After a single high dose of (8 or 10 mg/kg BW) of daptomycin IV, bone levels were measured in plasma and trabecular bone obtained during hip or knee surgery of 16 patients.[1]
At the time of surgery, mean concentrations in plasma and synovial fluid were 39 and 22 µg/mL, respectively. For femoral and tibial bone samples, the mean concentrations were 3.3 and 3.4 µg/mL.
The median penetration into synovial fluid was calculated as 54%, and into bone as 9%.
The study showed that daptomycin reliably achieves bone levels above the MIC breakpoint for Staphylococci (1 µg/mL) with a high dose regimen.
There was 1 serious adverse event (bullous pemphigoid) which occurred 28 days after surgery. It was considered possibly related to study drug.
Implications
Prosthetic joint infections (PJI) caused by S. aureus and post-operative osteomyelitis, esp. vertebral, are notoriously difficult to treat. With higher doses of daptomycin found to be reasonably safe, this study shows that a 8-10 mg/kg intravenous dose can provide adequate bone penetration. With animal data showing efficacy in acute osteomyelitis models, this study builds the case for use in recent bone infections, post-surgical osteomyelitis, and PJI.
It stands to reason that other long-acting (lipo)glycopeptide, i.e., dalbavancin (Dalvance®) and oritavancin (Orbactiv®), will try to replicate these results in their quest to expand the market beyond skin/skin structure infections. We should soon see a flurry of osteomyelitis studies.
This is a challenging arena as good clinical bone infection studies have not been done for a very long time and FDA Guidance is lacking. Entering uncharted territory should not frighten Cubist which has tackled similar challenges successfully in the past: Just think of their brilliant endocarditis program orchestrated by Francis Tally. Let’s hope his spirit is still alive and well.
References:
[1] Montange. Antimicrob Agents Chemother 58: 3991; 2014
