Stephen J. Kim

Nonsteroidal Anti-inflammatory Drugs in Ophthalmology

Nonsteroidal anti-inflammatory drugs (NSAIDs) are increasingly employed in ophthalmology to reduce miosis and inflammation, manage scleritis, and prevent and treat cystoid macular edema associated with cataract surgery. In addition, they may decrease postoperative pain and photophobia associated with refractive surgery and may reduce the itching associated with allergic conjunctivitis. In recent years, the U.S. Food and Drug Administration has approved new topical NSAIDs, and previously approved NSAIDs have been reformulated. These additions and changes result in different pharmacokinetics and dosing intervals, which may offer therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on NSAIDs and a summary of their current uses in ophthalmology with attention to potential future applications.

Antimicrobial Resistance and Ophthalmic Antibiotics: 1-Year Results of a Longitudinal Controlled Study of Patients Undergoing Intravitreal Injections

OBJECTIVE To determine antibiotic susceptibility patterns of conjunctival flora from patients undergoing intraocular injection for choroidal neovascularization after repeated exposure to ophthalmic antibiotics. METHODS We conducted a randomized, controlled, longitudinal study of 48 eyes of 24 patients undergoing unilateral intraocular injection for choroidal neovascularization. Bilateral conjunctival cultures from the treated eye and untreated (control) fellow eye were taken at baseline and after each injection (before the application of povidone-iodine). Patients were randomized to ofloxacin, 0.3%; azithromycin, 1%; gatifloxacin, 0.3%; or moxifloxacin hydrochloride, 0.5% and used only their assigned antibiotic after each injection. Bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics, and analysis of bacteria DNA was performed using pulse-field gel electrophoresis. Main outcome measures included changes in antibiotic susceptibility patterns of conjunctival flora after 1 year. RESULTS Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to older-generation (P = .002) and newer-generation (P < .01) fluoroquinolones. In contrast, CNS isolated from azithromycin-exposed eyes demonstrated significantly increased resistance to macrolides (95%; P < .001) and decreased resistance to older-generation (P = .03) and newer-generation (P < .001) fluoroquinolones. There were significant increases in multiple-drug resistance of CNS isolated from treated eyes, with 81.8% and 67.5% of isolates resistant to at least 3 (P = .01) and at least 5 (P = .009) antibiotics, respectively. CONCLUSION Repeated exposure of conjunctival flora to ophthalmic antibiotics selects for resistant strains. APPLICATION TO CLINICAL PRACTICE Repeated use of ophthalmic antibiotics after intraocular injection promotes the emergence of antimicrobial resistance. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00831961.

Anti–Vascular Endothelial Growth Factor Pharmacotherapy for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the evidence regarding the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS Literature searches last were conducted in September 2011, in PubMed with no date restrictions, limited to articles published in English, and in the Cochrane Library without a language limitation. The combined searches yielded 532 citations, of which 45 were deemed clinically relevant for the authors to review in full text and to assign ratings of level of evidence to each of the selected studies with the guidance of the panel methodologists. RESULTS At this time, there are 5 studies that provide level I evidence for intravitreal ranibizumab, alone or in combination with other treatments for DME. There is also 1 study that provides level I evidence for intravitreal pegaptanib sodium for DME. Nine studies reviewed were rated as level II, and 2 additional studies reviewed were graded as level III. Most studies do not provide information about long-term results (i.e., more than 2 years of follow-up) or the comparative efficacy of anti-VEGF pharmacotherapies. CONCLUSIONS Review of the available literature indicates that anti-VEGF pharmacotherapy, delivered by intravitreal injection, is a safe and effective treatment over 2 years for DME. Further evidence is required to support the long-term safety of these pharmacotherapies and their comparative efficacy.

Antibiotic resistance of conjunctiva and nasopharynx evaluation study: a prospective study of patients undergoing intravitreal injections.

