Eye (2009) 23, 2187–2193 & 2009 Macmillan Publishers Limited All rights reserved 0950-222X/09 $32.00 www.nature.com/eye Incidence and O Artunay, E Yuzbasioglu, R Rasier, A Sengu¨l CLINICAL STUDY and H Bahcecioglu management of acute endophthalmitis after intravitreal bevacizumab (Avastin) injection Abstract recognition and treatment are key in maximizing outcomes in patients who Introduction The aim of this study was to developed endophthalmitis after intravitreal report the incidence and management of acute injection of bevacizumab. endophthalmitis after intravitreal injection of Eye (2009) 23, 2187–2193; doi:10.1038/eye.2009.7; Avastin (bevacizumab), and visual acuity published online 13 February 2009 outcomes of three eyes of three patients who developed acute endophthalmitis following Keywords: intravitreal injection; bevacizumab; intravitreal injection of Avastin. endophthalmitis Methods This clinical retrospective, non-comparative study included 3022 Introduction intravitreal injections of 1.25 mg bevacizumab consecutively performed for 1822 eyes with Intravitreal injection of medications is becoming exudative age-related macular degeneration increasingly accepted for treatment of various and other retinal diseases. Of 3022 injections, retinal disorders, with effective intravitreal 1200 were reinjections. After clinical therapies being commonly administered in the appearance of post-injection endophthalmitis, vitreoretinal clinical or surgical environment. Department of immediate intervention was performed, With the increase in use of these agents, the risk Ophthalmology, Istanbul including injection of intravitreal antibiotics of endophthalmitis is becoming an important Bilim University, Istanbul, Turkey and early pars plana vitrectomy. concern. Off-label intravitreal injections of Results Three eyes of three patients with bevacizumab (Avastin; Genentech Inc., South Correspondence: O Artunay, acute postoperative endophthalmitis were San Francisco, CA, USA) have been given for Sisli Florence Nightingale identified in the first week following the treatment of neovascular and exudative Hastanesi, intravitreal injections of 1.25 mg bevacizumab. ocular diseases since May 2005.1,2 Since then, Abide-i Hurriyet Sok. No: 1 Among of these patients, two cases were the use of intravitreal bevacizumab (IVB) has Sisli, Istanbul, Turkey Tel: þ 90 212 224 49 66; culture-positive and one case was spread worldwide, but the drug-related adverse Fax: þ 90 212 224 49 culture-negative. Compared with presenting events associated with its use have been 50-5633. visual acuities, all of three patients improved reported in a few retrospective reviews. IVB is E-mail: artunay@ at the end of follow-up time. The overall increasingly being used for the treatment of gmail.com incidence rate of post-injection culture-proven ocular diseases. However, the treatment is not endophthalmitis was 0.066%. without risks. None of the adverse event rates Received: 19 November 2008 Discussion Acute culture-proven 3 exceeded 0.21%. Endophthalmitis is a serious Accepted in revised form: endophthalmitis is still a potential intraocular inflammatory disorder resulting 5 January 2009 complication of intravitreal bevacizumab from infection of the vitreous cavity. Exogenous Published online: injection (approximately 0.066%) despite using endophthalmitis occurs when infecting 13 February 2009 maximal sterile techniques. Acute organisms gain entry into the eye by direct All the authors have no post-injection endophthalmitis following inoculation through intraocular surgery, proprietary interest in any 4 intravitreal bevacizumab occurs rapidly and penetrating trauma, or intravitreal injection. products or concepts can result in severe loss of vision. Prompt The risk of endophthalmitis after intravitreal mentioned in this article. Incidence and management of acute endophthalmitis O Artunay et al 2188 injection may vary among agents that are employed.5 The understanding on the potential benefits and risks of IVB reported incidence of endophthalmitis per patient in treatment and other alternative treatment modalities. The multi-centre clinical trials with anti-vascular endothelial study protocol was complied with the provisions of the growth factor (VEGF) therapy ranged from 0.019 to Declaration of Helsinki Principles and was reviewed and 1.6%.6–8 Although cases of acute endophthalmitis approved by the ethics committee. Patients were following IVB have occurred, the exact incidence excluded from the study if the bevacizumab was used as rate remains unknown. Concerns have been raised part of another surgical procedure (ie cataract surgery, regarding injection technique and also about the use pars plana vitrectomy (PPV), air–fluid exchange). Eyes of bevacizumab because