantly higher (P < 0.05).
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Discussion |
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Following a 600 mg infusion in patients undergoing routine hip arthroplasty, linezolid penetrated rapidly into bone, fat and muscle at the operation site, reaching peak concentrations at between 10 and 20 min after the end of the infusion. For bone, these concentrations were c. 50% of the simultaneous blood levels, whereas for muscle and fat they were c. 90% and 30%, respectively. In all but one bone sample the concentration of linezolid exceeded the MIC for susceptible pathogens (4 mg/L);1,3 concentrations in the other two samples from the same patient exceeded the MIC, but this sample also had a significantly lower cefamandole concentration than other samples. Although we are unable to offer an explanation for the apparently lower levels of both agents in this sample, it does highlight the heterogeneous nature and variable penetration of antimicrobials into bone, and further illustrates the complexity of such studies.11,12
With the soft tissue samples, fat concentrations of linezolid at the time of operation were similar to its MIC for susceptible pathogens, whereas muscle concentrations exceeded the MIC by a factor of three or four, suggesting good penetration into the tissues surrounding the bone. This is supported by the concentrations of linezolid found in the drainage from these tissues, which exceeded simultaneous blood levels for up to 12 h after dosing and were above the MIC for susceptible pathogens throughout the dosing interval.
The concentrations of cefamandole found in this study are in agreement with the findings of our earlier studies,11,12 and we found broad similarities in the bone and soft tissue disposition of linezolid and cefamandole. Both agents exhibit rapid penetration into the bone and soft tissues, with concentrations similar to or exceeding their MICs for susceptible pathogens at the time of operation. Inhibitory levels of both agents were also maintained in the haematoma around the operation site for the entire dosing interval. However, in making such comparisons it must be recognized that the two agents differ in their mode of action and other aspects, and that similar pharmacokinetic disposition in bone may not necessarily predict similarities in efficacy. Although these data have been obtained for healthy, well perfused bone the values for linezolid are similar to the single reported level of 9.0 mg/L for necrotic bone from a patient with osteomyelitis,14 suggesting that our findings may be relevant to treatment of infected tissue.
In conclusion, we find that linezolid has a similar distribution and penetration profile in bone and associated soft tissues to cefamandole, an agent that may be used in the treatment of infections in these tissues. This would indicate a potential role for linezolid in the management of such patients, in line with an encouraging clinical report,14 but further clinical evaluation is needed.
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Acknowledgements |
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Footnotes |
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References |
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