PURPOSE To determine the baseline antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora isolated from patients undergoing intravitreal (IVT) injections for choroidal neovascularization (CNV). DESIGN Prospective, observational study. PARTICIPANTS Forty-eight eyes of 24 patients undergoing unilateral IVT injections for CNV. METHODS Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were taken before application of any topical medications. MAIN OUTCOME MEASURES Bacterial isolates were identified and tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. RESULTS A total of 57 bacterial isolates were obtained from the conjunctiva of 48 eyes. Coagulase-negative staphylococci (CNS) accounted for 37 of the 57 isolates (65%). The most common CNS organisms were Staphylococcus epidermidis and Staphylococcus lugdunensis accounting for 73% and 11% of CNS isolates, respectively. More than half of S. epidermidis isolates demonstrated some level of resistance to ofloxacin and levofloxacin, and 33% and 37% of isolates showed some level of resistance against gatifloxacin and moxifloxacin, respectively. Some 60% and 30% of CNS isolates were resistant to ≥ 3 and ≥ 5 antibiotics, respectively. Among the 24 nasopharyngeal cultures, 8 (33%) grew Staphylococcus aureus, and 1 of the 8 isolates (13%) was resistant to all penicillin, cephalosporin, macrolide, and fluoroquinolone antibiotics tested. CONCLUSIONS Our results demonstrate subtantial levels of resistance to third- and fourth-generation fluoroquinolones and multiresistance among ocular CNS isolated from patients undergoing IVT injections for CNV.

Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections.

PURPOSE To determine whether repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics promotes antimicrobial resistance in patients undergoing intravitreal injections for choroidal neovascularization (CNV). DESIGN Prospective, randomized, controlled, clinical trial. PARTICIPANTS Forty-eight eyes of 24 patients undergoing unilateral intravitreal injections for CNV. METHODS Patients were assigned randomly to 1 of 4 ophthalmic antibiotics (azithromycin 1%, ofloxacin 0.3%, gatifloxacin 0.3%, moxifloxacin 0.5%) to be used after each injection in the treatment eye only. Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were obtained at baseline and were repeated at each subsequent visit for 1 year. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. Genetic analysis of bacteria strains was performed using pulse-field gel electrophoresis. MAIN OUTCOME MEASURES Changes in antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora over time and emergence of resistant strains. RESULTS Eight subjects (33%) grew Staphylococcus aureus from the nasopharynx and 1 subject (13%) showed emergence of a resistant strain. Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to third- and fourth-generation fluoroquinolones compared with untreated eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P = 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P = 0.009) and 77% (P<0.001), respectively. In contrast, CNS isolated from eyes repeatedly exposed to azithromycin demonstrated significantly increased resistance (94%) to erythromycin and azithromycin when compared with control eyes (P = 0.009) and decreased resistance to third-generation (P<0.03) and fourth-generation (P<0.001) fluoroquinolones when compared with eyes exposed to fluoroquinolones. CONCLUSIONS Repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics selects for resistant strains.

Topical Nonsteroidal Anti-inflammatory Drugs and Cataract Surgery: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the available evidence on the effectiveness of prophylactic topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing vision loss resulting from cystoid macular edema (CME) after cataract surgery. METHODS Literature searches of the PubMed and the Cochrane Library databases were last conducted on January 21, 2015, with no date restrictions. The searches retrieved 149 unique citations. The first author reviewed the abstracts of these articles and selected 27 articles of possible clinical relevance for full-text review. Of these 27 articles, 12 were deemed relevant to analyze in full. Two additional articles were identified from the reference list of the selected articles, and another article was identified from a national meeting. The panel methodologist assigned ratings of level of evidence to each of the selected citations. RESULTS Nonsteroidal anti-inflammatory drug therapy was effective in reducing CME detected by angiography or optical coherence tomography (OCT) and may increase the speed of visual recovery after surgery when compared directly with placebo or topical corticosteroid formulations with limited intraocular penetration. However, the use of NSAIDs did not alter long-term (≥3 months) visual outcomes. Furthermore, there was no evidence that the benefits observed with NSAID therapy could not be obtained similarly with equivalent dosing of a corticosteroid. The reported impression that there is a pharmacologic drug synergy from the use of both an NSAID and a corticosteroid is not supported by the literature. There is no uniform method of reporting CME in the literature, which prevents accurate assessment of its incidence and response to anti-inflammatory therapies. CONCLUSIONS Cystoid macular edema after cataract surgery has a tendency to resolve spontaneously. There is a lack of level I evidence that supports the long-term benefit of NSAID therapy to prevent vision loss from CME at 3 months or more after cataract surgery. Although dosing of NSAIDs before surgery may hasten the speed of visual recovery in the first several weeks after cataract surgery, there is no evidence that this practice affects long-term visual outcomes. Standardized reporting of CME based on OCT may allow for more uniform quantitation of its incidence and more reliable assessment of treatment outcomes.

