FDA Advisory Committee Recommends Approval of Tedizolid and Dalbavancin

FDA Advisory Committee Recommends Approval of Tedizolid and Dalbavancin

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood

City, CA, Editor of Infectious Disease Alert

On March 21, 2014, two new antibiotics with activity against methicillin-resistant Staphylococcus aureus (MRSA) each received unanimous recommendations from FDA Advisory Committees for approval for treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive organisms.^1,2

Tedizolid is, like linezolid, an oxazolidinone with once daily administration by either the oral or intravenous route that was evaluated in 2 randomized clinical trials which have been reviewed by O’Riordan and colleagues.³ In ESTABLISH-1, 667 patients were randomized to receive tedizolid 200 mg daily orally for 6 days or linezolid 600 mg twice daily orally for 10 days. The primary endpoint, cessation of increase in size of the lesion at 48-72 hours and absence of fever, was met in 79.5% and 79.4%, respectively. In ESTABLISH-2, an examination of IV to oral switch was evaluated. Patients received tedizolid 200 mg daily for 6 days or linezolid for 10 days with, in each case, at least the first 2 doses administered intravenously, but with freedom to change to the oral route thereafter. The primary endpoint, a >20% reduction in lesion size at 48-72 hours, was achieved in 85.2% of tedizolid recipients and 82.6% of those given linezolid.

Thus, a 6 day course of once daily tedizolid was non-inferior to a 10 day course of linezolid. There was also no significant difference in overall adverse events. While tedizolid is reported to be a weaker inhibitor of monoamine oxidase, translation of this difference into clinical benefit is unproven.

Dalbavancin is a lipoglycopeptide for intravenous administration that has a remarkably prolonged serum elimination half-life that reportedly ranges from 147-258 hours.

In both DISCOVER 1 and 2, patients with ABSSSI were randomized to receive 2 intravenous doses of dalbavancin one week apart (1000 mg on day 1 and 500 mg on day 8) or to receive vancomycin 1000 mg or 15 mg/kg every 12 hours with an option to switch to orally administered linezolid after 3 days.⁴ The primary endpoint in each trial was the cessation of increase in size of the lesion at 48-72 hours and absence of fever. In DISCOVER 1, this endpoint was achieved in 83.3% of dalbavancin and 81.8% of vancomycin/linezolid recipients, while in DISCOVER 2, it was achieved in 76.8% and 78.3%, respectively.

Thus, dalbavancin is not inferior to vancomycin/linezolid in the treatment of ABSSSI and has the advantage of requiring administration of only 2 doses given one week apart. It should be noted that oritavancin, which is under development has an even longer half-life than dalbavancin and is administered intravenously as a single dose. One wonders, however, with regard to dalbavancin, whether a second dose is truly necessary.

References:

1. Anti-infective Drugs Advisory Committee Meeting for Tedizolid. March 31, 2014. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm392556.pdf
2. Anti-infective Drugs Advisory Committee Meeting for Dalbavancin. March 31, 2014.
3. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm392559.pdf
4. O’Riordan W, et al. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary. Clin Infect Dis 2014; 58 Suppl 1:S43-50.
5. Wilcox M, et al. An Integrated Analysis of the Efficacy of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the DISCOVER Program. IDWeek Poster #1339 (2013)