PK/PD of Oxazolidinones

  • Ursula Theuretzbacher


Linezolid, the first available compound in the group of oxazolidinones, provides an effective alternative for the treatment of multidrug-resistant (MDR) Gram-positive bacteria. Linezolid’s iv and oral availability expands its usage to the outpatient setting. In vitro, animal, and clinical studies have defined an appropriate PK/PD index for linezolid, its correlation with the dosage regimen, and clinical outcome. Due to linezolid’s wide interpatient variability, some patients may have increased risk of inadequate drug exposure. As these patients are not readily identified, therapeutic drug monitoring may be necessary for critically ill patient populations as well as in long-term treatment. As alternative antibiotics are scarce, resistance development requires special attention. The selection of linezolid resistant mutants, especially with enterococci, and the emergence of mobile resistance determinants that affect a wide range of other ribosome-targeting antibiotics, will most likely spur the emergence and spread of linezolid resistance. Increasing drug exposure in an attempt to reduce selection pressure may not be feasible due to concentration dependent toxicity. On the other hand, combination therapy may positively impact exposure/resistance relationship, but our knowledge in this area remains incomplete. Employing PK/PD models to define dosing strategies and using antibiotic combinations to reduce selection pressure on linezolid-resistant mutants are major tasks yet to be undertaken.


Linezolid Torezolid Oxazolidinones PK/PD Pharmacodynamics Pharmacokinetics Resistance 


  1. Adembri C, Fallani S, Cassetta MI, Arrigucci S, Ottaviano A, Pecile P et al (2008) Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents 31(2):122–129PubMedGoogle Scholar
  2. Alffenaar JWC, Kosterink JGW, Altena R, van der Werf TS, Uges DRA, Proost JH (2010) Limited sampling strategies for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Ther Drug Monit 32(1):97–101Google Scholar
  3. Allen GP, Bierman BC (2009) In vitro analysis of resistance selection by linezolid in vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium. Int J Antimicrob Agents 34(1):21–24PubMedGoogle Scholar
  4. Allen GP, Deshpande LM (2010) Determination of the mutant selection window for clindamycin, doxycycline, linezolid, moxifloxacin and trimethoprim/sulfamethoxazole against community-associated meticillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 35(1):45–49PubMedGoogle Scholar
  5. Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A et al (2007) pharmacokinetics/pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis 44(1):79–86Google Scholar
  6. Andes D, Van Ogtrop ML, Craig WA (1998) Pharmacodynamic activity of a new oxazolidinone, linezolid, in an animal model. In: 38th interscience conference on antimicrobial agents and chemotherapy, San Diego, CA. American Society for Microbiology, Washington, DC. p. Abstract A-9, p. 3Google Scholar
  7. Andes D, van Ogtrop ML, Peng J, Craig WA (2002) In vivo pharmacodynamics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother 46(11):3484–3489PubMedPubMedCentralGoogle Scholar
  8. Aoki H, Ke L, Poppe SM, Poel TJ, Weaver EA, Gadwood RC et al (2002) Oxazolidinone antibiotics target the P site on Escherichia coli ribosomes. Antimicrob Agents Chemother 46(4):1080–1085PubMedPubMedCentralGoogle Scholar
  9. Arias CA, Vallejo M, Reyes J, Panesso D, Moreno J, Castaneda E et al (2008) Clinical and microbiological aspects of linezolid resistance mediated by the cfr gene encoding a 23S rRNA methyltransferase. J Clin Microbiol 46(3):892–896PubMedPubMedCentralGoogle Scholar
  10. Ba BB, Arpin C, Bikie Bi Nso B, Dubois V, Saux M-C, Quentin C (2010) Activity of linezolid in an in vitro pharmacokinetic-pharmacodynamic model using different dosages and Staphylococcus aureus and Enterococcus faecalis strains with and without a hypermutator phenotype. Antimicrob Agents Chemother 54(4):1443–1452PubMedPubMedCentralGoogle Scholar
  11. Baos E, Candel FJ, Merino P, Pena I, Picazo JJ (2013) Characterization and monitoring of linezolid-resistant clinical isolates of Staphylococcus epidermidis in an intensive care unit 4 years after an outbreak of infection by cfr-mediated linezolid-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis 76(3):325–329 Google Scholar
  12. Barbour A, Scaglione F, Derendorf H (2010) Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices. Int J Antimicrob Agents 35(5):431–438Google Scholar
  13. Barnhill AE, Brewer MT, Carlson SA (2012) Adverse effects of antimicrobials via predictable or idiosyncratic inhibition of host mitochondrial components. Antimicrob Agents Chemother 56(8):4046–4051PubMedPubMedCentralGoogle Scholar
  14. Beekmann SE, Gilbert DN, Polgreen PM (2008) Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network survey. Diagn Microbiol Infect Dis 62(4):407–410PubMedGoogle Scholar
  15. Bhalodi AA, Papasavas PK, Tishler DS, Nicolau DP, Kuti JL (2013) Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults. Antimicrob Agents Chemother 57(3):1144–1149Google Scholar
  16. Bien P, Bartizal K, Louie A, Drusano G, Prokocimer P (2010) Rationale for the selection of a 200 mg therapeutic dose of oral torezolid phosphate for complicated skin infections. In: ESCMID (ed) 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2010; ViennaGoogle Scholar
