Endophthalmitis After Intravitreal Injections: Incidence, Presentation, Management, and Visual Outcome DENIS DOSSARPS, ALAIN M. BRON, PHILIPPE KOEHRER, LUDWIG S. AHO-GLE´LE´, AND CATHERINE CREUZOT-GARCHER, FOR THE FRCR NET (FRENCH RETINA SPECIALISTS NET)
PURPOSE:

To report the incidence and characteristics of endophthalmitis after intravitreal injections of anti– vascular endothelial growth factor agents or corticosteroids and to describe the clinical and bacteriologic characteristics, management, and outcome of these eyes with acute endophthalmitis in France.
DESIGN: Retrospective, nationwide multicenter case series.
METHODS: From January 2, 2008 to June 30, 2013, a total of 316 576 intravitreal injections from 25 French ophthalmic centers were included. For each center, the number of intravitreal injections was determined using billing codes and the injection protocol was recorded. A registry and hospital records were reviewed to identify patients treated for endophthalmitis after injection during the same time period. The main outcome measures were the incidence of clinical endophthalmitis and visual acuity of endophthalmitis cases.
RESULTS: During the study period, 65 cases of presumed endophthalmitis were found, giving an overall incidence of 0.021% (2.1 in 10 000 injections) (95% confidence interval [CI], 0.016%–0.026%). The median number of days from injection to presentation was 4 [1–26] days. The most common symptom was vision loss. Bacterial identification was achieved in 43.4%. The most frequent pathogens were gram-positive bacteria (91.3%), including coagulase-negative Staphylococcus in 78.3%. Neither the interval between injection and presentation for endophthalmitis nor the clinical signs differentiated culture-positive from culture-negative cases. In multivariate analysis, the use of a disposable conjunctival mould assist device and the use of prophylaxis with an antibiotic or antiseptic were significantly associated with an increased incidence of endophthalmitis (P [ .001). The majority of patients had worse visual acuity after 3 months of follow-up when compared with acuity before endophthalmitis.

Supplemental Material available at AJO.com. Accepted for publication Apr 10, 2015. From the Departments of Ophthalmology (D.D., A.M.B., P.K., C.C.G.) and Epidemiology (L.S.A.G.); and the Eye and Nutrition Research Group, CSGA, UMR 1324 INRA, 6265 CNRS, Burgundy University (A.M.B., C.C.G.), Dijon, France. Inquiries to Catherine Creuzot-Garcher, Service d’Ophtalmologie, CHU Dijon, 14 Rue Paul Gaffarel, 21079 Dijon, France; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.04.013

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CONCLUSIONS:

The incidence of presumed endophthalmitis after intravitreal injections of anti–vascular endothelial growth factors or corticosteroids was low and the prognosis poor. Prevention and management remain challenging. It remains to be determined whether the findings of this study are relevant for other countries using different techniques for intravitreal injections. (Am J Ophthalmol 2015;-:-–-. Ó 2015 by Elsevier Inc. All rights reserved.)

T

HE NUMBER OF INTRAVITREAL (IVT) INJECTIONS HAS

dramatically increased over the last 10 years owing to the efficacy of corticosteroids and anti–vascular endothelial growth factor (anti-VEGF) agents for various posterior segment diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), macular edema secondary to retinal vein occlusion, and uveitis. More than 1 million IVT injections were performed in the United States in 2009.1 IVT injections may induce complications, including endophthalmitis, retinal detachment, and cataract.2 Infectious endophthalmitis is one of the most feared complications after IVT injections because of its poor prognosis. In the literature, the incidence of endophthalmitis after IVT injections can vary from 0 to 0.092%.3,4 Recently 2 meta-analyses reported 0.056% and 0.049% incidence of infection following 350 535 and 105 536 IVT injections, respectively.5,6 Although the risk is low, infectious endophthalmitis after IVT injections remains the most preoccupying complication. Indeed, the treatment of these macular pathologies usually requires repeated IVT injections. Each injection carries a small risk of endophthalmitis, leading to a cumulative risk of more than 1% after 2 years.7 Many studies have identified modifiable risk factors to prevent endophthalmitis following IVT injections, and guidelines based on current best evidence and practices have been published in different countries.8,9 However, while some recommendations have been applied in current clinical practice, such as a dedicated setting for IVT injections, debate continues on the intraoperative and postoperative environment, such as the use of a surgical mask and prophylactic anti-infectious treatment. The purpose of this study was, first, to report the incidence of presumed endophthalmitis after IVT injections

ELSEVIER INC. ALL

RIGHTS RESERVED.

