Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kutscha-Lissberg, F. Articles by Köller, M. Search for Related Content PubMed PubMed Citation Articles by Kutscha-Lissberg, F. Articles by Köller, M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2003, p. 3964-3966, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3964-3966.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Linezolid Penetration into Bone and Joint Tissues Infected with Methicillin-Resistant Staphylococci

Friedrich Kutscha-Lissberg,^* Ute Hebler, Gert Muhr, and Manfred Köller

Department of Surgery-Trauma Center, BG Kliniken Bergmannsheil-Universitätsklinik, Ruhr University, Bochum, Germany

Received 21 January 2003/ Returned for modification 13 June 2003/ Accepted 30 August 2003

Top Abstract Text References

 
Penetration of linezolid into bone and joint tissues was studied by high-performance liquid chromatography in 13 patients suffering from implant-associated infections with methicillin-resistant staphylococci. Mean concentrations of linezolid in infected tissues were greater than 10 mg/liter in a sampling time range of 35 to 124 min after administration of the preoperative dose, except in bone specimens, where they reached 3.9 ± 2.0 mg/liter.

Top Abstract Text References

 
Infection of bone and joint tissues remains one of the most severe problems in orthopedic and trauma orthopedic surgery. Multiresistant gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), are frequently identified pathogens (4). Linezolid is the first available oxazolidinone antibiotic with potent activity against gram-positive cocci (1). Linezolid was clinically and microbiologically proven as effective as standard vancomycin therapy for patients with MRSA infections (8). Oral and intravenous (i.v.) administrations of linezolid are completely bioequivalent (3, 10). Adequate penetration of an antibiotic into bone and joint infection sites is a prerequisite for antibiotic therapy. Recently, penetration of linezolid into noninfected bone, muscle, and hematoma fluid was determined during routine total hip and knee replacements (5, 7). However, the penetration of linezolid into infected osteoarticular tissues has not been studied. We therefore determined the linezolid concentrations in the bone and joint tissues of patients with confirmed infections due to methicillin-resistant staphylococci.

This study was approved by the local medical research ethics committee, and all patients gave written informed consent. The study extended from April 2002 to November 2002. Patients were eligible for enrollment if they met the following criteria: (i) bone and/or joint infection; (ii) infection caused by MRSA, MRSE, or vancomycin-resistant enterococci; and (iii) indication for surgical debridement of infected or necrotic bone and soft tissues.

The exclusion criteria were (i) concomitant use of a drug known to show adverse effects in combination with linezolid and (ii) untoward effects of linezolid. Enrolled were 13 patients (7 male, 6 female) with an average age of 66 ± 11 (range, 47 to 81) years and an infected total hip (n = 7) or knee (n = 2) endoprosthesis or exacerbation of chronic osteomyelitis in the presence of orthopedic implants (n = 4). Infection was diagnosed 6 to 30 months before study enrolment. Table 1 shows the demographic and clinical data of the patients. A dose of 600 mg of linezolid (Zyvoxid; Pharmacia GmbH, Erlangen, Germany) was administered i.v. for 30 min during induction of anesthesia. Three patients were pretreated with linezolid for 24 h (two i.v. doses of 600 mg). In the postoperative period, 600 mg of linezolid was administered every 12 h i.v. or orally for different periods, as clinically indicated.

View this table: [in this window] [in a new window]