  17. Bien P, Prokocimer P, Munoz KA, Bethune C (2010) Absolute bioavailability OF TR-701 FA and pharmacokinetics after single and multiple dose intravenous administration in healthy adult subjects. In: 50th annual interscience conference on antimicrobial agents and chemotherapy; 2010; Boston. ASM; 2010Google Scholar
  18. Boak LM, Li J, Rayner CR, Nation RL (2007) Pharmacokinetic/pharmacodynamic factors influencing emergence of resistance to linezolid in an in vitro model. Antimicrob Agents Chemother 51(4):1287–1292PubMedPubMedCentralGoogle Scholar
  19. Bolhuis MS, van Altena R, Alffenaar J-WC (2012) daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients. J Antimicrob Chemother 67(8):2055–2056PubMedGoogle Scholar
  20. Boselli E, Breilh D, Rimmelé T, Djabarouti S, Toutain J, Chassard D et al (2005) Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med 33(7):1529–1533PubMedGoogle Scholar
  21. Boselli E, Breilh D, Caillault-Sergent A, Djabarouti S, Guillaume C, Xuereb F et al (2012) Alveolar diffusion and pharmacokinetics of linezolid administered in continuous infusion to critically ill patients with ventilator-associated pneumonia. J Antimicrob Chemother 67(5):1207–1210PubMedGoogle Scholar
  22. Bosso JA, Flume PA, Gray SL (2004) Linezolid pharmacokinetics in adult patients with cystic fibrosis. Antimicrob Agents Chemother 48(1):281–284PubMedPubMedCentralGoogle Scholar
  23. Bottger EC, Springer B, Prammananan T, Kidan Y, Sander P (2001) Structural basis for selectivity and toxicity of ribosomal antibiotics. EMBO Rep 2(4):318–323PubMedPubMedCentralGoogle Scholar
  24. Brier ME, Stalker DJ, Aronoff GR, Batts DH, Ryan KK, O’Grady M et al (2003) Pharmacokinetics of linezolid in subjects with renal dysfunction. Antimicrob Agents Chemother 47(9):2775–2780PubMedPubMedCentralGoogle Scholar
  25. 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(7):2455–2463PubMedPubMedCentralGoogle Scholar
  26. Burak E, Bortolon E, Molstad D, Jing H, Wu Y (2009) Radezolid, a novel oxazolidinone, accumulates in infected thigh tissue. In: ASM (ed) 49th ICAAC, San Francisco. p. A1-1938. 12–15 Sept 2009Google Scholar
  27. Burkhardt O, Borner K, von der Hoh N, Koppe P, Pletz MW, Nord CE et al (2002) Single- and multiple-dose pharmacokinetics of linezolid and co-amoxiclav in healthy human volunteers. J Antimicrob Chemother 50(5):707–712PubMedGoogle Scholar
  28. Butterfield JM, Lawrence KR, Reisman A, Huang DB, Thompson CA, Lodise TP (2012) Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of phase III and IV randomized clinical trial data. J Antimicrob Chemother 67(2):494–502PubMedGoogle Scholar
  29. Cai Y, Chai D, Falagas ME, Vouloumanou EK, Wang R, Guo D et al (2012) Immediate hematological toxicity of linezolid in healthy volunteers with different body weight: a phase I clinical trial. J Antibiot 65(4):175–178PubMedGoogle Scholar
  30. Casanova-Molla J, Morales M, Garrabou G, Solà-Valls N, Soriano A, Calvo M et al (2012) Mitochondrial loss indicates early axonal damage in small fiber neuropathies. J Peripher Nerv Syst 17(2):147–157PubMedGoogle Scholar
  31. Cattaneo D, Orlando G, Cozzi V, Cordier L, Baldelli S, Merli S et al (2013) Linezolid plasma concentrations and occurrence of drug-related haematological toxicity in patients with gram-positive infections. Int J Antimicrob Agents 41(6):586–589Google Scholar
  32. Chiang F-Y, Climo M (2003) Efficacy of linezolid alone or in combination with vancomycin for treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 47(9):3002–3004PubMedPubMedCentralGoogle Scholar
  33. Choi S, Im W, Bartizal K (2012) Activity of tedizolid phosphate (TR-701) in murine models of infection with penicillin-resistant and penicillin-sensitive Streptococcus pneumoniae. Antimicrob Agents Chemother 56(9):4713–4717PubMedPubMedCentralGoogle Scholar
  34. Colca JR, McDonald WG, Waldon DJ, Thomasco LM, Gadwood RC, Lund ET et al (2003) Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics. J Biol Chem 278(24):21972–21979PubMedGoogle Scholar
  35. Conte JE Jr, Golden JA, Kipps J, Zurlinden E (2002) Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 46(5):1475–1480PubMedPubMedCentralGoogle Scholar
  36. Cox H, Ford N (2012) Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis [Review article]. Int J Tuberc Lung Dis 16(4):447–454PubMedGoogle Scholar
  37. De Vriese AS, Coster Rudy V, Smet J, Seneca S, Lovering A, Van Haute LL et al (2006) Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 42(8):1111–1117PubMedGoogle Scholar
  38. Dehghanyar P, Burger C, Zeitlinger M, Islinger F, Kovar F, Muller M et al (2005) Penetration of linezolid into soft tissues of healthy volunteers after single and multiple doses. Antimicrob Agents Chemother 49(6):2367–2371PubMedPubMedCentralGoogle Scholar
  39. Denslow ND, O’Brien WT (1978) Antibiotic susceptibility of the peptidyl transferase locus of bovine mitochondrial ribosomes. Eur J Biochem 91(2):441–448PubMedGoogle Scholar
  40. Di Paolo A, Malacarne P, Guidotti E, Danesi R, Del Tacca M (2010) Pharmacological issues of linezolid: an updated critical review. Clin Pharmacokinet 49(7):439–447Google Scholar
  41. Diaz L, Kiratisin P, Mendes RE, Panesso D, Singh KV, Arias CA (2012) Transferable plasmid-mediated resistance to linezolid due to cfr in a human clinical isolate of Enterococcus faecalis. Antimicrob Agents Chemother 56(7):3917–3922PubMedPubMedCentralGoogle Scholar
