Research
`
`JAMA Ophthalmology I Original Investigation
`Association of Acute Endophthalmitis With lntravitreal
`Injections of Corticosteroids or Anti-Vascular Growth Factor
`Agents in a Nationwide Study in France
`
`Florian Baudin, MO; Eric Benzenine, MSc; Anne-Sophie Mariet, MO; Alain M. Bron, MO; Vincent Daien, MD, PhD;
`Jean Fra~ois Korobelnik, MD, PhD; Catherine Quantin, MD, PhD; Catherine Creuzot-Garcher, MD, PhD
`
`GI CMEQuizat
`jamanetwork.corn/learning
`
`IMPORTANCE The number of patients affected by retinal diseases treated with intravitreal
`injections (IVTs) has resulted in a rapidly growing number of procedures. One of the worst
`complications after these injections is endophthalmitis.
`
`OBJECTIVE To evaluate the incidence of acute endophthalmitis after IVTs of corticosteroids or
`anti-vascular endothelial growth factor (anti-VEGF) agents.
`
`DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study included patients
`undergoing IVTs from January 1, 2012, through December 31. 2015, in France. Data were
`acquired from the French medical-administrative database (Systeme National d'lnformation
`Inter-Regime de !'Assurance Maladie). which collects hospitalization discharge abstracts and
`out-of-hospital care information for the whole country. Data were analyzed from March
`through July 2017.
`
`EXPOSURES lntravitreal injections of corticosteroid or anti-VEGF agents.
`
`MAIN OUTCOMES AND MEASURES Incidence of acute endophthalmitis within 6 weeks after
`IVT by means of billing codes from a national database.
`
`RESULTS During the study period, 1811977 IVTs of corticosteroids or anti-VEGF agents
`performed on 254 927 patients (60.4% female; median age, 79 years [interquartile range,
`70-85 years]) were analyzed. A total of 444 acute endophthalmitis cases (crude incidence,
`0.0245%) were recorded. In multivariable analysis, which did not include adjustment for
`when the endophthalmitis occurred during the study period, the risk of endophthalmitis was
`lower in male patients (incidence rate ratio [IRR], 0.78; 95% Cl. 0.63-0.96; P = .02), higher
`for corticosteroids than for anti-VEGF agents (IRR. 3.21; 95% Cl, 2.33-4.44; P < .001), and
`higher for nonprefilled syringes of anti-VEGF medications than prefilled syringes for
`ranibizumab (IRR. 1.63; 95% Cl. 1.15-2.30) and aflibercept (IRR. 1.82; 95% Cl. 1.25-2.66;
`P< .001).
`
`CONCLUSIONS AND RELEVANCE The findings from this study of a nationwide database appear
`to have confirmed the low incidence rate of acute endophthalmitis after IVTs of
`corticosteroids or anti-VEGF agents. Although an association may not necessarily indicate a
`cause and effect. the risk for acute endophthalmitis after IVTs appeared to be higher for
`corticosteroids compared with anti-VEGF agents, while a lower risk of endophthalmitis
`appeared to be found with prefilled syringes of anti-VEGF medications.
`
`JAMA Ophthalmol. 2018:136(12):1352-1358. doi:10.1001/jamaophthalmol.20183939
`Published online September 13, 2018.
`
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`© 2018 American Medical Association. All rights reserved.
`
`Author Afflllatlons: Author
`affiliations are listed at the end of this
`article.
`Corresponding Author: Catherine
`Creuzot-Garcher, MD, PhD,
`Department of Ophthalmology, Dijon
`University Hospital, 14 rue Paul
`Gaffarel, 21000 Dijon, France
`(catherlne.creuzot-garcher
`@chu-dlJon.fr).
