Comparisons of Release of Several Antibiotics from Antimicrobial Polymer-Coated Allograft Bone Void Filler

Abstract

Abstract:Osteomyelitis remains a significant complication in orthopedic surgeries. Although infection rates remain steady at 1-3% for primary orthopedic surgeries, overall numbers of orthopedic procedures are increasing, corresponding to earlier and more frequent surgical intervention for an active, aging population. To address this dangerous surgical complication, degradable polycaprolactone (PCL) polymer/antibiotic solutions were coated over allograft bone void filler. Local in vitro release of ciprofloxacin, vancomycin, oxacillin, tobramycin, or rifampicin from a polymer-controlled, antibiotic-releasing bone graft void filler and monitored in vitro allowed the criterion for successful local antibiotic-releasing devices to be expanded. Although each antibiotic exhibited a different release profile based on their formulation and chemical structure, allowing the potential for engineering combinatorial therapy with microbicidal activity, bacterial killing activity in vitro was demonstrated efficacious out to a clinically relevant 8-week time point. In addition to proposing an expanded criterion for successful local antibiotic-releasing devices, this study demonstrates that allograft bone can act as a local, controlled drug release matrix in bone sites. This combination device provides osteoconductive potential in bone voids while mitigating the potential for operatively sourced opportunistic infectious complications during orthopedic repairs as well as primary and revision arthroplasties

Molded polymer‐coated composite bone void filler improves tobramycin controlled release kinetics

“…Unfortunately, very few BVFs release antibiotics and those that do release drugs (e.g., OSTEOSET ® T, etc.) suffer from early burst release, which limits their duration to far shorter than the clinical target of 6–8 weeks . Thus, extended antibiotic release, beyond the initial early burst release phase, is necessary to address the threat of persistor pathogens in the implant site and adjacent tissues.…”

“…suffer from early burst release, which limits their duration to far shorter than the clinical target of 6-8 weeks. 7,25 Thus, extended antibiotic release, beyond the initial early burst release phase, is necessary to address the threat of persistor pathogens in the implant site and adjacent tissues. Importantly, extended antibiotic release may eliminate these cells that can resist acute-phase antimicrobial exposure to produce later-stage infections and potentially give rise to antibiotic resistant pathogens.…”

Beyond conventional antibiotics — New directions for combination products to combat biofilm

“…Selection of antimicrobials that display favorable therapeutic indices for the target application as well as appropriate local pharmacokinetics (PK) and pharmacodynamics (PD) to ensure efficacy while minimizing toxic effects [59];…”

“…When the antimicrobial agent is released from the device surface, a time dependent diffusion driven concentration gradient is created at the device interface with surrounding fluids and tissue. The portion of the gradient above the minimal inhibitory or biocidal concentration is referred to as zone of inhibition (ZOI) or zone of kill [22, 59, 61, 62]. The depth (or volume) of the ZOI decreases and vanishes with time due to depletion of the antimicrobial agent in the carrier, diffusion, and elimination from the sight of potential microbial invasion.…”

“…Therefore, one needs to understand the rate of kill for a given antimicrobial in the context of the agent’s concentration versus time and distance from the device. It is important to relate these factors to the ZOI size considered suitable for the application and the period of time that it needs to be maintained in vivo in order to design an appropriate antimicrobial drug release mode [59, 63]. At the same time, the prevalence of biofilm forming pathogens found in clinical isolates [31] presents serious challenges; biofilms form rapidly within 24 hours [45] and this process is accompanied by development of tolerance to antibiotics.…”