  42. Dietze R, Hadad DJ, McGee B, Molino LPD, Maciel ELN, Peloquin CA et al (2008) Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis. Am J Respir Crit Care Med 178(11):1180–1185PubMedGoogle Scholar
  43. Dong H, Wang X, Dong Y, Lei J, Li H, You H et al (2011) Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients. Int J Antimicrob Agents 38(4):296–300PubMedGoogle Scholar
  44. Drlica K, Zhao X (2007) Mutant selection window hypothesis updated. Clin Infect Dis 44(5):681–688PubMedGoogle Scholar
  45. Drusano GL (2007) Pharmacokinetics and pharmacodynamics of antimicrobials. Clin Infect Dis 45(S1):S89–S95PubMedGoogle Scholar
  46. Drusano GL, Liu W, Kulawy R, Louie A (2011) Impact of granulocytes on the antimicrobial effect of torezolid in a mouse thigh infection model. Antimicrob Agents Chemother 55(11):5300–5305PubMedPubMedCentralGoogle Scholar
  47. Duewelhenke N, Krut O, Eysel P (2007) Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines. Antimicrob Agents Chemother 51(1):54–63PubMedPubMedCentralGoogle Scholar
  48. Egle H, Trittler R, Kummerer K, Lemmen SW (2005) Linezolid and rifampin: drug interaction contrary to expectations[quest]. Clin Pharmacol Ther 77(5):451–453PubMedGoogle Scholar
  49. Endimiani A, Blackford M, Dasenbrook EC, Reed MD, Bajaksouszian S, Hujer AM et al (2011) Emergence of linezolid-resistant Staphylococcus aureus after prolonged treatment of cystic fibrosis patients in Cleveland. Antimicrob Agents Chemother 55(4):1684–1692Google Scholar
  50. EUCAST Steering Committee (2006) EUCAST technical note on linezolid. Clin Microbiol Infect 12(12):1243–1245Google Scholar
  51. Farrell DJ, Mendes RE, Ross JE, Jones RN (2009) Linezolid surveillance program results for 2008 (LEADER Program for 2008). Diagn Microbiol Infect Dis 65(4):392–403PubMedGoogle Scholar
  52. Farrell DJ, Mendes RE, Ross JE, Sader HS, Jones RN (2011a) LEADER program results for 2009: an activity and spectrum analysis of linezolid using 6,414 clinical isolates from 56 medical centers in the united states. Antimicrob Agents Chemother 55(8):3684–3690PubMedPubMedCentralGoogle Scholar
  53. Farrell D, Mendes R, Sader H, Jones R (2011) Potency of radezolid (RX-1741) and torezolid (DA-7157) tested against a collection of linezolid-non-susceptible strains with genetically defined resistance mechanisms. 2011 In: ESCMID (ed) 21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)Google Scholar
  54. FDA (2010) FDA Zyvox label. [updated 2010 Revised June 2010; cited 2010 7/2010]; LAB-0139-20.0.
  55. FDA (2011) FDA Zyvox label. [updated 2011 Revised November 2011; cited 2011 7/2010]; LAB-0139-20.1.
  56. FDA (2011) FDA drug safety communication: serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications.
  57. FDA (2012) FDA adverse events reporting system.
  58. Feßler AT, Calvo N, Gutiérrez N, Muñoz Bellido JL, Fajardo M, Garduño E, Monecke S, Ehricht R, Kadlec K, Schwarz S (2013) Cfr-mediated linezolid resistance in methicillin-resistant Staphylococcus aureus and Staphylococcus haemolyticus associated with clinical infections in humans: two case reports. J Antimicrob Chemother doi: 10.1093/jac/dkt331Google Scholar
  59. Fiaccadori E, Maggiore U, Rotelli C, Giacosa R, Parenti E, Picetti E et al (2004) Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure. Crit Care Med 32(12):2437–2442PubMedGoogle Scholar
  60. Fiaccadori E, Maggiore U, Rotelli C, Giacosa R, Parenti E, Picetti E et al (2006) Does haemodialysis significantly affect serum linezolid concentrations in critically ill patients with renal failure? A pilot investigation. Nephrol Dial Transplant 21(5):1402–1406PubMedGoogle Scholar
  61. Flamm RK, Mendes RE, Ross JE, Sader HS, Jones RN (2013) An international activity and spectrum analysis of linezolid: ZAAPS Program results for 2011. Diagn Microbiol Infect Dis 76(2):206–213Google Scholar
  62. Flanagan S, Bartizal K, Minassian SL, Fang E, Prokocimer P (2013a) In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother 57(7):3060–3066Google Scholar
  63. Flanagan SD, Bien PA, Muñoz KA, Minassian SL, Prokocimer PG (2013b) Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug. Pharmacotherapy doi: 10.1002/phar.1337Google Scholar
  64. Forrest A, Rayner C, Meagher A, Birmingham M, JJ. S (2000) Pharmacostatistical modelling of hematologic effects of linezolid in seriously-ill patients. In: ASM (ed) ICAAC 2000Google Scholar
  65. Gao W, Chua K, Davies JK, Newton HJ, Seemann T, Harrison PF et al (2010) Two novel point mutations in clinical Staphylococcus aureus reduce linezolid susceptibility and switch on the stringent response to promote persistent infection. PLoS Pathog 6(6):e1000944PubMedPubMedCentralGoogle Scholar
  66. Garrabou G, Soriano A, López S, Guallar JP, Giralt M, Villarroya F et al (2007) Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother 51(3):962–967PubMedPubMedCentralGoogle Scholar
  67. Gebhart BC, Barker BC, Markewitz BA (2007) Decreased serum linezolid levels in a critically ill patient receiving concomitant linezolid and rifampin. Pharmacotherapy 27(3):476–479PubMedGoogle Scholar
  68. Gentry-Nielsen MJ, Olsen KM, Preheim LC (2002) Pharmacodynamic activity and efficacy of linezolid in a rat model of pneumococcal pneumonia. Antimicrob Agents Chemother 46(5):1345–1351PubMedPubMedCentralGoogle Scholar
