Transcript An Anterior Chamber Toxicity Study Evaluating Besivance, AzaSite

“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
From 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.
- This study is supported by unrestricted grants from Allergan, Inc. and
Research to Prevent Blindness, Inc.
Background
Postoperative 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/Materials
Subjects: 20 New Zealand White Rabbits
Study 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
Results
Clinical Slit-Lamp Exam (DuraSite-based groups)
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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
Results
Clinical Slit-Lamp Exam (Non-DuraSite-based groups)
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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
Table. Globe volume by gross measurements after enucleation
Globe volume
(standard
deviation) [cm3]
Besivance
AzaSite
Ciprofloxacin
BSS
3.05 (0.17)
3.16 (0.52)
2.46 (0.13)
2.56 (0.17)
Corneal vital staining
•
DuraSite-based eyes revealed:
•
Non-DuraSite-based eyes showed:
– Severe alteration of endothelial cell size and shape indicative of damage
– 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
Results
Histopathology
• DuraSite-based eyes showed (to varying degrees in each eye):
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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
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
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 nonDuraSite-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%)
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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:
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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
References
1.
2.
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4.
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