Oxazolidinones:

The Past, Present,

and Future
Pharm.D. Candidate, Class of 2015
University of Saint Joseph School of Pharmacy
September 3, 2014
Background

Acute bacterial skin and skin structure infections
(ABSSSIs) have increasingly been associated with
drug-resistant pathogens

Vancomycin has been the cornerstone for MRSA
infections
Currently, there are a few drugs that are FDA
approved for complicated SSSIs caused by MRSA
Resistant strains have been reported
The newly approved oxazolidinone, tedizolid, may
be used as an alternative


Management of Skin and
Soft Tissue Infections:
2014 Update
Stevens DL, et al. IDSA Practice Guidelines for SSTIs. 2014.
Drug Dosing
Vancomycin 30 mg/kg/d in 2 divided doses IV
Linezolid 600 mg every 12 h IV or 600 mg
BID PO
Clindamycin 600 mg every 8 h IV or 300450
mg QID PO
Daptomycin 4 mg/kg every 24 h IV
Ceftaroline 600 mg BID IV
Doxycycline, minocycline 100 mg BID PO
Sulfamethoxazole/Trimethoprim 1-2 DS tabs BID PO
MRSA SSTI
Tedizolid (Sivextro)
MOA: A prodrug that once converted in vivo will interact
with the 23S ribosomal RNA (rRNA) of the 50S subunit to
inhibit translation

Activity against gram-positive pathogens, including
linezolid-resistant S. aureus

Pharmacokinetics/Pharmacodynamics
o Oral bioavailability ~91%
o Protein binding 70-90%
o t
1/2
~12 hours
o AUC:MIC


Metabolism Tedizolid phosphate is converted by phosphatases
to tedizolid (active)
Excretion Inactive sulfate conjugated in feces (82%) and
urine (18%)
Perceived Benefits of
Tedizolid Over Linezolid
Key structural difference may increase the
interaction of tedizolid with the peptidyl-transferase-
center binding site
o Increase potency against resistant bacterial strains

Favorable PK profile:
o Once daily dosing
o Easy IV to oral conversion

Has not shown interactions with serotonergic agents

Duration of therapy: 6 days vs 10 days
Kisgen JJ, et al. AJHP. 2014;71(8):621-
33.
ESTABLISH-1
Randomized, double-blind, phase 3, non-inferiority trial

Intent-to-treat analysis of 667 patients who had:
o One of the following surrounded by erythema:
Cellulitis/erysipelas
Major cutaneous abscess
Wound infection
o Minimum total lesion surface area of 75 cm
2
o 1 local and 1 regional OR 1 systemic signs of infection
o Gram-positive pathogen suspected or documented

Oral: Tedizolid 200 mg QD for 6 days or Linezolid 600 mg
BID for 10 days
Prokocimer P, et al. JAMA. 2013;309(6):559-
569.
ESTABLISH-1
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
48-72 h End of Treatment Post-therapy Evaluation
P
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(
%
)

Tedizolid 200 mg once daily (n = 332)
Linezolid 600 mg twice daily (n = 335)
79.4%
69.3%
71.9%
85.5%
86%
79.5%
0.1%
[95% CI, -6.1% to 6.2%]
-2.6%
[95 % CI, -9.6% to 4.2%]
-0.5%
[95% CI, -5.8% to 4.9%]
Prokocimer P, et al. JAMA. 2013;309(6):559-
569.
ESTABLISH-2
Randomized, double-blind, multinational, phase 3
parallel-group, non-inferiority trial

Similar criteria to ESTABLISH-1 with some differences:
o Enrolled substantially more patients that were European, had
cellulitis, were febrile, and had larger lesions
o Widened the age group to >12 years old

IV: Tedizolid 200 mg QD for 6 days or Linezolid 600
mg BID for 10 days with optional oral step-down
Moran GJ, et al. Lancet. 2014;14:696-705.
ESTABLISH-2
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
48-72 h End of Treatment
P
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(
%
)

Tedizolid 200 mg once daily (n = 332)
Linezolid 600 mg twice daily (n = 334)
83%
87%
88%
85%
Moran GJ, et al. Lancet. 2014;14:696-705.
2.6%
[95% CI, -3.0% to 8.2%]
-1.0%
[95% CI, -6.1% to 4.1%]
Discussion
CW presents to the ED with purulent cellulitis on her left
leg. She is febrile, tachycardic, and has a WBC 20.3.
Culture results pending.

What empiric therapy would you select for this patient?

Final cultures indicate MRSA, but the patient had a
previous treatment failure with vancomycin.