  69. Gómez-Gil R, Romero-Gómez MP, García-Arias A, Ubeda MG, Busselo MS, Cisterna R et al (2009) Nosocomial outbreak of linezolid-resistant Enterococcus faecalis infection in a tertiary care hospital. Diagn Microbiol Infect Dis 65(2):175–179PubMedGoogle Scholar
  70. Gu B, Kelesidis T, Tsiodras S, Hindler J, Humphries RM (2013) The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 68(1):4–11Google Scholar
  71. Gullberg E, Cao S, Berg OG, Ilbäck C, Sandegren L, Hughes D et al (2012) Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathog 7(7):e1002158Google Scholar
  72. Hiraki Y, Tsuji Y, Hiraike M, Misumi N, Matsumoto K, Morita K et al (2012) Correlation between serum linezolid concentration and the development of thrombocytopenia. Scand J Infect Dis 44(1):60–64PubMedGoogle Scholar
  73. Honeybourne D, Tobin C, Jevons G, Andrews J, Wise R (2003) Intrapulmonary penetration of linezolid. J Antimicrob Chemother 51(6):1431–1434PubMedGoogle Scholar
  74. Housman ST, Pope JS, Russomanno J, Salerno E, Shore E, Kuti JL et al (2012) Pulmonary disposition of tedizolid following once-daily oral 200 mg tedizolid phosphate in healthy adult volunteers. Antimicrob Agents Chemother 56(5):2627–2634PubMedPubMedCentralGoogle Scholar
  75. Humphrey WR, Shattuck MH, Zielinski RJ, Kuo M-ST, Biermacher JJ, Smith DP et al (2003) Pharmacokinetics and efficacy of linezolid in a gerbil model of Streptococcus pneumoniae-induced acute otitis media. Antimicrob Agents Chemother 47(4):1355–1363PubMedPubMedCentralGoogle Scholar
  76. Jang H-C, Kim S-H, Kim KH, Kim CJ, Lee S, Song K-H et al (2009) Salvage treatment for persistent methicillin-resistant Staphylococcus aureus bacteremia: efficacy of linezolid with or without carbapenem. Clin Infect Dis 49(3):395–401PubMedGoogle Scholar
  77. Jones RN, Ross JE, Bell JM, Utsuki U, Fumiaki I, Kobayashi I et al (2009a) Zyvox® Annual Appraisal of Potency and Spectrum program: linezolid surveillance program results for 2008. Diagn Microbiol Infect Dis 65(4):404–413PubMedGoogle Scholar
  78. Jones RN, Moet GJ, Sader HS, Mendes RE, Castanheira M (2009b) TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens. J Antimicrob Chemother 63(4):716–720PubMedGoogle Scholar
  79. Jungbluth GL, Welshman IR, Hopkins NK (2003) Linezolid pharmacokinetics in pediatric patients: an overview. Pediatr Infect Dis J 22(9 Suppl):S153–S157PubMedGoogle Scholar
  80. Kalia V, Miglani R, Purnapatre KP, Mathur T, Singhal S, Khan S et al (2009) Mode of action of ranbezolid against staphylococci and structural modeling studies of its interaction with ribosomes. Antimicrob Agents Chemother 53(4):1427–1433PubMedPubMedCentralGoogle Scholar
  81. Kazuaki M, Ayumi T, Kazuro I, Akari S, Keiko Y, Yoshihiro S et al (2010) Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. Int J Antimicrob Agents 36(2):179–181Google Scholar
  82. Kearns GL, Abdel-Rahman SM, Blumer JL, Reed MD, James LP, Jacobs RF et al (2000) Single dose pharmacokinetics of linezolid in infants and children. Pediatr Infect Dis J 19(12):1178–1184PubMedGoogle Scholar
  83. Keel RA, Crandon JL, Nicolau DP (2012a) Pharmacokinetics and pulmonary disposition of tedizolid and linezolid in a murine pneumonia model under variable conditions. Antimicrob Agents Chemother 56(6):3420–3422PubMedPubMedCentralGoogle Scholar
  84. Keel RA, Tessier PR, Crandon JL, Nicolau DP (2012b) Comparative efficacy of human simulated exposures of tedizolid and linezolid against Staphylococcus aureus in the murine thigh infection model. Antimicrob Agents Chemother 56(8):4403–4407PubMedPubMedCentralGoogle Scholar
  85. Kiem S, Schentag JJ (2008) Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother 52(1):24–36PubMedPubMedCentralGoogle Scholar
  86. Koh W-J, Kang YR, Jeon K, Kwon OJ, Lyu J, Kim WS et al (2012) Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients. J Antimicrob Chemother 67(6):1503–1507PubMedGoogle Scholar
  87. Kuter DJ, Tillotson GS (2001) Hematologic effects of antimicrobials: focus on the oxazolidinone linezolid. Pharmacotherapy 21(8):1010–1013PubMedGoogle Scholar
  88. LaMarre JM, Locke JB, Shaw KJ, Mankin AS (2011) Low fitness cost of the multidrug resistance gene cfr. Antimicrob Agents Chemother 55(8):3714–3719PubMedPubMedCentralGoogle Scholar
  89. LaMarre J, Mendes RE, Szal T, Schwarz S, Jones RN, Mankin AS (2013) The genetic environment of the cfr gene and the presence of other mechanisms account for the very high linezolid resistance of Staphylococcus epidermidis isolate 426-3147L. Antimicrob Agents Chemother 57(3):1173–1179Google Scholar
  90. LaPlante KL, Rybak MJ (2004) Impact of high-inoculum Staphylococcus aureus on the activities of nafcillin, vancomycin, linezolid, and daptomycin, alone and in combination with gentamicin, in an in vitro pharmacodynamic model. Antimicrob Agents Chemother 48(12):4665–4672PubMedPubMedCentralGoogle Scholar
  91. Lawrence KR, Adra M, Gillman PK (2006) Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 42(11):1578–1583PubMedGoogle Scholar
  92. Leach KL, Swaney SM, Colca JR, McDonald WG, Blinn JR, Thomasco Lisa M et al (2007) The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell 26(3):393–402PubMedGoogle Scholar
