Pre-clinical evaluation of a third generation absorbable antibacterial envelope

Abstract

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background An absorbable antibacterial envelope (TYRX), which stabilizes cardiac implantable electronic devices (CIEDs) was shown to significantly reduce infections in a large randomized controlled trial (WRAP-IT). A 3rd generation envelope (T3) is being developed to improve the implanter experience and enable smoother device insertion with a redesigned, multifilament mesh, an enhanced form factor, and identical polymer coating and antibiotic concentrations as the currently available 2nd generation envelope (T2). Purpose To compare drug elution profiles of T3 vs T2 and evaluate the efficacy of T3 against bacteria commonly known to be associated with CIED infections. Methods The T3 drug elution profile was assessed in vitro by evaluating the amount of each drug, minocycline and rifampin, released at a given timepoint using an accelerated dissolution method. For comparative analysis with T2, elution curve equivalency was based on similarity factor values (f2) of ≥50 per FDA guidance. An in vivo elution study was also conducted (per the Principles of Laboratory Animal Care [NIH Publication no. 85-23 revised 1985]) to ensure drug concentrations met the minimal inhibitory concentration (MIC) through 7 days. Substantial equivalence was defined as rifampin and minocycline concentrations above MIC at 2hr post-implant and sustained through 7 days. In a further animal model, 12 pockets were created in 6 rabbits, for CIED insertion with and without T3 envelopes, to evaluate efficacy against gram+ and gram- bacteria. At day 7, implant sites were evaluated for signs of infection via macroscopic observations and microbial recovery procedures. A Fisher’s Exact Test was used for comparisons. Results The T3 envelope showed a similar elution profile to T2 in vitro (Figure) with f2 >50 (range 76-84). In the in vivo assessment, the T3 envelope eluted both antibiotics above the MIC at 2hr post-implant with sustained elution through 7 days, consistent with historical T2 performance. Further bacterial challenge studies in vivo showed a statistically significant reduction (p<0.05) in infections with 0/6 infected pockets in the CIED + T3 group vs 6/6 infected pockets in the CIED only group consistent with T2 performance (Table). Conclusion The 3rd generation absorbable antibacterial envelope demonstrated equivalent pre-clinical performance compared to the 2nd generation envelope as antibiotic elution curves were equivalent, elution was sustained at concentrations above MIC for 7 days, and infection rates were significantly reduced compared to no envelope. These results suggest equivalent clinical performance could be expected with the newly designed envelope.