Tolerance and pharmacokinetics of a ciprofloxacin‐coated sinus stent in a preclinical model

Abstract

Objectives Chronic rhinosinusitis (CRS) is often associated with persistent bacterial infection despite the use of systemic antibiotics. Topically administered antibiotics are an alternative strategy, but require effective local concentrations, prolonged mucosal contact time, minor systemic absorption, and minimal depletion. The objectives of the current study are to analyze the in vitro release rate and in vivo drug delivery tolerance and pharmacokinetics of a ciprofloxacin-coated sinus stent (CSS). Methods The CSS (2 mg) was created from biodegradable poly-D/L-lactic acid. After analyzing in vitro release profile, CSTs were placed unilaterally in maxillary sinuses of 16 rabbits via dorsal sinusotomy. Animals were sacrificed between 1 and 3 weeks postoperatively. Ciprofloxacin concentrations in the sinus tissue and plasmas were assessed using high-performance liquid chromatography. Radiological and histological evaluations were performed. Results In the in vitro release profile, an initial burst release was observed over the first 24 hrs, followed by sustained release through the 14 day time point. In the rabbit model, ciprofloxacin was continuously released from the stent up to 3 weeks at doses > 50 ng/ml. Histologic examination found no evidence of inflammation, epithelial ulceration or bony reaction upon sacrifice of the animals at 21 days. Computed tomography also demonstrated no signs of mucosal edema or opacification in the sinus. Conclusion The CST was safe in this preclinical model and sustained release was observed in both the in vitro and in vivo analyses. The innovative stent design coated with ciprofloxacin may provide a unique therapeutic strategy for CRS.

In‐vitro evaluation of a ciprofloxacin‐ and ivacaftor‐coated sinus stent against Pseudomonas aeruginosa biofilms

“…Simultaneously, ciprofloxacin was released at a more constant rate over a longer time frame, providing long‐term bactericidal activity against PAO‐1‒based biofilms. The ciprofloxacin concentrations coated in this model stent (60 μg) were calculated based on: (1) the area surface; (2) the previous analysis; and (3) the coating technique . The surface area of this model stent (5 mm in length) is approximately 40 mm, which is about 1/10 of the surface area of the future in‐vivo CISS stent .…”

“…The ciprofloxacin concentrations coated in this model stent (60 μg) were calculated based on: (1) the area surface; (2) the previous analysis; and (3) the coating technique . The surface area of this model stent (5 mm in length) is approximately 40 mm, which is about 1/10 of the surface area of the future in‐vivo CISS stent . The double coating in the CISS achieved a constant release of ciprofloxacin over time (week 1, 3.46 ± 0.56 μg/day; week 2, 1.58 ± 0.30 μg/day; and week 3, 1.52 ± 0.04 μg/day).…”

“…The CISS for in‐vivo studies will be coated with 0.6 mg, which should provide concentrations 10 times higher than with the in‐vitro stent and yield an AUC 0‐24 /MIC ratio well in excess of the minimum goal (>100) . By coating the hydrophilic drug in the inner layer and the hydrophobic ivacaftor with ciprofloxacin in the outer layer (double coating), the drug release is much higher than what was measured with the 2‐mg coating in the single‐layer ciprofloxacin stent used previously …”

“…As antibiotic treatments often involve a long course of therapy, sufficient antibiotic exposure is needed to ensure the eradication of the microorganism. To avoid systemic side effects, topical drug‐eluting implants with prolonged mucosal contact time and sustained drug release may provide a suitable therapeutic option . This approach allows for a larger dose and more efficient delivery of the drug to penetrate into biofilms, and thus result in a potent therapeutic effect.…”

“…This approach allows for a larger dose and more efficient delivery of the drug to penetrate into biofilms, and thus result in a potent therapeutic effect. We recently developed a ciprofloxacin‐eluting sinus stent that was shown to be effective in clearing P aeruginosa biofilms both in vitro and in vivo using a rabbit sinusitis model . In treating multidrug‐resistant bacterial pathogens, combining 2 or more distinct antibiotics represents a common strategy in treating bacterial infections with the aim to broaden the antimicrobial spectrum, generate synergistic effects, and counteract antibiotic resistance .…”