  93. Lee DG, Murakami Y, Andes DR, Craig WA (2013) Inoculum effects of ceftobiprole, daptomycin, linezolid, and vancomycin with Staphylococcus aureus and Streptococcus pneumoniae at inocula of 10(5) and 10(7) CFU injected into opposite thighs of neutropenic mice. Antimicrob Agents Chemother 57(3):1434–1441Google Scholar
  94. Lemaire S, Van Bambeke F, Appelbaum PC, Tulkens PM (2009) Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother 64(5):1035–1043PubMedGoogle Scholar
  95. Lemaire S, Tulkens PM, Van Bambeke F (2010a) Cellular pharmacokinetics of the novel biaryloxazolidinone radezolid in phagocytic cells: studies with macrophages and polymorphonuclear neutrophils. Antimicrob Agents Chemother 54(6):2540–2548PubMedPubMedCentralGoogle Scholar
  96. Lemaire S, Kosowska-Shick K, Appelbaum PC, Verween G, Tulkens PM, Van Bambeke F (2010b) Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: studies with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrob Agents Chemother 54(6):2549–2559PubMedPubMedCentralGoogle Scholar
  97. Livermore DM, Mushtaq S, Warner M, Woodford N (2009) Activity of oxazolidinone TR-700 against linezolid-susceptible and -resistant staphylococci and enterococci. J Antimicrob Chemother 63(4):713–715PubMedGoogle Scholar
  98. Locke JB, Hilgers M, Shaw KJ (2009) Novel ribosomal mutations in Staphylococcus aureus strains identified through selection with the oxazolidinones linezolid and torezolid (TR-700). Antimicrob Agents Chemother 53(12):5265–5274PubMedPubMedCentralGoogle Scholar
  99. Locke JB, Morales G, Hilgers M, G CK, Rahawi S, Jose Picazo J et al (2010) Elevated linezolid resistance in clinical cfr-positive Staphylococcus aureus isolates is associated with co-occurring mutations in ribosomal protein L3. Antimicrob Agents Chemother 54(12):5352–5355PubMedPubMedCentralGoogle Scholar
  100. Long KS, Vester B (2012) Resistance to linezolid caused by modifications at its binding site on the ribosome. Antimicrob Agents Chemother 56(2):603–612PubMedPubMedCentralGoogle Scholar
  101. Long KS, Munck C, Andersen TMB, Schaub MA, Hobbie SN, Bottger EC et al (2010) Mutations in 23S rRNA at the peptidyl transferase center and their relationship to linezolid binding and cross resistance. Antimicrob Agents Chemother 54(11):4705–4713Google Scholar
  102. Louie A, Heine HS, Kim K, Brown DL, VanScoy B, Liu W et al (2008) Use of an in vitro pharmacodynamic model to derive a linezolid regimen that optimizes bacterial kill and prevents emergence of resistance in Bacillus anthracis. Antimicrob Agents Chemother 52(7):2486–2496PubMedPubMedCentralGoogle Scholar
  103. Louie A, Liu W, Kulawy R, Drusano GL (2011) In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains in a mouse thigh infection model. Antimicrob Agents Chemother 55(7):3453–3460PubMedPubMedCentralGoogle Scholar
  104. Lovering AM, Zhang J, Bannister GC, Lankester BJA, Brown JHM, Narendra G et al (2002) Penetration of linezolid into bone, fat, muscle and haematoma of patients undergoing routine hip replacement. J Antimicrob Chemother 50(1):73–77PubMedGoogle Scholar
  105. Lovering AM, Le Floch R, Hovsepian L, Stephanazzi J, Bret P, Birraux G et al (2009) Pharmacokinetic evaluation of linezolid in patients with major thermal injuries. J Antimicrob Chemother 63(3):553–559PubMedGoogle Scholar
  106. MacGowan AP (2003) Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. J Antimicrob Chemother 51(suppl 2):ii17–ii25PubMedGoogle Scholar
  107. Matsumoto K, Takeshita A, Ikawa K, Shigemi A, Yaji K, Shimodozono Y et al (2010) Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. Int J Antimicrob Agents 36(2):179–181PubMedGoogle Scholar
  108. McGee B, Dietze R, Hadad DJ, Molino LPD, Maciel ELN, Boom WH et al (2009) Population pharmacokinetics of linezolid in adults with pulmonary tuberculosis. Antimicrob Agents Chemother 53(9):3981–3984PubMedPubMedCentralGoogle Scholar
  109. McKee EE, Ferguson M, Bentley AT, Marks TA (2006) Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother 50(6):2042–2049PubMedPubMedCentralGoogle Scholar
  110. Meagher AK, Forrest A, Rayner CR, Birmingham MC, Schentag JJ (2003) Population pharmacokinetics of linezolid in patients treated in a compassionate-use program. Antimicrob Agents Chemother 47(2):548–553PubMedPubMedCentralGoogle Scholar
  111. Meyer B, Kornek GV, Nikfardjam M, Karth GD, Heinz G, Locker GJ et al (2005) Multiple-dose pharmacokinetics of linezolid during continuous venovenous haemofiltration. J Antimicrob Chemother 56(1):172–179PubMedGoogle Scholar
  112. Miller K, O’Neill AJ, Wilcox MH, Ingham E, Chopra I (2008) Delayed development of linezolid resistance in Staphylococcus aureus following exposure to Low levels of antimicrobial agents. Antimicrob Agents Chemother 52(6):1940–1944PubMedPubMedCentralGoogle Scholar
  113. Miyazaki S, Fujikawa T, Kobayashi I, Matsumoto T, Tateda K, Yamaguchi K (2002) The in vitro and in vivo antibacterial characterization of vancomycin and linezolid against vancomycin-susceptible and -resistant enterococci. J Antimicrob Chemother 50(6):971–974PubMedGoogle Scholar
  114. Morales G, Picazo JJ, Baos E, Candel FJ, Arribi A, Pelaez B et al (2010) Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. Clin Infect Dis 50(6):821–825PubMedGoogle Scholar
  115. Morata L, Cuesta M, Rojas JF, Rodriguez S, Brunet M, Casals G et al (2013) Risk factors for a low linezolid trough plasma concentration in acute infections. Antimicrob Agents Chemother 57(4):1913–1917 Google Scholar