`
`Jamaophthalmology.com
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`

`Association of Acute Endophthalmitis With Intravitreal Injections
`
`Original Investigation Research
`
`T he number of patients affected by retinal diseases, the
`
`efficacy of anti–vascular endothelial growth factor (anti-
`VEGF) agents or corticosteroids, and their expanding in-
`dications have resulted in a rapidly growing number of intra-
`vitreal injections (IVTs).1 Ranibizumab (0.5 mg/0.05 mL
`[Lucentis; Novartis Pharma SAS]), bevacizumab (1.25 mg/
`0.05 mL [Avastin; Roche]), and aflibercept (2 mg/0.05 mL [Ey-
`lea; Bayer HealthCare]) have been used for the treatment of sev-
`eral retinal diseases, including exudative age-related macular
`degeneration, diabetic macular edema, and retinal vein
`occlusion.2,3 Triamcinolone acetonide (4 mg/0.1 mL [Kena-
`cort; Bristol-Myers Squibb]) and dexamethasone implant (0.7
`mg [Ozurdex; Allergan SAS]) are the 2 corticosteroid agents
`used in France for the treatment of diabetic macular edema,4
`retinal vein occlusion edema,5 and noninfectious intermedi-
`ate or posterior uveitis.6
`Acute endophthalmitis is one of the worst sight-
`threatening complications after IVTs. Its incidence is low, rang-
`ing from 0.02% to 0.08%.7-10 Among factors influencing en-
`dophthalmitis occurrence, previous studies suggested
`associations with the class of medication,11 topical antibiotic
`prophylaxis,12,13 and types 1 and 2 diabetes.11,14 However, ow-
`ing to the low rate of endophthalmitis, even large observa-
`tional studies are not sufficiently powered to analyze factors
`associated with this complication. 8 , 1 0 , 1 5 Medical-
`administrative databases (collecting all reimbursement claims,
`including hospital and out-of-hospital care) could overcome
`these limitations, providing more events to collect. The use of
`this type of database provides information at the scale of an
`entire country and, used with caution, could help decipher the
`associations between different events.16-18 In the present study,
`we aimed to assess the incidence and factors associated with
`acute endophthalmitis after IVTs of corticosteroids or anti-
`VEGF agents in France from 2012 to 2015.
`
`Methods
`Data Source
`This study is part of the French Epidemiology and Safety collab-
`orativeprogramdesignedtoassesstheepidemiologyandsafety
`of interventions in ophthalmology.19 The French medical-
`administrativedatabase(SystèmeNationald’InformationInter-
`régime de l’Assurance Maladie [SNIIRAM]) collects data for the
`whole country (ie, 66 million inhabitants). Briefly, this database
`containsthefullcoverageofhealthexpenditures,includinghos-
`pitalizationdischargeabstracts(withmedicaldiagnoses)andout-
`of-hospitalcare(visits,procedures,anddrugs).TheSNIIRAMwas
`created to link all interscheme and hospital outpatient claim re-
`imbursements of the French population with the national hos-
`pital discharge abstract database. After 2007, data were linked
`over time to allow for longitudinal analyses. The high quality of
`this database has previously been evaluated and has been used
`in several epidemiologic studies.16,18,20,21 This study adhered to
`thetenetsoftheDeclarationofHelsinki.22Thepresentstudywas
`approvedbytheFrenchInstituteofHealthDataandbytheFrench
`data protection authority, which did not require informed con-
`sent for the use of registry data.
`
`Key Points
`Question What are the risk factors of acute endophthalmitis after
`intravitreal injections of corticosteroids or anti–vascular
`endothelial growth factor agents?
`
`Findings In this population-based study that included 254 927
`patients, the risk of endophthalmitis was higher for patients who
`received corticosteroid injections than for those who received
`anti–vascular endothelial growth factor agents (incidence rate
`ratio, 3.21) and higher for those who received nonprefilled syringes
`of anti–vascular endothelial growth factor medications than
`prefilled syringes (incidence rate ratios, 1.63 for ranibizumab and
`1.82 for aflibercept).
`
`Meaning Although an association may not indicate cause and
`effect, these data suggest the use of prefilled anti–vascular
`endothelial growth factor syringes could lower the already very
`low risk of acute endophthalmitis.
`
`Data Extraction
`The data set available for this study included all patients in the
`database who received at least 1 IVT from January 1, 2012,
`through December 31, 2015. Data were not included when a
`look-back period or a follow-up of 42 days was not available
`or when the patient died within the 42-day follow-up period.
