REPEATED NONINFECTIOUS ENDOPHTHALMITIS AFTER INTRAVITREAL ADMINISTRATION OF BEVACIZUMAB: A REPORT OF TWO CASES Shiri Soudry, MD,*† Anat Loewenstein, MD,*† Joseph Moisseiev, MD†‡
Purpose: To report on two patients with sterile endophthalmitis recurring twice after intravitreal bevacizumab injection. Methods: Two cases of sterile intraocular inflammation recurring after repeated intravitreal injections of bevacizumab are described, followed by a review of the literature. Results: Two patients presented with painful eyes and decreased vision associated with endophthalmitis several days after intravitreal bevacizumab injection. In both patients, vitreous specimens were sterile. The intraocular inflammation recurred after additional intravitreal injection of bevacizumab that was performed during subsequent follow-up. Conclusion: This is the first report of sterile intraocular inflammation recurring after repeated intravitreal injections of bevacizumab. Awareness of the possible association between bevacizumab administration and sterile endophthalmitis may be warranted. RETINAL CASES & BRIEF REPORTS 4:220–223, 2010
repeated intravitreal injections of bevacizumab8 has been reported, the exact incidence rate has not yet been determined. We report on two patients with repeated sterile endophthalmitis recurring twice after intravitreal bevacizumab injections.
From the *Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; and ‡Department of Ophthalmology, Sheba Medical Center, Tel Hashomer, Israel.
I
ntravitreal injection of bevacizumab, an antivascular endothelial growth factor antibody, has become common practice in the treatment of neovascular age-related macular degeneration.1,2 This route of administration may be associated with potential risks, one of which is the development of intraocular infection. The reported rate of infectious endophthalmitis presenting after intravitreal injection of bevacizumab is up to 0.16%.3-5 The rate of sterile endophthalmitis after intravitreal injection was up to 1.9% for triamcinolone6,7 and up to 1.3% for ranibizumab. Although a case of sterile endophthalmitis after
Case Reports Case 1 A 57-year-old woman was referred to the Retina Outpatient Clinic at the Sheba Medical Center for evaluation of bilateral neovascular age-related macular degeneration. She had been treated elsewhere 5 months earlier with bilateral intravitreal bevacizumab injections. On examination, the best-corrected visual acuity was 20/30 for the right eye and 20/60 for the left eye. The anterior segment was normal bilaterally. Funduscopic examination revealed a small disciform process in the right eye. A large subfoveal pigment epithelial detachment with considerable overlying subretinal fluid (SRF) and intraretinal lipids at its temporal border were detected in the left eye. The patient had been treated with 3 monthly intravitreal injections of bevacizumab 1.25 mg/0.05 mL. On the day after the third injection, she experienced pain and decreased vision in the left eye but waited 2 days before seeking medical advice. Examination disclosed left visual acuity of 1/60,
The authors declare no proprietary interest. Reprint requests: Shiri Soudry, MD, Department of Ophthalmology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel; e-mail: [email protected]
220
221
STERILE ENDOPHTHALMITIS AFTER INTRAVITREAL BEVACIZUMAB with eyelid edema, ciliary injection, and dense cellular response with hypopion in the anterior chamber. There were posterior pupillary synechiae. The vitreous was hazy, and the retina could not be visualized. Acute postoperative endophthalmitis was suspected, and a diagnostic and therapeutic vitreous tap with intravitreal injection of vancomycin 1 mg/0.1 mL and ceftazidime 2.5 mg/0.1 mL was performed. Direct stains of the specimen from the vitreous revealed neutrophils without organisms. Cultures from the vitreous were sterile. There was a gradual improvement in visual acuity of the left eye to 20/400, with complete resolution of the intraocular inflammation. Four months later, there was still substantial SRF, and choroidal neovascularization leakage was demonstrated on repeat fluorescein angiogram. Despite the patient’s having undergone photodynamic therapy, the visual acuity in the left eye continued to deteriorate because of choroidal neovascularization leakage. After receiving explicit explanations of the treatment options available to her, the patient underwent a repeat intravitreal bevacizumab 1.25 mg/0.05 mL injection. One day after the fourth injection, she presented with ocular pain and decreased visual acuity in the left eye. Ophthalmic examination disclosed ciliary injection with dense cellular response in the anterior chamber with hypopion and fibrin content in that eye. This time, however, the vitreous was clear, and the retina appeared normal. The differential diagnosis was toxic anterior segment syndrome-like reaction, and intensive topical antibiotic and steroidal treatment was begun. There was gradual resolution of the inflammatory response with improvement of the visual acuity up to 20/40 in the left eye.