  116. Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL (2005) Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother 55(5):601–607PubMedGoogle Scholar
  117. Mulanovich VE, Huband MD, McCurdy SP, Lemmon MM, Lescoe M, Jiang Y et al (2010) Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization. J Antimicrob Chemother 65(9):2001–2004PubMedGoogle Scholar
  118. Munckhof WJ, Giles C, Turnidge JD (2001) Post-antibiotic growth suppression of linezolid against Gram-positive bacteria. J Antimicrob Chemother 47(6):879–883PubMedGoogle Scholar
  119. Muñoz KA, Bethune C, Bohn J, Wright R, Bien P, Prokocimer P (2010) Improved pharmacokinetics of the novel oxazolidinone antibiotic torezolid phosphate compared to linezolid in healthy subjects. In: 20th European congress of clinical microbiology and infectious diseases, Clinical Microbiology and Infection, Vienna, Austria, 10–13 Apr 2010Google Scholar
  120. Muzevich KM, Lee KB (2013) Subtherapeutic linezolid concentrations in a patient with morbid obesity and methicillin-resistant Staphylococcus aureus pneumonia: case report and review of the literature. Ann Pharmacother 47(6):e25Google Scholar
  121. Myrianthefs P, Markantonis SL, Vlachos K, Anagnostaki M, Boutzouka E, Panidis D et al (2006) Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother 50(12):3971–3976PubMedPubMedCentralGoogle Scholar
  122. Nagiec EE, Wu L, Swaney SM, Chosay JG, Ross DE, Brieland JK et al (2005) Oxazolidinones inhibit cellular proliferation via inhibition of mitochondrial protein synthesis. Antimicrob Agents Chemother 49(9):3896–3902PubMedPubMedCentralGoogle Scholar
  123. Narita M, Tsuji BT, Yu VL (2007) Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 27(8):1189–1197PubMedGoogle Scholar
  124. Ntokou E, Stathopoulos C, Kristo I, Dimitroulia E, Labrou M, Vasdeki A et al (2012a) Intensive care unit dissemination of multiple clones of linezolid-resistant Enterococcus faecalis and Enterococcus faecium. J Antimicrob Chemother 67(8):1819–1823PubMedGoogle Scholar
  125. Ntokou E, Stathopoulos C, Kristo I, Dimitroulia E, Labrou M, Vasdeki A et al (2012b) Intensive care unit dissemination of multiple clones of linezolid-resistant Enterococcus faecalis and Enterococcus faecium. J Antimicrob Chemother 67(8):1819–1823PubMedGoogle Scholar
  126. Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T, Hisaka A, Suzuki H et al (2013) High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 68(9):2128–2133Google Scholar
  127. Olofsson Sara K, Cars O (2007) Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis 45(S2):S129–S136Google Scholar
  128. Patel SN, Memari N, Shahinas D, Toye B, Jamieson FB, Farrell DJ (2013) Linezolid resistance in Enterococcus faecium isolated in Ontario, Canada. Diagn Microbiol Infect Dis doi:pii: S0732-8893(13)00458-6Google Scholar
  129. Pea F, Viale P, Furlanut M (2005) Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 44(10):1009–1034PubMedGoogle Scholar
  130. Pea F, Furlanut M, Cojutti P, Cristini F, Zamparini E, Franceschi L et al (2010) Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrob Agents Chemother 54(11):4605–4610PubMedPubMedCentralGoogle Scholar
  131. Pea F, Viale P, Cojutti P, Del Pin B, Zamparini E, Furlanut M (2012) Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother 67(8):2034–2042PubMedGoogle Scholar
  132. Pillai SK, Sakoulas G, Wennersten C, Eliopoulos G, Moellering JR, Ferraro MJ et al (2002) Linezolid resistance in Staphylococcus aureus: characterization and stability of resistant phenotype. J Infect Dis 186(11):1603–1607PubMedGoogle Scholar
  133. Plock N, Buerger C, Joukhadar C, Kljucar S, Kloft C (2007) 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 35(10):1816–1823Google Scholar
  134. Polacek N, Mankin AS (2005) The ribosomal peptidyl transferase center: structure, function, evolution, inhibition. Crit Rev Biochem Mol Biol 40(5):285–311PubMedGoogle Scholar
  135. Prokocimer P, Bien P, Surber J, Mehra P, DeAnda C, Bulitta JB et al (2011) Phase 2, randomized, double-blind, dose-ranging study evaluating the safety, tolerability, population pharmacokinetics, and efficacy of oral torezolid phosphate in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother 55(2):583–592PubMedPubMedCentralGoogle Scholar
  136. Prokocimer PP, Bien P, DeAnda C, Pillar CM, Bartizal K (2012) In vitro activity and microbiological efficacy of tedizolid (TR-700) against gram-positive clinical isolates from a phase 2 study of oral tedizolid phosphate (TR-701) in patients with complicated skin and skin structure infections. Antimicrob Agents Chemother 56(9):4608–4613PubMedPubMedCentralGoogle Scholar
  137. Prokocimer P, De Anda C, Fang E, Mehra P, Das A (2013) Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA 309(6):559–569Google Scholar
  138. Prystowsky J, Siddiqui F, Chosay J, Shinabarger DL, Millichap J, Peterson LR et al (2001) Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother 45(7):2154–2156PubMedPubMedCentralGoogle Scholar
  139. Rayner CR, Forrest A, Meagher AK, Birmingham MC, Schentag JJ (2003) Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clin Pharmacokinet 42(15):1411–1423PubMedGoogle Scholar
  140. Rodríguez-Avial I, Culebras E, Betriu C, Morales G, Pena I, Picazo JJ (2012) In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci. J Antimicrob Chemother 67(1):167–169PubMedGoogle Scholar
