Sophie J. Bakri

Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection

PURPOSE To describe the pharmacokinetics occurring after the direct injection of triamcinolone acetonide into the vitreous humor of humans. DESIGN Interventional case series. PARTICIPANTS Five patients who received a single 4-mg intravitreal injection of triamcinolone acetonide. METHODS An aqueous humor sample was obtained from 5 eyes via an anterior chamber paracentesis at days 1, 3, 10, 17, and 31 after injection. At each visit, visual acuity and intraocular pressure were measured and indirect ophthalmoscopy was performed. A fluorescein angiogram was carried out at day 10. Concentrations were determined using high performance liquid chromatography; pharmacokinetic analysis was carried out using PK Analyst, an iterative, nonlinear, weighted, least-squares regression program. MAIN OUTCOME MEASURES Intraocular concentrations of triamcinolone were measured and population pharmacokinetic parameters were calculated. RESULTS Pharmacokinetic data followed a two-compartment model. Peak aqueous humor concentrations ranged from 2151 to 7202 ng/ml, half-lives from 76 to 635 hours, and the integral of the area under the concentration-time curve (AUC(0-t)) from 231 to 1911 ng/h per milliliter. After a single intravitreal injection of triamcinolone, the mean elimination half-life was 18.6 days in nonvitrectomized patients. The half-life in a patient who had undergone a vitrectomy was shorter at 3.2 days. CONCLUSIONS There was considerable intrasubject variation among peak concentration, AUC(0-t) values, and elimination half-lives. After intravitreal injection, measurable concentrations of triamcinolone would be expected to last for approximately 3 months (93 +/- 28 days) in the absence of a vitrectomy. Because triamcinolone pharmacokinetics were characterized only in elderly patients with macular edema, the results cannot be extrapolated to other patient populations.

The effect of intravitreal triamcinolone acetonide on intraocular pressure.

BACKGROUND AND OBJECTIVE To ascertain whether a single 4-mg intravitreal triamcinolone acetonide injection is associated with elevated intraocular pressure (IOP). PATIENTS AND METHODS Retrospective noncomparative interventional case series. Forty-three consecutive eyes of 38 patients who had 12 weeks of follow-up were included. The IOPs before and after triamcinolone acetonide treatment were recorded by Goldmann applanation at each patient visit. RESULTS Within 12 weeks after intravitreal triamcinolone acetonide injection, 21 of 43 eyes (48.8%) demonstrated an increase in IOP of 5 mm Hg or greater, and 12 of 43 eyes (27.9%) had an increase in IOP of 10 mm Hg or greater. The mean time for an increase in IOP of 5 mm Hg or greater to occur was 4.1 weeks (standard deviation = 4.8 weeks), and the mean time to reach maximum IOP was 6.6 weeks (standard deviation = 5.1). The difference between the mean pre-injection IOP (15.12 mm Hg, n = 43) and the maximum post-injection IOP (20.74 mm Hg, n = 43) was statistically significant (P < .0001). CONCLUSION A single 4-mg intravitreal triamcinolone acetonide injection is associated with an increase in IOP of 10 mm Hg or greater in 27.9% of eyes after the first injection. All eyes responded to topical glaucoma medication.

Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing.

Purpose: To determine the change in anti–vascular endothelial growth factor (VEGF) activity of bevacizumab (Avastin, Genentech, Inc., San Francisco, CA) after refrigeration or freezing. Methods: Samples of bevacizumab were drawn up from new vials into plastic tuberculin syringes and refrigerated at 4°C for 1 week, 3 weeks, 1 month, 3 months, and 6 months. The vials and syringes were stored at 4°C, and the syringes were capped with a needle. One syringe was frozen at −10°C. The bevacizumab concentration was measured, via its binding to VEGF-165. Results: The percentage of degradation of bevacizumab in the previously pierced vials stored at 4°C compared with that in the unpierced vial was 9.6% at 3 months and 12.7% at 6 months. The bevacizumab drawn into the syringe and stored at 4°C was degraded by 1.6% at 1 week, 0% at 3 weeks, 8.8% at 3 months, and 15.9% at 6 months. The bevacizumab frozen in a syringe at −10°C was degraded by 12.0% at 6 months. Conclusion: The anti-VEGF activity of bevacizumab may degrade minimally over time, with storage.

Infectious endophthalmitis after intravitreal injection of antiangiogenic agents.

