“An Anterior Chamber Toxicity Study Evaluating Besivance, AzaSite, ciprofloxacin
and BSS”
Authors: Peter J. Ness, Nick Mamalis, Liliana Werner, Surekha Maddula, Don K. Davis, Eric D. Donnenfeld, Randall J. Olson Authors: Peter J. Ness, Nick Mamalis, Liliana Werner, Surekha Maddula, Don K. Davis, Eric D. Donnenfeld, Randall J. Olson
From the: John A. Moran Eye Center, University of UtahFrom the: John A. Moran Eye Center, University of Utah
- The authors have no financial or proprietary interest in any product mentioned in this poster; Randall J. Olson is a consultant for Allergan, Inc.
- The authors have no financial or proprietary interest in any product mentioned in this poster; Randall J. Olson is a consultant for Allergan, Inc.
- This study is supported by unrestricted grants from Allergan, Inc. and Research to Prevent Blindness, Inc.- This study is supported by unrestricted grants from Allergan, Inc. and Research to Prevent Blindness, Inc.
BackgroundPostoperative endophthalmitis is an uncommon but
devastating complication of cataract surgery.
• Postoperative endophthalmitis prophylaxis1
– Widely used around the world– All antibiotics are used “off-label” in this setting in the
US– Has been shown to decrease risk of endophthalmitis
• Sutureless clear corneal cataract surgery2,3
– Decreases astigmatism – Not all wounds are as well sealed as we wish– Leaky wounds allow the tear film to enter the anterior
chamber– The tear film entering the eye contains antibiotics and
other medications being administered
Background
• Besivance®* (besifloxacin) and AzaSite®** (azithromycin)– The first drugs using the DuraSite®*** bio-adhesive vehicle – Approved in the US to treat bacterial conjunctivitis
• DuraSite benefits: – Prolonged administration of the medication on the ocular
surface as the antibiotic-embedded polymer is slowly broken down
– Less frequent dosing is required for equivalent efficacy4
– Better patient compliance
• Why not use these helpful antibiotics for postoperative endophthalmitis prophylaxis?
* Bausch & Lomb, Rochester, NY, USA ** Inspire Pharmaceuticals, Inc., Durham, NC, USA *** InSite Vision Inc., Alameda, CA, USA
Objective
• No studies, to date, have investigated the effects of DuraSite-based medications in the anterior chamber.
• Our aim in this study was to evaluate the possible toxicity of DuraSite-based medications, delivered as a large bolus, into the anterior chamber of rabbit eyes, simulating an extremely leaky clear corneal wound.
Methods/MaterialsSubjects: 20 New Zealand White RabbitsStudy groups: Besivance 0.6%, AzaSite 1.0%, ciprofloxacin
0.3% and balanced salt solution (BSS) (10 eyes randomized into each group)
Surgical technique: sterile aspiration of 0.1 mL of aqueous from the anterior chamber using a 30 g needle, then injection of 0.1 mL of the study material through the same needle
Postoperative examinations: slit-lamp exams (by a masked physician) at 24 and 48 hours after injection, focusing on inflammatory signs
Sacrifice: each rabbit was humanely euthanized at 48 hours post-injection and all eyes enucleated
Data analysis: – Corneal vital staining: 2 eyes randomized from each group– Histopathology: remaining 8 eyes from each group– Analysis focused on damage to the corneal endothelial cell layer and
other signs of anterior segment damage
Outcome measures: clinical and pathologic signs of toxicity
* Falcon Pharmaceuticals, Fort Worth, TX, USA
ResultsClinical Slit-Lamp Exam (DuraSite-based groups)
– Severe, diffuse corneal edema (20 of 20 eyes)– Corneal ectasia and bullous keratopathy (20 of 20 eyes)– Profound conjunctival injection– Moderate limbal vascularity– Generally increased globe size– No statistically significant difference between Besivance and
AzaSite examination scores
Figure 1. Diffuse corneal edema after injection of Besivance
Figure 2. Ruptured bullae and corneal edema after injection of Besivance