`As a result, only index dates from February 12, 2012, through
`November 19, 2015, were considered. Intravitreal injections
`were tracked with the billing code for IVT (BGLB001). The date
`of the injection was used as the index date. A diagnosis of en-
`dophthalmitis was identified with the billing codes H440 or
`H441 from the International Statistical Classification of Dis-
`eases and Related Health Problems, Tenth Revision, within 42
`days after the injection index date.23 Data from injections that
`were related to surgical procedures with an occurrence of en-
`dophthalmitis within 6 weeks were censored and were not in-
`cluded in the analysis. All cases of endophthalmitis occurring
`within 6 weeks after an ocular operation were excluded from
`the analysis. The type of injected medication (corticosteroid
`or anti-VEGF agent), the type of packaging, and topical anti-
`biotic prescriptions were obtained from the records of medi-
`cations delivered and identified through the database. Pa-
`tients having any hospital discharge code mentioning diabetes
`as the main or associated diagnosis, repeated deliveries of the
`antidiabetic drug for more than 3 months, or a diabetes-
`related long-term disease reimbursement code were identi-
`fied as having diabetes.17 Insulin-treated diabetes was deter-
`mined by entries concerning continuous insulin deliveries.
`
`Statistical Analysis
`Data were analyzed from March through July 2017. Most of the
`continuous variables did not follow a normal distribution ac-
`cording to a Kolmogorov-Smirnov normality test. Therefore,
`median (interquartile range [IQR]) was provided for continu-
`ous variables, and nonparametric tests were used for compari-
`son. For categorical variables, numbers (percentage) were pro-
`vided and the χ2 test was performed to compare percentages.
`We estimated incidence rates as the number of events per 100
`
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`Research Orlglnal Investigation
`
`Association of Acute Endophthalmitis With lntravitreal Injections
`
`injection procedures. Incidence rate ratios (IRRs) were esti(cid:173)
`mated using a Poisson regression. We analyzed first the asso(cid:173)
`ciations between the variables studied and endophthalmitis
`using a univariate Poisson regression. Multivariable Poisson
`regressions were then performed, adjusting for potential con(cid:173)
`founders that included sex, age, diabetes, drug, drug prepa(cid:173)
`ration, and topical antibiotic prophylaxis. Analyses were based
`on repeated-measures Poisson regression models accounting
`for dependencies between repeated observations on the same
`study patient. In these models, the association between the
`variables studied and the outcome was estimated using IRRs
`and the corresponding 95% Cis. Statistical significance was set
`at P < .05 (2-tailed tests). All data processing and statistical
`analyses were performed using the SAS statistical analysis soft(cid:173)
`ware package (version 9.4; SAS Institute, Inc).
`
`Results
`
`From 2012 to 2015, 1959 462 IVTs were performed. A total of
`1811 977 IVTs from 254 927 patients (60.4% female and 39.6%
`male; median age, 79 years [IQR, 70-85 years]) were retained
`for analysis after excluding IVTs with an insufficient look(cid:173)
`back period or lacking 42 days of follow-up and those IVTs con-
`
`Table 1. Baseline Demographics of Patients With IVTs
`of Corticosteroids or Anti-VEGF Agents From 2012 to 2015
`
`Characteristic
`Age, median (IQR), y
`Female, No. (%}
`
`No. of injections, median (IQR)
`Follow-up, median (IQR), d
`Diabetes, No. (%}
`
`All
`Type 1
`
`Patient Data (n = 254 927)
`79 (70-85)
`153 976 (60.4)
`5 (3-10)
`302 (63-277)
`
`68 604 (26.9)
`31512 {45.9)
`
`Abbreviations: IQR, interquartile range: IVT, intravitreal injection,
`VEGF, vascular endothelial growth factor.
`
`comitant with ocular surgery (Table 1). Most IVTs were anti(cid:173)
`VEGF injections, accounting for 92.7%ofall procedures,3.7%
`were corticosteroids, and 3.6% were not identified in the da(cid:173)
`tabase. The most frequently injected agent was ranibizumab
`(70.9% of all injections), followed by aflibercept (21.6%). Pa(cid:173)
`tients receiving IVTs with corticosteroids were younger than
`those receiving anti-VEGF agents (median age, 73 years [IQR,
`64-80 years] vs 80 years [IQR, 72-85 years]; P < .001) and were
`more likely to have diabetes (34.6% [n = 22 326] vs 25.1%
`[n = 421858]; P < .001). Topical antibiotic prophylaxis was
`given in 73.6% of all injections, the most prescribed antibi(cid:173)
`otic class beingmacrolides (63.2% [n = 843 484]), followed by
`fluoroquinolones (18.2% [n = 242 098]) and aminoglyco(cid:173)
`sides (13.9% [n = 185 066]). Combination medications with a
`corticosteroid and antibiotic were administered to 4.4% of the
`patients (n = 58 444).
