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PURPOSE Intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) are the current standard of care for patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). There is a... more
PURPOSE Intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) are the current standard of care for patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). There is a growing subset of patients that does not respond to anti-VEGF monotherapy treatment. Some patients, however, do respond to combination therapy of corticosteroids and anti-VEGF. This treatment requires monthly/bimonthly injections of anti-VEGF and semi-annual injections of corticosteroid. A drug delivery system (DDS) that simultaneously releases multiple drugs could benefit these patients by reducing the number of injections. The purpose of this study was to characterize the simultaneous release of aflibercept and dexamethasone from a biodegradable microparticle- and nanoparticle-hydrogel DDS. METHODS Dexamethasone-loaded nanoparticles and aflibercept-loaded microparticles were created using modified single- and double-emulsion techniques, respectively. Then, microparticles and nanoparticles were embedded into a thermoresponsive, biodegradable poly(ethylene glycol)-co-(L-lactic acid) diacrylate (PEG-PLLA-DA)-N-isopropylacrylamide (NIPAAm) hydrogel DDS. Drug release studies and characterization of DDS were conducted with varying doses of microparticles and nanoparticles. RESULTS The combination aflibercept-loaded microparticle- and dexamethasone-loaded nanoparticle- hydrogel (Combo-DDS) achieved a total release time of 224 days. Small decreases were seen in swelling ratio and equilibrium water content for Combo-DDS compared to monotherapy aflibercept-loaded microparticle-hydrogel DDS (AFL-DDS) and monotherapy dexamethasone-loaded nanoparticle-hydrogel DDS (DEX-DDS). Bioactivity of aflibercept was maintained in Combo-DDS compared to AFL-DDS. CONCLUSIONS The Combo-DDS was able to extend and control the release of both aflibercept and dexamethasone simultaneously from a single DDS. This may eliminate the need for separate dosing regiments of anti-VEGF and corticosteroids for wet AMD patients.
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Research Interests: Medicine and Gatifloxacin
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The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release... more
The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These mod...
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To review our experience with combined pars plana lensectomy-vitrectomy and open-loop flexible anterior chamber intraocular lens (AC IOL) implantation for managing subluxated crystalline lenses. Retrospective review of 36 consecutive eyes... more
To review our experience with combined pars plana lensectomy-vitrectomy and open-loop flexible anterior chamber intraocular lens (AC IOL) implantation for managing subluxated crystalline lenses. Retrospective review of 36 consecutive eyes (28 patients), all of which had subluxated crystalline lenses, managed by pars plana lensectomy-vitrectomy with insertion of an open-loop flexible AC IOL. The study was performed at the Medical College of Wisconsin, Milwaukee, over an 8-year period. An average preoperative visual acuity of 20/163 (range, 20/25 to hand motions) improved to 20/36 (range, 20/20 to 4/200) with surgery after a mean follow-up of 14 months (range, 1 to 59 months) (P < .001, Student's paired t test). Final visual acuity of 20/40 or better was achieved in 75% of eyes (27/36). Complications included cystoid macular edema (8% [3/36]), pupillary block (6% [2/36]), retinal detachment (3% [1/36]), hyphema (3% [1/36]), wound leak (3% [1/36]), and transient vitreous hemorrh...