TABLE 1. Patients' demographic and clinical data

During surgical debridement of necrotic and infected tissues, samples were collected in a time range of 35 to 124 min after linezolid infusion began. Simultaneously, 2 ml of peripheral venous EDTA-anticoagulated blood was drawn separately. Transport of tissue and blood samples to the laboratory followed immediately. Plasma was obtained by blood centrifugation (5 min, 2,000 x g). All samples were frozen at -80°C prior to assay. Thawed tissue specimens (0.2 to 0.7 g) were rapidly rinsed with phosphate-buffered saline until a clear supernatant was obtained. Bone samples free of connective tissue were crushed with an analytic mill (IKA A11 basic; IKA-Werke GmbH, Staufen, Germany). Other tissue samples were sliced into small pieces (up to 5 mm). The hacked-up tissue samples were transferred into a porcelain mortar, covered with fluid nitrogen, and further ground up with a pestle. Subsequently, the ground material was transferred to a 20-ml glass tube, 5 ml of acetonitrile-methanol (50/50, vol/vol) was added, and the mixture was stirred for 2 h at room temperature with crosshead magnetic stirring bars. Linezolid was extracted from plasma by addition of 1.9 ml of acetonitrile-methanol (50/50, vol/vol) to a 100-µl sample volume. This mixture was vigorously vortexed and allowed to settle for 2 h at room temperature. Finally, the mixture was centrifuged at 16,000 x g (Biofuge pico; Kendro Laboratory Products, Hanau, Germany) and aliquots of 20 µl of the supernatants were subjected to reversed-phase high-performance liquid chromatography (HPLC). Isocratic HPLC was performed with a Waters 2690 separation module (Waters, Eschborn, Germany) consisting of a multiple-solvent delivery system and an automatic sample injection module (Waters Alliance System). Samples were separated by a Waters Symmetry C₁₈ reversed-phase column (4.6 by 150 mm, 5-µm particles) that was protected by a Waters Sentry C₁₈ guard column (3.9 by 20 mm, 5-µm particles). The absorbance of the column effluent was monitored with a Waters 2487 dual-wavelength absorbance detector adjusted to 254 nm. The peak areas were calculated with a chromatography manager program (Millennium 2.15.01; Waters). The linezolid detection solvent system was 30% methanol supplemented with 1% ortho-phosphoric acid and heptanesulfonic acid (2 g/liter), which was adjusted to pH 5.0 with sodium hydroxide (10 M) as previously described by Tobin et al. (9). The flow rates were maintained at 1 ml/min. The solvent was automatically degassed and constantly stirred during HPLC analysis. Identification and quantification of linezolid were performed by external standardization. The linearity of peak areas to drug concentration was r = 0.9999 across a concentration range of 0.02 to 200 mg of linezolid per liter. The lower limit of quantification (9) was calculated to be 0.01 mg/liter. Linezolid recovery from spiked tissue samples was in the range of 95 to 110%, similar to that reported by others (2, 5). Assay reproducibility was as follows: intraday, <5%; interday, <11%. Data are expressed as means ± standard deviations and data ranges (minimal and maximal values).

The linezolid concentrations in infected tissues (from either knee or hip joints) rapidly reached mean values greater than 10 mg/liter after administration of the preoperative 600-mg i.v. dose (sampling time range of 35 to 124 min after infusion start), except for bone specimens, in which they reached a mean of 3.9 ± 2.0 mg/liter (Table 2) in spite of sufficient parallel concentrations in plasma (>11 mg/liter). Mean penetration of linezolid into noninfected bone tissue has also been determined: 6.3 or 8.5 mg/liter (5, 7). Since our analytical linezolid detection method is more sensitive than previously described methods (2, 9) and we obtained linezolid tissue recoveries similar to those previously reported (2, 5, 9), we suggest that differences in linezolid concentrations in bone may be due to differences in sample preparation or to an inflammation-related decrease in the blood supply to the infected bone. In addition, two patients were admitted for revision surgery 9 and 15 days after the initial surgery. These patients continuously received standard linezolid therapy between the two operations. The linezolid concentrations in their bone samples were 4.6 and 2.5 mg/liter, respectively (not listed in Table 2). Furthermore, two pure corticalis bone specimens free of any adherent tissue and extracted without the washing step revealed linezolid concentrations of 0.8 and 1.4 mg/liter (not listed in Table 2).

View this table: [in this window] [in a new window]

TABLE 2. Resection time and linezolid concentration in tissue samples

In summary, our data indicate that linezolid rapidly reaches infected tissue compartments of joints and the tissues surrounding bone in concentrations greater than twice the MIC for 90% of the strains tested (1 to 2 mg/liter for MRSE, 1 to 4 mg/liter for MSSA, MRSA, and Enterococcus faecalis) (6). However, intra-bone tissue concentrations of linezolid below the MIC for 90% of the strains tested also occur; thus, an aggressive surgical approach to bone infection should be taken if possible.

 
This work was supported by a noncommercial institutional grant from the Wissenschaftskommission of the Bergmannsheil Bochum.

 
* Corresponding author. Mailing address: BG Kliniken Bergmannsheil-Universitätsklinik, Chirurgische Klinik, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany. Phone: 0049-234-3026500. Fax: 0049-234-3026542. E-mail: Friedrich.Kutscha-Lissberg{at}ruhr-uni-bochum.de.

