Those of you who use Journal Watch (strongly recommend by the way), likely saw the small blurb on a new antibiotics, dalbavancin, receiving approval by the FDA for treatment of MRSA skin and soft tissue infections. In the blurb was a line which caught my attention:
The intravenous drug is given in two doses, 1 week apart.
Very interesting! I immediately thought of our patients who for a variety of reasons are not good candidates for home Vancomycin or PO zyvox (IV drug users who a PICC is not an option but zyvox is too expensive; elderly who you are hesitant to send home with IV antibiotics; patients with difficulty adhering to medications). With my interest peaked, I have quickly done some research into dalbavancin to see if there is a catch.
Mechanism of Action
Dalbavancin is a lipoglycoprotien, which is similar to the glycoproteins (vancomycin) but has an additonal lipophilic tail. One article called it a second generation glycoprotein antibiotic, which I kind of like because it helps me better understand where it stands in relationship to vancomycin. Its mechanism of action is similar to vancomycin: binds to C-terminal d-alanyl-d-alanine of the peptoglycan wall, stoppng cell wall synthesis. What is really cool is the lipophilic tail! While stopping the synthesis of the cell wall, the lipophilic tail inserts into the cell membrane, disrupting the cell membrane and contributing to cell death (very similar to daptomycin). It is this second part which may explain its increased in vitro activity for MRSA as compared to vancomycin.
Activity and Spectrum
Dalbavancin is very potent, with MIC's that are very low and easily exceeded with a single dose. For MRSA, the MIC is 0.06 micrograms/L (compared to Vanc which is 1-2). Similar to Vancomycin though, the bacericidal level is higher than the MIC, and for dalbavancin it is 4 times the MIC. Luckily, dalbavancin will achieve levels over 30 micrograms/L for 1 week with a single dose, well above the bactericidal level (what a half life!). One study took a look at the concentration in "blister fluid", with dalbavancin concentration of 40. Pretty cool! Clearly it has a large volume of distribution.
Dalbavancin covers MRSA very well along with enterococcus, although it also can not cover VRE, raising quesitons about differences in the relationship of the cell wall and cell membrane between staph and enterococcus.
Addition coverage is as below:
Dalbavancin has variable activity against other pathogens, such as Lactobacillus spp. Its activity against corynebacteria is comparable with the activity of vancomycin. It also has potent activity against some Gram-positive anaerobes and fastidious aerobes including Actinomyces spp., Propionibacterium spp., andClostriudium spp. excluding Clostridium clostridioforme. Dalbavancin has minimal activity against Gram-negative bacteria, including Gram-negative anaerobic bacilli.
Safety
Dalbavancin appears pretty safe. It has the typical GI side effects, but there appears to be some bump in LFTs, especially those with prior liver disease. In looking at the numbers, this did not appear to be that significant, but because the FDA fast tracked the drug we do not have really large safety studies yet. I'm not sure if this will become an issue when the number of people exposed goes up from 1300 to 100,000, but we will see! For now, an author from mediscape recommended:
Some assessment of liver function, especially before the second dosing, is probably prudent, especially in patients with baseline liver function test abnormalities or history of liver disease.
My Conclusions
Dalbavancin seems like a pretty cool drug which could have some great clinical utility. There is certainly a need for this type of antibiotic, both for the ease of dosing and also for the growing rate of VISA (if MIC is over 2, Vanc really does not work well). My pause at this time is that I do not know how much it cost and I am also a bit anxious about the safety data. It appears very safe, but many meds look very safe initially and look very different after a much larger number of people have been exposed to it. I will take a wait and see approach, but I must admit, my trigger finger is a bit itchy for this one!
References (links)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890846/
http://www.medscape.com/viewarticle/825348
http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=preview&language=en-US&anchor=H22#H22
http://www.jwatch.org/fw108872/2014/05/27/fda-approves-dalbavancin-treat-acute-bacterial-skin?query=pfw
http://www.jwatch.org/fw108673/2014/04/02/fda-advisers-recommend-approval-two-antibiotics
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm398724.htm
And of course Wikipedia: http://en.wikipedia.org/wiki/Dalbavancin and http://en.wikipedia.org/wiki/Glycopeptide_antibiotic