Case 2 A healthy 40-year-old woman with myopia of 25.5 D in both eyes was evaluated in October 2006 at the Retina Clinic of the Tel Aviv Medical Center. She had a 7-year history of decreased vision, because of a disciform scar in the left eye. The right eye had been diagnosed a few years earlier with subfoveal choroidal neovascularization secondary to myopia, for which the patient had been treated with six sessions of photodynamic therapy. On examination, best-corrected visual acuity was 20/100 in the right eye and 1/18 in the left eye. The anterior segment was normal bilaterally. Funduscopic examination of the right eye revealed myopic changes and a small subfoveal scar with associated SRF temporally. Fluorescein angiogram revealed choroidal neovascularization leakage, and optical coherence tomography demonstrated SRF. The patient had been treated with 9 consecutive monthly intravitreal injections of bevacizumab 1.25 mg/0.05 mL. On the day after her ninth injection, she had pain and decreased vision in her right eye. Visual acuity was limited to finger counting in that eye. The ocular examination revealed eyelid chemosis, ciliary injection, and diffuse keratoprecipitates. The anterior chamber was deep with dense cellular response, hypopion, and marked fibrin content. The pupil was irregular and nonreactive due to formation of posterior synechiae. The posterior segment could not be visualized. Postoperative endophthalmitis was suspected. Vitreous samples were obtained, followed by an intravitreal injection of vancomycin 1 mg/0.1 mL and ceftazidime 2.25 mg/0.1 mL. Direct stains of a sample from the vitreous revealed no organisms, and the cultures were sterile. There was gradual subjective and objective improvement over the next few weeks until the intraocular inflammation resolved completely. Six weeks later, the visual acuity in the right eye was 20/200. Funduscopic examination revealed persistent prominent SRF. After careful consideration of the potential risks and benefits, it was decided to perform a repeat intravitreal injection of bevacizumab 1.25 mg/0.05 mL, which was undertaken
in the operating theater under aseptic conditions. Despite these precautions, the patient had photophobia and ocular pain in the right eye 1 day after the 10th injection. The visual acuity was 1/18 and the physical examination revealed eyelid edema, ciliary injection, edematous cornea, and deep anterior chamber with dense cellular and fibrinous content. The vitreous appeared opacified with cellular infiltration. An intravitreal injection of vancomycin was followed by a regimen of topical steroids and atropine eye drops, which led to rapid subjective improvement and clearing of the intraocular inflammation. The final clinical diagnosis was sterile intraocular inflammation secondary to intravitreal bevacizumab injection.