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performed in 25 nationwide ophthalmic centers throughout France and, second, to describe the prophylactic measures, the clinical and microbiological spectrum, the management, and the outcome of endophthalmitis following IVT injections.

METHODS ALL PATIENTS SIGNED INFORMED CONSENT BEFORE THE

injections. The protocol was in accordance with the tenets of the Declaration of Helsinki. The local Ethics Committee ruled that approval was not required for this retrospective study. This was a large multicenter retrospective study of endophthalmitis after intravitreal injections given from January 2, 2008, to June 30, 2013. Public and private practice retina ophthalmologists were contacted through the 2 main French retina societies (Fe´de´ration Franc¸aise de la Macula and Club Francophone des Spe´cialistes de la Re´tine) and were included in a group called FRenCh Retina specialists, the FRCR net, to participate in the study. For each participating center, both the number of IVT injections collected through billing codes for IVT injection and the setting in which IVT injections were performed were recorded. The treatments used in this study were ranibizumab (0.5 mg/0.05 mL; Lucentis; Novartis Pharma SAS, Basel, Switzerland), bevacizumab (1.25 mg/ 0.05 mL; Avastin; Roche, Basel, Switzerland), triamcinolone acetonide (4 mg/0.1 mL; Kenacort; Bristol-Myers Squibb, New York, New York, USA), and the dexamethasone implant (0.7 mg; Ozurdex; Allergan SAS, Irvine, CA, USA). Indications for injections consisted of macular edema secondary to retinal vein occlusion and diabetes, neovascularization occurring in AMD and degenerative myopia, and miscellaneous causes. Presumed endophthalmitis was defined as any acute intraocular inflammation occurring within 4 weeks after IVT injection and requiring intravitreal antibiotics. In each center, the cases of endophthalmitis during the same time period were identified by searching the operative code for endophthalmitis in registry or hospital records. Case-related data included patient demographics; Snellen visual acuity (VA) before infection, at presentation, and after 3 months; the number of days from injection to presentation; the number of injections preceding endophthalmitis; and the reason for performing IVT injection. Finally, the management of the endophthalmitis, namely intravitreal antibiotic injection, pars plana vitrectomy, bacterial culture and sensitivity results, and complications such as retinal detachment or phthisis, were reported.
INTRAVITREAL INJECTION TECHNIQUE:

All eyes were prepared using a standardized procedure according to the recommendations of the French Agency for the Safety of Health Products (Agence Nationale de Se´curite´ du

2

Me´dicament), with minor variations between centers.9 Briefly, before injection, local anesthesia was applied with 1 drop of tetracaine (Tetracaı¨ne Faure unidose 1%; Novartis, Basel, Switzerland). Five percent periocular and conjunctival povidone-iodine (Be´tadine; MEDA Pharma, Paris, France) was applied for 2 minutes and then a fenestrated self-adhesive sterile drape large enough to mask the patient’s nose and mouth was used. In all centers a lid speculum or a disposable conjunctival mould assist device (InVitria; FCI Ophthalmics, Pembroke, Massachusetts, USA) without a lid speculum was used. Each ophthalmologist administered anti-VEGF agents or steroids through the pars plana 3.5–4 mm from the limbus without any displacement of the conjunctiva. A 30 gauge needle was used to inject anti-VEGF agents while a 27 gauge needle was used for corticosteroids, except for the dexamethasone implant, where the device provided by the manufacturer was used. All ophthalmologists wore a face mask, a surgical hat, sterile gloves, and a surgical gown. All ophthalmologists were assisted for the injections. Assistants wore a disposable cap, a face mask, and a surgical gown. All patients wore a disposable cap. At the end of the procedure, the ability of the patient to see light was assessed in all cases. Oral and written information with a list of telephone numbers to contact in case of emergency were given, and written consent was obtained before IVT injection. The parameters studied are listed in Table 1. When antibiotic prophylaxis was used, topical 1.5% azithromycin (Azyter; Thea, Clermont-Ferrand, France) was given for 3 days either before or after IVT injection. Centers employing antiseptics used topical 0.05% picloxydine (Vitabact; Thea) 3 days before and 3 days after IVT injection in every case.
VISUAL OUTCOME:

