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Clinical Pharmacokinetics of Linezolid, a Novel Oxazolidinone Antibacterial

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Abstract

Linezolid is the first antibacterial to be approved from the oxazolidinone class. The drug has substantial antimicrobial activity against Gram-positive organisms such as streptococci, staphylococci and enterococci, including species resistant to conventional antibacterial treatment.

Linezolid is fully bioavailable following oral administration when compared with intravenous administration. Maximum plasma linezolid concentrations are usually achieved between 1 and 2 hours after oral administration. Food slightly decreases the rate, but not the extent, of absorption. The distribution of linezolid is approximately equivalent to total body water, and there is low protein binding (31%) to serum albumin.

The elimination half-life of linezolid is 5–7 hours, and twice-daily administration of 400–600mg provides steady-state concentrations in the therapeutic range. Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound. Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug. A small degree of nonlinearity has been observed, with a 30% decrease in clearance after a 5-fold increase in dose. The nonlinearity is not relevant over the therapeutic dosage range.

Plasma linezolid concentrations in elderly patients, patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those achieved in young or healthy volunteers. Higher concentrations are observed in women as compared with men, but the difference is not sufficient to warrant an adjustment in dosage. In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function. Therefore, linezolid should be used with caution in patients with severe renal insufficiency. A higher clearance of linezolid was found in children as compared with adults, and therefore higher daily dosages per kg bodyweight are required in children.

There is no pharmacokinetic interaction when linezolid is coadministered with aztreonam, gentamicin or warfarin. Linezolid is a mild, reversible, inhibitor of monoamine oxidases A and B. Coadministration of linezolid with the adrenergic agents pseudoephedrine and phenylpropanolamine resulted in increases in blood pressure relative to these agents alone or to placebo. The degree of the change in blood pressure was within that associated with normal daily activities. No interaction was observed when linezolid was coadministered with the serotonergic agent dextromethorphan.

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References

  1. Borek AP, Peterson LR, Noskin GA. Activity of linezolid against medically important gram-positive bacteria from 1997–2000 [abstract]. Proceedings of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, Ontario, Canada

    Google Scholar 

  2. Jones RN, Ballow CH, Biedenbach DJ. Multi-laboratory assessment of the linezolid spectrum of activity using the Kirby-Bauer disk diffusion method: report of the Zyvox Antimicrobial Potency Study (ZAPS) in the United States. Diagn Microbiol Infect Dis 2001; 40(1–2): 59–66

    Article  CAS  PubMed  Google Scholar 

  3. Noskin GA, Siddiqui F, Stosor V, et al. In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci. Antimicrob Agents Chemother 1999; 43: 2059–62

    CAS  PubMed  PubMed Central  Google Scholar 

  4. von Eiff C, Peters G. Comparative in-vitro activities of moxifloxacin, trovafloxacin, quinupristin/dalfopristin and linezolid against staphylococci. J Antimicrob Chemother 1999; 43: 569–73

    Article  Google Scholar 

  5. Zurenko GE, Yagi BH, Schaadt RD, et al. In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents. Antimicrob Agents Chemother 1996; 40: 839–45

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Swaney SM, Aoki H, Ganoza MC, et al. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998; 42: 3251–5

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Kloss P, Xiong L, Shinabarger DL, et al. Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center. J Mol Biol 1999; 294(1): 93–101

    Article  CAS  PubMed  Google Scholar 

  8. Prystowsky J, Siddiqui F, Chosay J, et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother 2001; 45(7): 2154–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dresser LD, Rybak MJ. The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 1998; 18: 456–62

    CAS  PubMed  Google Scholar 

  10. Cammarata SK, Schueman LK, Timm JA, et al. Oral linezolid in the treatment of community-acquired pneumonia: a phase III trial [abstract 654]. Program and abstracts of the American Thoracic Society; 2000 May 5–10; Toronto, Ontario.

  11. San Pedro GS, Cammarata SK, Oliphant TH, et al. Linezolid versus ceftrixone/cefpodoxime in patients hospitalised for the treatment of strepococcus pneumoniae pneumonia. Scand J Infect Dis 2002; 34: 720–8

    Article  PubMed  Google Scholar 

  12. Duvall SE, Seas C, Bruss JB, et al. Comparison of linezolid to oral clarithromycin in the treatment of uncomplicated skin infections: results from a multinational phase III trial [abstract]. Program and abstracts of the 9th International Congress on Infectious Disease; 2000 Apr 10–13; Buenos Aires, Argentina.

