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. Author manuscript; available in PMC: 2025 Sep 1.
Published in final edited form as: Laryngoscope. 2024 Apr 2;134(9):3953–3959. doi: 10.1002/lary.31431

Safety and pharmacokinetics of a ciprofloxacin and azithromycin stent for chronic rhinosinusitis

Dong-Jin Lim 1, Brenton T Bicknell 1, Nicholas Rivers 1, Martin P Jones 1, Adithya J Menon 1, Olivia Jo Kelly 1, Daniel Skinner 1, Shaoyan Zhang 1, Bradford A Woodworth 1,2,*, Do-Yeon Cho 1,2,3,*
PMCID: PMC11305968  NIHMSID: NIHMS1979600  PMID: 38563347

Abstract

Objectives:

Previously, we developed a novel double-coated sinus stent containing ciprofloxacin (inner layer) and azithromycin (outer layer) (CASS) but released drug concentrations were found to be insufficient for clinical usage. Our objectives are to improve drug release of CASS and assess safety and pharmacokinetics in rabbits.

Methods:

Dip-coating was used to create the CASS with 2mg ciprofloxacin and 5mg azithromycin. A uniformed double coating was assessed with scanning electron microscopy (SEM) and the release patterns of both drugs and LDH assay were evaluated over 14 days in vitro. Safety, tolerability, and pharmacokinetics of the CASS were tested in rabbits through insertion into the maxillary sinus and evaluated with nasal endoscopy, CT scans, histology, blood counts and chemistries, and in vivo drug release.

Results:

SEM confirmed the uniformity of the dual coating of CP and AZ, and thickness (µm) was found to be 14.7+/−2.4 and 28.1+/−4.6, respectively. The inner coated ciprofloxacin showed a sustained release over 14 days (release%) when soaked in saline solution (Day 7, 86.2+/−3.4 vs. Day 14,99.2+/−5.1). In vivo analysis showed that after 12 days, 78.92+/−7.67% of CP and 84.12+/−0.45% of AZ were released into the sinus. There were no significant differences in body weight, white blood cell counts, and radiographic changes before and after CASS placement. No significant histological changes were observed compared to the contralateral control side.

Conclusion:

Findings suggest that the CASS stent is an effective method for delivering therapeutic levels of antibiotics. Further studies are needed to validate efficacy in a preclinical sinusitis model.

Keywords: Antibiotic-eluting Sinus Stent, Antibiotic Stent, Ciprofloxacin, Azithromycin, Topical Delivery, Chronic Rhinosinusitis, Chronic Sinusitis, Sinusitis, Rabbits

Introduction

Chronic rhinosinusitis (CRS) is a common disease of the nose and paranasal sinuses characterized by persistent inflammation and bacterial infection of the mucosal surface.1–7 Symptoms can include nasal congestion, facial pain or pressure, anosmia (decreased smell), and purulent drainage, and occur more than 12 weeks. Several topical medications directly administered via nasal sprays, nasal irrigations, and nasal drops relieve the clinical symptoms of CRS.8–12 However, these strategies do not provide persistent, sustained drug levels and require repeated interventions.13

To achieve multi-week targeted local delivery of medications, implantable stents have been shown to be efficacious in delivering steroids for CRS.14 The mometasone-eluting sinus stent (Propel; Intersect®-Medtronic, Palo Alto, California, USA) improved clinical outcomes by reducing synechiae formation and polyposis after functional endoscopic sinus surgery (FESS).15 However, no commercially available sinus stents deal with persistent bacterial infections and biofilms in the management of recalcitrant CRS which are typically gram negative bacteria (i.e. Pseudomonas aeruginosa) that are frequently resistant to traditional routes of antibiotic treatment.16–21 The classic clinical example of recalcitrant bacterial CRS is in cystic fibrosis (CF), where congenital dysfunction or absence of the cystic fibrosis transmembrane conductance regulator channel (CFTR) causes widespread recalcitrant bacterial CRS due to underlying mucociliary dysfunction. 22–28 Furthermore, acquired CFTR dysfunction is also present in models of non-CF CRS where external perturbations such as hypoxia, lipopolysaccharide, viruses, and tobacco smoke induce diminished mucociliary transport. 29–32

We previously created several versions of a ciprofloxacin-eluting sinus stent that demonstrated efficacy in preclinical models but lacked sustained release. Ciprofloxacin exhibited a sustained release pattern from the stent over several weeks when coated with a hydrophobic drug, such as the CFTR modulator (e.g., ivacaftor).33–38 Because ivacaftor is under patent and expensive, we sought other hydrophobic candidate compounds that are either stimulate CFTR (i.e. flavonoids) or inexpensive antibiotics that are used for sinus infections.39–47 Since azithromycin is a hydrophobic antibiotic, our subsequent studies used an outer layer of azithromycin to control the release of ciprofloxacin.48,49 The ciprofloxacin-azithromycin sinus stent (CASS) provided sustained release of ciprofloxacin over 28 days.50