Discussion We present two patients with recurrent sterile endophthalmitis related to repeated intravitreal injection of bevacizumab for the treatment of choroidal neovascularization. In both patients, no infectious origin was identified in vitreous specimens, and the inflammation recurred after an additional injection of the drug, supporting the noninfectious nature of the reaction. Failure to differentiate between infectious and noninfectious endophthalmitis and to provide timely, sufficient treatment may lead to grave consequences or to the performance of unnecessary interventions. However, clinical differentiation between these entities may be difficult and hazardous, and we believe that diagnosis of sterile inflammation should be established only after an infectious etiology has been ruled out. In both our patients, the bevacizumab for injection was directly withdrawn from the commercial vial into single-use syringes under aseptic conditions at the hospital pharmacy and kept under refrigeration, thus decreasing the likelihood of contamination. Furthermore, all injections were performed in a sterile fashion using eyelid draping, insertion of eyelid speculum, and application of 5% topical povidoneiodine 2 minutes before injection. Taken together, the precautions used, lack of positive cultures in both cases, and, above all, the recurrent nature of the inflammatory response after consecutive injections argue in favor of sterile endophthalmitis in both our patients. Furthermore, in our first patient antibiotics were not injected in the second episode, and the inflammation subsided nonetheless. There are several previous reports describing sterile intraocular inflammation after intravitreal bevacizumab injections.8,9 Yenerel et al8 described a case of delayed sterile endophthalmitis after 3 intravitreal injections of 1.25 mg bevacizumab, which improved without sequelae after topical steroid and antibiotic treatment. Bakri et al9 reported on four cases of uveitis after intravitreal bevacizumab injections. In all four patients, the inflammation
222
RETINAL CASES & BRIEF REPORTS´ 2010 VOLUME 4 NUMBER 3
resolved within 1 to 2 weeks. Nonetheless, we are unaware of any previous reports of patients receiving additional intravitreal injections of bevacizumab after resolution of the intraocular inflammation. Both our patients presented with sterile intraocular inflammation recurring twice after repeated intraocular injections of bevacizumab. There are several explanations for the formation of sterile intraocular inflammation after intravitreal bevacizumab injection. Bevacizumab is a humanized full-length murine antibody binding all isoforms of vascular endothelial growth factor-A.1 Ranibizumab, an antibody fragment related to bevacizumab, has been reported both in preclinical and clinical studies to induce transient increased ocular inflammation.10-12 However, this property was later related to the lyophilized formulation, which was then switched to a liquid one, because of its lower tendency to induce inflammation. Given that both ranibizumab and bevacizumab are derived from the same molecule, it could be expected that their association with intraocular inflammation would also be similar. Furthermore, intraocular administration of bevacizumab, a murine-derived IgG antibody may have the potential to incite an inflammatory response by activation of the complement cascade or to elicit an immunologic response in humans, whereas antibodies directed at the Fc portion may be formed.13 Nonetheless, in vitro studies have revealed that even though bevacizumab binds the human Fcg receptor and C1q protein, no cell-mediated or complement-mediated cytotoxicity was observed in human cell lines.14 It was suggested that bevacizumab is unlikely to mediate lysis of vascular endothelial growth factor target cells.14 Furthermore, no inflammatory response was detected clinically or by the laser flare meter in a series of 61 patients treated with intravitreal bevacizumab injection for neovascular age-related macular degeneration.15 Similarly, other studies reported only a slight and transient increase in aqueous flare after intravitreal bevacizumab injection for age-related macular degeneration.16 It is unclear why both our patients exhibited an intraocular inflammatory response for the first time only after repeat intravitreal bevacizumab injections. Although speculative, it is possible that intraocular administration of a potentially immunogenic antibody resulted in absorption and accumulation in the systemic circulation, thus triggering an immunologic reaction. The recurrent nature of the inflammatory response to repeated injections in both our patients may support this possibility, but to the best of our knowledge, there is no solid proof of such an underlying pathophysiologic mechanism. It is also possible
that the sterile endophthalmitis resulted from other components in the bevacizumab preparation, such as bacterial endotoxins remaining after sterilization, but no direct analysis of the vitreous specimens regarding this was performed. Our findings suggest that sterile intraocular inflammation may occur after intravitreal antivascular endothelial growth factor administration and that the inflammation may recur after additional intravitreal injection. The occurrence of these events is probably low, because we have conducted .4,000 intravitreal injections of bevacizumab with an incidence of 1:2,000 so far. Nonetheless, awareness of the potential association between intravitreal bevacizumab injection and intraocular inflammation may be warranted. Key words: age-related macular degeneration, intravitreal bevacizumab, sterile endophthalmitis, repeat injection.