Research Interests: Ophthalmology, Adolescent, Medicine, Visual acuity, Humans, and 15 moreFemale, Pubmed, Retinal detachment, Male, Marfan syndrome, Aged, Middle Aged, Adult, Retrospective Studies, Vitrectomy, Intraocular Lens, Postoperative Period, Postoperative Complications, Exfoliation Syndrome, and Anterior Chamber
Research Interests: Clinical Trial, Medicine, Photodynamic Therapy, Macular Degeneration, Survey, and 12 moreHumans, Suspensions, Age related macular degeneration, Optometry and Ophthalmology, Photochemotherapy, Drug evaluation, Combination drug therapy, Clinical Trials as Topic, Adverse effect, Adjunctive Treatment, Angiogenesis inhibitors, and sclera
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The Silicone Study is a multicentered, randomized surgical trial designed to compare the tamponade effectiveness of silicone oil versus long-acting gas in the treatment of proliferative vitreoretinopathy (PVR) by vitrectomy and associated... more
The Silicone Study is a multicentered, randomized surgical trial designed to compare the tamponade effectiveness of silicone oil versus long-acting gas in the treatment of proliferative vitreoretinopathy (PVR) by vitrectomy and associated techniques. Fundus photographs are taken to provide documentation of the anatomic status of eyes proposed for entry and are graded at an independent Reading Center. This article describes the protocol for photographic documentation of PVR as a continuum of increasing pathology, in which the pathology may only be present in the anterior retina, and the retina is usually highly elevated. In a validity and reliability study, agreement between photographic and clinical observation within one step was obtained for 88% of the eyes; intra- and inter-observer agreement within one step was 85 and 80%, respectively. Differences between the surgeon&#39;s grade and the Reading Center&#39;s were caused about equally by disagreement regarding extent of fixed folds and width of the funnel. Rarely did peripheral folds not visible in the photographs appear to be the sole explanation of the disagreement. Differences among readers were concerned mainly with differentiation of true full-thickness fixed folds from folds due to simple redundancy of the detached retina. These results demonstrate that complicated retinal detachment (RD) can be photographically documented and independently assessed.
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The Silicone Study is a multicenter randomized clinical trial that compares a long-acting gas with silicone oil for the surgical treatment of proliferative vitreoretinopathy (PVR). As part of the study, a topographic classification of PVR... more
The Silicone Study is a multicenter randomized clinical trial that compares a long-acting gas with silicone oil for the surgical treatment of proliferative vitreoretinopathy (PVR). As part of the study, a topographic classification of PVR has been developed that is based on the characteristic patterns of retinal distortion produced by the contraction of proliferative membranes on the retina or within the vitreous base. This classification is used to document the extent and anatomic distribution of PVR present preoperatively and to help standardize the surgical treatment. Experience has shown that this classification facilitates the identification of these membranes and their systematic dissection, and the authors therefore suggest that it be used to augment the Retina Society classification of PVR.
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Research Interests: Medicine, Endophthalmitis, Biological Sciences, Humans, Fluconazole, and 15 moreMale, Candidiasis, Follow-up studies, Antifungal, Clinical Sciences, Middle Aged, Optometry and Ophthalmology, Public health systems and services research, Voriconazole, Antifungal Agents, Vitrectomy, Aspergillosis, Clinical Infectious Diseases, Posaconazole, and Medical and Health Sciences
We describe a technique to facilitate visualization of the vitreous base, pars plana, and pars plicata during vitreous surgery. This technique takes advantage of an externally applied fiberoptic light source coupled with scleral... more
We describe a technique to facilitate visualization of the vitreous base, pars plana, and pars plicata during vitreous surgery. This technique takes advantage of an externally applied fiberoptic light source coupled with scleral depression to enable direct viewing of the ciliary processes and anterior vitreous base. No special instrumentation or alteration in pars plana vitrectomy techniques is required. We have used this technique to enhance anterior dissection during vitrectomy surgery in the aphakic and pseudophakic eye associated with proliferative vitreoretinopathy, diabetic retinopathy, epithelial down-growth syndromes, and postvitrectomy fibrin formation.
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Tissue Plasminogen Activator (TPA) has been used as an adjunct in the surgical removal of submacular hemorrhage. It is usually used intraoperatively, but may not provide enough time for effective fibrinolysis, especially for a large... more
Tissue Plasminogen Activator (TPA) has been used as an adjunct in the surgical removal of submacular hemorrhage. It is usually used intraoperatively, but may not provide enough time for effective fibrinolysis, especially for a large hemorrhage. The present study was conducted to evaluate the efficiency and safety of preoperative use of TPA for large submacular hemorrhages. Five eyes with large submacular hemorrhage secondary to age-related macular degeneration underwent subretinal injection of TPA in the office 24 hours before surgery. All hemorrhages were less than seven days old and at least 3 mm thick. Preoperative visual acuity ranged from counting fingers to hand motion (HM). Patient follow-up ranged from 3 months to 24 months (mean, 11 months). Final visual acuity ranged from 20/30 to HM. Four of the five eyes (80%) showed improved visual acuity after surgery and 3/5 (60%) attained visual acuity of 20/200 or better. Preoperative use of TPA for drainage of large submacular hemorrhage appears to be safe and may result in efficient clot removal. The true efficacy of TPA in the treatment of submacular hemorrhage can only be proven by a prospective randomized trial.