Ophthalmic Antibiotic Use and Multidrug-Resistant Staphylococcus epidermidis: A Controlled, Longitudinal Study

PURPOSE To analyze the emergence of multidrug-resistant Staphylococcus epidermidis after repeated conjunctival exposure to topical macrolide or fluoroquinolone antibiotics. DESIGN Prospective, controlled, longitudinal study with 1-year follow-up. PARTICIPANTS Forty-eight eyes of 24 patients undergoing serial unilateral intravitreal (IVT) injections for choroidal neovascularization. METHODS Subjects received 4 consecutive monthly unilateral IVT injections and then were treated as needed. Each subject was assigned randomly to 1 of 4 antibiotics (azithromycin 1%, gatifloxacin 0.3%, moxifloxacin 0.5%, ofloxacin 0.3%) and used only their assigned antibiotic after each injection. Conjunctival culture specimens of the treated and untreated fellow eye (control) were obtained at baseline and after each injection. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. MAIN OUTCOME MEASURES Antibiotic susceptibility patterns and multidrug resistance of S. epidermidis. RESULTS After 4 consecutive treatments, a total of 58 isolates of S. epidermidis each were isolated from control and treated eyes. Resistance to 3 or more antibiotics was present in 69% of S. epidermidis isolated from control eyes compared with 90% from treated eyes (P<0.02). A total of 46 and 38 isolates of S. epidermidis were cultured from control and treated eyes, respectively, from the fifth until the final injection. Resistance to 5 or more antibiotics was present in 48% of control eyes compared with 71% of treated eyes (P<0.05). In a significant number of fluoroquinolone-treated eyes, S. epidermidis developed resistance to third-generation (P<0.01) and fourth-generation (P<0.01) fluoroquinolones compared with control eyes. In addition, these organisms developed resistance to trimethoprim/sulfamethoxazole (P<0.01), gentamicin (P<0.03), and clindamycin (P<0.05). Similarly, a significant number of azithromycin-treated eyes developed S. epidermidis resistant to macrolides (P<0.01) compared with control eyes and also developed increased resistance to trimethoprim/sulfamethoxazole (P<0.02) and doxycycline (P<0.01). CONCLUSIONS Conjunctival S. epidermidis repeatedly exposed to fluoroquinolone or azithromycin antibiotics rapidly develop resistance. Coresistance to other antibiotics also was observed. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Efficacy and pharmacokinetics of intravitreal non-steroidal anti-inflammatory drugs for intraocular inflammation

Objective: To determine the efficacy and pharmacokinetics of intraocularly delivered non-steroidal anti-inflammatory drugs in an animal model of ocular inflammation. Methods: Lipopolysaccharide was injected into the vitreous of rabbit eyes to induce inflammation. Treated eyes were injected with 3 mg of ketorolac or 0.3 mg of diclofenac. Twenty-four hours later, total leucocyte concentrations and prostaglandin E2 concentrations were determined. For intraocular pharmacokinetics, 0.1 ml of ketorolac (3 mg) and 0.1 ml of diclofenac (0.3 mg) were injected into rabbit eyes. Reverse-phase high-performance liquid chromatography was used to analyse drug levels within the retina/choroid at 0.25 (15 min), 1, 2, 4, 24, and 48 h after injection. Results: Eyes treated with ketorolac and diclofenac demonstrated reduced aqueous leucocyte concentrations of 62% and 64% respectively, compared with untreated controls (p<0.05). Ketorolac and diclofenac reduced aqueous prostaglandin E2 levels by 85% (p<0.005) and 59% (p<0.005), respectively. Ketorolac and diclofenac achieved a peak vitreous concentration of 234 and 73 μg/ml, respectively. After 48 h, ketorolac was barely detectable (0.06 μg/ml) in the vitreous, and diclofenac was undetectable. The peak concentration of each drug in the retina/choroid was 201 μg/g for ketorolac and 4.1 μg/g for diclofenac. Both drugs were undetectable in the retina/choroid after 48 h. Conclusions: Both ketorolac and diclofenac have potent anti-inflammatory effects after intraocular injection. Pharmacokinetic analysis demonstrated good penetration into the retina/choroid but rapid clearance by 48 h.

