Zyvox Medical Drug

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Description

Linezolid (INN) is a synthetic antibiotic of the oxazolidinone class used for the treatment of infections caused by multi-resistant bacteria including streptococci[1] and methicillin-resistant Staphylococcus aureus (MRSA).[2] It is marketed by Pfizer under the trade name Zyvox (in the United States and several other countries), Zyvoxam (in Canada and Mexico), or Zyvoxid (in Europe).

Linezolid was the first commercially available oxazolidinone antibiotic. Therapy using linezolid can be quite expensive, with prices for a course of treatment ranging up to several thousands of dollars; nonetheless, it appears to be more cost-effective than vancomycin or teicoplanin.[3]

History

The oxazolidinone class was discovered by researchers at E.I. duPont de Nemours and reported in 1987.[4] Early compounds were found to produce liver toxicity, however, and development was discontinued.[5] Pharmacia & Upjohn (now part of Pfizer) started their own oxazolidinone research program in the 1990s, and two compounds were taken to Phase I clinical trials: linezolid and eperezolid.[5][6] Linezolid was found to have better pharmacokinetic properties, and it proceeded to further trials; Food and Drug Administration (FDA) approval was granted on April 18, 2000.[7] It is sold in the U.S. under the tradename Zyvox in either tablet form, oral suspension powder, or in an inactive medium for intravenous injection.

Initially there was hope that bacteria would be unable to develop resistance to it. However, resistance was reported as early as 1999, in two patients with severe, multidrug-resistant Enterococcus faecium infection who received the drug through a compassionate use program.[8] Linezolid-resistant Staphylococcus aureus was first isolated in 2001.[9]

Clinical use

It is usually reserved for the treatment of serious bacterial infections where older antibiotics have failed due to antibiotic resistance. Conditions such as skin infections or nosocomial pneumonia where methicillin or penicillin resistance is found are indicators for linezolid use.

Linezolid is effective against Gram-positive pathogens, notably Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. It has almost no effect on gram-negative bacteria and is only bacteriostatic against most Enterococcus species. Linezolid also provides some anaerobic coverage.

In combination with other drugs, linezolid has been used to treat tuberculosis.[10] The optimal dose for use in tuberculosis is not known. In adults, 600 mg daily[11] or 600 mg twice daily[12] have both been used to good effect. The treatment often needs to be continued for many months and the rate of adverse effects is high.[11] The lower dose is not associated with a lower rate of adverse effects.[11]

Adverse effects

Side effects include diarrhea, headache, nausea, rashes, loss of appetite, constipation and fever. A small number of patients will incur a severe allergic reaction, or tinnitus, or pseudomembranous colitis. Thrombocytopenia is uncommon in patients who receive linezolid for 14 days or fewer (as recommended by the manufacturer), but in patients who receive longer courses, or who have renal failure, the rate is much higher.[13] The anemia and thrombocytopenia caused by linezolid are not prevented by concurrent administration of pyridoxine 125 mg daily.[14]

Linezolid is toxic to mitochondria (probably because of the similarity between mitochondrial and bacterial ribosomes).[15] Signs of mitochondrial toxicity include lactic acidosis and peripheral neuropathy.[16] Painful sensory neuropathy.[17]

Mechanism of action

Linezolid works on the initiation of protein synthesis. (This is in contrast to most other protein synthesis inhibitors, which inhibit elongation.)[18]

It does this by stopping the 30S and 50S subunits of the ribosome from binding together. Linezolid binds on the 23S portion of the 50S subunit close to the peptidyl transferase and chloramphenicol binding sites. This then stops the interaction with the 30S subunit.

Resistance

Resistance to linezolid usually develops as the result of a point mutation known as G2576T, in which a guanine base is replaced with thymine in base pair 2576 of the genes coding for 23S ribosomal RNA.[19][20] This is the most common mechanism of resistance in staphylococci, and the only one known to date in isolates of Enterococcus faecium.[21]

In the United States, resistance to linezolid has been monitored and tracked since 2004 through a program named LEADER, which (as of 2007) was conducted in 60 medical institutions throughout the country. Resistance has remained stable and extremely low (less than one-half of one percent of isolates).[22] Some authors have predicted that resistance in E. faecium will increase if linezolid use continues at current levels or increases.[21]

Interactions

Linezolid is a weak monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, tyramine-containing foods, or pseudoephedrine; there have been postmarketing reports of serotonin syndrome when linezolid was given with serotonergic drugs.[23][24]

Linezolid may enhance the blood pressure-increasing effects of sympathomimetic drugs such as pseudoephedrine or phenylpropanolamine.[25]