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Research Interests: Ophthalmology, Medicine, Endophthalmitis, Visual acuity, Humans, and 15 moreFemale, Male, American, Incidence, Clinical Sciences, Aged, Middle Aged, Optometry and Ophthalmology, Triamcinolone Acetonide, Public health systems and services research, Retrospective Studies, Vitrectomy, Injections, Postoperative Complications, and Acute Disease
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Thermo-responsive hydrogels have shown promise as injectable materials for local drug delivery. However, the phase-induced changes in polymer properties of N-isopropylacrylamide (NIPAAm) can pose additional challenges for achieving... more
Thermo-responsive hydrogels have shown promise as injectable materials for local drug delivery. However, the phase-induced changes in polymer properties of N-isopropylacrylamide (NIPAAm) can pose additional challenges for achieving controlled protein release. In this work, thermo-responsive hydrogels derived from NIPAAm and cross-linked with poly(ethylene glycol) diacrylate (PEG-DA) were synthesized via free radical polymerization. The volume phase transition temperature (VPTT) of the hydrogels ranged from 32.9 degrees C to 35.9 degrees C. Below the VPTT, swelling ratios of the hydrogels decreased with cross-linker concentration, and showed a sharp drop (at least 4-fold) upon phase change. Protein encapsulation efficiency was high (84-90%) and decreased with cross-linker concentration. Release of bovine serum albumin, a model protein, at body temperature was significantly higher than at room temperature (67% at 37 degrees C compared to 44% at 23 degrees C after 48 h). The release kinetics of proteins from the hydrogels were initially expected to be a function of cross-link density. However, at the hydrogel compositions explored in this work, protein release did not change significantly with cross-linker mol fraction. The thermo-responsive hydrogels offer a promising platform for the localized delivery of proteins.
Research Interests: Materials Engineering, Chemical Engineering, Free Radicals, Kinetics, Drug delivery, and 15 moreHydrogels, Polymerization, Animals, Phase transition, Phase Change, Body Temperature, Cattle, Room Temperature, Poly Ethylene Glycol, Acrylic Resins, Bovine Serum Albumin, Drug Carriers, Polyethylene Glycols, immunoglobulin G, and Free radical polymerization
Ferromagnetic (FM) hyperthermia has previously been evaluated in a rabbit tumour model of ocular melanoma. To study the effect of focal heating in normal rabbit eyes, FM seeds were implanted into a 14-mm episcleral plaque an heated to... more
Ferromagnetic (FM) hyperthermia has previously been evaluated in a rabbit tumour model of ocular melanoma. To study the effect of focal heating in normal rabbit eyes, FM seeds were implanted into a 14-mm episcleral plaque an heated to operating temperatures of 48 or 58 degrees C. Thermal induction was performed by placing rabbits in a uniform, oscillating (11 kHz) magnetic field operating at 1200 W and as H-field strength of 265 A/m. Eyes were heated for 60 min with continuous scleral temperature monitoring. Hyperthermic effects were monitored by direct opthalmic examination, fundus photography, serial electroretinography and histopathology. Intraocular temperatures were mapped with direct fiberoptic thermometry. All treatment effects were confined to the area covered by the episcleral plaque. Direct ophthalmoscopic examination revealed early retinal whitening during heat induction followed by localized exudative retinal detachments, limited to the area of the retinal surface overlying the plaque, that resolved spontaneously. Serial electroretinography was virtually indistinguishable between the 48 and 54 degrees C temperature groups. We noted a minimal alteration in a- and b-wave amplitudes with no changes in implicit times. Histopathology at 3 weeks post-treatment documented chorioretinal scarring overlying the thermal plaque treatment zone. No evidence of heamorrhage infection, cataract or scleral thinning was noted. This study documents the apparent focal containment of thermal effects with FM heating utilizing operating temperatures ad high as 54 degrees C for 60 min, and discloses no evidence of diffuse ocular toxicity.