Visual acuity was measured with Snellen charts and secondarily converted to the logarithm of the minimal angle of resolution (logMAR) values for statistical analysis. According to Holladay, VA equal to count fingers (CF) and hand motion (HM) corresponds to logMAR 2 and logMAR 3, respectively.10 Baseline VA was defined as VA measured at presentation with endophthalmitis, and final VA was measured 3 months later.


ENDOPHTHALMITIS MANAGEMENT:

All eyes in which presumed infectious endophthalmitis developed were treated in either the center where they were injected or a nearby reference center. All patients benefited from bacteriologic samples (vitreous and/or aqueous tap). All patients received antibiotic IVT injections of vancomycin (1 mg/0.1 mL) (Vancomycin; Mylan, Canonsburg, Pennsylvania, USA) associated with ceftazidime (2.25 mg/0.1 mL) (Fortum; GlaxoSmithKline, Brentford, UK). All patients received a systemic broad-spectrum antibiotic regimen, intravenous imipenem (Tienam; MSD, Courbevoie, France) 1.5 g daily combined with oral ciprofloxacin (Ciflox; Bayer Sante, Loos, France) 1 g daily, and dexamethasone phosphate

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TABLE 1. Factors Influencing the Incidence of Endophthalmitis After Intravitreal Injections of Corticosteroids or Anti–Vascular Endothelial Growth Factor Agents in 25 French Centers

1. Room Dedicated room Filtration airflow 2. Operator Surgical sterile smock changed for each patient 3. Patient Disposable smock 4. Technique for intravitreal injection Disposable conjunctival fixed mould assist device Intravitreal injections never done in superior hemisphere Intravitreal injections never done in inferior hemisphere 5. Prophylaxis Topical antibiotic started before intravitreal injections Topical antibiotic started after intravitreal injections Topical antiseptic No prophylaxis with antibiotic or antiseptic

Centers, Number (%)

Univariate Analysis, P

Multivariate Analysis, P

24 (96.0) 10 (40.0)

.242 .079

ND ND

4 (16.0)

.412

ND

22 (88.0)

.174

ND

4 (16.0)

.011

.001

3 (12.0)

.548

ND

7 (28.0)

.180

ND

10 (40.0)

.844

ND

11 (44.0)

.645

ND

2 (8.0) 2 (8.0)

.534 .021

ND .001

ND ¼ not done. A negative binomial regression model was used when the data did not fit the Poisson model satisfactorily. Multivariate analysis included variables with P < .05 in univariate analysis.

sodium (Dexafree; Thea, Clermont-Ferrand, France) eye drops for 8 days. The parameters studied are listed in Table 2.
STATISTICAL ANALYSIS:

All analyses were conducted using STATA software version 12.0 (STATACORP, College Station, Texas, USA) and R software version 3, ‘‘meta’’ and ‘‘metaphor’’ packages (R Foundation for Statistical Computing, Vienna, Austria). The distribution of quantitative variables was determined using histograms followed by normality tests based on Ladder of Power (logarithmic and powers). They are given as median (range). Qualitative variables were described using percentages. Ninety-five percent confidence intervals (95% CI) were estimated using the binomial exact method. Qualitative variables were compared using the x2 or Fisher exact test. Continuous variables were compared using nonparametric tests. Logistic regression was also performed. Variance of beta coefficients was assessed using bootstrap or robust variance (Hubert/White/Sandwich). A meta-analysis of the incidence of endophthalmitis was performed using the inverse variance method and a Freeman-Tukey double-arcsine transformation to stabilize the variance of proportions. The Sidik-Jonkman method

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for random effects meta-analysis was used in the presence of heterogeneity.11 An influential analysis of the randomeffects model was performed. The Clopper-Pearson confidence interval was used for individual studies and a funnel plot was performed to assess center bias. The number of endophthalmitis cases was modeled using univariate or multivariate negative binomial regression with the number of injections as the exposure variable. Statistical significance was set at P < .05 and the tests were 2-tailed.

