- Email: [email protected]
Comparison of endophthalmitis rates following intravitreal injection of compounded bevacizumab, ranibizumab, and aflibercept
Comparison of endophthalmitis rates following intravitreal injection of compounded bevacizumab, ranibizumab, and aflibercept Farzin Forooghian, MSc, MD, FRCSC, David A. Albiani, EMBA, MD, FRCSC, Andrew W. Kirker, MD, FRCSC, Andrew B. Merkur, MD, FRCSC ABSTRACT ● Objective: Whereas the incidence of endophthalmitis after compounded intravitreal bevacizumab is known to be low, the rates of endophthalmitis after intravitreal injection of compounded ranibizumab and aflibercept are not known. The purpose of this study was to determine the incidence of endophthalmitis after treatment with compounded intravitreal ranibizumab and aflibercept and to compare this to the incidence with compounded intravitreal bevacizumab. Design: Retrospective chart review. Participants: All patients with post-injection endophthalmitis who were seen over a 6.5-year period at a tertiary retina referral practice. Methods: We identified all cases of endophthalmitis by searching for patients who received intravitreal antibiotics and had antecedent intravitreal injection of bevacizumab, ranibizumab, or aflibercept. Results: A total of 54,101 injections of bevacizumab, 5,614 injections of ranibizumab, and 3,468 injections of aflibercept were performed. The incidence of suspected endophthalmitis was 0.041% (95% CI: 0.026–0.062) for bevacizumab, 0.036% (95% CI: 0.0043–0.13) for ranibizumab, and 0.06% (95% CI: 0.007–0.2) for aflibercept. For culture-positive cases, the incidence was 0.017% (95% CI: 0.0076–0.032) for bevacizumab, 0.02% (95% CI: 0.0005–0.1) for ranibizumab, and 0.03% (95% CI: 0.0007–0.2) for aflibercept. There was no statistically significant difference in endophthalmitis rate between the 3 different compounded drugs with respect to both overall suspected endophthalmitis rate and culture-positive endophthalmitis rate (p ¼ 0.87). Conclusion: Compounding of ranibizumab and aflibercept for intravitreal use appears to be safe because the endophthalmitis rate does not appear to be different from that of intravitreal bevacizumab.
The off-label use of compounded intravitreal bevacizumab (Avastin; Genentech, San Francisco, Calif.) has become part of standard of care in retina practices around the world. The compounding and subsequent refrigerated storage of this medication in plastic syringes has raised concerns over its functional stability and the potential for microbial contamination. Numerous in vitro studies have demonstrated that the functional stability of compounded bevacizumab is maintained for up to 6 months when this medication is stored in refrigerated conditions.1–4 Concerns over sterility have been prompted by reports of isolated outbreaks of endophthalmitis after intravitreal injection of bevacizumab.5,6 However, laboratory analysis of compounded plastic syringes of bevacizumab has not shown evidence of bacterial or endotoxin contamination.7 Furthermore, a large retrospective cohort study comparing endophthalmitis rate between intravitreal injections of compounded bevacizumab and intravitreal injections of ranibizumab (Lucentis; Genentech) drawn from single-use vials has not found any difference in endophthalmitis rate.8 Although concerns over the functional stability and sterility of compounded bevacizumab have been
addressed, similar data for ranibizumab and aflibercept (Eylea; Regeneron, Tarrytown, N.Y.; Bayer Healthcare, Leverkusen, Germany) are lacking. The Provincial Retinal Diseases Program in British Columbia, Canada, is a government-funded program that supplies anti-vascular endothelial growth factor (VEGF) drugs to retina specialists in this province. As part of this program, all 3 antiVEGF drugs are compounded from single-use glass vials into multiple prefilled plastic syringes by a compounding pharmacy and stored at 41C until used. Since the inception of the program in 2009, single-use vials of bevacizumab have been compounded into 80 plastic syringes (1.25 mg in 50 μL per syringe), and single-use vials of ranibizumab have been compounded into 3 plastic syringes (0.50 mg in 50 μL per syringe). Aflibercept, which became available in 2015, is compounded from single-use vials into 3 plastic syringes (2.0 mg in 50 μL per syringe). We have recently shown that both ranibizumab and aflibercept, similar to bevacizumab, maintain their functional activity in vitro when compounded and stored in refrigerated plastic syringes for up to 4 weeks.9 The purpose of this study was to address concerns over the sterility of compounded ranibizumab and aflibercept by
& 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.04.016 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
Endophthalmitis rates after intravitreal injection—Forooghian et al. Table 1—Characteristics of suspected endophthalmitis cases Age, y 84 68 70 58 72 58 35 94 71 71 82 93 86 89 68 81 85 81 33 82 69 60 90 90 86 82
Sex
Drug
Indication
Gram Stain
