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Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients

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Abstract

Objectives

We aimed to assess linezolid pharmacokinetics in the plasma and interstitial space fluid (ISF) of patients with sepsis, diabetic foot infections or cystic fibrosis and healthy volunteers. The impacts of joint characteristics and disease on plasma and target-site exposure were to be identified together with the benefit of dose intensification in critically ill patients.

Methods

Rich plasma (n = 1598) and ISF concentrations in subcutaneous adipose (n = 1430) and muscle tissue (n = 1089) measured by microdialysis were pooled from three clinical trials with 51 individuals receiving 600 mg of intravenous and oral linezolid. All data were analysed simultaneously by a population approach also considering methodological aspects of microdialysis. The impact of covariates on the attainment of the pharmacokinetic/pharmacodynamic targets, AUC/MIC = 100 (area under the concentration-time curve/minimum inhibitory concentration) and fT>MIC = 99 % (time that unbound concentrations exceed the MIC), was assessed by deterministic and Monte Carlo simulations.

Results

A two-compartment pharmacokinetic model with nonlinear elimination and tissue distribution factors accounting for differences between plasma and ISF concentrations adequately predicted all measurements. Clearance (CL) was highest in septic patients (11.2 L/h vs. CLHealthy/CLCystic fibrosis/CLDiabetic = 7.67/6.87/6.35 L/h). Penetration into subcutaneous adipose ISF was lowest in diabetic patients (−34.9 % compared with healthy volunteers). Creatinine clearance and total body weight further impacted linezolid exposure. To achieve timely efficacious therapy, front-loaded dosing and continuous infusion seemed beneficial in septic patients.

Conclusions

Our analysis suggests that after standard linezolid doses, particularly patients with sepsis and conserved renal function are at risk of not attaining pharmacokinetic/pharmacodynamic targets and would benefit from initial dose intensification.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Pfizer. Zyvox®: summary of product characteristics. 2011. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021132s027lbl.pdf. Accessed 28 Jul 2016.

  3. Plock N, Buerger C, Joukhadar C, et al. Does linezolid inhibit its own metabolism? Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients. Drug Metab Dispos. 2007;35:1816–23.

    Article  CAS  PubMed  Google Scholar 

  4. Wiskirchen DE, Shepard A, Kuti JL, Nicolau DP. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infections using in vivo microdialysis. Antimicrob Agents Chemother. 2011;55:4170–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Stolle LB, Plock N, Joukhadar C, et al. Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis. Scand J Infect Dis. 2008;40:24–9.

    Article  CAS  PubMed  Google Scholar 

  7. Chaurasia CS, Müller M, Bashaw ED, et al. AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res. 2007;24:1014–25.

    Article  CAS  PubMed  Google Scholar 

  8. Tunblad K, Hammarlund-Udenaes M, Jonsson EN. An integrated model for the analysis of pharmacokinetic data from microdialysis experiments. Pharm Res. 2004;21:1698–707.

    Article  CAS  PubMed  Google Scholar 

  9. Pea F, Furlanut M, Cojutti P, et al. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob Agents Chemother. 2010;54:4605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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;42:1411–23.

    Article  CAS  PubMed  Google Scholar 

  11. Di Paolo A, Malacarne P, Guidotti E, et al. Pharmacological issues of linezolid: an updated critical review. Clin Pharmacokinet. 2010;49:439–47.

    Article  PubMed  Google Scholar 

  12. Sandberg A, Jensen KS, Baudoux P, et al. Intra- and extracellular activity of linezolid against Staphylococcus aureus in vivo and in vitro. J Antimicrob Chemother. 2010;65:962–73.

    Article  CAS  PubMed  Google Scholar 

  13. Sasaki T, Takane H, Ogawa K, et al. Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients. Antimicrob Agents Chemother. 2011;55:1867–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boak LM, Rayner CR, Grayson ML, et al. Clinical population pharmacokinetics and toxicodynamics of linezolid. Antimicrob Agents Chemother. 2014;58:2334–43.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sisson L, 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 

  16. Tsuji Y, Yukawa E, Hiraki Y, et al. Population pharmacokinetic analysis of linezolid in low body weight patients with renal dysfunction. J Clin Pharmacol. 2013;53:967–73.

    Article  CAS  PubMed  Google Scholar 

  17. Keel RA, Schaeftlein A, Kloft C, et al. Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis. Antimicrob Agents Chemother. 2011;55:3393–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Swoboda S, Ober MC, Lichtenstern C, et al. Pharmacokinetics of linezolid in septic patients with and without extended dialysis. Eur J Clin Pharmacol. 2010;66:291–8.

    Article  CAS  PubMed  Google Scholar 

  19. Bhalodi AA, Papasavas PK, Tishler DS, et al. Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults. Antimicrob Agents Chemother. 2013;57:1144–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Beringer P, Nguyen M, Hoem N, et al. Absolute bioavailability and pharmacokinetics of linezolid in hospitalized patients given enteral feedings. Antimicrob Agents Chemother. 2005;49:3676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Duffull SB, Wright DFB. What do we learn from repeated population analyses? Br J Clin Pharmacol. 2015;79:40–7.