`During the study period, we recorded 444 endophthalrni(cid:173)
`tis cases of 1811 977 IVTs (1 of 4082 injections; crude inci(cid:173)
`dence, 0.0245%) (Table 2). The incidence of endophthalmitis
`after anti-VEGF and corticosteroid injections was 0.0204%and
`0.0667%, respectively. Patients with endophthalmitis after cor(cid:173)
`ticosteroid IVTs were younger than those infected after anti(cid:173)
`VEGF IVTs (median age, 73 years [IQR, 65-80 years] vs 79 years
`[IQR, 71-84 years]; P < .001). No statistical differences were
`found for age, sex, and diabetes when considering IVTs with
`or without endophthalmitis. In univariate analysis, acute post(cid:173)
`IVT endophthalrnitis was more likely to occur in younger pa(cid:173)
`tients. An injection performed among patients older than 85
`years was associated with a decreased IRR of endophthalmi(cid:173)
`tis compared with patients younger than 70 years (IRR, 0.64;
`95% CI, 0.48-0.84). Associations were also found for patients
`receiving corticosteroid IVTs (IRR, 3.26; 95% CI, 2.38-4.48) and
`those with nonprefilled anti-VEGF syringes (vs prefilled ra(cid:173)
`nibizumab) (IRR for nonprefilled ranibizumab, 1.60 [95% CI,
`1.14-2.25]; IRR for aflibercept, 1.80 [95% CI, 1.24-2.61]) and, at
`the beginning of the study period, injections performed in 2013
`and 2014 were at higher risk than in 2012 (IRRs, 1.43-1.67;
`P < .01) (Table 3). In multivariable analysis, acute endophthal-
`
`Table 2. Acute Endophthalmitis Incidence After IVTs of Corticosteroids or Anti·VEGF Agents from 2012 to 2015
`
`Variable
`Agent
`Aflibercept (2.00 mg/ 0.05 ml)
`Bevac izumab (1.25 mg/0.05 ml)
`Ranibizumab (0.50 mg/0.05 ml)
`Nonprefilled
`Prefilled
`Dexamethasone implant
`Triamcinolone acetonide
`Unknown
`Yea r
`
`2012
`2013
`2014
`
`2015
`
`No. of lntravltreal Inject ions
`Without Endophthalmltls With Enclophthalmltls Crude Incidence,%
`
`392 082
`2 592
`1284 785
`
`969 790
`314 995
`
`60689
`3747
`
`67 638
`
`266313
`473 544
`543 432
`528244
`
`94
`
`0
`249
`
`207
`42
`41
`
`2
`58
`
`47
`
`139
`137
`121
`
`0.0240
`
`0
`0.0194
`
`0.0213
`0.0133
`0.0676
`0.0533
`0.0858
`
`0.0176
`0.0293
`0.0252
`0.0229
`
`Abbreviations: IVT, intravitreal
`injection, VEGF, vascular endothelial
`growth factor.
`
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`Association of Acute Endophthalmitis With lntravitreal Injections
`
`Original Investigation Research
`
`Table 3. Univariate Analysis of Factors Associated
`With Acute Endophthalmitis After IVTs of Corticosteroids
`or Anti-VEGF Agents From 2012 to 2015
`
`Univariate Poisson Regression
`IRR(95% Cl)
`PValue
`
`mitis after IVTs was more likely to occur in female patients (IRR,
`1.28; 95% CI, 1.04-1.59), those who received corticosteroids
`(IRR, 3.21; 95% CI 2.33-4.44), and those who received nonpre(cid:173)
`filled syringes of anti-VEGF agents, regardless of the drug in(cid:173)
`jected (IRR for ranibizumab, 1.63 [95% CI 1.15-2.30]; IRR for
`aflibercept, 1.82 [95% CI, 1.25-2.66]) (Table 4).
`
`Discussion
`In this study examining a large sample ofIVTs, we observed a
`postinjection endophthalmitis rate of0.0245% (1 of 4082 in(cid:173)
`jections). This rate agrees with those of other reports in which
`rates range from 0.02% to 0.08%.7· 10 After adjusting for agent
`class or type, preparation of the drug (prefilled vs nonpre(cid:173)
`filled syringes), sex, age, use of topical antibiotic prophy(cid:173)
`laxis, and diabetes, an association between endophthalmitis
`incidence and the type of drug injected was found.