Culture
F F F F F F F M F M F F F F M M M F F F M M F F F M
Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Ranibizumab Ranibizumab Aflibercept Aflibercept
AMD RVO AMD RVO RVO RVO PIC/CNV AMD AMD AMD AMD AMD AMD AMD DME AMD AMD DME DME AMD RVO DME AMD AMD AMD AMD
Gram-positive cocci Negative Negative Gram-negative bacilli Negative Negative Negative Negative Negative Gram-positive cocci Gram-positive cocci Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Gram-positive cocci Negative Negative Negative
Coagulase-negative Staphylococcus No growth Staphylococcus epidermidis Haemophilus influenzae No growth No growth Staphylococcus epidermidis No growth No growth Coagulase-negative Staphylococcus Staphylococcus epidermidis No growth No growth No growth No growth Staphylococcus epidermidis, Bacillus species No growth Staphylococcus epidermidis No growth No growth No growth No growth Staphylococcus epidermidis Bacillus species No growth Staphylococcus epidermidis
AMD, age-related macular degeneration; RVO, retinal venous occlusion; DME, diabetic macular edema; PIC, punctate inner choroidopathy; CNV, choroidal neovascularization
examining the rates of clinical endophthalmitis secondary to these medications.
METHODS We performed a retrospective chart review of all patients seen by the authors, whose medical/surgical retina practice serves the Greater Vancouver Region. The date range for the chart review was June 1, 2009, to November 30, 2016. During this time period, povidone–iodine 5% was routinely applied to the conjunctiva before injection. Post-injection topical antibiotics were used routinely until 2010, after which they were no longer used. Topical antibiotics were also used in patients who refused povidone–iodine 5% because of intolerance. A sterile speculum and topical tetracaine 1% minims were used for all injections. Face masks, gloves, and lids scrubs with povidone–iodine 10% were not used during injection procedures. Suspected endophthalmitis cases were identified based on prescriptions for intravitreal antibiotics (vancomycin and ceftazidime/amikacin). We obtained a list of all patients who received these antibiotics during our time window from the inpatient pharmacy at Vancouver General Hospital (VGH), where all intravitreal antibiotics for our practice are prepared. We then performed an extensive chart review to identify all cases of suspected endophthalmitis that had intravitreal anti-VEGF injection at our practice within 1 week of endophthalmitis presentation. Patients with any other ocular procedures performed within 1 month of endophthalmitis presentation were excluded. Furthermore, we excluded patients who presented with endophthalmitis within 24 hours of
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
anti-VEGF injection, as these were presumed to represent cases of sterile endophthalmitis. Data collected from charts included age, sex, indication for anti-VEGF treatment, anti-VEGF drug injected, vitreous gram stain result, and vitreous culture results. The total number of each type of anti-VEGF drug was also collected. Incidence rates of endophthalmitis were calculated for each drug and compared using χ2 analysis (version 6.0; GraphPad Software, La Jolla, Calif.). The Research Ethics Board at the University of British Columbia approved this study.
RESULTS We reviewed the charts of 550 patients who received intravitreal antibiotics prepared by VGH pharmacy during the 6.5-year time period of this study. A total of 291 of these suspected endophthalmitis cases were patients from our practice. Four cases of suspected endophthalmitis were excluded because of presentation within 24 hours of antiVEGF injection. All of these excluded cases had negative vitreous gram stains, had no growth on vitreous cultures, Table 2—Incidence rates of suspected and culture-positive endophthalmitis after compounded intravitreal administration of bevacizumab, ranibizumab, and aflibercept Injections Suspected endophthalmitis Bevacizumab 54 101 Ranibizumab 5 614 Aflibercept 3 468 Culture-positive endophthalmitis Bevacizumab 54 101 Ranibizumab 5 614 Aflibercept 3 468
Cases
Incidence (95% CI)
22 2 2
0.041% (0.026–0.062) 0.036% (0.0043–0.13) 0.06% (0.007–0.2)
9 1 1
0.017% (0.0076–0.032) 0.02% (0.0005–0.1) 0.03% (0.0007–0.2)
Endophthalmitis rates after intravitreal injection—Forooghian et al. and were injected with bevacizumab. A total of 26 cases of suspected endophthalmitis were identified from the 291 cases that we reviewed. Of these, 11 were confirmed to be culture positive. Two cases (1 culture-negative after bevacizumab and 1 culture-positive after aflibercept) occurred in patients who refused povidone–iodine 5%. A summary of the cases is shown in Table 1, and the results of our study are shown in Table 2. There was no statistically significant difference in endophthalmitis rate among the 3 different compounded anti-VEGF drugs with respect to both overall suspected endophthalmitis rate (p ¼ 0.87) and culturepositive endophthalmitis rate (p ¼ 0.87).