An area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC, concentration-dependent killing) ratio > 100 is considered the minimum goal, while an AUC:MIC > 125 is found to be predictive of microbiological and clinical cure in patients with serious gram-negative infections with biofilm. Based on our initial in vivo study, the total amount of ciprofloxacin coated in the stent should be at least 2 mg to reach the AUC:MIC > 125.51 However, the current CASS contains 60 µg of ciprofloxacin, insufficient for preclinical/clinical usage. Therefore, the present study aimed to fabricate and characterize a next-generation, high dose CASS and evaluate its safety and toxicity in an in vivo animal model.

Materials and Methods

A. Fabrication of a high dose CASS

Based on our previous studies, we implemented a dip coating technique for substantial loading of ciprofloxacin HCl (GenHunter Co., Nashville, TN) and azithromycin (TCI America, Portland, OR.) on biodegradable poly-D/L-lactic acid (D,L-PLA) stents (Figure 1A-D).33,48 Instead of generating azithromycin and ciprofloxacin PLGA nanoparticles for the coating, the current strategy was to dip-coat just the drug onto the D,L-PLA stents to simplify the process for manufacturing and provide consistency for future clinical trials.

Figure 1.

Figure 1.

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Representative images of the bare stent and ciprofloxacin and azithromycin sinus stent (CASS) (measuring rule: 1mm unit)

A. Lateral view of a bare biodegradable poly-D/L-lactic acid (D,L-PLA) stent

B. Top-down view of a bare biodegradable D,L-PLA stent

C. Lateral view of a prepared CASS stent

D. Top-down view of a prepared CASS stent

E. In vitro release profile of ciprofloxacin (inner layer) from the CASS (n=3) shows sustained release over the 14 days.

F. In vitro release profile of azithromycin (outer layer) from the CASS for 14 days (n=3) demonstrates a burst release of azithromycin by four days.

To create a high ciprofloxacin-loaded inner layer, an aqueous ciprofloxacin solution (10 mg/ml) and an Eudragit polymer solution (2% w/v solution) were mixed in a one-to-one ratio and used to create an inner layer onto a model stent. Similarly, an azithromycin ethanol solution (50 mg/ml) containing an Eudragit polymer (4% w/v solution) and 2-amino-2-methyl-1-propanol (2% w/v solution) was prepared for an outer layer of the CASS. 2-amino-2-methyl-1-propanol is a pH adjuster that can dissolve into water and ethanol, enabling us to fabricate the CASS within a desired pH range (6.20 +/− 0.0713 over seven days). Azithromycin is a stable macrolide without a chemically reactive functional group that can be altered by alcohol.

We next applied an innovative dip coating technique to create dual coating layers on the D,L-PLA stents (Biogeneral, Inc., San Diego, CA). For the inner ciprofloxacin layer, a dip coater was used with the prepared ciprofloxacin aqueous solution described above (Biolin Scientific, Espoo, Finland). Once the ciprofloxacin layer was completely dried, the stent was placed in a vacuum to coat the outer layer with azithromycin. For the outer azithromycin layer, the polymeric ethanol azithromycin solution with 2-amino-2-methyl-1-propanol (2% w/v) was applied in the same coating process with a dip coater and placed in a vacuum for two days at room temperature before sterilization. This approach loaded high drug concentrations: 2 mg of ciprofloxacin and 5 mg of azithromycin. A field emission scanning electron microscope (SEM) was used (FE-SEM, Quanta FEG-650, USA) to examine the dual coating as previously described.33,52,53

B. In vitro drug release from the CASS

To assess the in vitro drug release patterns from the newly coated CASS stent, each fabricated stent was placed in 1mL of sterilized saline solution in 1.5 mL Eppendorf tubes in a 37°C incubator with a shaker for up to 14 days (n=3). The concentrations of both drugs (ciprofloxacin, azithromycin) were measured as described previously.54

C. Rabbit model

This preclinical study was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Alabama Birmingham (UAB) under Animal Project Number: IACUC-22555. Our established methodologies were strictly adhered to for animal care and procedures. The study spanned a 12-day duration, as depicted in Figure 2.

Figure 2.

Figure 2.