  13. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of mehticillin-resistant staphylococcus aureus infections. Clin Infect Dis 2002; 34: 1401–9

    Article  Google Scholar 

  14. Rubinstein E, Cammarata SL, Oliphant TH, et al. Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32: 402–12

    Article  CAS  PubMed  Google Scholar 

  15. Stevens DL, Smith LG, Bruss JB, et al. Linezolid Skin and Soft Tissue Infections Study Group. Randomized comparison of linezolid (PNU-100766) versus oxacillin/dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000; 44: 3408–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pawsey SD, Daley-Yates PT, Wajszczuk CP, et al. U-100766 safety, toleration and pharmacokinetics after oral and intravenous administration. Abstracts of European Congress of Antimicrobial Chemotherapy; 1996 May 15–17; Glasgow.

  17. Stalker DJ, Jungbluth GL, Hopkins NK, et al. Pharmacokinetics and tolerance of single and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemo 2003; 51(5): 1239–46

    Article  CAS  Google Scholar 

  18. Welshman IR, Sisson TA, Jungbluth GL, et al. Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 2001; 22: 91–7

    Article  CAS  PubMed  Google Scholar 

  19. Welshman IR, Stalker DJ, Hopkins NK, et al. Linezolid: comparative bioavailability of single doses of 600mg tablet and oral suspension formulations. Data on file, Kalamazoo, USA: Pharmacia Corporation, 1998

    Google Scholar 

  20. Jungbluth GL, Welshman IR, Hopkins NK, et al. Linezolid: single- and multiple-dose pharmacokinetics evaluation of dose proportionality. Data on file, Kalamazoo, USA: Pharmacia Corporation, 1999

    Google Scholar 

  21. Cirincione B, Phillips L, Grasela T, et al. Influence of dose responses for linezolid efficacy using Monte Carlo simulations. Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists; 2000 Oct 29–Nov 2; Indianapolis (IN)

  22. Rayner CR, Forrest A, Meagher AK, et al. Clinical pharmacokinetics of linezolid efficacy in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet 2003; In Press

  23. Slatter JG, Stalker DJ, Feenstra KL, et al. Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [14C]linezolid to healthy human subjects. Drug Metab Dispos 2001; 29(8): 1136–45

    CAS  PubMed  Google Scholar 

  24. Lasher S, Jungbluth G, Hopkins N. A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam. J Clin Pharmacol 1999; 39(12): 1277–82

    Article  Google Scholar 

  25. Jungbuth GL, Lasher TA, Hopkins NK, et al. Linezolid and aztreonam: a pharmacokinetic evaluation of intravenous coadministration in healthy volunteers [abstract]. Clin Infect Dis 1997; 25(2): 487

    Google Scholar 

  26. Chiba K, Uda F, Yamazaki S, et al. U-100766: In vitro protein binding of U-100766 in plasma of rats, dogs and humans. Data on file, Kalamazoo, USA: Pharmacia Corporation, 1995

    Google Scholar 

  27. Conte JE, Golden JA, Kipps J, et al. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 2002 May; 46(5): 1475–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gee T, Ellis R, Marshall G, et al. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 2001; 45: 1843–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rana B, Murnaghan C, Butcher I, et al. Penetration of linezolid into osteo-articular tissues. Southampton, UK: The British Orthopaedic Research Society, 2001 Sep 24–25

    Google Scholar 

  30. Hopkins N, Welshman I, Jungbluth, et al. Linezolid bone levels after a single 600mg oral dose. Data on file, Kalamazoo, USA: Pharmacia Corporation, 2002

    Google Scholar 

  31. Wynalda MA, Hauer MJ, Wienkers LC. Oxidation of the novel oxazolidinone antibiotic linezolid in human liver microsomes. Drug Metab Dispos 2000; 28: 1014–7

    CAS  PubMed  Google Scholar 

  32. Wienkers LC, Wynalda MA, Feenstra KL, et al. In vitro metabolism of linezolid (PNU-100766): lack of induction or inhibition of cytochrome P450 enzymes and studies on the mechanism of formation of the major human metabolite, PNU-142586. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1999 Sep 26–29; San Francisco (CA)

    Google Scholar 

  33. Azie N, Stalker D, Jungbluth G, et al. Effect of linezolid on CYP2C9 using racemic warfarin (W) as a probe [abstract]. Clin Pharmacol Ther 2001; 69(2): 21

