(WHS-P3) Efficacy and safety of dressing containing novel antimicrobial peptide for managing wound biofilm
Friday, May 17, 2024
7:30 AM – 5:00 PM East Coast USA Time
Purpose Biofilm colonization, delayed healing and drug resistance remain important challenges in wound care. The purpose of this work was to evaluate a wound treatment comprising a novel broad-spectrum antimicrobial peptide (ASP-2) formulated in a biodegradable chitosan sponge (Gatekeeper™) for activity against multi-drug resistant bacterial biofilm, to assess the propensity for ASP-2 resistance to evolve with exposure, and to evaluate product safety. Methods Efficacy was evaluated using an ex vivo porcine skin biofilm model. Disks of porcine skin were incubated in bacterial culture (106 CFU/mL of Methicillin resistant Staphylococcus aureus, USA 300 ATCC BAA-1717 (MRSA) or Pseudomonas aeruginosa ATCC 15692 (P. aeruginosa)) for 72h to develop biofilm. Skin disks were then treated once with Gatekeeper™ and bacteria CFU remaining on skin were measured after 24, 48, and 72 hours. To evaluate potential for resistance development, MRSA was serially passaged in 0.5 MIC ASP-2 for 30 days. MICs for ASP-2, vancomycin, and mupirocin, were measured daily for ASP-2 exposed cultures with the CLSI M07-A8 microdilution method. The tolerability and toxicokinetics (TK) of ASP-2 and Gatekeeper™ in minipigs were determined following daily administration over 7 days, respectively. Results In the ex vivo porcine skin biofilm model, Gatekeeper™ application resulted in a 5.7 log reduction in MRSA CFU/mL by 24 hours with full eradication by 48 hours. P. aeruginosa biofilms experienced 3-4 log reductions in CFU/mL by 24 and 48 hours and were eradicated by 72 hours. All reductions were statistically significant relative to saline controls (p≤0.05, n=3 for all groups). Exposure to subinhibitory concentrations of ASP-2 did not select for resistance in MRSA. There was a 2-fold increase in ASP-2 MICs after the first passage, with no significant increases measured over the remaining 29 days of passaging. Moreover, bacteria exposed to thirty passages of sub-MIC ASP-2 did not display cross-resistance to vancomycin or mupirocin. In toxicology studies, the no observable adverse effect level of ASP-2 in rats with subcutaneous administration (N=10) was 100 mg/kg (>20X the equivalent human clinical dose). In minipigs, no toxicologically meaningful effects were found with Gatekeeper™ treatment of full thickness wounds over 2.5% body surface area (BSA) (N=2) or abraded skin over 10% BSA (N=2). Systemic exposure to ASP-2 in minipig TK studies was also found to be minimal. Conclusions Gatekeeper™ exhibited strong activity against MRSA and P. aeruginosa biofilms and initial toxicology studies indicate a good therapeutic window for its active component, ASP-2. Serial passaging of MRSA in subinhibitory concentrations of ASP-2 did not result in emergence of ASP-2 resistance or cross resistance to front line antibiotics tested. Collectively, data presented indicate a promising efficacy and safety profile for Gatekeeper™ in managing wound biofilm.