`Corticosteroids, and more specifically the dexametha(cid:173)
`sone implant, were associated with more than 3 times more
`endophthalmitis cases than anti-VEG F agents. This finding is
`in line with that of a previous study24 in which a 3-fold higher
`risk of endophthalmitis after triamcinolone injection oc(cid:173)
`curred compared withanti-VEGF administration and amedical(cid:173)
`administrative study (national US medical claims database) that
`found a 7-fold higher risk. 11 Several reasons have been postu(cid:173)
`lated to explain this difference. First, owing to their immuno(cid:173)
`suppressive properties, 25,26 corticosteroids could lead to greater
`susceptibility to bacterial endophthalmitis. 27 Second, the gauge
`of the needle of the dexamethasone implant is larger than that
`of anti-VEGF agents (22-gauge vs 30- or 32-gauge), inducing a
`larger scleral wound, which could lead to a greater risk of bac(cid:173)
`terial penetration in the vitreous. 28,29
`One finding in this study, not previously reported to our
`knowledge, was the difference in the risk ofpostinjection en(cid:173)
`dophthalmitis owing to the preparation type. The prefilled sy(cid:173)
`ringe- available only forranibizumab- had decreased the rate
`of endophthalmitis after IVTs, specifically by 40% compared
`with room preparation of nonpreftlled ranibizumab and by 46%
`for aflibercept, only available as a nonprefilled medication. Al(cid:173)
`though a ready-to-use material prepared by a pharmaceuti(cid:173)
`cal company vs a homemade preparation has been demon(cid:173)
`strated to decrease endophthalmitis incidence after cataract
`surgery, 16 to the best of our knowledge, this is the first time
`that the relative risk of the anti-VEGF agent preparation
`type for endophthalmitis after IVTs has been identified, al(cid:173)
`though it had been previously hypothesized.30 The main rea(cid:173)
`son could lie in fewer manipulations and the professional
`preparation in a controlled environment, leading to better
`safety and accuracy. This reason is in line with previous de(cid:173)
`scriptions of endophthalmitis outbreak associated with re(cid:173)
`packaged bevacizumab.3 1•32 This association, however, does
`not indicate a cause and effect. Although numerous potential
`confounders were adjusted in the analyses, other confound(cid:173)
`ing factors could contribute in part or completely to the re(cid:173)
`sults, which also were associated with the use ofprefilled sy(cid:173)
`ringes. For example, the year ofinjection was not included in
`the multi variable analysis, but more cases of endophthalmitis
`
`Variable
`Age category, y
`<70
`70 -79
`80 -84
`285
`Sex
`Female
`Male
`Diabetes
`None
`Diabetes
`I nsu Un dependence
`Type 2 diabetes
`Type 1 diabetes
`Top ica l antibiotic prophylaxis
`None
`All
`Type of antibiotic prophylaxis
`Antibiotic alone
`Top ica l antibiotic-corticosteroid
`combination
`Agent class•
`Anti-VEGF agent
`Corticosteroid
`Agent preparation•·•
`Prefilled ranibizumab (0.50 mg/0.05 ml) 1 [Reference]
`Nonprefilled ranibizumab (0.50 mg/ 0.05 1.60 (1.14-2.25)
`ml)
`Aflibercept (2.00 mg/ 0.05 ml)
`Dexamethasone implant
`Triamcinolone acetonide
`Year
`2012
`2013
`2014
`2015
`
`1 [Reference]
`0.84 (0.65 -1.07)
`0.80 (0.61-1.04)
`0.64 (0.48 -0.84)
`
`1 [Reference]
`0.87 (0.71 -1.06)
`
`1 [Reference]
`1.08 (0.88 -1.34)
`
`1 [Reference]
`1.04 (0.73 -1.50)
`
`1 [Reference]
`0.88 (0.72-1.09)
`
`1 [Reference]
`1.67 (1.08 -2.58)
`
`1 [Reference]
`3.26 (2.38 -4.48)
`
`1.80 (1.24-2.61)
`5.06 (3.27 -7.83)
`4.00 (0.96 -1 6.57)
`
`1 [Reference]
`1.67 (1.20 -2.32)
`1.43 (1.03 -1.99)
`1.30 (0.93 -1.82)
`
`.01
`
`.16
`
`.46
`
`.82
`
`.26
`
`.06
`
`<.001
`
`<.001
`
`.01
`
`Abbreviations: I RR. incidence rate ratio: IVT, intravitreal injection,
`VEGF, vascular endothelial growth factor.