Purpose: To evaluate the rate of infectious endophthalmitis associated with intravitreal injection of bevacizumab, ranibizumab, and pegaptanib sodium. Methods: A retrospective review of patients who received intravitreal injections of bevacizumab, ranibizumab, and pegaptanib sodium was undertaken. Cases of clinical diagnoses of endophthalmitis or suspected endophthalmitis resulting from intravitreal injection were identified and reviewed. From these data, the risk per injection was estimated. Results: Three patients developed endophthalmitis after the intravitreal injection. The risk per injection was 0.00077 (0.077%). The rate of endophthalmitis was 1 per 1,291 injections. Conclusion: A similar risk of endophthalmitis per injection compared with some trials was obtained in this study. Although no definite risk factors could be identified, intravitreal injections performed by nonretina specialist physicians may be a risk factor for the development of endophthalmitis.

Intravitreal injection technique and monitoring: updated guidelines of an expert panel.

Purpose: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring. Methods: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists. Results: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone–iodine to and avoiding eyelid contact with the intended injection site and needle. Conclusion: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.

Applying the CONSORT and STROBE Statements to Evaluate the Reporting Quality of Neovascular Age-related Macular Degeneration Studies

PURPOSE To evaluate the quality of reporting in the neovascular age-related macular degeneration (nvAMD) literature by applying the Consolidated Standards for Reporting Trials (CONSORT) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement writing standards. DESIGN CONSORT and STROBE impact analysis; literature review. PARTICIPANTS Phase III randomized controlled trials (RCTs) of verteporfin photodynamic therapy, pegaptanib, and ranibizumab, and interventional case studies of bevacizumab for nvAMD. METHODS A literature search identified eligible articles published before October 31, 2007. We assessed the report quality of Phase III RCTs using the CONSORT statement and case series publications using the STROBE statement, both with indicators relevant to nvAMD. MAIN OUTCOME MEASURES Presence or absence of CONSORT or STROBE statement indicators. RESULTS Seven publications of Phase III RCTs and 29 publications on bevacizumab interventional case studies for nvAMD met our inclusion criteria. Of 37 possible CONSORT writing guideline items, the mean report quality for RCTs was 30.6 (83%), with a range from 23 to 35 (65%-95%). Of 35 possible STROBE writing guideline items, the mean report quality grade for intravitreal bevacizumab case series was 23 (70%), with a range from 16 to 31 (46%-94%). Among the bevacizumab studies, more than 90% reported scientific background, drug dose and administration, baseline characteristics, unadjusted results, and adverse events. Fewer than 20% reported study size calculations, handling of missing data, or a discussion of bias. CONCLUSIONS Since the adoption of the CONSORT standards by Ophthalmology and other journals in 1996, the reporting quality for RCTs has further improved among this cohort of nvAMD articles. On the other hand, no reporting standards for case series have existed until the recent publication of the STROBE statement. In this first application of the STROBE standards to ophthalmology, we found that the small interventional studies in our series had an average reporting score lower than the RCTs, but also that some individual scores were higher than the RCTs. This outcome demonstrates that good, useful articles can be written about small studies. Although not a direct measure of the quality of a study, good reporting allows a reader to assess the validity and applicability of the studys findings. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

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.

Intravitreal silicone oil droplets after intravitreal drug injections.

Purpose: To present the finding of tiny silicone oil droplets in 15 eyes of 15 patients after intravitreal injections of an anti–vascular endothelial growth factor agent or triamcinolone acetonide and to discuss the likely source of silicone oil. Methods: In an observational case series, charts of patients who had undergone intravitreal injections by one surgeon were reviewed retrospectively. The finding of intravitreal silicone oil droplets was noted. The following information was also documented: number and type of injections before the appearance of silicone oil droplets, symptoms and evidence of ocular inflammation, visual acuity before and after silicone oil droplets, length of follow-up, and visual acuity at the last examination. Results: Fifteen eyes of 15 patients were found to have silicone oil droplets documented after a various number of injections (range, 1–16). Patients were asymptomatic, and there were no adverse side effects associated with the presence of silicone oil droplets at examination. Conclusions: Silicone oil droplets may occur in the vitreous cavity after intravitreal drug injections. There were no adverse effects found associated with silicone oil in the vitreous after injections of anti–vascular endothelial growth factor agents or triamcinolone acetonide. The likely source of silicone oil is the needles and syringes used for the injections.