Top Abstract Text References

 

1
1. Batts, D. H. 2000. Linezolid—a new option for treating gram-positive infections. Oncology (Huntington) 14:23-29.
2
2. Borner, K., E. Borner, and H. Lode. 2001. Determination of linezolid in human serum and urine by high-performance liquid chromatography. Int. J. Antimicrob. Agents 18:253-258.[CrossRef][Medline]
3
3. Gee, T., R. Ellis, G. Marshall, J. Andrews, J. Ashby, and R. Wise.2001 . Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob. Agents Chemother. 45:1843-1846.[Abstract/Free Full Text]
4
4. Haddadin, A. S., S. A. Fappiano, and P. A. Lipsett. 2002. Methicillin resistant Staphylococcus aureus (MRSA) in the intensive care unit. Postgrad. Med. J. 78:385-392.[Abstract/Free Full Text]
5
5. Lovering, A. M., J. Zhang, G. C. Bannister, B. J. Lankester, J. H. Brown, G. Narendra, and A. P. MacGowan. 2002. Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. J. Antimicrob. Chemother. 50:73-77.[Abstract/Free Full Text]
6
6. Norrby, R. 2001. Linezolid—a review of the first oxazolidinone. Expert Opin. Pharmacother. 2:293-302.[CrossRef][Medline]
7
7. Rana, B., I. Butcher, P. Grigoris, C. Murnaghan, R. A. Seaton, and C. M. Tobin. 2002. Linezolid penetration into osteo-articular tissues. J. Antimicrob. Chemother. 50:747-750.[Abstract/Free Full Text]
8
8. Stevens, D. L., D. Herr, H. Lampiris, J. L. Hunt, D. H. Batts, and B. Hafkin. 2002. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin. Infect. Dis. 34:1481-1490.[CrossRef][Medline]
9
9. Tobin, C. M., J. Sunderland, L. O. White, and A. P. MacGowan. 2001. A simple, isocratic high-performance liquid chromatography assay for linezolid in human serum. J. Antimicrob. Chemother. 48:605-608.[Abstract/Free Full Text]
10
10. Welshman, I. R., T. A. Sisson, G. L. Jungbluth, D. J. Stalker, and N. K. Hopkins.2001 . Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm. Drug Dispos. 22:91-97.[CrossRef][Medline]

---

Antimicrobial Agents and Chemotherapy, December 2003, p. 3964-3966, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3964-3966.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Bayston, R., Nuradeen, B., Ashraf, W., Freeman, B. J. C. (2007). Antibiotics for the eradication of Propionibacterium acnes biofilms in surgical infection. J Antimicrob Chemother 60: 1298-1301 [Abstract] [Full Text]  
• Stein, G. E., Schooley, S., Peloquin, C. A., Missavage, A., Havlichek, D. H. (2007). Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections. J Antimicrob Chemother 60: 819-823 [Abstract] [Full Text]  
• Buerger, C., Plock, N., Dehghanyar, P., Joukhadar, C., Kloft, C. (2006). Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis.. Antimicrob. Agents Chemother. 50: 2455-2463 [Abstract] [Full Text]  
• De Beeck, V. O., Dhif, N., Philipp, J., De Bels, D. (2006). Comment on: Linezolid use in sepsis due to methicillin-susceptible Staphylococcus aureus. J Antimicrob Chemother 57: 577-577 [Full Text]  
• De Gascun, C., Rajan, L., O'Neill, E., Smyth, E. G. (2006). Linezolid use in sepsis due to methicillin-susceptible Staphylococcus aureus. J Antimicrob Chemother 57: 150-151 [Full Text]  
• Weigelt, J., Itani, K., Stevens, D., Lau, W., Dryden, M., Knirsch, C., the Linezolid CSSTI Study Group, (2005). Linezolid versus Vancomycin in Treatment of Complicated Skin and Soft Tissue Infections. Antimicrob. Agents Chemother. 49: 2260-2266 [Abstract] [Full Text]  
• De Bels, D., Garcia-Filoso, A., Jeanmaire, M., Preseau, T., Miendje, Y., Devriendt, J. (2005). Successful treatment with linezolid of septic shock secondary to methicillin-resistant Staphylococcus aureus arthritis. J Antimicrob Chemother 55: 812-813 [Full Text]  
• Schriever, C., Zeitz-Colaizzi, L., Quinn, A., Schriever, A. E., Cannon, J. P. (2005). Considerations for the Management of Gram-Positive Pathogens in the Intensive Care Unit. Journal of Pharmacy Practice 18: 100-108 [Abstract]  
• Bassetti, M., Vitale, F., Melica, G., Righi, E., Di Biagio, A., Molfetta, L., Pipino, F., Cruciani, M., Bassetti, D. (2005). Linezolid in the treatment of Gram-positive prosthetic joint infections. J Antimicrob Chemother 55: 387-390 [Abstract] [Full Text]  
• Stein, G. E, Schooley, S. L, Peloquin, C. A, Kak, V., Havlichek, D. H, Citron, D. M, Tyrrell, K. L, Goldstein, E. J. (2005). Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis. The Annals of Pharmacotherapy 39: 427-432 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kutscha-Lissberg, F. Articles by Köller, M. Search for Related Content PubMed PubMed Citation Articles by Kutscha-Lissberg, F. Articles by Köller, M.