Letters to the Editor
`
`Endophthalmitis After Anti-VEGF
`Injections
`
`Dear Editor:
`lntravitreal injections of anti-vascular endothelial growth
`factor (VEGF) agents have become the standard of care for
`the treatment of neovascular age-related macular degenera(cid:173)
`tion. They are increasingly being used to treat other types of
`choroidal neovascularization and retinal vascular diseases.
`Endophthalmitis is the most dreaded complication of intravit(cid:173)
`real injection. Several studies have reported on the incidence of
`endophthalmitis after intravitreal injection. l-5 Unfortunately,
`little data exist regarding outcomes of endophthalmitis after
`intravitreal injection of anti-VEGF agents.
`We have examined a cohort of 30,736 injections-128
`pegaptanib, 8039 bevacizumab, and 22,579 ranibizumab(cid:173)
`performed in 5 community-based retinal practices around
`the country between August I, 2006 and July 31, 2007. We
`identified 15 cases of presumed endophthalmitis (Table I,
`available online at http://aaojournal.org) from these 30,736
`injections (0.049%; 0.03- 0.08% 95% confidence interval
`[Cl]). Five of these cases followed injections of bevaci(cid:173)
`zumab (5/8039 = 0.062%; 0.02- 0. 15% 95% Cl), IO fol(cid:173)
`lowed injections of ranibizumab (10/22579 = 0.044%;
`0.02-0.08% 95% Cl), and none followed injections of pe(cid:173)
`gaptanib (0.00%; 0.00- 2.31 % 95% Cl). Endophthalmitis
`rates for these 3 types of intravitreal injections did not differ
`significantly. As assessed by survey, physicians in our prac(cid:173)
`tices used various intravitreal injection techniques, e.g.,
`some used preinjection topical antibiotics, whereas some
`did not. A lid speculum was used in 14 of the 15 incident
`cases. All used 5%- 10% povidone iodine to cleanse the eye
`before injection.
`Fourteen of 15 endophthalmitis patients were tapped and
`injected intravitreally with vancomycin and ceftazidime.
`One of the 15 patients was tapped then injected intravit(cid:173)
`really with vancomycin only. Four patients also received a
`subtenons injection of triamcinolone acetonide. One patient
`was placed on oral ciprofloxacin, and 2 were placed on oral
`moxifloxacin. Four patients subsequently had vitrectomies.
`Thirteen of these 15 cases were diagnosed within 4 days
`of the intravitreal injection. Mean time to diagnosis was 3.5
`days (range, 1-8 days). Three cases were diagnosed j ust I
`day after injection; 2 of these cases were culture positive.
`Six of 13 (46%) cases were culture positive. Culture data
`were not available for 2 of the cases. Only gram positive
`organisms were isolated: Staphylococcus epidermidis X 3,
`coagulase-negative staphylococcus X I (not speciated),
`Streptococcus salivarius X I , and S. viridans X I.
`Ten of the 15 patients returned to baseline vision (± 1
`line). Two patients lost between 3 and 5 lines of vision. One
`patient dropped from 20/30 to hand motions vision and was
`pre-phthisical. Two patients lost all vision (no light percep(cid:173)
`tion), and I of these patients developed phthisis bulbi.
`Of note, 20% of our patients were diagnosed with pre(cid:173)
`sumed endophthalmitis on the first post-injection day. Two
`of those 3 patients were culture positive. Additionally, 87%
`
`of our cases of endophthalmitis were diagnosed within 4
`days of anti-VEGF injection. Therefore, a high index of
`suspicion for endophthalmitis is necessary in regarding pa(cid:173)
`tient complaints, especially in the first I to 4 days after
`intravitreal injection.
`Anti-VEGF drugs have greatly enhanced our abilities to
`treat neovascular AMO, as well as a host of other retinal
`conditions. Unlike previous treatments such as vertepor(cid:173)
`forin photodynamic therapy, anti-VEGF therapy involves
`injecting medication directly into the vitreous, thus putting
`the eye at risk for endophthalmitis. We have found an
`incidence of presumed endophthalmitis similar to previous
`studies.3•5 Given that we have amassed the largest series
`(based on a recent PubMed search) of endophthalmitis cases
`after intravitreal anti-VEGF injections, we are in a unique
`position to additionally comment on outcomes of these
`endophthalmitis patients. Some earlier reports4 •5 had sug(cid:173)
`gested that patients with endophthalmitis following anti(cid:173)
`VEGF agents do well, typically with a return to baseline
`vision. Unfortunately, this does not seem to be the case in
`our series, in which 2/3 of patients returned to baseline
`vision at last follow-up, but 20% of patients had very poor
`outcomes.
