Linezolid - Tigecycline Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Catholic University of Louvain, Brussels, Belgium With the support of Wallonie-Bruxelles-International 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 1 Dong-A pharmaceuticals and tedizolid: step #1 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 2 Mode of action: • Protein synthesis inhibition: LZD binds to the 23S portion of the ribosomal 50S subunit (the centre of peptidyl transferase activity) → no initial complex 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 3 RNA interaction Karen L. Leach et al, Molecular Cell (2007) 26,393-402 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 4 Spectrum of activity No useful activity against other Gram-negative organisms because of constitutive efflux ! 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 5 Registered clinical indications Linezolid is often used off-label (endocarditis, osteomyelitis, ….) in pace of vancomycin 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 6 Linzezolid: mechanism of resistance 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 7 Can linzolid induce resistance ? 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 8 Linzolid can induce resistance… Locke et al. Antimicrob Agent Chemother 2009;53:5265-5274. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 9 Linezolid pharmacokinetics 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 10 Linezolid human pharmacokinetics Oral therapeutic doses (600mg linezolid q12h for 21 days) Linezolid Tedizolid MIC 90 MIC90 Muñoz et al. ECCMID 2010; P1594 Flanagan SD, et al. Pharmacotherapy 2014;34(3):240–250. 12-11-2015 WBI - HUP Cooperation - Bach Mai HospitalMunoz KA, et al. ECCMID 2010. Poster1594. 11 Linezolid human pharmacokinetics: adults Oral therapeutic doses (600mg linezolid q12h) Tedizolid MIC90 Flanagan SD, et al. Pharmacotherapy 2014;34(3):240–250. 12-11-2015 WBI - HUP Cooperation - Bach Mai HospitalMunoz KA, et al. ECCMID 2010. Poster1594. 12 Linezolid human pharmacokinetics: children MIC90 Flanagan SD, et al. Pharmacotherapy 2014;34(3):240–250. 12-11-2015 WBI - HUP Cooperation - Bach Mai HospitalMunoz KA, et al. ECCMID 2010. Poster1594. 13 Pharmacokinetics/Pharmacodynamics 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 14 PK parameters governing the activity of antibiotics Cmax / MIC Cmax f T > MIC AUC24h / MIC f T > MIC Concentration MIC Time (h) 0 6 12 18 24 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 15 Tedizolid vs linezolid: human pharmacokinetics drug dosage Cmax (mg/L) apparent t1/2 Clearance Total AUC24h (h) (ml/min) (mg·h/L) linezolid IV 1 600 mg 15.1 ± 2.5 4.8 ± 1.7 123 ± 40 89.7 ± 31.0 Q12 h 1. Zyvox US Prescription Information (multiple doses) 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 16 Linezolid adverse effects • Drug interactions: – cytochrome P450: no special effect – antibiotics: rifampin causes a 21 % in LZD serum levels – Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) • Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) • Hypoglycemia • Lactic acidosis (PRECAUTION – Immediate medical attention) • Peripheral and optic neuropathy (>28 days) • Convulsions Zyvox US Prescribing Information, 2014. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 17 Linezolid adverse effects • Drug interactions: – cytochrome P450: no special effect – antibiotics: rifampin causes a 21 % in LZD serum levels – Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) • Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) • Hypoglycemia • Lactic acidosis (PRECAUTION – Immediate medical attention) • Peripheral and optic neuropathy (>28 days) • Convulsions Zyvox US Prescribing Information, 2014. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 18 Monoamine oxidase (MAO) substrate specificity Consequences of MAO-A Inhibition MAO-A MAO-B Serotonin Syndrome Benzylamine Serotonin Phenylethylamine Hypertensive Dopamine Noradrenaline N-phenylamine crisis Tyraminea Adrenaline Octylamine Octopamine Tryptamine Kynuramine N-acetylputrescine 3-methoxytyramine Milacemide N-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine a MAO-A is the predominate form for oxidation of tyramine Elmer & Bertoni. Expert Opin Pharmacother 2008;9:2759–2772. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 19 Is serotonergic syndrome an important problem? Boyer & Shannonl New Eng J Med 2005;352:1112–1120. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 20 This is what we tell the pharmacists in Belgium…. