Co-release of dicloxacillin and thioridazine from catheter material containing an interpenetrating polymer network for inhibiting device-associated Staphylococcus aureus infection

• Published in: Journal of controlled release 2016-11, Vol.241, p.125-134
• Main Authors: Stenger, Michael, Klein, Kasper, Grønnemose, Rasmus B., Klitgaard, Janne K., Kolmos, Hans J., Lindholt, Jes S., Alm, Martin, Thomsen, Peter, Andersen, Thomas E.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Catheter; Catheter-Related Infections - microbiology; Catheter-Related Infections - prevention & control; Co-loading; Cross Infection; Dicloxacillin - chemistry; Dicloxacillin - pharmacology; Drug Delivery Systems; Drug Liberation; Infection; Interpenetrating polymer network; Polyhydroxyethyl Methacrylate - chemistry; Polymers - chemistry; Release; S. aureus; Silicones - chemistry; Staphylococcal Infections - microbiology; Staphylococcal Infections - prevention & control; Staphylococcus aureus - drug effects; Thioridazine - chemistry; Thioridazine - pharmacology; Vascular Access Devices - microbiology
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.09.018

Approximately half of all nosocomial bloodstream infections are caused by bacterial colonization of vascular catheters. Attempts have been made to improve devices using anti-adhesive or antimicrobial coatings; however, it is often difficult to bind coatings stably to catheter materials, and the low amounts of drug in thin-film coatings limit effective long-term release. Interpenetrating polymer networks (IPNs) are polymer hybrid materials with unique drug release properties. While IPNs have been extensively investigated for use in tablet- or capsule-based drug delivery systems, the potential for use of IPNs in drug release medical devices remains largely unexplored. Here, we investigated the use of silicone-hydrogel IPNs as a catheter material to provide slow anti-bacterial drug-release functionality. IPN catheters were produced by the sequential method, using supercritical CO2 as a solvent to polymerize and crosslink poly(2-hydroxyethyl methacrylate) (PHEMA) in silicone elastomer. The design was tested against Staphylococcus aureus colonization after loading with dicloxacillin (DCX) alone or in combination with thioridazine (TDZ), the latter of which is known to synergistically potentiate the antibacterial effect of DCX against both methicillin-sensitive and methicillin-resistant S. aureus. The hydrophilic PHEMA component allowed for drug loading in the catheters by passive diffusion and provided controlled release properties. The drug-loaded IPN material inhibited bacterial growth on agar plates for up to two weeks and in blood cultures for up to five days, and it withstood 24h of seeding with resilient biofilm aggregates. The combined loading of DCX+TDZ enhanced the antibacterial efficiency in static in vitro experiments, although release analyses revealed that this effect was due to an enhanced loading capacity of DCX when co-loaded with TDZ. Lastly, the IPN catheters were tested in a novel porcine model of central venous catheter-related infection, in which drug-loaded IPN catheters were found to significantly decrease the frequency of infection. [Display omitted]