    Article  PubMed  Google Scholar 

  22. Kerbusch T, Wählby U, Milligan PA, Karlsson MO. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol. 2003;56:639–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eslam RB, Burian A, Vila G, et al. Target site pharmacokinetics of linezolid after single and multiple doses in diabetic patients with soft tissue infection. J Clin Pharmacol. 2014;54:1058–62.

    Article  CAS  PubMed  Google Scholar 

  24. Thallinger C, Buerger C, Plock N, et al. Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother. 2008;61:173–6.

    Article  CAS  PubMed  Google Scholar 

  25. Dehghanyar P, Bu C, Zeitlinger M, et al. Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses. Antimicrob Agents Chemother. 2005;49:2367–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Buerger C, Plock N, Dehghanyar P, et al. Pharmacokinetics of unbound linezolid in plasma and tissue interstitium of critically ill patients after multiple dosing using microdialysis. Antimicrob Agents Chemother. 2006;50:2455–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Plock N, Kloft C. Microdialysis: theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci. 2005;25:1–24.

    Article  CAS  PubMed  Google Scholar 

  28. Chaurasia CS. In vivo microdialysis sampling: theory and applications. Biomed Chromatogr. 1999;13:317–32.

    Article  CAS  PubMed  Google Scholar 

  29. Buerger C, Joukhadar C, Muller M, Kloft C. Development of a liquid chromatography method for the determination of linezolid and its application to in vitro and human microdialysis samples. J Chromatogr B. 2003;796:155–64.

    Article  CAS  Google Scholar 

  30. Schaeftlein A, Minichmayr IK, Kloft C. Population pharmacokinetics meets microdialysis: benefits, pitfalls and necessities of new analysis approaches for human microdialysis data. Eur J Pharm Sci. 2014;57:68–73.

    Article  CAS  PubMed  Google Scholar 

  31. Minichmayr IK, Schaeftlein A, Zeitlinger M, Kloft C. Population pharmacokinetics of linezolid in diabetic patients with soft tissue infections: are standard doses adequate? 23rd European Congress of Clinical Microbiology and Infectious Diseases. Poster P-927. 2013. Available from: https://www.escmid.org/escmid_publications/escmid_elibrary/material/?mid=10424. Accessed 6 Aug 2016.

  32. Boselli E, Breilh D, Caillault-Sergent A, et al. Alveolar diffusion and pharmacokinetics of linezolid administered in continuous infusion to critically ill patients with ventilator-associated pneumonia. J Antimicrob Chemother. 2012;67:1207–10.

    Article  CAS  PubMed  Google Scholar 

  33. 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;27:108–12.

    Article  CAS  PubMed  Google Scholar 

  34. European Committee on Antimicrobial Susceptibility Testing. Linezolid: rationale for the clinical breakpoints, version 1.0. 2005. Available from: http://www.eucast.org/documents/rd. Accessed 8 Oct 2015.

  35. Stenken JA, Lunte CE, Southard MZ, Ståhle L. Factors that influence microdialysis recovery: comparison of experimental and theoretical microdialysis recoveries in rat liver. J Pharm Sci. 1997;86:958–66.

    Article  CAS  PubMed  Google Scholar 

  36. Adembri C, Fallani S, Cassetta MI, et al. Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents. 2008;31:122–9.

    Article  CAS  PubMed  Google Scholar 

  37. Bosso JA, Flume PA, Gray SL. Linezolid pharmacokinetics in adult patients with cystic fibrosis. Antimicrob Agents Chemother. 2004;48:281–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Touw DJ. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. Pharm World Sci. 1998;20:149–60.

    Article  CAS  PubMed  Google Scholar 

  39. Dostalek M, Akhlaghi F, Puzanovova M. Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs. Clin Pharmacokinet. 2012;51:481–99.

    Article  CAS  PubMed  Google Scholar 

  40. Traunmüller F, Schintler MV, Spendel S, et al. Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections. Int J Antimicrob Agents. 2010;36:84–6.

    Article  PubMed  Google Scholar 

  41. Stein GE, Schooley S, Peloquin CA, et al. 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. 2007;60:819–23.

    Article  CAS  PubMed  Google Scholar 

  42. Majcher-Peszynska J, Haase G, Sass M, et al. Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections. Eur J Clin Pharmacol. 2008;64:1093–100.

    Article  CAS  PubMed  Google Scholar 

  43. Yagi T, Naito T, Doi M, et al. Plasma exposure of free linezolid and its ratio to minimum inhibitory concentration varies in critically ill patients. Int J Antimicrob Agents. 2013;42:329–34.

    Article  CAS  PubMed  Google Scholar 

  44. Matsumoto K, Shigemi A, Takeshita A, et al. Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients. Int J Antimicrob Agents. 2014;44:242–7.

    Article  CAS  PubMed  Google Scholar 

  45. Luque S, Grau S, Alvarez-Lerma F, et al. Plasma and cerebrospinal fluid concentrations of linezolid in neurosurgical critically ill patients with proven or suspected central nervous system infections. Int J Antimicrob Agents. 2014;44:409–15.