RESULTS TWENTY-FIVE CENTERS INCLUDING 16 PUBLIC AND 9 PRI-

vate practices throughout France participated in the study. The median (range) number of IVT injections in each center was 8390 (680–39 857), for a total of 316 576 IVT injections. Over the time period studied, a total of 65 presumed infections were observed. Therefore, the overall incidence of presumed endophthalmitis was 0.021% (2.1 in 10 000 injections) (95% CI, 0.016%–0.026%). The median number of presumed cases of endophthalmitis

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TABLE 2. Demographics, Management, Bacteriology and Visual Outcome of Suspected Endophthalmitis Cases (N ¼ 60) After Intravitreal Injections, in 25 French Centers Characteristics Sex (F/M) Age (y) Diabetes Indications Age-related macular degeneration Diabetic macular edema Vein occlusion High myopia Miscellaneous causes Agents Ranibizumab Bevacizumab Triamcinolone acetonide Dexamethasone implant Number of intravitreal injections before endophthalmitis Initial Presentation Days to presentation Vision loss Pain Redness Tyndall Hypopyon Vitritis Management Second intravitreal injection of antibioticsa Intravitreal injection of betamethasone Third intravitreal injection of antibioticsa Topical fortified antibiotics Systemic corticosteroids Subconjunctival injections of betamethasone Early pars plana vitrectomy Delayed vitrectomy Bacteriology Aqueous sampling (n ¼ 53)b Positivity rate Vitreous sampling (n ¼ 53) Positivity rate Bacterial identification (culture positive) Coagulase-negative staphylococci Staphylococcus aureus Streptococcus sp Pseudomonas aeruginosa Visual Outcome (logMAR)c Visual acuity before endophthalmitis Baseline visual acuity Limited to light perception (n/%)

43/17 81 (42–96) 12 (20.0) 42 (70.0) 6 (10.0) 6 (10.0) 1 (1.7) 5 (8.3) 41 (68.3) 9 (15.0) 6 (10.0) 4 (6.7) 7 (1–28)

4 (1–26) 57 (95.0) 53 (88.3) 59 (98.3) 60 (100.0) 40 (66.7) 59 (98.3)

Visual acuity, 8 days after endophthalmitis Visual acuity, 1 month after endophthalmitis Visual acuity, 3 months after endophthalmitis

2.0 (0.9–3.0) 0.7 (0.6–1.3) 0.7 (0.4–1.0)

LogMAR ¼ logarithm of the minimal angle of resolution. Values are displayed as median (range) for continuous variables and number (%) for categorical variables. a Vancomycin 1 mg and ceftazidime 2.25 mg. b Five patients had both aqueous and vitreous sampling. c For visual outcome, values are displayed as median (25th percentile–75th percentile).

in each center was 1 (0–12). Taking into account the great heterogeneity of the number of injections among participating centers, a complementary analysis that stabilized the variance of proportions was performed as detailed above, providing a corrected incidence of endophthalmitis of 0.011% (95% CI, 0.005%–0.019%). A funnel plot was made to confirm the absence of bias attributable to the heterogeneity between centers (data not shown). Of the 65 cases of presumed endophthalmitis, we collected complete data at 3 months for 60 of them (Table 2).