Vitreous Penetration Of Topical Moxifloxacin And Gatifloxacin In Humans

Purpose: To determine the vitreous penetration of the new fourth-generation topical fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3%. Methods: A prospective randomized clinical trial comprising 12 eyes of 12 patients scheduled for pars plana vitrectomy between August 2003 and September 2003 was performed in a clinical practice. The patients were randomly assigned to receive topical moxifloxacin 0.5% (n = 6) or gatifloxacin 0.3% (n = 6). One half the patients in each antibiotic group received 1 drop every 15 minutes for a total of 3 doses starting 1 hour before surgery, and the other one half self-administered the antibiotic drop 4 times daily for 3 days before surgery and at 7 am on the day of surgery. Undiluted vitreous samples were obtained and analyzed using high-performance liquid chromatography. Results: Either moxifloxacin 0.5% or gatifloxacin 0.3% was detected in the vitreous in all 12 patients in the study. There was no significant difference between the mean vitreous concentration of moxifloxacin 0.5% given over 1 hour preoperatively (0.012 ± 0.011 &mgr;g/mL) and that given in the 3-day regimen (0.011 ± 0.008 &mgr;g/mL) (P = 0.93). There was also no significant difference between the mean vitreous concentration of gatifloxacin 0.3% given over 1 hour preoperatively (0.001 ± 0.0003&mgr;g/mL) and that given over 3 days (0.008 ± 0.006 &mgr;g/mL) (P = 0.11). Vitreous concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% in each eye were all lower than the 90% minimum inhibitory concentration for the commonest bacterial isolates causing endophthalmitis. With both dosing regimens, the mean vitreous concentration of moxifloxacin 0.5% was higher than that of gatifloxacin 0.3% administered at the same regimen, but this was not statistically significant. Conclusion: Both topical moxifloxacin 0.5% and gatifloxacin 0.3% penetrated the vitreous in the uninflamed eye, but the vitreous concentrations attained were all lower than the 90% minimum inhibitory concentration for the commonest bacterial pathogens causing acute postoperative endophthalmitis.

Same-day triple therapy with photodynamic therapy, intravitreal dexamethasone, and bevacizumab in wet age-related macular degeneration.

Purpose: To report the results of same-day triple therapy with reduced fluence photodynamic therapy, intravitreal dexamethasone, and bevacizumab in patients with neovascular age-related macular degeneration. Methods: Retrospective case series. Records of patients who received same-day triple therapy with reduced fluence photodynamic therapy (25 J/cm2), intravitreal dexamethasone (200 &mgr;g), and intravitreal bevacizumab (1.25 mg) were reviewed. All patients had neovascular subfoveal age-related macular degeneration with at least 1 year of follow-up. Snellen visual acuity (VA), central macular thickness on optical coherence tomography, intraocular pressure, and endophthalmitis occurrence were recorded. Results: The 31 patients were observed for a mean of 13.7 months. In all patients, mean baseline VA was 20/80 and vision at final follow-up was 20/60 (P = 0.69). In patients who received previous treatment for exudative age-related macular degeneration (n = 18), mean baseline VA was 20/100 and vision at final follow-up (mean, 13.7 months) was 20/100 (P = 0.31). In treatment-naïve patients (n = 13), mean baseline VA was 20/60 and vision at final follow-up (mean, 13.5 months) was 20/40 (P = 0.31). In all patients, mean central macular thickness was 293 &mgr;m at baseline and 245 &mgr;m at final follow-up (P = 0.053). In previously treated patients (n = 18), mean central macular thickness was 325 &mgr;m at baseline and 265 &mgr;m at final follow-up (P = 0.10). In treatment-naïve patients, mean central macular thickness was 249 &mgr;m at baseline (n = 13) and 218 &mgr;m at final follow-up (P = 0.34). Previously treated patients required more antivascular endothelial growth factor injections (mean = 3.6) than treatment-naïve patients (mean = 0.8), but the mean number of repeat triple therapy treatments was 0.3 in both groups. Changes in intraocular pressure and endophthalmitis were not observed during follow-up. Conclusion: Same-day triple therapy maintained VA and decreased macular thickness in patients with and without previous antivascular endothelial growth factor therapy. Triple therapy may reduce the number of antivascular endothelial growth factor injections in some patients and stabilize vision in some patients not responding to antivascular endothelial growth factor therapy.