logo

Oxazolidones

Disclaimer - Please see package insert if applicable for additional information. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.   Read the disclaimer   |   <BACK

Oxazolidones

Background:     "Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. Oxazolidinones are mainly used as antimicrobials. The antibacterial effect of oxazolidinones is by working as protein synthesis inhibitors, targeting an early step involving the binding of N-formylmethionyl-tRNA to the ribosome. Some of the most important oxazolidinones are the last generation of antibiotics used against gram-positive pathogens, including superbugs such as methicillin-resistant Staphylococcus aureus. These antibiotics are considered as a choice of last resort where every other antibiotic therapy has failed."
  [Source: http://en.wikipedia.org/wiki/2-Oxazolidone ]
Linezolid (Zyvox®) Tedizolid phosphate (SIVEXTRO™) --

Investigational drugs  - Monographs not available

Posizolid Torezolid - phase-III clinical trials Radezolid (RX-1741) -phase-II clinical trials.
  Infectious Disease -ALL Agents (INDEX)  
     

Antimicrobials - Infectious Disease

Aminoglycosides Ansamycins/Rifamycins Antibiotics (Other)
Anti- Fungals Anti-Herpetic Agents Anti-Influenza Agents
Anti-Malarials Carbapenems Cephalosporins
Fluoroquinolones Glycopeptides HIV (anti) Agents
Lincosamides Lipopeptides Macrolides
Monobactams Oxazolidones Penicillins
Sulfonamide antibiotics Tetracyclines Tuberculosis (anti) agents

 Linezolid (Zyvox®): top of page

Microbiology:
Mechanism of Action
Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of isolates.

Mechanisms of Resistance
In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg every 12 hours, lower than the recommended dose, and 2 patients received 600 mg every 12 hours). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 × 10 –9 to 1 × 10 –11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during clinical use. The linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.

Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.

Interaction with Other Antimicrobials
In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.

Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section (1).

Gram-positive bacteria
Enterococcus faecium (vancomycin-resistant isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria
Enterococcus faecalis (including vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
Viridans group streptococci

Gram-negative bacteria
Pasteurella multocida

INDICATIONS AND USAGE:
ZYVOX is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. ZYVOX is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.

---------------------------------
Pneumonia
---------------------------------
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae.

Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [see Clinical Studies (14)].

---------------------------------
Skin and Skin Structure Infections
---------------------------------
Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. ZYVOX has not been studied in the treatment of decubitus ulcers.

Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
---------------------------------
Vancomycin-resistant Enterococcus faecium Infections
---------------------------------
Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.


---------------------------------
Usage
---------------------------------
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZYVOX and other antibacterial drugs, ZYVOX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

The safety and efficacy of ZYVOX formulations given for longer than 28 days have not been evaluated in controlled clinical trials.

CONTRAINDICATIONS
Hypersensitivity
ZYVOX formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.

Monoamine Oxidase Inhibitors
Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

WARNING AND PRECAUTIONS:
  • Myelosuppression: Monitor complete blood counts weekly. Consider discontinuation in patients who develop or have worsening myelosuppression.
  • Peripheral and optic neuropathy: Reported primarily in patients treated for longer than 28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended.
  • Serotonin syndrome: Patients taking serotonergic antidepressants should receive ZYVOX only if no other therapies are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation.
  • A mortality imbalance was seen in an investigational study in linezolid-treated patients with catheter-related bloodstream infections.
  • Clostridium difficile associated diarrhea: Evaluate if diarrhea occurs.
  • Potential interactions producing elevation of blood pressure: monitor blood pressure.
  • Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents.

DOSAGE AND ADMINISTRATION:
General Dosage and Administration
The recommended dosage for ZYVOX formulations for the treatment of infections is described in Table 1.

Table 1. Dosage Guidelines for ZYVOX:



Infection*
Dosage and Route of Administration Recommended Duration of Treatment (consecutive days)
Pediatric Patients† (Birth through 11 Years of Age) Adults and Adolescents
(12 Years and Older)
Nosocomial pneumonia 10 mg/kg intravenously or oral‡ every 8 hours
600 mg intravenously or oral‡ every 12 hours 10 to 14
Community-acquired pneumonia, including concurrent bacteremia
Complicated skin and skin structure infections
Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenously or oral‡ every 8 hours
600 mg intravenously or oral‡ every 12 hours 14 to 28
Uncomplicated skin and skin structure infections <5 yrs: 10 mg/kg oral‡ every 8 hours
5–11 yrs: 10 mg/kg oral‡ every
12 hours
Adults: 400 mg oral‡ every
12 hours
Adolescents: 600 mg oral‡ every 12 hours

10 to 14

*Due to the designated pathogens [see Indications and Usage (1)]

† Neonates <7 days: Most pre-term neonates <7 days of age (gestational age <34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life.

‡ Oral dosing using either ZYVOX Tablets or ZYVOX for Oral Suspension.

No dose adjustment is necessary when switching from intravenous to oral administration.