`• Data were missing for 67 657 injections.
`• Because no endopht halmitis occurred after bevaclzumab IVTs, these 2592
`injections were not considered for the by-agent analysis.
`
`occurred in the earlier years, before prefilled syringes were
`available. Thus, confounding factors, such as greater atten(cid:173)
`tion to use ofantiseptics over the injection site or greater over(cid:173)
`all experience with injections in the latter years when pre(cid:173)
`filled syringes became available, might have accounted for the
`decreased rate. Also, the absolute rate of endophthalmitis with(cid:173)
`out prefilled syringes was quite low, which could influence the
`cost-effectiveness of prefilled syringes.
`In univariate analysis, we found a significant association
`between the early years of the study and endophthalmitis. This
`period effect is a consequence of the change in the presenta(cid:173)
`tion of the ranibizumab syringe. Indeed, the year of injection
`
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`Research Orlglnal Investigation
`
`Association of Acute Endophthalmitis With lntravitreal Injections
`
`Table 4. Multivariable Analysis of Factors Associated With Acute Endophthalmitis
`After IVTs of Corticosteroids or Anti-VEGF Agents From 2012 to 2015
`
`Multlvarlable Poisson Regression
`
`Model 1
`IRR (95% Cl)
`
`1 [Reference]
`3.21 (2.33 -4.44)
`
`Covariate
`Model 1•
`Agent class
`Anti-VEGF agent
`Corticosteroids
`Model 2•
`Agent prepara tion
`Prefilled ra nibizumab (0.50 mg/0.05 ml)
`NA
`Nonprefilled ra nibizumab (0.50 mg/ 0.05 ml) NA
`Aflibercept (2.00 mg/0.05 ml)
`NA
`Dexamethasone implant
`NA
`Triamcinolone acetonide
`NA
`Both Models
`Sex
`Female
`
`Male
`Age category, y
`
`<70
`70 -79
`80 -84
`
`285
`Diabetes
`None
`
`All
`Top ica l antibiotic prophylaxis
`None
`
`All
`
`1 [Reference]
`0. 78 (0.63 -0.96)
`
`1 [Reference]
`1.00 (0.75 -1.32)
`0.97 (0.71 -1.31)
`0.78 (0.57 -1.07)
`
`1 [Reference]
`1.04 (0.83 -1.32)
`
`1 [Reference]
`0.92 (0.73 -1.16)
`
`Model 2
`IRR (95% Cl)
`
`PValue
`
`PValue
`
`<.001
`
`NA
`NA
`
`NA
`NA
`
`NA
`NA
`NA
`NA
`NA
`
`.02
`
`.27
`
`. 72
`
`.49
`
`1 [Reference]
`1.63 (1.15-2.30)
`1.82 (1.25-2.66)
`5.04 (3.23-7.86)
`3.98 (0.96-16.45)
`
`<.001
`
`1 [Reference]
`0.78 (0.63-0.96)
`
`1 [Reference]
`0.97 (0.74- 1.29)
`0.95 (0.70-1.28)
`0. 77 (0.56-1.05)
`
`1 [Reference]
`1.06 (0.84- 1.34)
`
`1 [Reference]
`0.89 (0.71-1.12)
`
`.02
`
`.28
`
`.60
`
`.34
`
`Abbreviations: IRR, incidence rate
`ratio: IVT, intravitreal injection,
`NA, not available: VEGF, vascular
`endothelial growth factor.
`• Includes 1744 201 injections.
`• includes 1741609 injections .
`Because no endophthalmitis
`occurred after bevad zumab IVTs,
`these 2592 injections were not
`considered for the by-agent
`analysis.
`
`and the type of drug were highly correlated. Therefore, this
`variable was not included in the multivariable analysis. The
`variable age did not remain significant in multivariable analy(cid:173)
`ses, probably because the agent injected significantly de(cid:173)
`pended on the patient's age.
`Women were at greater risk of developing endophthalmi(cid:173)
`tis. Few studies on endophthalmitis after IVTs report the
`patients' sex. Moshfeghi et al14 found a sex ratio for endoph(cid:173)
`thalmitis of 6 female to 2 male patients, and in a case series,
`Irigoyen et al33 found 12 female and 8 male cases.