DISCUSSION The results of our study suggest that compounding of ranibizumab and aflibercept for intravitreal use is a safe practice. The observed rate of endophthalmitis for these drugs in our study was not statistically different from that of bevacizumab. Furthermore, the rates that we observed are consistent with those of large clinical trials (0.06%; 95% CI: 0.03–0.11)10 and the largest meta-analyses of endophthalmitis after anti-VEGF injection (0.056%; 95% CI: 0.049–0.065).11 These results have potential implications for reducing drug costs for anti-VEGF treatment. Ranibizumab and aflibercept are not cost-effective compared with bevacizumab.12,13 The compounding of these drugs as part of our provincial drug program has made these drugs available to patients in British Columbia through our publicly funded health care system. Other health care regions in the world could consider implementation of a similar anti-VEGF medication-compounding program to help reduce costs. Two of our cases occurred in patients who refused povidone–iodine 5% because of intolerance. This likely increased the chances of developing endophthalmitis in these cases.14 In cases in which patients refuse this form of antisepsis, an alternative agent such as aqueous chlorhexidine needs to be considered.15 Although our study supports the compounding of ranibizumab and aflibercept for intravitreal use, several caveats need to be heeded. To our knowledge, this is the first study to examine endophthalmitis rates after compounded intravitreal ranibizumab and aflibercept. The total number of injections for ranibizumab and aflibercept were approximately 10% and 5%, respectively, that of bevacizumab. Our study may have been underpowered to detect small differences in endophthalmitis rates among these 3 compounded anti-VEGF drugs. Thus, our results will need further validation with larger sample sizes. The final caveat is that the compounding of ranibizumab and aflibercept from single-use vials violates the manufacturer’s recommended usage guidelines for these drugs. Our experience in British Columbia, where no endophthalmitis outbreaks have been reported, as well as the results of our current study and the previous study,9
suggest that the compounding of these medications for intravitreal use is safe and effective. REFERENCES 1. Bakri SJ, Snyder MR, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing. Retina. 2006;26:519-22. 2. Khalili H, Sharma G, Froome A, Khaw PT, Brocchini S. Storage stability of bevacizumab in polycarbonate and polypropylene syringes. Eye (Lond). 2015;29:820-7. 3. Signorello L, Pucciarelli S, Bonacucina G, et al. Quantification, microbial contamination, physico-chemical stability of repackaged bevacizumab stored under different conditions. Curr Pharm Biotechnol. 2014;15:113-9. 4. Chen YH, Wu PC, Shiea J, Lo LH, Wu YC, Kuo HK. Evaluation of the sterility, stability, and efficacy of bevacizumab stored in multipledose vials for 6 months. J Ocul Pharmacol Ther. 2009;25:65-9. 5. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. JAMA Ophthalmol. 2013;131:864-9. 6. Goldberg RA, Flynn HW Jr., Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120:1448-53. 7. Yannuzzi NA, Klufas MA, Quach L, et al. Evaluation of compounded bevacizumab prepared for intravitreal injection. JAMA Ophthalmol. 2015;133:32-9. 8. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133:1159-64. 9. Cao S, Cui J, Matsubara J, Forooghian F. Long-term in vitro functional stability of compounded ranibizumab and aflibercept. Can J Ophthalmol. In press. 10. Meredith TA, McCannel CA, Barr C, et al. Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2015;122:817-21. 11. Fileta JB, Scott IU, Flynn HW Jr.. Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retin. 2014;45:143-9. 12. Ross EL, Hutton DW, Stein JD, et al. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. JAMA Ophthalmol. 2016;134:888-96. 13. Stein JD, Newman-Casey PA, Mrinalini T, Lee PP, Hutton DW. Costeffectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration. Ophthalmology. 2014;121:936-45. 14. Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE 2nd, Eliott D. Endophthalmitis after intravitreal injections in patients with selfreported iodine allergy. Am J Ophthalmol. 2016;170:68-74. 15. Merani R, McPherson ZE, Luckie AP, et al. Aqueous chlorhexidine for intravitreal injection antisepsis: a case series and review of the literature. Ophthalmology. 2016;123:2588-94.