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Preclinical study plan and procedures

A. Overview of the study plan

B. Planned incision line (red) on the dorsal surface of the rabbit’s head

C. Creation of an opening to place the stent in the maxillary sinus using a hand drill

D. Insertion of a CASS stent in the rabbit’s left maxillary sinus

CT: computed tomography

CASS: ciprofloxacin and azithromycin sinus stent

Pasteurella-free New Zealand white female rabbits (3–4 kg) were used for the study. All rabbits were acclimated within the UAB animal facility for at least one week. In a warm animal procedure core, the rabbits were sedated with ketamine (20 mg/kg) (MWI, Boise, ID), dextomitor (0.25 mg/kg) (Zoetis Inc., Kalamazoo, MI), buprenorphine (0.03 mg/kg) (Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA), and carprofen (5 mg/kg) (Zoetis Inc., Kalamazoo, MI). All rabbits were endoscopically examined with a nasal endoscopy (1.7mm 30-degree scope, Karl Storz, Tuttlingen, Germany) to confirm no pre-existing infection or abnormal lesions. No rabbits were intubated or provided with any inhalational anesthetic or antibiotic agents.

A midline incision was made in the dorsal surface of the rabbit’s head after shaving the planned incision site. Then, a 4mm hole was created using a sterilized electric drill on the roof of the left maxillary sinus to insert the prepared CASS through the opening. After completing the insertion of the CASS, the periosteum, subcutaneous tissue, and skin were closed with 4–0 Vicryl® suture (Ethicon, Inc, Somerville, NJ). No oral or parenteral antibiotics were applied during or after the surgical procedure.

Six saline injections (1ml sterile saline per injection) were performed during the study period (every other day) to simulate sinonasal saline irrigation in humans. Saline injections were made using an 18-gauge syringe inserted in the maxillary sinus through a small hiatus/foramen located approximately 2 cm laterally from the midline and 1.5 cm below the eye. For each irrigation, rabbits were mildly sedated with isoflurane. Injection sites were carefully observed for possible infections.

D. Evaluation of safety, tolerability, and pharmacokinetics

Observation of weight changes:

The rabbits’ weights were taken at regular intervals to assess any changes in weight throughout the study. Changes in appetite or a decreased weight could indicate a response to pain or stress in an otherwise normal rabbit. Weights (kg) were recorded at baseline (day 0) and at regular intervals of two days following CASS placement.

Nasal Endoscopic Examination:

Nasal endoscopic examinations using a 1.7mm nasal endoscopy were performed in all rabbits on days 0 and 12 per protocol.

Blood collection:

Blood samples were collected under aseptic conditions using standard venipuncture techniques. The preferred site for blood collection in rabbits is the marginal ear vein, which was carefully cleaned and sterilized before the procedure.

Computed Tomography (CT) Scans:

On day 12, all rabbits were scanned to address the presence of sinus opacification (radiographic evidence of sinusitis). Preclinical CT (High-resolution U-CT, MILab, Houten, Netherlands) images were taken at the UAB cystic fibrosis center - Animal imaging shared facility. The images of the maxillary sinus where the CASS was visualized were analyzed.

Histological Examinations:

After the removal of the CASS on day 12, rabbits were euthanized, and the sinuses were harvested. The demineralized sinuses were used to create histological sections, and ten representative areas of the maxillary sinus were selected for hematoxylin and eosin (H&E) staining.55 The epithelial and subepithelial thickness, and inflammatory characteristics of the slides were identified by at least two independently trained individuals, including a veterinary pathologist as previously described.56

Morphological observations by a Scanning Electron Microscopy (SEM):

A Quanta FEG 650 Scanning Electron Microscope (FEI, Hillsboro, OR) at an accelerating voltage of 20 kV was used. Photomicrographs of the CASS were taken before and after the placement.

Quantitative analysis of residual drug amounts in CASS after the study period:

Retrieved stents (n = 3) were dissolved within hot ethanolic solutions, and the ciprofloxacin enzyme-linked immunosorbent assay (ELISA) kit (REAGEN™, Moorestown NJ) was used to measure the remaining amount of ciprofloxacin. A spectrophotometric assay protocol utilizing the reduction of potassium permanganate in an alkaline solution with azithromycin was used to measure the remaining amount of azithromycin.57 Briefly, 200 μL of potassium permanganate (0.012M) and 200 μL of potassium carbonate (0.1M) were mixed. Then, 200 μL of a diluted sample solution and deionized water were added to make a solution of 2 mL. After proper mixing and incubation for 1 hour, the absorbance of the mixture was obtained at 547 nm (Synergy HK, BIO-TEK Instruments, Winooski, VT).