36 (60.0)


INTRAVITREAL INJECTION PROCEDURE:

17 (28.3) 3 (5.0) 19 (31.7) 22 (36.7) 39 (65.0) 8 (13.3) 3 (5.0) 37 (69.8) 11 (29.7) 21 (39.6) 17 (81.0) 23 (43.4) 18 (78.3) 2 (8.7) 1 (4.3) 2 (8.7) 0.5 (0.4–0.7) 3.0 (2.0–3.0) 14 (23.3) Continued

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TABLE 2. Demographics, Management, Bacteriology and Visual Outcome of Suspected Endophthalmitis Cases (N ¼ 60) After Intravitreal Injections, in 25 French Centers (Continued )

The details of the IVT injection procedures between the 25 centers are shown in Table 1. In univariate analysis, use of a disposable conjunctival fixed mould and prophylaxis with an antibiotic or antiseptic were statistically associated with an increased incidence of endophthalmitis (P ¼ .011 and P ¼ .021, respectively). In multivariate analysis, use of a disposable conjunctival fixed mould remained positively associated with the incidence of endophthalmitis (incidence rate ratio [IRR] ¼ 2.38) (95% CI, 1.64–3.47) (P ¼ .001). Prophylaxis with an antibiotic or antiseptic remained statistically associated with an increased incidence of endophthalmitis (IRR ¼ 2.77) (95% CI, 1.54–5.00) (P ¼ .001).
ENDOPHTHALMITIS MANAGEMENT:

The characteristics of endophthalmitis management are displayed in Table 2. The first intravitreal antibiotic injection (vancomycin and ceftazidime) was performed in the emergency setting on presentation immediately after bacterial sampling, or the following day at the latest in 3 cases. The second intravitreal antibiotic injection was performed 2 (1–8) days after the first antibiotic IVT injection. When needed, the third intravitreal antibiotic injection was performed 4 (3–13) days after the first antibiotic IVT injection. Systemic administration of corticosteroids was started after a median delay of

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TABLE 3. Univariate Analysis of Factors Influencing Visual Acuity Recovery at 3 Months in Patients With Endophthalmitis After Intravitreal Injections

Age (y) Diabetes Indication, AMD Agent, anti-VEGF Number of intravitreal injections before endophthalmitis Days to presentation Vision loss Pain Redness Hypopyon Vitritis Second intravitreal injection of antibiotics Intravitreal injection of betamethasone Topical fortified antibiotics Systemic corticosteroids Subconjunctival injections of betamethasone Early pars plana vitrectomy Bacterial identification (culture-positive)a Baseline visual acuity limited to light perception

Visual Acuity Loss (N ¼ 36)

Visual Acuity Recovery (N ¼ 24)

P

80 (42–96) 7 (19.4) 27 (75.0) 31 (86.1) 8 (1–25)

79 (72–86) 5 (20.8) 15 (62.5) 19 (79.2) 6 (1–28)

.131 .999 .391 .501 .279

3 (1–26) 36 (100.0) 33 (91.7) 35 (97.2) 25 (69.4) 36 (100.0) 21 (58.3) 11 (30.6) 13 (36.1) 13 (36.1) 24 (66.7) 3 (8.3) 11 (34.4) 9 (25.0)

4 (1–8) 21 (87.5) 20 (83.3) 24 (100.0) 15 (62.5) 23 (95.8) 15 (62.5) 6 (25.0) 6 (25.0) 9 (37.5) 15 (62.5) 5 (20.8) 12 (57.1) 5 (20.8)

.957 .059 .422 .999 .590 .400 .793 .773 .410 .999 .788 .247 .157 .765

AMD ¼ age-related macular degeneration; anti-VEGF ¼ anti–vascular endothelial growth factor. Values are displayed as median (range) for continuous variables and percentage for categorical variables. Comparisons were made with the Fisher exact test for dichotomous data. A nonparametric Mann-Whitney test was used for continuous variables; the level of statistical significance was set at P < .05. a Done in 53 patients.