`Our study showed no significant association between en(cid:173)
`dophthalmitis and diabetes. This finding contradicts the con(cid:173)
`troversial hypothesis that, because of relative immune sup(cid:173)
`pression, patients with diabetes were at higher risk for
`endophthalmitis, 8 •9 but supports previous findings reported
`by VanderBeek et al, 11 where diabetes was not associated with
`endophthalmitis risk after IVTs.
`Similarly, no significant association between endophthalmi(cid:173)
`tis after IVTs and the use of topical antibiotic prophylaxis was
`found in our cohort. Topical antibiotics applied before or after
`the injection have been the standard clinical practice for many
`years. However, several reports on large series and systematic
`35 have led to the conclusion that antibiotic prophy(cid:173)
`reviews34
`•
`laxis for IVTs is no longer recommended. The guidelines on the
`
`perioperative strategy to minimize the risk of post-IVT endoph(cid:173)
`thalmitis have been updated, and in France a topical antibiotic
`is no longer recommended after anti-VEGF IVTs.36 We would
`probably need a longer observational period to measure the in(cid:173)
`fluence of this change in recommendations in France.
`
`Strengths and limitations
`The strength of this study is the large collection ofIVTs reg(cid:173)
`istered in a single administrative database. The subgroup size
`is large enough to detect a statistically significant difference
`between exposure groups. Moreover, the French medical(cid:173)
`administrative database includes all patients, especially
`those who are usually excluded from clinical trials (eg, older
`patients with comorbidities) or from Medicare studies
`(eg, younger patients with diabetes), 37 who could be at differ(cid:173)
`ent risk for endophthalmitis.
`We also acknowledge several limitations to this study. First,
`post-IVT endophthalmitis was diagnosed based on clinical find(cid:173)
`ings and not bacteriologic identification. This distinction could
`lead to misclassification if sterile endophthalmitis or uveitis were
`clinically diagnosed as endophthalmitis. However, this rate is very
`close to what was found in a previous study examining310 000
`IVTs with data collected from 25 centers in France. 10 Further(cid:173)
`more, sterile endophthalmitis is mostly associated with triam-
`
`1356
`
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`

`Association of Acute Endophthalmitis With Intravitreal Injections
`
`Original Investigation Research
`
`cinoloneinjections,whichaccountforonly0.2%oftheIVTscol-
`lectedinthepresentstudy.38Arecentdatabasestudy39reported
`an incidence of 0.012% of noninfectious endophthalmitis after
`IVTs.Furthermore,thesamecaveatwasfoundinotherstudies.11
`Biological confirmation is missing in 40% of post-IVT endoph-
`thalmitis cases, as reported by Lyall et al.40
`Second, given that the definition of diabetes was based on
`an algorithm, we could not fully ascertain that all patients were
`classified in the proper group. To avoid this uncertainty, we
`used a validated algorithm, based on long-term disease and
`hospital diagnostic codes as well as the drugs used.17
`Third, we limited our main outcome measures to infec-
`tious events occurring after 42 days, as defined by the En-
`dophthalmitis Vitrectomy Study Group.23 However, we sup-
`port previous findings that most acute endophthalmitis cases
`occur within the first 2 weeks. In our study, 90% of endoph-
`thalmitis cases occurred within this time frame. When con-
`sidering only acute endophthalmitis after IVT occurring within
`15 days, we drew the same conclusion in the univariate and
`multivariable analyses, except for the increased risk in fe-
`male patients in the univariate analysis.
`Fourth, the agent injected was unknown in 3.6% of the
`IVTs; other studies have reported this weakness in as many as
`10% of cases.11 The results did not change after including them
`as a specific agent category in the statistical analysis.
`Fifth, our findings cannot fully extend to another country;
`FrenchguidelinesforIVTsaresomewhatdifferentfromUSguide-
`
`lines,forexample.41,42InFrance,performingIVTsinadedicated
`room wearing sterile gloves is recommended. By contrast, simi-
`larrecommendationsinbothcountriesincludetopicalpovidone-
`iodine use, surgical mask wear, and no topical antibiotics.38
`Sixth, certain variables such as the number of IVTs before
`endophthalmitis could not be reliably analyzed because some
`patients may have been treated with bilateral injections. How-
`ever, a recent study did not identify an increased risk of en-
`dophthalmitis with each successive IVT.39
`Seventh, the conclusions drawn from big data always need
`to be interpreted cautiously due to their limitations, as has al-
`ready been pointed out in the ophthalmic literature.43 In-
`deed, an association does not necessarily indicate a cause and
`effect, and although numerous potential confounders were ad-
`justed in the analyses, other confounders not included or stud-
`ied could be associated with the risk of endophthalmitis.