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Research Interests: Biomaterials, Drug delivery, Optical coherence tomography, Polymers, Multidisciplinary, and 12 moreAnimals, Hydrogel, Retina, Rats, Poly Ethylene Glycol, Sustained Drug Release, Blood Flow, Acrylic Resins, Long Term Effect, Optical Coherence Tomography (OCT) Market, Ophthalmoscopy, and Optical Coherence Tomography OCT
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Research Interests: Archives, Prospective studies, Humans, Candida, Candida albicans, and 15 moreHigh Performance Liquid Chromatography, High Pressure Liquid Chromatography, Aged, Middle Aged, Spectrum, Optometry and Ophthalmology, Topical Drug Administration, Adult, Voriconazole, Antifungal Agents, Microbial Sensitivity Tests, Triazoles, Biological Availability, Vitrectomy, and Pars plana vitrectomy
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Current standard of care for neovascular eye diseases require repeated intravitreal bolus injections of anti-vascular endothelial growth factors (anti-VEGFs). The purpose of this study was to validate a degradable... more
Current standard of care for neovascular eye diseases require repeated intravitreal bolus injections of anti-vascular endothelial growth factors (anti-VEGFs). The purpose of this study was to validate a degradable microsphere-thermoresponsive hydrogel drug delivery system (DDS) capable of releasing bioactive aflibercept in a controlled and extended manner for 6 months. The DDS was fabricated by suspending aflibercept-loaded poly(lactic-co-glycolic acid) microspheres within a biodegradable poly(ethylene glycol)-co-(l-lactic acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) thermoresponsive hydrogel. Encapsulation efficiency of DDSs and in vitro release profiles were characterized by iodine-125 radiolabeled aflibercept. The degradation of hydrogel was determined by dry weight changes. The cytotoxicity from degraded DDS byproducts was investigated by quantifying cell viability using LIVE/DEAD® assay. In addition, dot blot and enzyme-linked immunosorbent assay were used to det...
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Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of... more
Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV). Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS.The DDS was shown previously to release bioactive anti-VEGF for ~200 days. CNV was induced using an Ar-green laser. The four experimental groups were as follows: (i) non-treated, (ii) drug-free DDS, (iii) anti-VEGF-loaded DDS, and (iv) bolus injection of anti-VEGF. CNV lesion areas were measured based on fluorescein angiograms and quantified using a multi-Otsu thresholding technique. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also obtained pre- and post-treatment (1, 2, 4, 8, and...
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The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution,... more
The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight. The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year. High dose and long dur...
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The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the... more
The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues. Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed. Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should b...
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Research Interests: Treatment, Prospective studies, Humans, Gram Positive, Female, and 14 moreMale, High Pressure Liquid Chromatography, Aged, Middle Aged, Spectrum, Gram-negative bacteria, Optometry and Ophthalmology, Adult, Penetration, Microbial Sensitivity Tests, Biological Availability, Vitrectomy, Fluoroquinolones, and minimal inhibitory concentration
We studied the use of a 15-W argon blue-green laser in the treatment of choroidal melanoma in a rabbit model. Greene melanoma cells were used to produce 2- to 4-mm thick tumors posteriorly in the suprachoroidal space in pigmented rabbits.... more
We studied the use of a 15-W argon blue-green laser in the treatment of choroidal melanoma in a rabbit model. Greene melanoma cells were used to produce 2- to 4-mm thick tumors posteriorly in the suprachoroidal space in pigmented rabbits. Endophotocoagulation delivered through a 600-micron fiberoptic probe was performed to ablate the tumor tissue and a surrounding margin of normal tissue. A vitreous cutter was used simultaneously to remove liberated necrotic debris. The effect of the laser on tumor and normal ocular tissue was evaluated by light microscopy and the extent of the proliferative response by tritiated thymidine radioautography. Application of 100 to 400 pulses of laser energy using treatment parameters of 12 to 14 W of power and 0.1-s pulses resulted in complete ablation of melanoma tissue, overlying retina, and choroid. There was no substantial intraoperative or postoperative hemorrhage. Material liberated during the laser treatment was found to be nonviable. The effect of the laser on tissue appeared localized to within approximately 1.25 mm of the margin of the central lesion. The high-energy argon laser seems to offer a means of effectively ablating melanoma tissue via an internal resection approach.