2 (0–4) days after initial presentation for a median period of 3 (1–30) days. Subconjunctival injections of betamethasone were started after a median delay of 2.5 (1–9) days after initial presentation, for a median period of 3.5 (1–7) days. Median baseline logMAR VA in patients undergoing early vitrectomy was significantly worse than in patients who did not undergo early vitrectomy (P ¼ .032), but this difference was no longer statistically significant at 3 months (P ¼ .332). Among the 14 patients with a baseline VA limited to light perception (LP), 5 patients underwent a pars plana vitrectomy. The VA of these patients did not reach statistical significance when compared to those who did not benefit from an early vitrectomy: 0.7 (0.4–3.0) vs 0.9 (0.3–2.0) (P ¼ .919).
BACTERIOLOGY: The bacteriologic results are shown in Table 2. The median time from IVT injection to sampling in culture-positive endophthalmitis was not significantly different from that of culture-negative endophthalmitis: 4 (1–26) days vs 3 (1–14) days, P ¼ .122. The clinical characteristics on admission and recovery of initial VA were not significantly different between culture-positive and culture-negative patients, P ranging from .249 to .999 and P ¼ .157, respectively. The median number of IVT in-

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jections before endophthalmitis was not statistically different between culture-positive and culture-negative cases: 3 (1–33) vs 8 (1–28) (P ¼ .114). Aqueous or vitreous samples were not taken in 7 patients.
VISUAL OUTCOME: The visual outcome is summarized in Table 2. After a 3-month follow-up, VA was significantly better than baseline VA (P < .001) but still less than the VA found before infection occurred (P < .001). The majority of patients (39/60, 65.0%) had worse VA after the 3-month follow-up when compared with VA just before endophthalmitis. At 3 months, 6 of 60 patients (10%) ended up with nonambulating vision: 4 with countfingers visual acuity and 2 with light perception. We did not have patients with hand motion visual acuity or non–light perception. Risk factors influencing visual acuity at the 3-month follow-up visit were not identified in univariate or multivariate analysis (Table 3; only univariate analysis is displayed). During the follow-up, 1 case of phthisis occurred 105 days after the presentation with endophthalmitis. After endophthalmitis, corticosteroid or anti-VEGF IVT injections to treat initial macular disease were restarted in 37 of 60 patients (61.7%) after a median time of 113 (25–770) days.

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TABLE 4. Incidence of Endophthalmitis After Intravitreal Injection of Corticosteroids or Anti–Vascular Endothelium Growth Factor Agents: Selected Larger Case Series and Meta-analyses Endophthalmitis Study, Publication Year

Treatment(s)

Injections (n)

Cases (n)

Current study, 2015 Fileta et al,5 2014a McCannel,6 2011a Lyall et al,16 2012 Storey et al,20 2014 Moshfeghi et al,17 2011 Day et al,4 2011 Casparis et al,12 2014 Chen et al,13 2011 Klein et al,15 2009 Shah et al,19 2011 Fintak et al,14 2008 Nentwich et al,18 2014 Brynskov et al,3 2014

A, C A A A A A A A A, C A A A A, C A

316 576 350 535 105 536 186 972 117 171 60 322 40 903 40 011 33 580 30 736 27 736 26 905 20 179 20 293

65 197 52 47 44 12 38 3 13 15 23 6 6 0

Rate (%) (95% CI)

0.021 (0.016–0.026) 0.056 (0.049–0.065) 0.049 (0.038–0.065) 0.025 0.038 0.019 (0.011–0.035) 0.092 0.008 (0.003–0.022) 0.04 (0.02–0.07) 0.049 (0.03–0.08) 0.083 (0.049–0.12) 0.02 (0.00–0.06) 0.03 0 (0–0.019)

A ¼ anti–vascular endothelial growth factor agents; C ¼ corticosteroids. Meta-analysis.

a

DISCUSSION THIS STUDY IS THE LARGEST SINGLE RETROSPECTIVE STUDY

evaluating the incidence of endophthalmitis after IVT injections, except for 1 previously published meta-analysis. Overall, 65 cases of presumed endophthalmitis were detected after 316 576 injections, giving an incidence of 0.021% and a corrected incidence of 0.011%. This is consistent with reported rates ranging from 0.0% to 0.092%3–6,12–20 and very close to the incidence reported in the largest prospective study to date.16 Only studies involving over 20 000 IVT injections are presented in Table 4. To date, the largest study reporting endophthalmitis rates following anti-VEGF injections was the metaanalysis published by Fileta and associates.5 This analysis included both retrospective and prospective studies and found a total of 197 cases of endophthalmitis out of 350 535 IVT injections, with an overall endophthalmitis rate of 0.056% (95% CI, 0.049%–0.065%). However, the same weight was given to small and large series. Of the 45 studies included in the analysis, 13 had fewer than 1000 IVT injections and 64.7% (11/17) of the retrospective studies reported fewer than 20 000 IVT injections. In the meta-analysis reported by McCannel,6 this bias was assessed with a funnel plot but without weighted statistical analysis (such as inverse variance weighting). The authors found that the incidence of endophthalmitis after IVT injections was 0.049% (95% CI, 0.038%–0.065%). These results may have been influenced by the exclusion of series with no endophthalmitis and series with no microbiological data, unlike the analysis of Fileta and associates.5 6