Would you consider Linezolid? Tedizolid?

Limitations
Linezolid is not commonly seen at St. Francis for SSSIs

Treatment course of tedizolid is just as expensive
o Linezolid cost per treatment course = $214/day x 10 days = $2,140
o Tedizolid cost per treatment course = $235/day x 6 days = $ 1,410

Both studies had relatively healthy, community
patients with little to no comorbidities

Would you put tedizolid on formulary?

Pulmonary Disposition
For Tedizolid
Prospective, open-label, multiple-dose
pharmacokinetic study

Clinical Research Center and Same Day Surgi-
Center at Hartford Hospital

20 healthy adult volunteers

Tedizolid 200 mg PO QD for 3 days to steady state
Housman ST, et al. Antimicrob Agents Chemother. 2012;56(5):2627-2634.
Pulmonary Disposition
For Tedizolid
% Penetration AUC
0-24
AUC/MIC
Target*
Tedizolid 41.2 109.3 20
Linezolid 5.2 960 57.2
% Penetration AUC
0-24
AUC/MIC
Target*
Tedizolid 20.0 52.95 20
Linezolid 0.2 40.8 57.2
*Target PK using serum AUC (tedizolid) and total drug target adjusted for protein
binding (linezolid)
Housman ST, et al. Antimicrob Agents Chemother. 2012;56(5):2627-2634.
Potential Role in Therapy
Monte Carlo simulation for lung penetration
o Mean tedizolid concentrations (at 24 hours):





o Given an MIC
90
of 0.5 mg/mL for tedizolid against S. aureus,
AUC:MIC ratios of 219 and 106 are achieved in the ELF and AM
Exceeds the target mean fAUC:MIC ratio of 20

Possible HABP and VABP indications?
Free Plasma Epithelial Lining Fluid
(ELF)
Alveolar
Macrophages (AM)
0.043 g/mL 1.33 g/mL 1.04 g/mL
Housman ST, et al. Antimicrob Agents Chemother. 2012;56(5):2627-2634.
Schaadt R, et al. Antimicrob Agents Chemother. 2009;53:3236-3239.
Discussion

MH is a 70 YO male who was brought in from a SNF
with a productive cough. He also had a temperature
of 101.3 and WBC 15,000. Chest X-ray showed bilateral
infiltrates. Sputum cultures showed presence of MRSA.

PMH: Asthma, Depression
Medications: Proair 2 puffs q4-6h prn
Advair 250/50 1 inhalation BID
Fluoxetine 40 mg QAM
The Future For Tedizolid
Benefits over linezolid
o Increased potency over bacterial resistant strains
o Once daily dosing

Role in ABSSSI would be limited

Benefit may be seen more with pneumonia
o Great pulmonary penetration
o Also penetrates into macrophages which would be beneficial for
intracellular agents

Also, vancomycin and linezolid have been seeing
more treatment failures due to MRSA resistance

References
1. Stevens DL, Bisno AL, Chambers HF, Dellinger EP , Goldstein EJC, Gorbach SL, et al.
Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue
Infections: 2014 Update by the Infectious Diseases Society of America.
2. Tedizolid [Internet]. Hudson (OH): Lexicomp (US). C1978-2013 [cited 2014 Aug 11].
Available from:
http://ezproxy.usj.edu:2063/lco/action/doc/retrieve/docid/patch_f/5231522.
3. Kisgen JJ, Mansour H, Unger NR, Childs LM. Tedizolid: a new oxazolidinone
antimicrobial. AJHP. 2014 Apr 15;71(8):621-33.
4. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid Phosphate vs
Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections: The
ESTABLISH-1 Randomized Trial. JAMA. 2013 Feb 13;309(6):559-569.
5. Moran GJ, Fang E, Corey GR, Das AF, De Anda C, Prokocimer P. Tedizolid for 6
days versus linezolid for 10 days for acute bacterial skin and skin-structure
infections (ESTABLISH-2): a randomised, double-blind, phase 3, non-inferiority trial.
Lancet. 2014 Aug;14:696-705.
6. Housman ST, Pope JS, Russomanno J, Salerno E, Shore E, Kuti, JL, et al. Pulmonary
Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram
Tedizolid Phosphate in Healthy Adult Volunteers. Antimicrob Agents Chemother.
2012;56(5):2627-2634.
7. Schaadt R, Sweeney D, Shinabarger D, Zurenko G. In vitro activity of TR-700, the
active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone
antibacterial agent. Antimicrob, Agents Chemother. 2009;53:3236-3239.