Footnotes and Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. From the Department of Ophthalmology, University of British Columbia, Vancouver, B.C. Originally received Feb. 28, 2017. Accepted Apr. 23, 2017. Correspondence to Farzin Forooghian, MD, FRCSC, Department of Ophthalmology, St. Paul’s Hospital, 1081 Burrard St., Vancouver, B.C. V6Z 1Y6; [email protected].
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
3
The off-label use of compounded intravitreal bevacizumab (Avastin; Genentech, San Francisco, Calif.) has become part of standard of care in retina practices around the world. The compounding and subsequent refrigerated storage of this medication in plastic syringes has raised concerns over its functional stability and the potential for microbial contamination. Numerous in vitro studies have demonstrated that the functional stability of compounded bevacizumab is maintained for up to 6 months when this medication is stored in refrigerated conditions.1–4 Concerns over sterility have been prompted by reports of isolated outbreaks of endophthalmitis after intravitreal injection of bevacizumab.5,6 However, laboratory analysis of compounded plastic syringes of bevacizumab has not shown evidence of bacterial or endotoxin contamination.7 Furthermore, a large retrospective cohort study comparing endophthalmitis rate between intravitreal injections of compounded bevacizumab and intravitreal injections of ranibizumab (Lucentis; Genentech) drawn from single-use vials has not found any difference in endophthalmitis rate.8 Although concerns over the functional stability and sterility of compounded bevacizumab have been
addressed, similar data for ranibizumab and aflibercept (Eylea; Regeneron, Tarrytown, N.Y.; Bayer Healthcare, Leverkusen, Germany) are lacking. The Provincial Retinal Diseases Program in British Columbia, Canada, is a government-funded program that supplies anti-vascular endothelial growth factor (VEGF) drugs to retina specialists in this province. As part of this program, all 3 antiVEGF drugs are compounded from single-use glass vials into multiple prefilled plastic syringes by a compounding pharmacy and stored at 41C until used. Since the inception of the program in 2009, single-use vials of bevacizumab have been compounded into 80 plastic syringes (1.25 mg in 50 μL per syringe), and single-use vials of ranibizumab have been compounded into 3 plastic syringes (0.50 mg in 50 μL per syringe). Aflibercept, which became available in 2015, is compounded from single-use vials into 3 plastic syringes (2.0 mg in 50 μL per syringe). We have recently shown that both ranibizumab and aflibercept, similar to bevacizumab, maintain their functional activity in vitro when compounded and stored in refrigerated plastic syringes for up to 4 weeks.9 The purpose of this study was to address concerns over the sterility of compounded ranibizumab and aflibercept by
& 2017 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2017.04.016 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
1
Endophthalmitis rates after intravitreal injection—Forooghian et al. Table 1—Characteristics of suspected endophthalmitis cases Age, y 84 68 70 58 72 58 35 94 71 71 82 93 86 89 68 81 85 81 33 82 69 60 90 90 86 82
Sex
Drug
Indication
Gram Stain
Culture
F F F F F F F M F M F F F F M M M F F F M M F F F M
Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Ranibizumab Ranibizumab Aflibercept Aflibercept
AMD RVO AMD RVO RVO RVO PIC/CNV AMD AMD AMD AMD AMD AMD AMD DME AMD AMD DME DME AMD RVO DME AMD AMD AMD AMD
Gram-positive cocci Negative Negative Gram-negative bacilli Negative Negative Negative Negative Negative Gram-positive cocci Gram-positive cocci Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Gram-positive cocci Negative Negative Negative
Coagulase-negative Staphylococcus No growth Staphylococcus epidermidis Haemophilus influenzae No growth No growth Staphylococcus epidermidis No growth No growth Coagulase-negative Staphylococcus Staphylococcus epidermidis No growth No growth No growth No growth Staphylococcus epidermidis, Bacillus species No growth Staphylococcus epidermidis No growth No growth No growth No growth Staphylococcus epidermidis Bacillus species No growth Staphylococcus epidermidis
AMD, age-related macular degeneration; RVO, retinal venous occlusion; DME, diabetic macular edema; PIC, punctate inner choroidopathy; CNV, choroidal neovascularization
examining the rates of clinical endophthalmitis secondary to these medications.