    Article  CAS  PubMed  Google Scholar 

  46. Meagher AK, Forrest A, Rayner CR, et al. Population pharmacokinetics of linezolid in patients treated in a compassionate-use program. Antimicrob Agents Chemother. 2003;47:548–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abe S, Chiba K, Cirincione B, et al. Population pharmacokinetic analysis of linezolid in patients with infectious disease: application to lower body weight and elderly patients. J Clin Pharmacol. 2009;49:1071–8.

    Article  CAS  PubMed  Google Scholar 

  48. Whitehouse T, Cepeda JA, Shulman R, et al. Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother. 2005;55:333–40.

    Article  CAS  PubMed  Google Scholar 

  49. Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004;58:119–33.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Huisinga W, Solms A, Fronton L, Pilari S. Modeling interindividual variability in physiologically based pharmacokinetics and its link to mechanistic covariate modeling. CPT Pharmacometrics Syst Pharmacol. 2012;1:e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Joukhadar C, Frossard M, Mayer BX, et al. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001;29:385–91.

    Article  CAS  PubMed  Google Scholar 

  52. Zeitlinger MA, Dehghanyar P, Mayer BX, et al. Relevance of soft-tissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother. 2003;47:3548–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Müller M, Peña A, Derendorf H. Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue. Antimicrob Agents Chemother. 2004;48:1441–53.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Skhirtladze K, Hutschala D, Fleck T, et al. Impaired target site penetration of vancomycin in diabetic patients following cardiac surgery. Antimicrob Agents Chemother. 2006;50:1372–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stein GE, Throckmorton JK, Scharmen AE, et al. Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection. J Antimicrob Chemother. 2013;68:2852–8.

    Article  CAS  PubMed  Google Scholar 

  56. Morata L, Cuesta M, Rojas JF, et al. Risk factors for a low linezolid trough plasma concentration in acute infections. Antimicrob Agents Chemother. 2013;57:1913–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Matsumoto K, Takeshita A, Ikawa K, et al. Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. Int J Antimicrob Agents. 2010;36:179–81.

    Article  CAS  PubMed  Google Scholar 

  58. Dong H, Wang X, Dong Y, et al. Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill intensive care unit patients. Int J Antimicrob Agents. 2011;38:296–300.

    Article  CAS  PubMed  Google Scholar 

  59. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med. 2010;38:1045–53.

    Article  PubMed  Google Scholar 

  60. Kees MG, Minichmayr IK, Moritz S, et al. Population pharmacokinetics of meropenem during continuous infusion in surgical ICU patients. J Clin Pharmacol. 2016;56:307–15.

    Article  CAS  PubMed  Google Scholar 

  61. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  PubMed  Google Scholar 

  62. FDA. Guidance for industry: pharmacokinetics in patients with impaired renal function. 1998. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072127.pdf. Accessed 1 Aug 2016.

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Acknowledgements

The authors thank the High-Performance Computing Service at Freie Universitaet Berlin (http://www.zedat.fu-berlin.de/Compute) for providing high-performance computing capacities enabling our modelling activities. We acknowledge the clinical investigators at DRK Kliniken Berlin Westend, Berlin, Germany, the Vienna General Hospital, Vienna, Austria and the Hartford Hospital, Hartford, CT, USA, for the provision of data from previously published studies. Last, Dr. Sebastian Wicha of Uppsala Universitet (Uppsala, Sweden) is gratefully acknowledged for helpful discussions and suggestions.

Parts of this work were presented at the 22nd and 24th Population Approach Group Europe meeting (2013 and 2015) and the 24th European Congress of Clinical Microbiology and Infectious Diseases (2014).

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    Authors and Affiliations

    1. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany

      Iris K. Minichmayr, André Schaeftlein & Charlotte Kloft

    2. Graduate Research Training Program PharMetrX, Berlin, Germany

      Iris K. Minichmayr & André Schaeftlein

    3. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA

      Joseph L. Kuti

    4. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

      Markus Zeitlinger

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    1. Iris K. Minichmayr
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    Correspondence to Charlotte Kloft.

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    Conflict of interest

    IKM and AS declare that they have no conflicts of interest. JLK has received an honorarium for consulting and speaking by Pfizer Inc. and research grants from Pfizer Inc. MZ received a grant from Pfizer for a research project not involving linezolid. CK reports grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA and Sanofi) and the Innovative Medicines Initiative-Joint Undertaking (“DDMoRe”), both outside the submitted work.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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    Informed consent was obtained from all individual participants included in the study or respective legal representatives.

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    I. K. Minichmayr and A. Schaeftlein contributed equally to this work.

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    Minichmayr, I.K., Schaeftlein, A., Kuti, J.L. et al. Clinical Determinants of Target Non-Attainment of Linezolid in Plasma and Interstitial Space Fluid: A Pooled Population Pharmacokinetic Analysis with Focus on Critically Ill Patients. Clin Pharmacokinet 56, 617–633 (2017). https://doi.org/10.1007/s40262-016-0463-7

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