  141. Ruiz M, Guerrero I, Tuazon C (2002) Endocarditis caused by methicillin-resistant Staphylococcus aureus: treatment failure with linezolid. Clin Infect Dis 35(8):1018–1020PubMedGoogle Scholar
  142. Ryan DM, Cars O, Hoffstedt B (1986) The use of antibiotic serum levels to predict concentrations in tissues. Scand J Infect Dis 18(5):381–388PubMedGoogle Scholar
  143. Rybak MJ, Cappelletty DM, Moldovan T, Aeschlimann JR, Kaatz GW (1998) Comparative in vitro activities and postantibiotic effects of the oxazolidinone compounds eperezolid (PNU-100592) and linezolid (PNU-100766) versus vancomycin against Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Antimicrob Agents Chemother 42(3):721–724PubMedPubMedCentralGoogle Scholar
  144. Rybak MJ, Hershberger E, Moldovan T, Grucz RG (2000) In vitro activities of daptomycin, vancomycin, linezolid, and quinupristin-dalfopristin against Staphylococci and Enterococci, including vancomycin- intermediate and -resistant strains. Antimicrob Agents Chemother 44(4):1062–1066PubMedPubMedCentralGoogle Scholar
  145. Sahre M, Sabarinath S, Grant M, Seubert C, DeAnda C, Prokocimer P et al (2012) Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers. Int J Antimicrob Agents 40(1):51–54PubMedPubMedCentralGoogle Scholar
  146. Sanchez Garcia M, De la Torre MA, Morales G, Pelaez B, Tolon MJ, Domingo S et al (2010) Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA 303(22):2260–2264PubMedGoogle Scholar
  147. Sandberg A, Jensen KS, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Moller N (2010) Intra- and extracellular activity of linezolid against Staphylococcus aureus in vivo and in vitro. J Antimicrob Chemother 65(5):962–973PubMedGoogle Scholar
  148. Santayana EM, Grim SA, Janda WM, Layden JE, Lee TA, Clark NM (2012) Risk factors and outcomes associated with vancomycin-resistant Enterococcus infections with reduced susceptibilities to linezolid. Diagnostic microbiology and infectious disease. Diagn Microbiol Infect Dis 74(1):39–42PubMedGoogle Scholar
  149. Santos RP, Prestidge CB, Brown ME, Urbancyzk B, Murphey DK, Salvatore CM et al (2009) Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. Pediatr Pulmonol 44(2):148–154PubMedGoogle Scholar
  150. Sasaki T, Takane H, Ogawa K, Isagawa S, Hirota T, Higuchi S et al (2011) Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients. Antimicrob Agents Chemother 55(5):1867–1873PubMedPubMedCentralGoogle Scholar
  151. Schaadt R, Sweeney D, Shinabarger D, Zurenko G (2009) The in vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent. Antimicrob Agents Chemother 53(8):3236–3239Google Scholar
  152. Schmidt S, Sabarinath SN, Barbour A, Abbanat D, Manitpisitkul P, Sha S et al (2009) Pharmacokinetic-pharmacodynamic modeling of the in vitro activities of oxazolidinone antimicrobial agents against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 53(12):5039–5045PubMedPubMedCentralGoogle Scholar
  153. Schumacher A, Trittler R, Bohnert JA, Kummerer K, Pages J-M, Kern WV (2007) Intracellular accumulation of linezolid in Escherichia coli, Citrobacter freundii and Enterobacter aerogenes: role of enhanced efflux pump activity and inactivation. J Antimicrob Chemother 59(6):1261–1264PubMedGoogle Scholar
  154. Shen J, Wang Y, Schwarz S (2013) Presence and dissemination of the multiresistance gene cfr in Gram-positive and Gram-negative bacteria. J Antimicrob Chemother 68(8):1697–1706Google Scholar
  155. Sierra JM, Ortega M, Tarrago C, Albet C, Vila J, Terencio J et al (2009) Decreased linezolid uptake in an in vitro-selected linezolid-resistant Staphylococcus epidermidis mutant. J Antimicrob Chemother 64(5):990–992PubMedGoogle Scholar
  156. Sisson TL, Jungbluth GL, Hopkins NK (1999) A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam. J Clin Pharmacol 39(12):1277–1282PubMedGoogle Scholar
  157. Skripkin E, McConnell TS, DeVito J, Lawrence L, Ippolito JA, Duffy EM et al (2008) R-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob Agents Chemother 52(10):3550–3557PubMedPubMedCentralGoogle Scholar
  158. Slatter JG, Stalker DJ, Feenstra KL, Welshman IR, Bruss JB, Sams JP et al (2001) Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [14C]linezolid to healthy human subjects. Drug Metab Dispos 29(8):1136–1145PubMedGoogle Scholar
  159. Smith PF, Birmingham MC, Noskin GA, Meagher AK, Forrest A, Rayner CR et al (2003) Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia. Ann Oncol 14(5):795–801PubMedGoogle Scholar
  160. Sorlozano A, Gutierrez J, Martinez T, Yuste ME, Perez-Lopez JA, Vindel A et al (2010) Detection of new mutations conferring resistance to linezolid in glycopeptide-intermediate susceptibility Staphylococcus hominis subspecies hominis circulating in an intensive care unit. Eur J Clin Microbiol Infect Dis 29(1):73–80PubMedGoogle Scholar
  161. Sousa R, Lopez R, Martinez-Pastor JC, Cervera C, Bori G, Garcia-Ramiro S et al (2011) Usefulness of monitoring linezolid trough serum concentration in prolonged treatments. Rev Esp Quimioter 24(3):151–153PubMedGoogle Scholar
  162. Srivastava BK, Soni R, Patel JZ, Jain MR, Patel PR (2008) Oxazolidinone antibacterials and Our experience. Antiinfect Agents Med Chem 7(4):258–280Google Scholar
  163. Stalker DJ, Jungbluth GL, Hopkins NK, Batts DH (2003) Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 51(5):1239–1246PubMedGoogle Scholar
