Skip to main content
SpringerLink
Log in

Comparison of the Pharmacokinetics of Two Dosage Regimens of Linezolid in Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Patients

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In order to reduce its adverse effects and maintain efficacy, we investigated whether linezolid in a reduced dosage resulted in drug serum concentrations exceeding a ratio of the in vitro minimum inhibitory concentration (MIC) to the area under the serum concentration-time curve (AUC) over 24 hours (AUC24) [AUC24/MIC] of >100.

Patients and Methods

This open-label, prospective pharmacokinetic study evaluated two doses (300 and 600 mg) of linezolid in MDR-TB patients, who received linezolid as part of their treatment. They received linezolid 300 mg twice daily for 3 days, followed by 600 mg twice daily. Blood samples taken at predefined intervals for measuring serum linezolid concentrations were processed by a validated liquid chromatography-tandem mass spectrometry procedure. The AUC24/MIC ratio was used as a predictive model of efficacy. Adverse effects of linezolid, including peripheral neuropathy, were evaluated by clinical and laboratory assessments.

Results

Eight patients were included in this study. The median duration of linezolid treatment was 56 days (interquartile range [IQR 44-82] days), with a median cumulative dose of 51000 mg (IQR 33 850-60 450 mg). The median linezolid AUC over 12 hours (AUC12) values were 57.6mg ·h/L (IQR 38.5–64.2 mg•h/L) with the 300mg dose and 145.8mg•h/L (IQR 101.2–160.9mg•h/L) with the 600mg dose. The AUC24/MIC ratios were 452 (IQR 343-513) with the 300mg dose and 1151 (IQR 656-1500) with the 600mg dose. Linezolid was well tolerated.

Conclusion

Seemingly effective serum concentrations were reached after 3 days of administration of linezolid 300 mg twice daily, i.e. the AUC24/MIC ratio was at least 100 in 7 of 8 patients. Larger numbers of patients should be studied to confirm the efficacy of the linezolid 300 mg twice-daily dosage in MDR-TB or XDR-TB treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Table II
Table III
Fig. 2

Similar content being viewed by others

References

  1. Maartens G, Wilkinson RJ. Tuberculosis. Lancet 2007; 370(9604): 2030–43

    Article  PubMed  Google Scholar 

  2. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167(4): 603–62

    Article  PubMed  Google Scholar 

  3. Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drugresistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372(9647): 1403–9

    Article  PubMed  Google Scholar 

  4. Geerligs WA, van Altena R, De Lange WCM, et al. Multidrug-resistant tuberculosis: long-term treatment outcome in the Netherlands. Int J Tuberc Lung Dis 2000; 4(8): 758–64

    PubMed  CAS  Google Scholar 

  5. Turett GS, Telzak EE, Torian LV, et al. Improved outcomes for patients with multidrug-resistant tuberculosis. Clin Infect Dis 1995; 21(5): 1238–44

    Article  PubMed  CAS  Google Scholar 

  6. Salomon N, Perlman DC, Friedmann P, et al. Predictors and outcome of multidrug-resistant tuberculosis. Clin Infect Dis 1995; 21(5): 1245–52

    Article  PubMed  CAS  Google Scholar 

  7. Cohn DL. Treatment of multidrug-resistant tuberculosis. J Hosp Infect 1995; 30(Suppl.): 322–8

    Article  PubMed  Google Scholar 

  8. Rodriguez JC, Ruiz M, Lopez M, et al. In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis. Int J Antimicrob Agents 2002; 20(6): 464–7

    Article  PubMed  CAS  Google Scholar 

  9. Brickner SJ, Hutchinson DK, Barbachyn MR, et al. Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem 1996; 39(3): 673–9

    Article  PubMed  CAS  Google Scholar 

  10. Alcala L, Ruiz-Serrano MJ, Perez-Fernández Turégano C, et al. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother 2003; 47(1): 416–7