Visual outcomes and incidence of recurrent vitreous hemorrhage after vitrectomy in diabetic eyes pretreated with bevacizumab (avastin).

Purpose: To evaluate the safety and effect of bevacizumab pretreatment on the incidence of recurrent vitreous hemorrhage and visual acuity after vitrectomy for proliferative diabetic retinopathy. Methods: This was a consecutive, retrospective, and comparative cohort study. Patients undergoing vitrectomy from September 2006 through November 2007 at the Emory Eye Center for complications of proliferative diabetic retinopathy were identified and reviewed. A total of 33 eyes pretreated with bevacizumab and 104 untreated eyes were observed for postoperative vitreous hemorrhage and final visual acuity. Results: Patients in the bevacizumab group were significantly younger than those in the untreated group (average age, 46.4 vs. 58.4 years) and were more likely to have 20-gauge instrumentation (58% vs. 36%). An average of 9.6 days passed between injection and surgery. Early (4-6 weeks) rebleed rates were 15% versus 13% in the bevacizumab and untreated groups, respectively, and not statistically different. Preoperative (7/200 vs. count finger at 4′), 1-month postoperative (20/200−3 vs. 20/150), and 3-month postoperative visual acuity (20/100−3 vs. 20/100+2) were not statistically different between groups. No statistical difference was found in rebleed rates regarding the gauge of vitrectomy. Conclusion: Bevacizumab pretreatment for diabetic vitrectomy was not associated with any observed complications but did not influence rates of postoperative vitreous hemorrhage or final visual acuity in this retrospective series. The overall incidence of postoperative early vitreous hemorrhage in this series was 13% and seems lower than historically reported rates.

Long-term trends in intraocular pressure after pars plana vitrectomy.

Purpose: To evaluate the effect of vitrectomy on intraocular pressure (IOP). Methods: Retrospective cohort study. Medical records of 101 eyes of 101 patients undergoing nonemergent vitrectomy were reviewed for rates of open-angle glaucoma, increased IOP of >4 mmHg from baseline, change in IOP from baseline, and cataract formation. Preoperative and last measured IOPs were recorded. Baseline risk characteristics including lens status and diabetes were analyzed. Main outcome measures were 1) incidence of open-angle glaucoma; 2) increase in IOP of >4 mmHg; and 3) change in IOP. Results: Mean follow-up was 49 months (range, 12-105 months). Mean baseline IOP was 15.3 mmHg, and mean final IOP was 15.8 mmHg (P = 0.3). At the most recent examination, 35 study eyes had a decrease in IOP from baseline, while 14 eyes had no change and 52 eyes had an increase in IOP. Four study eyes were newly diagnosed with ocular hypertension. No study eye developed open-angle glaucoma or required medical, laser, or surgical treatment for glaucoma. Incidence of increased IOP of >4 was 7% at 4 years and 34% at 8 years. Subgroup analysis of 66 patients comparing study eyes with nonvitrectomized fellow eyes demonstrated no significant difference in rates of increased IOP of >4 (P = 0.85). Neither diabetes nor pseudophakia was associated with significantly increased IOP. Conclusion: In this series, vitrectomy does not appear to increase IOP even after removal of the crystalline lens.