References 1. Rosenfeld PJ, Moshfegi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36: 331–335. 2. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372. 3. Jonas JB, Spandau UH, Rensch F, et al. Infectious and noninfectious endophthalmitis after intravitreal bevacizumab. J Ocul Pharmacol Ther 2007;23:240–242. 4. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008;246:81–87. 5. Mason JO III, White MF, Feist RM, et al. Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008;28:564–567. 6. Nelson ML, Tenant MT, Sivalingam A, et al. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina 2003;23: 686–691. 7. Taban M, Singh RP, Chung JY, et al. Sterile endophthalmitis after triamcinolone: a possible association with uveitis. Am J Ophthalmol 2007;144:50–54. 8. Yenerel NM, Dinc UA, Gorgun E. A case of sterile endophthalmitis after repeated intravitreal bevacizumab injection. J Ocul Pharmacol Ther 2008;24:362–363. 9. Bakri SJ, Larson TA, Edwards AO. Intraocular inflammation following intravitreal injection of bevacizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:779–781. 10. Husain D, Kim I, Gauthier D, et al. Safety and efficacy of intravitreal injection of ranibizumab in combination with verteporfin PDT on experimental choroidal neovascularization in the monkey. Arch Ophthalmol 2005;123:509–516.
STERILE ENDOPHTHALMITIS AFTER INTRAVITREAL BEVACIZUMAB 11. Rosenfeld PJ, Schwartz SD, Blumenkrantz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 2005;112: 1048–1053. 12. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am 2006;19: 361–372. 13. Grisanti S, Tatar O, Gelisken F, et al. Histopathologic evaluation of choroidal neovascular membranes following intravitreal bevacizumab injection. Paper presented at: Com-
223
bined Meeting of Club Jules Gonin and The Retina Society; Cape Town, South Africa. October 15–20, 2006. 14. Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 2004;7:335–345. 15. Kiss C, Michels S, Prager F, et al. Evaluation of anterior chamber inflammatory activity in eyes treated with intravitreal bevacizumab. Retina 2006;26:877–881. 16. Ziemssen F, Warga M, Neuhann IM, et al. Does intravitreal injection of bevacizumab have an effect on the blood-aqueous barrier function? Br J Ophthalmol 2006;90:922.
Purpose: To report on two patients with sterile endophthalmitis recurring twice after intravitreal bevacizumab injection. Methods: Two cases of sterile intraocular inflammation recurring after repeated intravitreal injections of bevacizumab are described, followed by a review of the literature. Results: Two patients presented with painful eyes and decreased vision associated with endophthalmitis several days after intravitreal bevacizumab injection. In both patients, vitreous specimens were sterile. The intraocular inflammation recurred after additional intravitreal injection of bevacizumab that was performed during subsequent follow-up. Conclusion: This is the first report of sterile intraocular inflammation recurring after repeated intravitreal injections of bevacizumab. Awareness of the possible association between bevacizumab administration and sterile endophthalmitis may be warranted. RETINAL CASES & BRIEF REPORTS 4:220–223, 2010
repeated intravitreal injections of bevacizumab8 has been reported, the exact incidence rate has not yet been determined. We report on two patients with repeated sterile endophthalmitis recurring twice after intravitreal bevacizumab injections.
From the *Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; and ‡Department of Ophthalmology, Sheba Medical Center, Tel Hashomer, Israel.