of compounding issues. were also excluded from the study if another intraocular Generalized categories that lump adverse events are less procedure was performed at least 4 weeks before useful than a clear statement of the rate of individual, injection. clinically relevant endophthalmitis. Treating physician IVB injection was performed as an outpatient wants to know the specific rates of endophthalmitis and procedure under strict aseptic technique. Local its management. The purpose of our study was to report anaesthesia was achieved using 0.5% proparacaine the incidence rates of culture-positive and culture- (Alcaine; Alcon Laboratories Inc., Fort Worth, TX, USA) negative endophthalmitis for patients receiving IVB. and 10% povidone-iodine solution was applied to the The current study also includes the clinical findings, eyelids and in the conjunctival sac for 5 min, followed by causative organisms, management, and visual acuity draping and insertion of a lid speculum. Intravitreal outcomes of three eyes of three patients who developed injection of 1.25 mg bevacizumab in 0.05 ml was then acute postoperative endophthalmitis after IVB injection. carried out using a separate, sterile 30-gauge needle at 4-mm post-limbus in the inferior or inferotemporal quadrant. The needle was removed simultaneously with Materials and methods the application of a cotton tip over the entry site. This is a retrospective, interventional case series of 3022 Immediately after injection, 10% povidone-iodine consecutive eyes that were administered IVB injection at solution was applied on the ocular surface. Bevacizumab our reference clinic for miscellaneous retinal disease, (100 mg/4 ml; Roche; Genentech Inc.) was kept which was presented after March 2005. The indications refrigerated at 41C in its 4 ml original vial, and the for injection included predominately exudative studied volume of 0.05 ml was directly withdrawn from age-related macular degeneration (AMD; n ¼ 1453), the vial just before each injection. Ten patients were choroidal neovascular membranes secondary to myopic grouped together for treatment to provide multiple doses degeneration (n ¼ 21), idiopathic, and other secondary from a single vial. The top of the container was cleaned causes (n ¼ 18); cystoid or diffuse macular oedema from with alcohol wipe before injection. Any unused drug was central and branch vein occlusions, diabetes, uveitis and discarded after the vial had been opened for 4 h to retinitis pigmentosa (n ¼ 310); and proliferative prevent drug contamination. The optic nerve head was retinopathies (n ¼ 20). All patients included in the then examined for arterial pulsation to look for study were identified using comprehensive billing complications, and indirect ophthalmoscopy was records. A search of the office database was conducted performed to ensure correct placement of the injection for endophthalmitis diagnosis codes and intravitreal and to evaluate the retina. Tonometry was carried out injection procedure codes to identify all patients having after the procedure. Patients were given topical ofloxacin IVB and those who developed endophthalmitis. Patients (Exocin; Allergan Pharmaceuticals Ltd, Westport, were included in the study if they had clinical evidence Ireland) 3 mg/ml q.i.d. (four times a day) for 1 week after of acute postoperative endophthalmitis after receiving an each injection. Following the injection, the patients were IVB injection. Acute postoperative endophthalmitis was educated about symptoms of endophthalmitis. defined as the presence of progressive inflammation in At baseline and during the follow-up period, patients the vitreous cavity (vitritis) and/or anterior chamber received a comprehensive ophthalmic examination. Post- (iritis) within 4 weeks following intravitreal injections injection examinations were scheduled between 1 and 7 of bevacizumab. Culture-positive endophthalmitis was days, 4 weeks, and 8 weeks. considered to be present if the patient had either a positive gram stain or a positive culture. If the fungal, Results aerobic, and anaerobic culture were all negative, then this case was accepted as culture-negative endophthalmitis. A total of 3022 intravitreal injections of bevacizumab Common clinical findings were hypopyon, pain, red eye, were performed for 1822 eyes with exudative AMD and and decreased vision. Informed consents were obtained other exudative, proliferative retinal diseases during this from all participants after thorough discussion and full time period. Of 3022 injections, 1200 were reinjections. Eye Incidence and management of acute endophthalmitis O Artunay et al 2189 Follow-up after each injection was at least 6 weeks. Three loss. Orbital ultrasonograms before PPV showed dense patients were identified with signs