METHODS We performed a retrospective chart review of all patients seen by the authors, whose medical/surgical retina practice serves the Greater Vancouver Region. The date range for the chart review was June 1, 2009, to November 30, 2016. During this time period, povidone–iodine 5% was routinely applied to the conjunctiva before injection. Post-injection topical antibiotics were used routinely until 2010, after which they were no longer used. Topical antibiotics were also used in patients who refused povidone–iodine 5% because of intolerance. A sterile speculum and topical tetracaine 1% minims were used for all injections. Face masks, gloves, and lids scrubs with povidone–iodine 10% were not used during injection procedures. Suspected endophthalmitis cases were identified based on prescriptions for intravitreal antibiotics (vancomycin and ceftazidime/amikacin). We obtained a list of all patients who received these antibiotics during our time window from the inpatient pharmacy at Vancouver General Hospital (VGH), where all intravitreal antibiotics for our practice are prepared. We then performed an extensive chart review to identify all cases of suspected endophthalmitis that had intravitreal anti-VEGF injection at our practice within 1 week of endophthalmitis presentation. Patients with any other ocular procedures performed within 1 month of endophthalmitis presentation were excluded. Furthermore, we excluded patients who presented with endophthalmitis within 24 hours of
2
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
anti-VEGF injection, as these were presumed to represent cases of sterile endophthalmitis. Data collected from charts included age, sex, indication for anti-VEGF treatment, anti-VEGF drug injected, vitreous gram stain result, and vitreous culture results. The total number of each type of anti-VEGF drug was also collected. Incidence rates of endophthalmitis were calculated for each drug and compared using χ2 analysis (version 6.0; GraphPad Software, La Jolla, Calif.). The Research Ethics Board at the University of British Columbia approved this study.
RESULTS We reviewed the charts of 550 patients who received intravitreal antibiotics prepared by VGH pharmacy during the 6.5-year time period of this study. A total of 291 of these suspected endophthalmitis cases were patients from our practice. Four cases of suspected endophthalmitis were excluded because of presentation within 24 hours of antiVEGF injection. All of these excluded cases had negative vitreous gram stains, had no growth on vitreous cultures, Table 2—Incidence rates of suspected and culture-positive endophthalmitis after compounded intravitreal administration of bevacizumab, ranibizumab, and aflibercept Injections Suspected endophthalmitis Bevacizumab 54 101 Ranibizumab 5 614 Aflibercept 3 468 Culture-positive endophthalmitis Bevacizumab 54 101 Ranibizumab 5 614 Aflibercept 3 468
Cases
Incidence (95% CI)
22 2 2
0.041% (0.026–0.062) 0.036% (0.0043–0.13) 0.06% (0.007–0.2)
9 1 1
0.017% (0.0076–0.032) 0.02% (0.0005–0.1) 0.03% (0.0007–0.2)
Endophthalmitis rates after intravitreal injection—Forooghian et al. and were injected with bevacizumab. A total of 26 cases of suspected endophthalmitis were identified from the 291 cases that we reviewed. Of these, 11 were confirmed to be culture positive. Two cases (1 culture-negative after bevacizumab and 1 culture-positive after aflibercept) occurred in patients who refused povidone–iodine 5%. A summary of the cases is shown in Table 1, and the results of our study are shown in Table 2. There was no statistically significant difference in endophthalmitis rate among the 3 different compounded anti-VEGF drugs with respect to both overall suspected endophthalmitis rate (p ¼ 0.87) and culturepositive endophthalmitis rate (p ¼ 0.87).