`
`KATHRYN S. KLEIN, MD, MPH
`New York, New York
`
`MARK K. WALSH, MD, PHO
`T AREK S. H ASSAN, MD
`Royal Oak, Michigan
`
`L AWRENCE S. H ALPERIN, MD
`Fort Lauderdale, Fwrida
`
`ALESSANDRO A. CASTELLARIN, MD
`Santa Barbara, California
`
`DANIEL RoTH, MD
`SARAH DRISCOLL, BS
`JONATHAN L. PRENNER, M D
`New Brunswick, New Jersey
`
`References
`
`I. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of
`intravitreous injection: a comprehensive review. Retina 2004;
`24:676- 98.
`2. Rosenfeld PJ, Brown OM, Heier JS, et al. Ranibizumab for
`neovascular age-related macular degeneration. N Engl J Med
`2006;355:1419- 31.
`3. Fintak DR, Shah GK, Blinder KJ, et al. Incidence of endoph(cid:173)
`thalmitis related to intravitreal injection of bevacizumab and
`ranibizumab. Retina 2008;28:1395- 9.
`4. Pilli S, Kotsolis A, Spaide RF, et al. Endophthalmitis
`associated with intravitreal anti-vascular growth factor
`therapy injections in an office setting. Am J Ophthalmol
`2008;145:879 - 82.
`5. Mason JO 3rd, White MF, Feist RM, et al. Incidence of acute
`onset endophthalmitis following intravitreal bevacizumab
`(A vastin) injection. Retina 2008;28:564- 7.
`
`1225
`
`Novartis Exhibit 2312.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Ophthalmology Volume 116, Number 6, June 2009
`
`Table 1. Presumed Endophthalmitis after Intravitreal Anti-VEGF Injection Patient Data
`
`Dz
`
`Time to Presentation
`
`Culture
`
`PPV
`
`Pre-Rx VA
`
`Final VA
`
`AMD
`AMD
`AMD
`AMD
`AMD
`AMD
`Myopic CNV
`AMD
`AMD
`AMD
`AMD
`AMD
`AMD
`AMD
`AMD
`
`2 days
`2 days
`1 day
`1 day
`1 day
`2 days
`3 days
`8 days
`5 days
`3 days
`4 days
`4 days
`4 days
`2 days
`2 days
`
`No growth
`No growth
`S. salivarius
`No growth
`S. viridans
`S. epi
`S. epi
`S. epi
`No growth
`Coag neg staph
`N/A
`No growth
`No growth
`N/A
`No growth
`
`No
`No
`Yes
`No
`Yes
`No
`No
`No
`No
`No
`No
`Yes
`No
`No
`Yes
`
`20/40
`20/50
`10/200
`20/160
`20/30
`CF
`20/30
`20/40
`20/400
`20/50
`20/60
`20/150
`20/200
`20/400
`20/150
`
`20/40
`20/60
`5/200
`20/160
`HM
`CF
`20/60
`20/40
`20/200
`20/60
`20/200
`20/200
`20/400
`NLP
`NLP
`
`F/U
`
`1 mo
`1 mo
`1 mo
`1 mo
`6 wk
`2 mo
`6 mo
`1 wk
`3 wk
`1 y
`3 mo
`7 mo
`11 mo
`6 mo
`1 mo
`
`Pt
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`
`Medication
`
`bevacizumab
`bevacizumab
`bevacizumab
`ranibizumab
`bevacizumab
`ranibizumab
`bevacizumab
`ranibizumab
`ranibizumab
`ranibizumab
`ranibizumab
`ranibizumab
`ranibizumab
`ranibizumab
`ranibizumab
`
`AMD ⫽ age-related macular degeneration; CF ⫽ counting fingers; CNV ⫽ choroidal neovascularization; Coag neg staph ⫽ coagulase-negative
`staphylococcus; Dz ⫽ disease; F/U ⫽ follow-up; HM ⫽ hand motions; N/A ⫽ not available; NLP ⫽ no light perception; PPV ⫽ pars plana vitrectomy;
`Pre-Rx ⫽ pretreatment; Pt ⫽ patient; S. salivarius ⫽ Strep salivarius; S. viridians ⫽ Strep viridans; S. epi ⫽ Staph epidermidis; VA ⫽ visual acuity.
`
`1225.e1
`
`Novartis Exhibit 2312.002
`Regeneron v. Novartis, IPR2021-00816
`
`