I
ntravitreal injection of bevacizumab, an antivascular endothelial growth factor antibody, has become common practice in the treatment of neovascular age-related macular degeneration.1,2 This route of administration may be associated with potential risks, one of which is the development of intraocular infection. The reported rate of infectious endophthalmitis presenting after intravitreal injection of bevacizumab is up to 0.16%.3-5 The rate of sterile endophthalmitis after intravitreal injection was up to 1.9% for triamcinolone6,7 and up to 1.3% for ranibizumab. Although a case of sterile endophthalmitis after
Case Reports Case 1 A 57-year-old woman was referred to the Retina Outpatient Clinic at the Sheba Medical Center for evaluation of bilateral neovascular age-related macular degeneration. She had been treated elsewhere 5 months earlier with bilateral intravitreal bevacizumab injections. On examination, the best-corrected visual acuity was 20/30 for the right eye and 20/60 for the left eye. The anterior segment was normal bilaterally. Funduscopic examination revealed a small disciform process in the right eye. A large subfoveal pigment epithelial detachment with considerable overlying subretinal fluid (SRF) and intraretinal lipids at its temporal border were detected in the left eye. The patient had been treated with 3 monthly intravitreal injections of bevacizumab 1.25 mg/0.05 mL. On the day after the third injection, she experienced pain and decreased vision in the left eye but waited 2 days before seeking medical advice. Examination disclosed left visual acuity of 1/60,
The authors declare no proprietary interest. Reprint requests: Shiri Soudry, MD, Department of Ophthalmology, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel; e-mail: [email protected]
220
221
STERILE ENDOPHTHALMITIS AFTER INTRAVITREAL BEVACIZUMAB with eyelid edema, ciliary injection, and dense cellular response with hypopion in the anterior chamber. There were posterior pupillary synechiae. The vitreous was hazy, and the retina could not be visualized. Acute postoperative endophthalmitis was suspected, and a diagnostic and therapeutic vitreous tap with intravitreal injection of vancomycin 1 mg/0.1 mL and ceftazidime 2.5 mg/0.1 mL was performed. Direct stains of the specimen from the vitreous revealed neutrophils without organisms. Cultures from the vitreous were sterile. There was a gradual improvement in visual acuity of the left eye to 20/400, with complete resolution of the intraocular inflammation. Four months later, there was still substantial SRF, and choroidal neovascularization leakage was demonstrated on repeat fluorescein angiogram. Despite the patient’s having undergone photodynamic therapy, the visual acuity in the left eye continued to deteriorate because of choroidal neovascularization leakage. After receiving explicit explanations of the treatment options available to her, the patient underwent a repeat intravitreal bevacizumab 1.25 mg/0.05 mL injection. One day after the fourth injection, she presented with ocular pain and decreased visual acuity in the left eye. Ophthalmic examination disclosed ciliary injection with dense cellular response in the anterior chamber with hypopion and fibrin content in that eye. This time, however, the vitreous was clear, and the retina appeared normal. The differential diagnosis was toxic anterior segment syndrome-like reaction, and intensive topical antibiotic and steroidal treatment was begun. There was gradual resolution of the inflammatory response with improvement of the visual acuity up to 20/40 in the left eye.
Case 2 A healthy 40-year-old woman with myopia of 25.5 D in both eyes was evaluated in October 2006 at the Retina Clinic of the Tel Aviv Medical Center. She had a 7-year history of decreased vision, because of a disciform scar in the left eye. The right eye had been diagnosed a few years earlier with subfoveal choroidal neovascularization secondary to myopia, for which the patient had been treated with six sessions of photodynamic therapy. On examination, best-corrected visual acuity was 20/100 in the right eye and 1/18 in the left eye. The anterior segment was normal bilaterally. Funduscopic examination of the right eye revealed myopic changes and a small subfoveal scar with associated SRF temporally. Fluorescein angiogram revealed choroidal neovascularization leakage, and optical coherence tomography demonstrated SRF. The patient had been treated with 9 consecutive monthly intravitreal injections of bevacizumab 1.25 mg/0.05 mL. On the day after her ninth injection, she had pain and decreased vision in her right eye. Visual acuity was limited to finger counting in that eye. The ocular examination revealed eyelid chemosis, ciliary injection, and diffuse keratoprecipitates. The anterior chamber was deep with dense cellular response, hypopion, and marked fibrin content. The pupil was irregular and nonreactive due to formation of posterior synechiae. The posterior segment could not be visualized. Postoperative endophthalmitis was suspected. Vitreous samples were obtained, followed by an intravitreal injection of vancomycin 1 mg/0.1 mL and ceftazidime 2.25 mg/0.1 mL. Direct stains of a sample from the vitreous revealed no organisms, and the cultures were sterile. There was gradual subjective and objective improvement over the next few weeks until the intraocular inflammation resolved completely. Six weeks later, the visual acuity in the right eye was 20/200. Funduscopic examination revealed persistent prominent SRF. After careful consideration of the potential risks and benefits, it was decided to perform a repeat intravitreal injection of bevacizumab 1.25 mg/0.05 mL, which was undertaken
in the operating theater under aseptic conditions. Despite these precautions, the patient had photophobia and ocular pain in the right eye 1 day after the 10th injection. The visual acuity was 1/18 and the physical examination revealed eyelid edema, ciliary injection, edematous cornea, and deep anterior chamber with dense cellular and fibrinous content. The vitreous appeared opacified with cellular infiltration. An intravitreal injection of vancomycin was followed by a regimen of topical steroids and atropine eye drops, which led to rapid subjective improvement and clearing of the intraocular inflammation. The final clinical diagnosis was sterile intraocular inflammation secondary to intravitreal bevacizumab injection.
