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 WBI - HUP Cooperation - Bach Mai Hospital 36 Tetra- and glycyl-cyclines: activity and resistance
species phenotype tetracycline minocycline tigecycline
E. coli susceptible 1 1 0.25 Efflux (Tet) > 32 16 0.5 Ribosomal > 32 > 32 0.25 protection S. aureus susceptible 0.12 0.06 0.25 Efflux (Tet) > 32 0.25 0.5 Ribosomal > 32 4 0.25 protection
Petersen et al., AAC (1999) 43:738-44
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 37 Tigecycline: registered indications (US)
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 38 Tigecycline: known clinical failures
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 39 Tigecycline: known clinical failures
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 40 Tigecycline: pharmacokinetics
AUC serum/tissue AUC tissue 24h (mg.h/L) ratio
bile 2815 537
bladder 120 23
colon 17.3 2.6
lung 9.19 2
bone 2.05 0.4
Single dose: 100 mg 100 dose: Single synovial fluid 1.68 0.31
CSF 0.46 0.11
ELF 4.54 1.31
q12h alveolar MΦ 268 77.5 6x50 mg mg 6x50 100 mg mg 100 +
Rodvold, JAntimicrob Chemother (2006) 58:1221-9 Conte et al., Int J Antimicrob Agents (2005) 25:523-9
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 41 PK/PD of tigecycline – animal models
Mouse thigh - S. pneumoniae
Efficacy for AUC24h/MIC of • 1-5 (free fraction) • ~ 10-50 (total conc.)
van Ogtrop et al., AAC (2000) 44:943-9
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 42 Tigecycline EUCAST breakpoints
100 tigecycline 80 But will this 60 last ? (T.E.S.T. will
of strains 40 tell but TK 20 reports MIC90 cumulative percentage 0 at 0.75 1 2 4
0.5 In 2008) 0.25 0.125 0.0625 MIC (mg/L) Denis et al., AAC (2006) 50:2680-5
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 43 Could we use higher doses than recommended ?
The recommended dosage regimen for TYGACIL is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of TYGACIL should be administered over approximately 30 to 60 minutes every 12 hours.
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 44 Could we use higher doses than recommended ?
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 45 When do we use tigecycline ?
• skin and skin structures / abdominal infections with multi-resistant organisms susceptible to tigecyline • Because of increased mortality compared to other antibiotics, tigecycline uts only be used when alternatives are not available
12-11-2015 WBI - HUP Cooperation - Bach Mai Hospital 46