    Article  PubMed  CAS  Google Scholar 

  11. Fortun J, Martin-Davila P, Navas E, et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 2005; 56(1): 180–5

    Article  PubMed  CAS  Google Scholar 

  12. Slebos DJ, van Altena R. Linezolid, an agent from a new class of antibiotics. Ned Tijdschr Geneeskd 2004; 148(49): 2462–3

    PubMed  CAS  Google Scholar 

  13. Condos R, Hadgiangelis N, Leibert E, et al. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008; 134(1): 187–92

    Article  PubMed  CAS  Google Scholar 

  14. Yew WW, Chau CH, Wen KH. Linezolidinthe treatmentof ‘difficult’ multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2008; 12(3): 345–6

    PubMed  CAS  Google Scholar 

  15. von Der LB, Sandven P, Brubakk O. Efficacy and safety of linezolid in multi-drug resistant tuberculosis (MDR-TB): a report of ten cases. J Infect 2006; 52(2): 92–6

    Article  Google Scholar 

  16. Koh WJ, Kwon OJ, Gwak H, et al. Daily 300mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother 2009; 64(2): 388–91

    Article  PubMed  CAS  Google Scholar 

  17. Bernstein WB, Trotta RF, Rector JT, et al. Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother 2003; 37(4): 517–20

    Article  PubMed  Google Scholar 

  18. Rucker JC, Hamilton SR, Bardenstein D, et al. Linezolid-associated toxic optic neuropathy. Neurology 2006; 66(4): 595–8

    Article  PubMed  CAS  Google Scholar 

  19. Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy 2006; 26(12): 1784–93

    Article  PubMed  CAS  Google Scholar 

  20. Bishop E, Melvani S, Howden BP, et al. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections:a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50(4): 1599–602

    Article  PubMed  CAS  Google Scholar 

  21. Park IN, Hong SB, Oh YM, et al. Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. J Antimicrob Chemother 2006; 58(3): 701–4

    Article  PubMed  CAS  Google Scholar 

  22. Andes D, van Ogtrop ML, Peng J, et al. In vivo pharmacodynamics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother 2002; 46(11): 3484–9

    Article  PubMed  CAS  Google Scholar 

  23. Boak LM, Li J, Rayner CR, et al. Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model. Antimicrob Agents Chemother 2007; 51(4): 1287–92

    Article  PubMed  CAS  Google Scholar 

  24. Boselli E, Breilh D, Rimmele T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med 2005; 33(7): 1529–33

    Article  PubMed  CAS  Google Scholar 

  25. Craig WA. Does the dose matter? Clin Infect Dis 2001; 33 Suppl. 3: S233–7

    Article  PubMed  CAS  Google Scholar 

  26. Rayner CR, Forrest A, Meagher AK, et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet 2003; 42(15): 1411–23

    Article  PubMed  CAS  Google Scholar 

  27. Rodriguez JC, Cebrian L, Lopez M, et al. Mutant prevention concentration: comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis. J Antimicrob Chemother 2004; 53(3): 441–4

    Article  PubMed  CAS  Google Scholar 

  28. Zyvoxid®: prescribing information. Bridgewater (NJ): Pharmacia USA, 2006 Apr 20 [online]. Available from URL: http://www.health.gov.il/units//pharmacy/trufot/alonim/2192.pdf [Accessed 2010 Jun 18]

  29. van Klingeren B, Dessens-Kroon M, van der Laan T, et al. Drug susceptibility testing of Mycobacterium tuberculosis complex by use of a high-throughput, reproducible, absolute concentration method. J Clin Microbiol 2007; 45(8): 2662–8

    Article  PubMed  Google Scholar 

  30. Islinger F, Dehghanyar P, Sauermann R, et al. The effect of food on plasma and tissue concentrations of linezolid after multiple doses. Int J Antimicrob Agents 2006; 27(2): 108–12