Discussion We present two patients with recurrent sterile endophthalmitis related to repeated intravitreal injection of bevacizumab for the treatment of choroidal neovascularization. In both patients, no infectious origin was identified in vitreous specimens, and the inflammation recurred after an additional injection of the drug, supporting the noninfectious nature of the reaction. Failure to differentiate between infectious and noninfectious endophthalmitis and to provide timely, sufficient treatment may lead to grave consequences or to the performance of unnecessary interventions. However, clinical differentiation between these entities may be difficult and hazardous, and we believe that diagnosis of sterile inflammation should be established only after an infectious etiology has been ruled out. In both our patients, the bevacizumab for injection was directly withdrawn from the commercial vial into single-use syringes under aseptic conditions at the hospital pharmacy and kept under refrigeration, thus decreasing the likelihood of contamination. Furthermore, all injections were performed in a sterile fashion using eyelid draping, insertion of eyelid speculum, and application of 5% topical povidoneiodine 2 minutes before injection. Taken together, the precautions used, lack of positive cultures in both cases, and, above all, the recurrent nature of the inflammatory response after consecutive injections argue in favor of sterile endophthalmitis in both our patients. Furthermore, in our first patient antibiotics were not injected in the second episode, and the inflammation subsided nonetheless. There are several previous reports describing sterile intraocular inflammation after intravitreal bevacizumab injections.8,9 Yenerel et al8 described a case of delayed sterile endophthalmitis after 3 intravitreal injections of 1.25 mg bevacizumab, which improved without sequelae after topical steroid and antibiotic treatment. Bakri et al9 reported on four cases of uveitis after intravitreal bevacizumab injections. In all four patients, the inflammation
222
RETINAL CASES & BRIEF REPORTS´ 2010 VOLUME 4 NUMBER 3
resolved within 1 to 2 weeks. Nonetheless, we are unaware of any previous reports of patients receiving additional intravitreal injections of bevacizumab after resolution of the intraocular inflammation. Both our patients presented with sterile intraocular inflammation recurring twice after repeated intraocular injections of bevacizumab. There are several explanations for the formation of sterile intraocular inflammation after intravitreal bevacizumab injection. Bevacizumab is a humanized full-length murine antibody binding all isoforms of vascular endothelial growth factor-A.1 Ranibizumab, an antibody fragment related to bevacizumab, has been reported both in preclinical and clinical studies to induce transient increased ocular inflammation.10-12 However, this property was later related to the lyophilized formulation, which was then switched to a liquid one, because of its lower tendency to induce inflammation. Given that both ranibizumab and bevacizumab are derived from the same molecule, it could be expected that their association with intraocular inflammation would also be similar. Furthermore, intraocular administration of bevacizumab, a murine-derived IgG antibody may have the potential to incite an inflammatory response by activation of the complement cascade or to elicit an immunologic response in humans, whereas antibodies directed at the Fc portion may be formed.13 Nonetheless, in vitro studies have revealed that even though bevacizumab binds the human Fcg receptor and C1q protein, no cell-mediated or complement-mediated cytotoxicity was observed in human cell lines.14 It was suggested that bevacizumab is unlikely to mediate lysis of vascular endothelial growth factor target cells.14 Furthermore, no inflammatory response was detected clinically or by the laser flare meter in a series of 61 patients treated with intravitreal bevacizumab injection for neovascular age-related macular degeneration.15 Similarly, other