  164. Stein GE, Wells EM (2010) The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid. Curr Med Res Opin 26(3):571–588PubMedGoogle Scholar
  165. Stein GE, Schooley SL, Peloquin CA, Kak V, Havlichek DH, Citron DM et al (2005) Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis. Ann Pharmacother 39(3):427–432PubMedGoogle Scholar
  166. Stein GE, Schooley S, Peloquin CA, Missavage A, Havlichek DH (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(4):819–823PubMedGoogle Scholar
  167. Strukova EN, Smirnova MV, Vostrov SN, Lubenko IY, Firsov AA, Zinner SH et al (2009) Linezolid pharmacodynamics with Staphylococcus aureus in an in vitro dynamic model. Int J Antimicrob Agents 33(3):251–254PubMedGoogle Scholar
  168. Swoboda S, Ober MC, Lichtenstern C, Saleh S, Schwenger V, Sonntag HG et al (2010) Pharmacokinetics of linezolid in septic patients with and without extended dialysis. Eur J Clin Pharmacol 66(3):291–298PubMedGoogle Scholar
  169. Takahashi Y, Takesue Y, Nakajima K, Ichiki K, Tsuchida T, Tatsumi S et al (2011) Risk factors associated with the development of thrombocytopenia in patients who received linezolid therapy. J Infect Chemother 17(3):382–387PubMedGoogle Scholar
  170. Tanel T, Alexander M (2006) Antibiotics and the ribosome. Mol Microbiol 59(6):1664–1677Google Scholar
  171. Thallinger C, Buerger C, Plock N, Kljucar S, Wuenscher S, Sauermann R et al (2008) Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother 61(1):173–176PubMedGoogle Scholar
  172. The European Committee on Antimicrobial Susceptibility Testing Steering Committee (2006) EUCAST technical note on linezolid. Clin Microbiol Infect 12(12):1243–1245Google Scholar
  173. Theuretzbacher U (2007) Tissue penetration of antibacterial agents: how should this be incorporated into pharmacodynamic analyses? Curr Opin Pharmacol 7(5):498–504PubMedGoogle Scholar
  174. Theuretzbacher U (2009) Future antibiotics scenarios: is the tide starting to turn? Int J Antimicrob Agents 34(1):15–20PubMedGoogle Scholar
  175. Theuretzbacher U (2012) Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer. Clin Infect Dis 54(12):1785–1792PubMedGoogle Scholar
  176. Theuretzbacher (2013) Global antibacterial resistance: The never-ending story. J Global Antimicrob Resistance 1(2):63–69Google Scholar
  177. Toh S-M, Xiong L, Arias CA, Villegas MV, Lolans K, Quinn J et al (2007) Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Mol Microbiol 64(6):1506–1514PubMedPubMedCentralGoogle Scholar
  178. Tsuji Y, Hiraki Y, Matsumoto K, Mizoguchi A, Kobayashi T, Sadoh S et al (2011) Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction. J Infect Chemother 17(1):70–75PubMedGoogle Scholar
  179. Tsuji Y, Hiraki Y, Matsumoto K, Mizoguchi A, Sadoh S, Kobayashi T et al (2012a) Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient. Scand J Infect Dis 44(8):626–629PubMedGoogle Scholar
  180. Tsuji BT, Bulitta JB, Brown T, Forrest A, Kelchlin PA, Holden PN et al (2012b) Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations. J Antimicrob Chemother 67(9):2182–2190PubMedGoogle Scholar
  181. Wagenlehner FME, Wydra S, Onda H, Kinzig-Schippers M, Sorgel F, Naber KG (2003) Concentrations in plasma, urinary excretion, and bactericidal activity of linezolid (600 milligrams) versus those of ciprofloxacin (500 milligrams) in healthy volunteers receiving a single oral dose. Antimicrob Agents Chemother 47(12):3789–3794PubMedPubMedCentralGoogle Scholar
  182. Whitehouse T, Cepeda JA, Shulman R, Aarons L, Nalda-Molina R, Tobin C et al (2005) Pharmacokinetic studies of linezolid and teicoplanin in the critically ill. J Antimicrob Chemother 55(3):333–340PubMedGoogle Scholar
  183. Wilson DN, Schluenzen F, Harms JM, Starosta AL, Connell SR, Fucini P (2008) The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning. Proc Natl Acad Sci USA 105(36):13339–13344PubMedGoogle Scholar
  184. Wiskirchen DE, Shepard A, Kuti JL, Nicolau DP (2011) Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infections using in vivo microdialysis. Antimicrob Agents Chemother 55(9):4170–4175PubMedPubMedCentralGoogle Scholar
  185. Witte W, Cuny C (2011) Emergence and spread of cfr-mediated multiresistance in staphylococci: an interdisciplinary challenge. Future Microbiol 6(8):925–931PubMedGoogle Scholar
  186. Woytowish MR, Maynor LM (2013) Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother 47(3):388–397Google Scholar
  187. Wynalda MA, Hauer MJ, Wienkers LC (2000) Oxidation of the novel oxazolidinone antibiotic linezolid in human liver microsomes. Drug Metab Dispos 28(9):1014–1017PubMedGoogle Scholar
  188. Yagi T, Naito T, Doi M, Nagura O, Yamada T, Maekawa M, Sato S, Kawakami J (2013) Plasma exposure of free linezolid and its ratio to minimum inhibitory concentration varies in critically ill patients. Int J Antimicrob Agents 42(4):329–334 Google Scholar
  189. Yogev R, Damle B, Levy G, Nachman S (2010) Pharmacokinetics and distribution of linezolid in cerebrospinal fluid in children and adolescents. Pediatr Infect Dis J 29(9):827–830Google Scholar
  190. Zinner SH, Gilbert D, Lubenko IY, Greer K, Firsov AA (2008) Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline. J Antimicrob Chemother 61(3):629–635PubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Center for Anti-Infective AgesViennaAustria

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