Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement

Abstract

Twelve patients undergoing total hip replacement were given 600 mg of linezolid as a 20 min iv infusion along with conventional prophylaxis of 1 g of cefamandole immediately before surgery. Routine total hip arthroplasty was carried out, and at timed intervals during surgery samples of bone, fat, muscle and blood were collected for assay by high-performance liquid chromatography analysis. Samples of the haematoma fluid that formed around the operation site and further blood samples for assay were also collected at timed intervals following the operation. The penetration of linezolid into bone was rapid, with mean concentrations of 9.1 mg/L (95% CI 7.7-10.6 mg/L) achieved at 10 min after the infusion, decreasing to 6.3 mg/L (95% CI 3.9-8.6 mg/L) at 30 min. Correction for the simultaneous blood concentrations gave mean values for bone penetration of 51% at 10 min, 60% at 20 min and 47% at 30 min. Although the penetration of linezolid into fat was also rapid, mean concentrations and degree of penetration were c. 60% of those in bone; at 10 min they were 4.5 mg/L (95% CI 3.0-6.1 mg/L; penetration 27%); at 20 min they were 5.2 mg/L (95% CI 4.0-6.4 mg/L; penetration 37%); and at 30 min, 4.1 mg/L (95% CI 3.3-4.8 mg/L; penetration 31%). For muscle the corresponding values were 10.4 mg/L (95% CI 8.1-12.7 mg/L; penetration 58%) at 10 min, 13.4 mg/L (95% CI 10.2-16.5 mg/L; penetration 94%) at 20 min and 12.0 mg/L (95% CI 9.2-14.8 mg/L; penetration 93%) at 30 min. Mean concentrations of linezolid in the haematoma fluid drained from around the operation site were 8.2 mg/L at 6-8 h and 5.6 mg/L at 10-12 h after the infusion, and 7.0 mg/L at 2-4 h following a second 600 mg infusion given 12 h post-operatively. We conclude that linezolid exhibits rapid penetration into bone, fat and muscle of patients undergoing hip arthroplasty, to achieve levels in excess of its MIC for susceptible organisms (< or=4 mg/L); therapeutic concentrations were maintained in the haematoma fluid that surrounds the operation site for >16 h.

Linezolid versus Vancomycin in Treatment of Complicated Skin and Soft Tissue Infections

“…In addition, the MSSA group was smaller, making statistical significance more difficult to achieve. The better outcomes among MRSA-infected patients also could be related to the enhanced skin and tissue penetration of linezolid (12,20,26,34) or to the inadequate dosing of vancomycin. The consensus on evidence-based guidelines for dosing vancomycin is poor (43).…”

Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses

“…Most of the recent PK data for linezolid available in the literature focused on plasma concentrations (15), skin blister studies (8), and tissue biopsy specimens (14). Nevertheless, none of these techniques are capable of the assessment of the free concentrations of linezolid in tissues, which more accurately reflect the site of infection and drug action.…”

Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production <i>via</i> Phosphorylation of Myosin Light Chain 2

“…Indeed, in a previous study, the penetration efficacy of LZD into bone and muscle was 60 and 94%, respectively, at 20 min post-infusion. 4) Meanwhile, Komatsu et al reported LZD penetration efficacies of 88 and 84% into the bone marrow and iliopsoas muscles of rabbits, respectively, at 0.33 h post-injection. 33) Moreover, the LZD concentration was reported to be 1.6-fold higher in the cerebrospinal fluid than in the plasma of patients with central nervous system infections.…”

“…Furthermore, LZD is expected to maintain its therapeutic efficacy in tissues associated with poor blood flow (e.g., bronchoalveolar lavage, inflammatory fluid, bone, fat, muscle, and cerebrospinal fluid), making it an ideal option for treatment of deep-tissue infections. [2][3][4][5] Lastly, as the bioavailability of LZD is approximately 100%, 6) it is possible to switch from intravenous to oral administration while using the same dosage. Although these advantages make LZD an excellent antimicrobial agent, administration of LZD has been reported to cause adverse side effects such as gastrointestinal disturbances, thrombocytopenia, decreased hemoglobin/hematocrit levels, and cutaneous reactions.…”