studies reported only a slight and transient increase in aqueous flare after intravitreal bevacizumab injection for age-related macular degeneration.16 It is unclear why both our patients exhibited an intraocular inflammatory response for the first time only after repeat intravitreal bevacizumab injections. Although speculative, it is possible that intraocular administration of a potentially immunogenic antibody resulted in absorption and accumulation in the systemic circulation, thus triggering an immunologic reaction. The recurrent nature of the inflammatory response to repeated injections in both our patients may support this possibility, but to the best of our knowledge, there is no solid proof of such an underlying pathophysiologic mechanism. It is also possible
that the sterile endophthalmitis resulted from other components in the bevacizumab preparation, such as bacterial endotoxins remaining after sterilization, but no direct analysis of the vitreous specimens regarding this was performed. Our findings suggest that sterile intraocular inflammation may occur after intravitreal antivascular endothelial growth factor administration and that the inflammation may recur after additional intravitreal injection. The occurrence of these events is probably low, because we have conducted .4,000 intravitreal injections of bevacizumab with an incidence of 1:2,000 so far. Nonetheless, awareness of the potential association between intravitreal bevacizumab injection and intraocular inflammation may be warranted. Key words: age-related macular degeneration, intravitreal bevacizumab, sterile endophthalmitis, repeat injection.
References 1. Rosenfeld PJ, Moshfegi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36: 331–335. 2. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–372. 3. Jonas JB, Spandau UH, Rensch F, et al. Infectious and noninfectious endophthalmitis after intravitreal bevacizumab. J Ocul Pharmacol Ther 2007;23:240–242. 4. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al. Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 2008;246:81–87. 5. Mason JO III, White MF, Feist RM, et al. Incidence of acute onset endophthalmitis following intravitreal bevacizumab (Avastin) injection. Retina 2008;28:564–567. 6. Nelson ML, Tenant MT, Sivalingam A, et al. Infectious and presumed noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina 2003;23: 686–691. 7. Taban M, Singh RP, Chung JY, et al. Sterile endophthalmitis after triamcinolone: a possible association with uveitis. Am J Ophthalmol 2007;144:50–54. 8. Yenerel NM, Dinc UA, Gorgun E. A case of sterile endophthalmitis after repeated intravitreal bevacizumab injection. J Ocul Pharmacol Ther 2008;24:362–363. 9. Bakri SJ, Larson TA, Edwards AO. Intraocular inflammation following intravitreal injection of bevacizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:779–781. 10. Husain D, Kim I, Gauthier D, et al. Safety and efficacy of intravitreal injection of ranibizumab in combination with verteporfin PDT on experimental choroidal neovascularization in the monkey. Arch Ophthalmol 2005;123:509–516.
STERILE ENDOPHTHALMITIS AFTER INTRAVITREAL BEVACIZUMAB 11. Rosenfeld PJ, Schwartz SD, Blumenkrantz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 2005;112: 1048–1053. 12. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am 2006;19: 361–372. 13. Grisanti S, Tatar O, Gelisken F, et al. Histopathologic evaluation of choroidal neovascular membranes following intravitreal bevacizumab injection. Paper presented at: Com-
223
bined Meeting of Club Jules Gonin and The Retina Society; Cape Town, South Africa. October 15–20, 2006. 14. Wang Y, Fei D, Vanderlaan M, et al. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis 2004;7:335–345. 15. Kiss C, Michels S, Prager F, et al. Evaluation of anterior chamber inflammatory activity in eyes treated with intravitreal bevacizumab. Retina 2006;26:877–881. 16. Ziemssen F, Warga M, Neuhann IM, et al. Does intravitreal injection of bevacizumab have an effect on the blood-aqueous barrier function? Br J Ophthalmol 2006;90:922.