References

1. ^ Pfizer (June 20, 2008). "ZYVOX (linezolid) Label Information" (PDF). http://www.fda.gov/cder/foi/label/2008/021130s016,021131s013,021132s014lbl.pdf. Retrieved on 2008-08-24.
2. ^ Burkhardt O, Pletz MW, Mertgen CP, Welte T (2007). "Linezolid - the first oxazolidinone in the treatment of nosocomial MRSA pneumonia". Recent Patents Anti-Infect Drug Disc 2 (2): 123-30. doi:10.2174/157489107780832659. PMID 18221168.
3. ^ Grau S, Rubio-Terrés C (April 2008). "Pharmacoeconomics of linezolid". Expert Opin Pharmacother 9 (6): 987-1000. doi:10.1517/14656566.9.6.987. PMID 18377341.
4. ^ Slee AM, Wuonola MA, McRipley RJ, et al (November 1987). "Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721". Antimicrob Agents Chemother 31 (11): 1791-7. PMID 3435127. PMC: 175041. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=3435127.
5. ^ a b Livermore DM (September 2000). "Quinupristin/dalfopristin and linezolid: where, when, which and whether to use?". J Antimicrob Chemother 46 (3): 347-50. PMID 10980159. http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10980159.
6. ^ Ford CW, Zurenko GE, Barbachyn MR (August 2001). "The discovery of linezolid, the first oxazolidinone antibacterial agent". Curr Drug Targets Infect Disord 1 (2): 181-99. doi:10.2174/1568005014606099. PMID 12455414.
7. ^ "Drug Approval Package: Zyvox". FDA Center for Drug Evaluation and Research. November 20, 2001. http://www.fda.gov/cder/foi/nda/2000/21130_Zyvox.htm. Retrieved on 2009-01-17.Comprehensive review of the FDA approval process. Includes detailed reviews of the chemistry and pharmacology of linezolid, correspondence between the FDA and Pharmacia & Upjohn, and administrative documents.
8. ^ [No authors listed] (2001). "Linezolid". Drug Ther Perspect 17 (9): 1-6. http://www.medscape.com/viewarticle/406493.Free full text with registration at Medscape.
9. ^ Tsiodras S, Gold HS, Sakoulas G, et al (July 2001). "Linezolid resistance in a clinical isolate of Staphylococcus aureus". Lancet 358 (9277): 207-8. doi:10.1016/S0140-6736(01)05410-1. PMID 11476839.
10. ^ von der Lippea B, Sandvenb P, Brubakk O. (2006). "Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB)-a report of ten cases". J Infect 52 (2): 92-6. doi:10.1016/j.jinf.2005.04.007.
11. ^ a b c Park IN, Hong SB, Oh YM, et al. (2006). "Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis". J Antimicrob Chemother 58 (3): 701-4. doi:10.1093/jac/dkl298. PMID 16857689.
12. ^ Fortun J, Martin-Davila P, Navas E, et al. (2005). "Linezolid for the treatment of multidrug-resistant tuberculosis". J Antimicrob Chemother 56 (1): 180-5. doi:10.1093/jac/dki148. PMID 15911549.
13. ^ Lin Y-H, Wu V-C, Tsai I-J, et al. (2006). "High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency". Int J Antimicrob Agents 28 (4): 345-51. doi:10.1016/j.ijantimicag.2006.04.017.
14. ^ Plachouras D, Giannitsioti E, Athanassia S, et al. (2006). "No effect of pyridoxine on the incidence of myelosuppression during prolonged linezolid treatment". Clin Infect Dis 43 (9): e89-91. doi:10.1086/508280. http://www.journals.uchicago.edu/doi/full/10.1086/508280.
15. ^ McKee EE, Ferguson M, Bentley AT, Marks TA (June 2006). "Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones". Antimicrob Agents Chemother 50 (6): 2042-9. doi:10.1128/AAC.01411-05. PMID 16723564.
16. ^ Soriano A, Miró O, Mensa J (2005). "Mitochondrial Toxicity Associated with Linezolid". N Engl J Med 353 (21): 2305-6. doi:10.1056/NEJM200511243532123. PMID 16306535.
17. ^ Chao CC, Sun HY, Chang YC, Hsieh ST (2008). "Painful neuropathy with skin denervation after prolonged use of linezolid". J. Neurol. Neurosurg. Psychiatr. 79 (1): 97-9. doi:10.1136/jnnp.2007.127910. PMID 17766431. http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=17766431.
18. ^ Ament PW, Jamshed N, Horne JP (February 2002). "Linezolid: its role in the treatment of gram-positive, drug-resistant bacterial infections". Am Fam Physician 65 (4): 663-70. PMID 11871684. http://www.aafp.org/afp/20020215/663.html.
19. ^ Saager B, Rohde H, Timmerbeil BS, et al (September 2008). "Molecular characterisation of linezolid resistance in two vancomycin-resistant (VanB) Enterococcus faecium isolates using Pyrosequencing". Eur J Clin Microbiol Infect Dis 27 (9): 873-8. doi:10.1007/s10096-008-0514-6. PMID 18421487.
20. ^ Besier S, Ludwig A, Zander J, Brade V, Wichelhaus TA (April 2008). "Linezolid resistance in Staphylococcus aureus: gene dosage effect, stability, fitness costs, and cross-resistances". Antimicrob Agents Chemother 52 (4): 1570-2. doi:10.1128/AAC.01098-07. PMID 18212098.
21. ^ a b Scheetz MH, Knechtel SA, Malczynski M, Postelnick MJ, Qi C (June 2008). "Increasing incidence of linezolid-intermediate or -resistant, vancomycin-resistant Enterococcus faecium strains parallels increasing linezolid consumption". Antimicrob Agents Chemother 52 (6): 2256-9. doi:10.1128/AAC.00070-08. PMID 18391028.
22. ^ Jones RN, Ross JE, Castanheira M, Mendes RE (December 2008). "United States resistance surveillance results for linezolid (LEADER Program for 2007)". Diagn Microbiol Infect Dis 62 (4): 416-26. doi:10.1016/j.diagmicrobio.2008.10.010. PMID 19022153.
23. ^ Huang V, Gortney JS (December 2006). "Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists". Pharmacotherapy 26 (12): 1784-93. doi:10.1592/phco.26.12.1784. PMID 17125439.
24. ^ Waknine, Yael (September 5, 2008). "FDA Safety Changes: Mirena, Zyvox, Orencia". Medscape. http://www.medscape.com/viewarticle/580101. Retrieved on 2008-09-06.Freely available with registration.
25. ^ Stalker DJ, Jungbluth GL (2003). "Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial". Clin Pharmacokinet 42 (13): 1129-40. PMID 14531724.

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