E. Statistical Analysis

All experiments were performed in triplicate. Statistical analysis was performed with GraphPad Prism 6.0 (La Jolla, Ca) using unpaired Student t-tests. Significance was set at p < 0.05. Each value was represented as +/− standard error of the mean.

Results

The high dose CASS provided controlled release of drug over two weeks in vitro

The inner coated ciprofloxacin showed a sustained release over 14 days (release%) when soaked in saline solution (Day 7, 86.2+/−3.4 vs. Day 14,99.2+/−5.1). At the 7-day mark, approximately 86.23 +/− 3.38% of ciprofloxacin and 79.12 +/− 2.31% of azithromycin had been released (Figure 1E-F). The outer coated azithromycin was released in about four days when soaked in saline solution as it caused a burst release.

Rabbits exhibited normal radiography, nasal endoscopy, weight, blood composition, and histology

CT images were obtained at the end of the study period to identify radiographic evidence of sinusitis after placement. As shown in Figure 3, all stents were present in the rabbits’ left maxillary sinus, and all rabbits had no sinus opacification on the experimental side. On day 0 (placement of CASS) and 12 (removal of CASS), nasal endoscopic examination was performed in all four rabbits. Both sides of the middle and superior meatus were inspected bilaterally, and there was no evidence of purulent drainage or signs of infection on days 0 or 12.

Figure 3.

Figure 3.

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Representative CT images on day 12 after placement of the ciprofloxacin and azithromycin sinus stent (CASS). A yellow arrow indicates the location of the CASS stent in the maxillary sinus.

A. Coronal view

B. Axial view

C. Sagittal view

The average weight of rabbits was 3.76 +/− 0.17 kg on day 0 and 3.69 +/− 0.20 kg on day 12 (paired t-test, p=0.08). A blood sample was taken from each rabbit on the day of sacrifice to compare CBC and blood chemistry to a previously collected healthy rabbit cohort (n = 4). After 12 days of replacement, the average White Blood Cell (WBC) count (103 cells/μL) in the experimental group was 5.38 +/− 2.41, whereas the cohort control was 7.05 +/− 1.14 (p = 0.32).

There were no statistically meaningful changes in the thickness of the epithelial and subepithelial layers (n = 4) (Figure 4). The average height of the epithelial layer on the side with stent insertion was 21.47 +/− 5.38 µm, whereas the thickness of the contralateral side was 14.8 +/− 4.42 µm (p=0.15). In the subepithelial layer, the average thickness of the experimental side was 82.68 +/− 40.81 µm, compared to 78 +/− 31.25 µm for the contralateral side (p=0.88). There was no significant infiltration of acute inflammatory cells (neutrophils) between the experimental and internal control side of the maxillary sinus mucosa.

Figure 4.

Figure 4.

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Histological assessment of the rabbit’s maxillary sinus after inserting the high dose ciprofloxacin and azithromycin sinus stent (CASS) for 12 days.

A. H&E staining of the lateral wall of the right maxillary sinus (contralateral side, internal control)

B. H&E staining of the lateral wall of the left maxillary sinus (experimental side)

C. Epithelial thickness on day 12 (each dot represents the average thickness of three different sites from individual rabbits). Control = Contralateral side, Stent = Experimental side

D. Subepithelial thickness on day 12 (each dot represents the average thickness of three different sites from individual rabbits). Control = Contralateral side, Stent = Experimental side

Morphological changes and in vivo drug release from the CASS

SEM images demonstrated a uniform dual-coated structure of the CASS stent with distinct dual layers (Figure 5A). The inner ciprofloxacin layer displayed an average thickness of 14.68 +/− 2.35 µm, while the outer azithromycin layer measured an average thickness of 28.06 +/− 4.60 µm. After retrieval from the sinus, the SEM image revealed the decreased thickness of the polymer layers, exposing a bare D,L-PLA stent, as shown in Figure 5B. The dual-layer coating degraded following drug release over the study period. Regarding the analysis of the remaining drug at the end of the study period, it was determined that 78.92 +/− 7.67% of azithromycin and 84.12 +/− 0.45% of ciprofloxacin were released throughout the 12 days in vivo (Figure 5C).

Figure 5.

Figure 5.

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Scanning electron microscopy images of the ciprofloxacin, azithromycin sinus stent (CASS), and the remaining drug %.