Figure 3. Corneal ectasia and bullous keratopathy after injection of AzaSite
ResultsClinical Slit-Lamp Exam (Non-DuraSite-based groups)
– No corneal opacity (19 of 20 eyes)– Mild conjunctival injection (12 of 20 eyes)– Mild limbal vascularity (16 of 20 eyes)– Mild conjunctival injection & discharge with moderate diffuse
corneal opacification and limbal vascularity (1 eye injected with ciprofloxacin [Figure 6])
– No statistically significant difference between ciprofloxacin and BSS examination scores
Figure 4. Clear cornea and mild conjunctival injection after injection of ciprofloxacin
Figure 5. Clear cornea with no signs of inflammation after injection of ciprofloxacin
Figure 6. Diffuse moderate corneal edema after injection of ciprofloxacin
Results
Corneal vital staining• DuraSite-based eyes revealed:
– Severe alteration of endothelial cell size and shape indicative of damage• Non-DuraSite-based eyes showed:
– Mild intracellular edema – Iintact hexagonal shape of endothelial cells
Figure 7. Corneal vital staining with morphologically damaged endothelial cells after injection of AzaSite
Figure 8. Corneal vital staining with mild intracellular edema after injection of BSS
Besivance AzaSite Ciprofloxacin BSS
Globe volume (standard
deviation) [cm3]3.05 (0.17) 3.16 (0.52) 2.46 (0.13) 2.56 (0.17)
Table. Globe volume by gross measurements after enucleation
Results
Figure 9. Histopathologic slide showing fibrin, amorphous material in iridocorneal angle and acute inflammatory cells after injection of Besivance, H&E, 100x
Figure 10. Histopathologic slide showing a large epithelial bulla, corneal edema and fibrin in the anterior chamber after injection of Besivance, H&E, 40x
Histopathology• DuraSite-based eyes showed (to varying degrees in each eye):
– Bullous keratopathy– Corneal stromal thinning– Anterior chamber fibrin– Extensive endothelial cell attenuation– Peripheral anterior synechia (in some eyes) – Amorphous eosinophilic material within the iridocorneal angle and trabecular
meshwork• Non-DuraSite-based eyes showed:
– No signs of inflammation or anterior segment damage
Discussion• Although the literature has clearly shown benefits of
Besivance and AzaSite, their safety in the setting of sutureless clear corneal wounds (i.e. post cataract surgery) has not been investigated.
• DuraSite medications seem to cause glaucomatous and toxic damage in the anterior chamber when injected intracamerally as a large bolus.
• The difference in effect between DuraSite-based and non-DuraSite-based medications was statistically significant.
Discussion/Conclusions• Each medication is composed of various components: antibiotic, benzalkonium
chloride (BAK) preservative, vehicle and other inactive ingredients.
• BAK is contained in all 3 medications at differing concentrations (Besivance: 0.01%, AzaSite: 0.003%, ciprofloxacin: 0.006%)
– These concentrations are within the range previously reported to possibly cause endothelial toxicity in rabbits5; therefore, it is logical to conclude that BAK caused the toxic reaction
– If BAK had caused this toxicity, we would expect some dose-response relationship, BUT instead there was a poor correlation between BAK concentration and toxicity (e.g. Besivance and AzaSite appeared equally toxic); therefore, it is unlikely to have caused the noted toxicity
• The vehicle (DuraSite) alone was not used as a control due to commercial unavailability, so the authors used a variety of DuraSite and non-DuraSite medications (all commonly used in ophthalmic practice) for comparison
• We deduce that the DuraSite component of Besivance and AzaSite caused the toxicity and glaucomatous damage
• We recommend:– Further study of these medications at lower volumes in the anterior chamber– Until the safety is better established, surgeons should consider placing a suture over a clear
corneal wound if DuraSite-based medications may be used
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