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Trius Therapeutics, Inc. (TSRX) Message Board

  • patchen76 patchen76 May 29, 2013 3:29 PM Flag

    Does anyone know why tedizolid prevents Daptomycin resistance?

    Just curious if this has been explained biochemically. Why it does this and linezolid doesn't. Somewhat new here holding 15k shares at 7.4, seems like that is the floor.
    Trying to put together personal valuation on the company. If priced right will take a lot of share from linezolid. Throw in the combo use with dapto and it could be a seller. Pricing will matter in the choice between linezolid and tedizolid as they are pretty comparable. Price close and choice is tedizolid. Just my thoughts.

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    • Wouldn't be the first time having a drug with clinical efficacy surprises that cant be fully explained scientifically, but what works works! This drug is now seperating from the competition with many additional uses and benefits.

    • Daptomycin binds to a phospholipid in the cell wall of the bacteria, causing membrane depolarization (changes charge of the membrane) and the bacteria dies. Linezolid/tedizolid are oxazolidinone which bind to a ribosome necessary for protein synthesis. I am an immunologist, not a microbiologist, but the synergy isn't completely intuitive to me. Interestingly most agents that bind to ribosomes like linezolid (macrolides such as erythromycin/azithromycin or tetracyclines such as doxy or minocycline are mostly bacteriostatic- meaning they block bacterial growth, but don't cause bacterial death, meaning your immune system has to clear the bacteria). Even though linezolid is also bacteriostatic, for some reason tedezolid is also bactericidal by itself, just like daptomycin or other cell wall acting agents such as penicillin and cephalosporins (probably because it is blocking the production of a really important protein). This is just speculation by me but my guess is daptomycin resistance by a bacteria involves the production of a protein that can transport daptomycin out of the cell wall, resulting in no damage. Tedezolid may be blocking the synthesis of that protein that transports the daptomycin out of the bacteria, leading to more daptomycin build up, and bacterial cell death. Makes the most sense to me.

      Go Trius, kill 'em bugs!!

    • Daptomycin like Tedizolid is wide spectrum bactericidal against Gram-positive bacteria only. Although it has been proven in vitro activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus MRSA), streptococci and corynebacteria. there are some Dapto resistant strains showing up. Daptomycin also doesn't work on pneumonia indications as it binds avidly to pulmonary surfaces on the alveolar cells and therefore cannot be dispersed effectively in the lungs. Tedizolid looks more promising for pneumonia infection indications and according to the companies fwd pipeline statements; "Under our tedizolid phosphate clinical program, we plan to develop tedizolid phosphate to treat multiple clinical indications, including ABSSSI and other important indications involving infections of the lung and blood, such as, hospital acquired pneumonia (HAP), ventilator acquired pneumonia (VAP) and bacteremia." ...this is where the Cubist Dapto combo patent comes in.
      As to Zyvox;" we believe tedizolid phosphate offers a number of important potential advantages over linezolid, including greater potency, once daily dosing, predictable drug exposure, a shorter course of therapy, in vivo bactericidal (i.e., bacterial killing) activity, lower frequency of resistance, activity against linezolid-resistant bacterial strains and an improved safety profile"...this where Tedizolid will replace linezolid.

    • 2 antibiotics together may have an advantage. If the bug is on the ropes from Daptomycin but not totally destroyed or resistant to Daptomycin then the 2nd antibiotic could have use to push it over the edge and kill it off. If the bug is resistant to Zyvox, then you have your answer for using TED. There is a ton of info in presentations, posters, papers, available on the TSRX website for any who want to dig deeper. Also, keep in mind that Zyvox is dosed BID at a much higher mg/day than TED, which is dosed QD. There is some evidence that TED may be useful in treating infections that require a Longer course of antibiotic therapy without the side-effects and tox. issues.

      Sentiment: Strong Buy

      • 1 Reply to siamesekitty711
      • Definitely a fan of the QD dosing and less side effects. It didn't read as simply another antibiotic there as reinforcement. Great additional benefit regardless of reason. "Ted unexpectedly prevents the formation of daptomycin resistant mutants of Staphylococcus aureus. Tedizolid appears to be unique in this mutant prevention activity given that seven other medicines tested, including linezolid, the only other drug of the same class as tedizolid, failed to show the same mutant prevention activity."

 
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