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 21 Linezolid contraindications Monoamine oxidase inhibitors Drugs that elevate blood pressure Serotonergic drugs Precaution Tyramine-containing food 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 22 Linezolid adverse effects • Drug interactions: – cytochrome P450: no special effect – antibiotics: rifampin causes a 21 % in LZD serum levels – Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) • Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) • Hypoglycemia • Lactic acidosis (PRECAUTION – Immediate medical attention) • Peripheral and optic neuropathy (>28 days) • Convulsions Zyvox US Prescribing Information, 2014. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 23 Thrombocytopenia caused by linezolid may be more frequent than previously thought Minson et al. Pharmacother 2010;30:895–903. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 24 Cellular models -HL-60 (Human promyelocytic leukemia cells) -THP1 (Human monocytic cell line) 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 25 Linezolid-induced thombocytopenia is indeed frequent ... Patients with thrombocytopenia no yes grade 1-2 grade 3-4 435 64 38 26 (87.2%) (12.8%) (7.6%) (5.2%) grade 1: 75–99.9 x 103/mm3; grade 2: 50–74.9 x 103/mm3; grade 3: 20–49.9 x 103/mm3; grade 4: < 20 x 103/mm3. Minson et al. Pharmacother 2010;30:895–903. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 26 ...and related to initial low platelet levels Patients with thrombocytopenia no yes grade 1-2 grade 3-4 435 64 38 26 (87.2%) (12.8%) (7.6%) (5.2%) grade 1: 75–99.9 x 103/mm3; grade 2: 50–74.9 x 103/mm3; grade 3: 20–49.9 x 103/mm3; grade 4: < 20 x 103/mm3. Minson et al. Pharmacotherapy 2010;30:895-903 Minson et al. Pharmacother 2010;30:895–903. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 27 ...and aggravated by renal failure… Wu et al. Clin Infect Dis 2006;42:66–72. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 28 Linezolid adverse effects • Drug interactions: – cytochrome P450: no special effect – antibiotics: rifampin causes a 21 % in LZD serum levels – Monoamine oxidase inhibition (reversible, nonselective inhibitor): adrenergic and serotonergic agents (PRECAUTIONS) • Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) (WARNING) • Hypoglycemia • Lactic acidosis (PRECAUTION – Immediate medical attention) • Peripheral and optic neuropathy (>28 days) • Convulsions Zyvox US Prescribing Information, 2014. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 29 Mitochondrial RNA interaction Karen L. Leach et al, Molecular Cell (2007) 26,393-402 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 30 Cytox I expression in cells exposed to linezolid incubation with drug washout 140 140 120 120 0 12 24 48 72 96 hours 0 24 48 72 96 hours 100 100 oxidase 80 80 c 60 LZD 15mg/L LZD 60 (%of control) 40 40 subunit I expression cytochrome 20 20 0 0 0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96 hours of incubation hours post washing → inhibition time -dependent, effect fully reversibly 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 31 When do we use linezolid ? • as substitute to vancomycin when – patient leaves the hospital (oral form) – intolerance – MICs of vancomycin > 2 and no other alternative • with close control of the patient (weakly) for – thrombocytopenia and anemia – lactic acidosis – risk of serotoninegic syndrome 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 32 Tygecycline (in very short) 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 33 Tigecycline: historical landmarks …. 1993 1999 Disvovery of glycylcyclines as a novel class of antibiotics In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Testa et al. Antimicrob Agents Chemother. 1993 37:2270-7 Demonstration of the spectrm of activity and candidate selection In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Petersen et al. (1999) Antimicrob Agents Chemother. 43:738-44. 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 34 Tigecycline: chemical structure minocycline glycyl- H3C CH3 H3C CH3 t-butyl NH NH OH O H H3C N C N C O H3C H OH CH3 OH O OH O NH2 12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 35 Mode of action of tigecycline tigecycline • same binding site as tetracyclines in ribosome 16S RNA; additional interaction site tetracycline • Unaffected by resistance due to minocycline - ribosomal protection - Tet efflux pumps; • But remains susceptible to broad spectrum efflux pumps of Gram(-) (MexXY in P. aeruginosa) Olson et al., AAC (2006) 50:2156-66 12-11-2015