A. Cross-sectional view representing the dual layers of ciprofloxacin and azithromycin in a CASS stent before placement (* Outer (Azithromycin) layer, ** Inner (Ciprofloxacin) layer)

B. A magnified view of the retrieved CASS after 12 days of placement in vivo

C. Remaining % amounts of ciprofloxacin and azithromycin from retrieved CASS stents (n = 3)

Discussion

CRS is a prevalent condition characterized by persistent bacterial inflammation and infection of the paranasal sinuses.58 While Type 2 inflammation in CRS can be targeted by steroids and biologics, recalcitrant infections with organisms, such as Pseudomonas aeruginosa, remain difficult to treat with current antibiotic strategies due to inability to deliver high doses to the tissues. Our previous studies have demonstrated the preclinical safety, tolerability, and efficacy of antibiotic-eluting stents in preclinical rabbit models of infection. Antibiotic-eluting stents are capable of eluting drug directly to the infected tissues while minimizing potential side effects.33,34,48–51,54,59 One of our model antibiotic-eluting stents incorporated hydrophobic azithromycin (a macrolide commonly used for its anti-inflammatory properties in CRS) as an outer layer to slow the release of hydrophilic ciprofloxacin to provide sustained concentrations for recalcitrant infection.49,54 However, the concentration of ciprofloxacin delivered via the earlier version of the CASS was insufficient for preclinical studies.48 For practical antibacterial efficacy and to prevent the emergence of antibacterial resistance during preclinical trials, we deemed that a minimum ten-fold increase in daily ciprofloxacin release from the CASS was required to reach the AUC:MIC > 125.51

In the current study, a next-generation high dose CASS was fabricated and tested for its drug release, tolerability, safety, and pharmacokinetics in vivo. CASS placed in saline exhibited sustained release of ciprofloxacin over two weeks, but a burst release of azithromycin indicated that essentially all the azithromycin was released within four days. Almost 80 percent of each drug was released in vivo from the stents by the end of the 12 days, indicating the release of azithromycin was more sustained with mucosal contact and every other day saline rinse instead of being wholly merged into saline (Figure 5). In our previous CASS model, the in vitro release of both drugs was sustained over four weeks.54 In this new high dose CASS, the step involving the fabrication of ciprofloxacin and azithromycin PLGA nanoparticles was removed to simplify and streamline the process for eventual human clinical trials. It is possible that the coating of azithromycin without composing into nanoparticles increased the release in the in vitro situation. Regardless, the in vivo measurements support the current strategy of topical delivery in the sinonasal microenvironment.

The next-generation CASS did not cause significant tissue inflammation or systematic adverse reactions in our in vivo study. While the epithelial and subepithelial heights were not significantly different, it was notable that both were slightly increased on the stent side, which may reflect an underpowered study. It is also possible that the increase in ciprofloxacin HCl loading from CASS stents induces a mild inflammatory response in the rabbit’s normal sinus epithelium without any pathogenic purulence or mucus.

This study has several limitations. There are no comprehensive studies evaluating the impact of various topical ciprofloxacin doses on the sinus epithelium. A series of preclinical investigations employing graded levels of ciprofloxacin and azithromycin doses could be strategically designed to examine the effect on normal sinus epithelium. It is also unclear what role saline irrigation played in the release of the drug. The in vitro release profile clearly shows all the azithromycin is released within the first four days. However, the stents will not be continuously exposed to saline in vivo, and equivalent percentages of each drug were released over the 12 days with every other day irrigation. Upcoming investigations with different saline irrigations will help determine the release patterns under these circumstances and help inform future human clinical trials. Further studies are planned to evaluate the efficacy of the high dose CASS stent using our CRS preclinical rabbit model infected with Pseudomonas aeruginosa.

Conclusion

Our findings demonstrated that the high dose CASS delivered ciprofloxacin and azithromycin in a sustained manner over 12 days without significant tissue inflammation or systematic adverse reactions. Providing local therapeutic ranges of antibiotics via placement of the CASS is an important strategy to treat recalcitrant CRS without the disadvantages of systemic delivery. Future studies evaluating the efficacy of the CASS in preclinical studies are planned.

Funding Sources:

This work was supported by National Institutes of Health (NIH)//National Heart, Lung, and Blood Institute (1 R01 HL133006–05)/National Center for Complementary and Integrative Health (R21AT01223–01) and the Cystic Fibrosis Foundation Research Grant (002481G221) to BAW; and NIH/National Institutes of Allergy and Infectious disease (K08AI146220, 1R21AI168894–01), Triological Society Career Development Award, and Cystic Fibrosis Foundation K08 Boost Award (CHO20A0-KB) to DYC.

Footnotes

Manuscript was presented at the American Rhinologic Society Annual Meeting at Nashvill,e TN, on September 30th, 2023.

Level of Evidence: N/A

Bradford A. Woodworth, M.D. is a consultant for Cook Medical and Medtronic. The authors whose names are listed other than Bradford A. Woodworth, M.D. certify that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.

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