`
`Conclusions
`This study supports previous findings on the higher inci-
`dence of post-IVT endophthalmitis with corticosteroids vs
`anti-VEGF agents. It also demonstrates a nearly halved rate of
`endophthalmitis after IVTs with a prefilled anti-VEGF agent sy-
`ringe, although this association does not necessarily indicate
`a cause and effect relationship between prefilled syringes and
`decreased rate of endophthalmitis.
`
`ARTICLE INFORMATION
`Accepted for Publication: June 26, 2018.
`Published Online: September 13, 2018.
`doi:10.1001/jamaophthalmol.2018.3939
`Author Affiliations: Department of
`Ophthalmology, Dijon University Hospital, Dijon,
`France (Baudin, Bron, Creuzot-Garcher);
`Department of Biostatistics and Bioinformatics,
`Dijon University Hospital, Franche-Comté
`University, Dijon, France (Benzenine, Mariet,
`Quantin); Institut National de la Santé et de la
`Recherche Medicale (INSERM), Centre
`d’Investigation Clinique 1432, Dijon, France (Mariet,
`Quantin); Clinical Investigation Center, Clinical
`Epidemiology/Clinical Trials Unit, Dijon University
`Hospital, Dijon, France (Mariet, Quantin);
`Department of Biostatistics, Biomathematics,
`Pharmacoepidemiology and Infectious Diseases,
`INSERM, Université de Versailles Saint-Quentin-en-
`Yvelines, Institut Pasteur, Université Paris-Saclay,
`Paris, France (Mariet, Quantin); Eye and Nutrition
`Research Group, Bourgogne Franche-Comté
`University, Dijon, France (Bron, Creuzot-Garcher);
`Department of Ophthalmology, University Hospital
`of Montpellier, Montpellier, France (Daien); INSERM
`U1061, University of Montpellier, Montpellier,
`France (Daien); Department of Ophthalmology,
`University Hospital of Bordeaux, Bordeaux, France
`(Korobelnik); INSERM U1219, Population Health
`Research Center, Bordeaux, France (Korobelnik).
`Author Contributions: Drs Quantin and
`Creuzot-Garcher had full access to all the data in the
`study and take responsibility for the integrity of the
`data and the accuracy of the data analysis.
`Concept and design: Baudin, Bron, Korobelnik,
`Creuzot-Garcher.
`
`Acquisition, analysis, or interpretation of data:
`Baudin, Benzenine, Mariet, Daien, Korobelnik,
`Quantin.
`Drafting of the manuscript: Baudin, Benzenine,
`Mariet.
`Critical revision of the manuscript for important
`intellectual content: Baudin, Benzenine, Bron,
`Daien, Korobelnik, Quantin, Creuzot-Garcher.
`Statistical analysis: Baudin, Benzenine, Mariet,
`Bron, Quantin.
`Obtained funding: Baudin, Creuzot-Garcher.
`Administrative, technical, or material support:
`Baudin, Benzenine, Korobelnik, Creuzot-Garcher.
`Supervision: Baudin, Daien, Korobelnik,
`Creuzot-Garcher.
`Conflict of Interest Disclosures: All authors have
`completed and submitted the ICMJE Form for
`Disclosure of Potential Conflicts of Interest. Dr Bron
`reported consulting for Aerie, Allergan SAS, Bausch
`& Lomb, Carl Zeiss Meditec, Horus Pharma, and
`Théa. Dr Daien reported consulting for Bayer
`HealthCare, Horus Pharma, Novartis Pharma SAS,
`and Théa. Dr Korobelnik reported consulting for
`Alcon, Alimera, Bayer HealthCare, Carl Zeiss
`Meditec, Novartis Pharma SAS, Roche, and Théa.
`Dr Creuzot-Garcher reported consulting for
`Allergan SAS, Bayer HealthCare, Horus Pharma,
`Novartis Pharma SAS, Roche, and Théa. No other
`disclosures were reported.
`Funding/Support: This study was supported by an
`institutional grant from Dijon-Bourgogne University
`Hospital and the University of Dijon.
`Role of the Funder/Sponsor: The funding
`organization had no role