    Google Scholar 

  34. Lasher Sisson T, Jungbluth GL, Hopkins NK. Age and sex effects on the pharmacokinetics of linezolid. Eur J Clin Pharmacol 2002; 57: 793–7

    Article  PubMed  Google Scholar 

  35. Hendershot P, Jungbluth G, Cammarata S, et al. Pharmacokinetics of linezolid in patients with liver disease [abstract]. J Antimicrob Chemother 1999; 44 Suppl. A: 55

    Google Scholar 

  36. Brier ME, Stalker DJ, Aronoff GR, et al. Pharmacokinetics of linezolid in subjects with renal dysfunction. Antimicrob Agents Chemother 2003; 47(9): 2775–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zyvox® (linezolid): prescribing information. Peapack, NJ: Pharmacia Corporation, 2002 Jan. Available from URL: www.pharmacia.com/prescription/PDF_Current/Zyvox.pdf [Accessed 2003 Sep 2]

  38. Kearns GL, Abdel-Rahman SM, Blumer JL, et al. Single dose pharmacokinetics of linezolid in infants and children. Pediatr Infect Dis J 2000; 19(12): 1178–84

    Article  CAS  PubMed  Google Scholar 

  39. Jungbluth GL. Linezolid injection: single dose pharmacokinetic assessment in pediatric patients following an intravenous infusion. Data on file, Kalamazoo, USA: Pharmacia Corporation, 2002

    Google Scholar 

  40. Jungbluth GL, Welshman IR, Hopkins NK, et al. Linezolid pharmacokinetics in adolescents. Proceedings of the Pediatric Academic Societies Annual Meeting. 2002 May 4–7; Baltimore (MD)

  41. Jungbluth GL, Welshman IR, Hopkins NK, et al. Impact of gestational and postnatal age on linezolid disposition in neonates and young infants. Proceedings of the Pediatrie Academic Societies Annual Meeting. 2002 May 4–7; Baltimore (MD)

  42. Sweeney MT, Baldwin KF, Zurenko GE. In vitro activity of linezolid combined with other antibacterial agents. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco (CA)

    Google Scholar 

  43. Martin Jr JP, Herberg JT, Slatter JG, et al. Although a novel IV 364/18 microtitre plate assay demonstrates that linezolid (PNU-100766) is a weak competitive (reversible) inhibitor of human MAO-A, no clinical evidence of MAO-A inhibition in clinical trials has been observed. Proceedings of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego (CA)

    Google Scholar 

  44. Martin JP, Dupuis MJ, Herberg JT. The development of microtiter plate-based assays for monoamine oxidases (MAO) A and B. Data on file, Kalamazoo, USA: Pharmacia Corporation, 1998

    Google Scholar 

  45. Antal EJ, Hendershot PE, Batts DH, et al. Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. J Clin Pharmacol 2001; 41(5): 552–62

    Article  CAS  PubMed  Google Scholar 

  46. Hendershot PE, Antal EJ, Welshman IR, et al. Linezolid: pharmacokinetic and pharmacodynamic evaluation of coadministration with pseudoephedrine HCl, phenylpropanolamine HCl, and dextromethorphan HBr. J Clin Pharmacol 2001; 41(5): 563–72

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Cheryl J. Sweet and Dorleda Royster for their assistance in manuscript preparation. Funding was received by a grant from Pharmacia Corporation. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Pharmacia Corporation, Kalamazoo, Michigan, USA

    Dennis J. Stalker & Gail L. Jungbluth

  2. Department of Biopharmaceutical Sciences, Fujisawa Healthcare Inc, 3 Parkway North, Deerfield, Illinois, 60015, USA

    Dennis J. Stalker

  3. Clinical Pharmacokinetics and Pharmacodynamics, Clinical Sciences, Pfizer Global Research and Development, Ann Arbor, Michigan, USA

    Gail L. Jungbluth

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  1. Dennis J. Stalker
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Correspondence to Dennis J. Stalker.

Additional information

Dr Stalker and Dr Jungbluth are currently affiliated with Fujisawa Heathcare Inc., and Pfizer Global Research and Development, respectively, but at the time of submitting this manuscript both were affiliated with Pharmacia Corporation.

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Stalker, D.J., Jungbluth, G.L. Clinical Pharmacokinetics of Linezolid, a Novel Oxazolidinone Antibacterial. Clin Pharmacokinet 42, 1129–1140 (2003). https://doi.org/10.2165/00003088-200342130-00004

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