DISCUSSION The results of our study suggest that compounding of ranibizumab and aflibercept for intravitreal use is a safe practice. The observed rate of endophthalmitis for these drugs in our study was not statistically different from that of bevacizumab. Furthermore, the rates that we observed are consistent with those of large clinical trials (0.06%; 95% CI: 0.03–0.11)10 and the largest meta-analyses of endophthalmitis after anti-VEGF injection (0.056%; 95% CI: 0.049–0.065).11 These results have potential implications for reducing drug costs for anti-VEGF treatment. Ranibizumab and aflibercept are not cost-effective compared with bevacizumab.12,13 The compounding of these drugs as part of our provincial drug program has made these drugs available to patients in British Columbia through our publicly funded health care system. Other health care regions in the world could consider implementation of a similar anti-VEGF medication-compounding program to help reduce costs. Two of our cases occurred in patients who refused povidone–iodine 5% because of intolerance. This likely increased the chances of developing endophthalmitis in these cases.14 In cases in which patients refuse this form of antisepsis, an alternative agent such as aqueous chlorhexidine needs to be considered.15 Although our study supports the compounding of ranibizumab and aflibercept for intravitreal use, several caveats need to be heeded. To our knowledge, this is the first study to examine endophthalmitis rates after compounded intravitreal ranibizumab and aflibercept. The total number of injections for ranibizumab and aflibercept were approximately 10% and 5%, respectively, that of bevacizumab. Our study may have been underpowered to detect small differences in endophthalmitis rates among these 3 compounded anti-VEGF drugs. Thus, our results will need further validation with larger sample sizes. The final caveat is that the compounding of ranibizumab and aflibercept from single-use vials violates the manufacturer’s recommended usage guidelines for these drugs. Our experience in British Columbia, where no endophthalmitis outbreaks have been reported, as well as the results of our current study and the previous study,9
suggest that the compounding of these medications for intravitreal use is safe and effective. REFERENCES 1. Bakri SJ, Snyder MR, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing. Retina. 2006;26:519-22. 2. Khalili H, Sharma G, Froome A, Khaw PT, Brocchini S. Storage stability of bevacizumab in polycarbonate and polypropylene syringes. Eye (Lond). 2015;29:820-7. 3. Signorello L, Pucciarelli S, Bonacucina G, et al. Quantification, microbial contamination, physico-chemical stability of repackaged bevacizumab stored under different conditions. Curr Pharm Biotechnol. 2014;15:113-9. 4. Chen YH, Wu PC, Shiea J, Lo LH, Wu YC, Kuo HK. Evaluation of the sterility, stability, and efficacy of bevacizumab stored in multipledose vials for 6 months. J Ocul Pharmacol Ther. 2009;25:65-9. 5. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. JAMA Ophthalmol. 2013;131:864-9. 6. Goldberg RA, Flynn HW Jr., Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120:1448-53. 7. Yannuzzi NA, Klufas MA, Quach L, et al. Evaluation of compounded bevacizumab prepared for intravitreal injection. JAMA Ophthalmol. 2015;133:32-9. 8. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133:1159-64. 9. Cao S, Cui J, Matsubara J, Forooghian F. Long-term in vitro functional stability of compounded ranibizumab and aflibercept. Can J Ophthalmol. In press. 10. Meredith TA, McCannel CA, Barr C, et al. Postinjection endophthalmitis in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology. 2015;122:817-21. 11. Fileta JB, Scott IU, Flynn HW Jr.. Meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retin. 2014;45:143-9. 12. Ross EL, Hutton DW, Stein JD, et al. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the Diabetic Retinopathy Clinical Research Network Comparative Effectiveness Trial. JAMA Ophthalmol. 2016;134:888-96. 13. Stein JD, Newman-Casey PA, Mrinalini T, Lee PP, Hutton DW. Costeffectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration. Ophthalmology. 2014;121:936-45. 14. Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE 2nd, Eliott D. Endophthalmitis after intravitreal injections in patients with selfreported iodine allergy. Am J Ophthalmol. 2016;170:68-74. 15. Merani R, McPherson ZE, Luckie AP, et al. Aqueous chlorhexidine for intravitreal injection antisepsis: a case series and review of the literature. Ophthalmology. 2016;123:2588-94.
Footnotes and Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. From the Department of Ophthalmology, University of British Columbia, Vancouver, B.C. Originally received Feb. 28, 2017. Accepted Apr. 23, 2017. Correspondence to Farzin Forooghian, MD, FRCSC, Department of Ophthalmology, St. Paul’s Hospital, 1081 Burrard St., Vancouver, B.C. V6Z 1Y6; [email protected].
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2017
3