Intravenous Administration
ZYVOX I.V. Injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. ZYVOX I.V. Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.

ZYVOX I.V. Injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If ZYVOX I.V. Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.

If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of ZYVOX I.V. Injection with an infusion solution compatible with ZYVOX I.V. Injection and with any other drug(s) administered via this common line.

Compatibilities
Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.

Constitution of Oral Suspension

ZYVOX for Oral Suspension is supplied as a powder/granule for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake. Store constituted suspension at room temperature. Use within 21 days after constitution.


SUPPLIED:
ZYVOX I.V. Injection: 100-mL (200 mg linezolid), 200-mL (400 mg linezolid) and 300-mL (600 mg linezolid) single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags and ports are latex-free.

ZYVOX 600 mg Tablet: white, capsule-shaped, film-coated tablet printed with "ZYVOX 600 mg"

ZYVOX for Oral Suspension: dry, white to off-white, orange-flavored granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL.


SOURCE: Package insert data:

 Tedizolid phosphate (SIVEXTRO™): top of page

Updates:
Drug:  SIVEXTRO (tedizolid phosphate) for injection, for intravenous use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014


Microbiology:
Tedizolid belongs to the oxazolidinone class of antibacterial drugs.

Mechanism of Action
The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.

INDICATIONS AND USAGE:
Acute Bacterial Skin and Skin Structure Infections
SIVEXTRO™ is an oxazolidinone-class antibacterial indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis.

Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of SIVEXTRO and other antibacterial drugs, SIVEXTRO should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION:
Recommended Dosage
The recommended dosage of SIVEXTRO is 200 mg administered once daily for six (6) days either orally (with or without food) or as an intravenous (IV) infusion in patients 18 years of age or older.

No dose adjustment is necessary when changing from intravenous to oral SIVEXTRO.

If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.

Preparation and Administration of Intravenous Solution
SIVEXTRO is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.

SIVEXTRO vials contain no antimicrobial preservatives and are intended for single use only.

Preparation
The contents of the vial should be reconstituted using aseptic technique as follows:

Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
  1. Reconstitute the SIVEXTRO vial with 4 mL of Sterile Water for Injection.
  2. Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses.
  3. Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total storage time should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
  4. Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution. Do not invert the vial during extraction.
  5. The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 4 mL of reconstituted solution into a 250 mL bag of 0.9% Sodium Chloride Injection, USP. Invert the bag gently to mix. Do NOT shake the bag as this may cause foaming.
 Administration
Administer as an intravenous infusion only.

Do not administer as an intravenous push or bolus. Do not mix SIVEXTRO with other drugs when administering. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration. Discard if visible particles are observed. The resulting solution is clear and colorless to pale-yellow in color.

After reconstitution and dilution, SIVEXTRO is to be administered via intravenous infusion using a total time of 1 hour.

Stability:
The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).

Compatible Intravenous Solutions
SIVEXTRO is compatible with 0.9% Sodium Chloride Injection, USP.

Incompatibilities
SIVEXTRO for injection is incompatible with any solution containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Injection and Hartmann's Solution.

Limited data are available on the compatibility of SIVEXTRO for injection with other intravenous substances, additives or other medications and they should not be added to SIVEXTRO single-use vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of SIVEXTRO with 0.9% Sodium Chloride Injection, USP.

WARNINGS AND PRECAUTIONS
Patients with neutropenia: The safety and efficacy of SIVEXTRO in patients with neutropenia (neutrophil counts <1000 cells/mm3) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of SIVEXTRO was reduced in the absence of granulocytes. Consider alternative therapies in neutropenic patients.
Clostridium difficile-associated diarrhea: Evaluate if diarrhea occurs.


ADVERSE REACTIONS
The most common adverse reactions (>/=2%) are nausea, headache, diarrhea, vomiting, and dizziness.

To report SUSPECTED ADVERSE REACTIONS, contact Cubist Pharmaceuticals at 1-877-282-4786 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See package insert for PATIENT COUNSELING INFORMATION.

SUPPLIED:
Tablets
SIVEXTRO tablets are yellow film-coated oval tablets containing 200 mg of tedizolid phosphate; each tablet is debossed with "TZD" on one side and "200" on the other side.

They are supplied as follows:
HDPE bottles of 30 tablets with child-resistant closure (NDC 67919-041-01)
Unit dose blister packs of 6 tablets (NDC 67919-041-02)

For Injection
SIVEXTRO is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.

They are supplied as follows:
Package of ten 200 mg single-dose vials (NDC 67919-040-01)

Storage and Handling
SIVEXTRO tablets and SIVEXTRO for injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

SOURCE: Package insert data:

 ®: top of page

Microbiology:
INDICATIONS AND USAGE:
DOSAGE AND ADMINISTRATION:
Renal Dosing:
SUPPLIED:
SOURCE: Package insert data:

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.
Disclaimer - Please see package insert if applicable for additional information. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.   Read the disclaimer   |   <BACK
more Career Center image description
Medical Calculators - A thru Z
Lab Values - A thru Z