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Approximately three dozen medications have been associated with retinal toxicity, and it is important to be aware of such associations. Several medications, such as acetazolamide and latanoprost, are commonly prescribed by the... more
Approximately three dozen medications have been associated with retinal toxicity, and it is important to be aware of such associations. Several medications, such as acetazolamide and latanoprost, are commonly prescribed by the ophthalmologist. Most of the other medications are commonly administered by the patient's primary physician. When assessing any patient for a retinal disturbance, it is imperative to question the patient regarding the use of systemic medications. This is especially important as more and more medications are brought to the market each year.
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Retained intraocular foreign bodies (IOFBs) are associated with endophthalmitis in approximately 7 to 13% of cases. The role of prompt surgical removal of the foreign body along with the use of intravitreal antibiotics in reducing this... more
Retained intraocular foreign bodies (IOFBs) are associated with endophthalmitis in approximately 7 to 13% of cases. The role of prompt surgical removal of the foreign body along with the use of intravitreal antibiotics in reducing this figure is uncertain. Retained IOFBs presenting to The Medical College of Wisconsin between July 1986 and June 1989 were reviewed. A total of 27 cases were evaluated and surgically treated. None of the 27 cases presented with or developed clinical signs of endophthalmitis, yet bacterial cultures of the removed intraocular material were positive in seven cases (foreign body in 5 cases, the aqueous fluid and the vitreous fluid in 1 case each). All eyes presenting within 24 hours of injury underwent immediate surgery (average, 4.5 hours after presentation). Of the seven eyes with positive intraocular cultures, all had pars plana vitrectomy removal of the IOFB and three of these eyes received intravitreal antibiotics at the time of surgery over concern of a high risk of infection. Two of these eyes eventually grew out the Bacillus sp. All eyes received subconjunctival antibiotics and postoperative topical and systemic antibiotics. Even after the positive cultures, no signs of clinical infection developed in any of the eyes. All seven eyes retained excellent visual acuity of 20/70 or better at an average of 10 months&#39; follow-up. Follow-up ranged from 1 to 31 months. Prompt surgical intervention, the use of intravitreal antibiotics in high-risk-type injuries, and the possible use of vitrectomy surgery may reduce the incidence and severity of endophthalmitis.
Research Interests: Ophthalmology, Treatment, Adolescent, Endophthalmitis, Visual acuity, and 14 moreHumans, Child, Male, Bacteria, Follow-up studies, Clinical Sciences, Eye, Middle Aged, Anti-Bacterial Agents, Optometry and Ophthalmology, Adult, Public health systems and services research, Retrospective Studies, and Vitrectomy
Research Interests: Pigmentation and Toxicity
PurposeTo determine whether the use of mupirocin ointment for preoperative eradication of nasal bacterial carriage was effective in reducing conjunctival bacterial flora.MethodsProspective, double-arm, blinded clinical trial of 37 eyes of... more
PurposeTo determine whether the use of mupirocin ointment for preoperative eradication of nasal bacterial carriage was effective in reducing conjunctival bacterial flora.MethodsProspective, double-arm, blinded clinical trial of 37 eyes of 37 patients undergoing intraocular surgery (cataract extraction or pars plana vitrectomy) randomized to either control or mupirocin treatment groups. Treated patients received mupirocin nasal ointment twice daily for 5 days prior to surgery. Nasal cultures were obtained in all patients. All patients received a standard 5% povidone-iodine preparation before the surgical procedure, and conjunctival cultures were obtained in all patients before and after the povidone-iodine preparation.ResultsAll 37 patient nasal swabs were positive for bacterial growth (cultures were obtained prior to the use of mupirocin ointment in the treatment group). One of 15 eyes (6.7%) in the treatment group had positive conjunctival cultures prior to povidone-iodine preparation, compared with nine of 22 eyes (41%) in the control group (P < .05). Even after povidone-iodine preparation, eight of 22 eyes (36%) in the control group demonstrated persistent positive cultures, whereas one (6.7%) of the treatment eyes exhibited growth (P < .05).ConclusionsProphylactic use of mupirocin nasal ointment resulted in significant reduction of conjunctival flora with or without preoperative topical 5% povidone-iodine preparation. The use of mupirocin nasal ointment prior to intraocular surgery or intravitreal injections is a novel method for reducing conjunctival contamination rates, which theoretically should reduce the incidence of endophthalmitis.