    Article  PubMed  CAS  Google Scholar 

  31. 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 Chemother 2003; 51(5): 1239–46

    Article  PubMed  CAS  Google Scholar 

  32. Harmelink IM, Alffenaar JWC, Wessels AMA, et al. A rapid and simple liquid chromatography-tandem mass spectrometry method for the determination of linezolid in human serum. Eur J Hosp Pharm 2008; 14(1): 5–8

    Google Scholar 

  33. Proost JH, Meijer DK. MW/Pharm, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Comput Biol Med 1992; 22(3): 155–63

    Article  PubMed  CAS  Google Scholar 

  34. Peters EW, Bienfait HM, de Visser M, et al. The reliability of assessment of vibration sense. Acta Neurol Scand 2003; 107(4): 293–8

    Article  PubMed  CAS  Google Scholar 

  35. Egle H, Trittler R, Kummerer K, et al. Linezolid and rifampin: drug interaction contrary to expectations? Clin Pharmacol Ther 2005; 77(5): 451–3

    Article  PubMed  CAS  Google Scholar 

  36. Gebhart BC, Barker BC, Markewitz BA. Decreased serum linezolid levels in a critically ill patient receiving concomitant linezolid and rifampin. Pharmacotherapy 2007; 27(3): 476–9

    Article  PubMed  CAS  Google Scholar 

  37. Dietze R, Hadad DJ, McGee B, et al. Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med 2008; 178(11): 1180–5

    Article  PubMed  Google Scholar 

  38. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003; 42(13): 1129–40

    Article  PubMed  CAS  Google Scholar 

  39. Hui M, Au-Yeang C, Wong KT, et al. Post-antibiotic effects of linezolid and other agents against Mycobacterium tuberculosis. Int J Antimicrob Agents 2008; 31(4): 395–6

    Article  PubMed  CAS  Google Scholar 

  40. Nam HS, Koh WJ, Kwon OJ, et al. Daily half-dose linezolid for the treatment of intractable multidrug-resistant tuberculosis. Int J Antimicrob Agents 2009; 33(1): 92–3

    Article  PubMed  CAS  Google Scholar 

  41. Migliori GB, Eker B, Richardson MD, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J 2009; 34(2): 387–93

    Article  PubMed  CAS  Google Scholar 

  42. Ntziora F, Falagas ME. Linezolid for the treatment of patients with mycobacterial infections a systematic review. Int J Tuberc Lung Dis 2007; 11(6): 606–11

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The purified linezolid drug substance was kindly provided by Pfizer Inc. (New York, NY, USA). This study was financially supported by Stichting Beatrixoord Noord-Nederland (Groningen, the Netherlands). The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Hospital and Clinical Pharmacy and Toxicology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands

    Jan-Willem C. Alffenaar, Ilse M. Harmelink, A. Mireille A. Wessels, Jos G. W. Kosterink & Donald R. A. Uges

  2. Tuberculosis Centre Beatrixoord, University Medical Center Groningen, University of Groningen, Haren, The Netherlands

    Richard van Altena & Patricia Filguera

  3. Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Esther Molenaar

  4. National Mycobacteria Reference Laboratory, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

    Dick van Soolingen

  5. Department of Internal Medicine and Department of Pulmonary Diseases & Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Tjip S. van der Werf

Authors
  1. Jan-Willem C. Alffenaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard van Altena
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ilse M. Harmelink
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patricia Filguera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esther Molenaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Mireille A. Wessels
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dick van Soolingen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jos G. W. Kosterink
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Donald R. A. Uges
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tjip S. van der Werf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan-Willem C. Alffenaar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alffenaar, JW.C., van Altena, R., Harmelink, I.M. et al. Comparison of the Pharmacokinetics of Two Dosage Regimens of Linezolid in Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis Patients. Clin Pharmacokinet 49, 559–565 (2010). https://doi.org/10.2165/11532080-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11532080-000000000-00000

Keywords

Search

Navigation