Considering the 0.021% overall incidence of the present study calculated simply from the number of endophthalmitis occurrences among the 316 576 injections, the incidence found herein is lower, and even lower with the weighted statistical analysis. This incidence was lower than that reported in Storey and associates20 and lower than the 2 pivotal trial studies, the MARINA and ANCHOR studies, which reported an endophthalmitis rate of 0.05%.7,21 This difference may be attributable to the injection conditions. In most published reports, clinicians did not wear a face mask, they did not use a sterile drape to cover the patient’s nose and mouth, and IVT injections were often performed in an office-based setting. A recent study on IVT injection techniques used by retinal specialists in the United States reached the same conclusions in that 88.0% of them did not use a sterile drape and only 33.0% of them wore sterile gloves.22 Our incidence of endophthalmitis was comparable to those of 3 other European studies in which IVT injections were performed in hyperaseptic conditions (operating room, laminar airflow, surgical masks, surgical drapes, sterile gloves, etc).3,12,18 In a retrospective study, Abell and associates reported a significant reduction in the rate of endophthalmitis by performing IVT injection in an operating room, in conditions similar to ours.23 During the IVT injection procedure, prevention of endophthalmitis should be a priority because of the multiple sources of contamination. The main sources of ocular contamination are pathogens of the lid margin and conjunctiva with a possible inoculation into the vitreous cavity

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by means of the injection needle.24 The only proven endophthalmitis prophylaxis for IVT injections remains topical povidone-iodine.25,26 In contrast with povidoneiodine, the benefit of antibiotics in preventing endophthalmitis after IVT injection remains controversial.20,25,27–29 Antibiotics may induce an increased rate of bacterial resistance30 with no real additional benefit in combination with povidone-iodine.31 In the present study, 20 centers (80%) used prophylactic topical postinjection antibiotics in accordance with a majority of retinal specialists worldwide, as observed before 2011 in the United States with an 81% rate.22 All French ophthalmologists followed the guidelines edited by the French Agency for the Safety of Health Products, with 5% periocular and conjunctival povidone-iodine application, sterile drape use, and the use of a device to avoid lid contact (a sterile speculum for most of them or a disposable conjunctival fixed mould).9 A face mask for the ophthalmologist during IVT injection is widely used in France, and it was shown in an experimental setting that wearing a face mask could decrease contamination from oral and nasal sources.32 Use of a lid speculum can be an additional prevention modality by displacing eyelashes, which could potentially contaminate the needle tip, without any influence on the conjunctival bacterial counts.33 Indeed, in the VISION trial, 8 of the 12 cases of endophthalmitis were associated with protocol violations, the most common being failure to use an eyelid speculum.34 Other factors such as lack of surgical hand antisepsis, sterile glove wear, and topical anesthetics are even more questionable.35,36 In the present study, after multivariate analysis, the use of a disposable conjunctival fixed mould was positively related to the IRR of endophthalmitis after IVT injection (IRR ¼ 2.38), as was prophylaxis with an antibiotic or antiseptic (IRR ¼ 2.77). These results must be interpreted with great caution because of the low number of centers that did not use prophylaxis or a disposable conjunctival fixed mould. To date, there has been only 1 published study on the use of this device: the authors concluded that it was beneficial in terms of speed, cost, and comfort for the patient and surgeon, without any data reporting endophthalmitis occurring with this device.37 In the present study, the mean number of IVT injections before endophthalmitis was 9.0 6 7.9 (1– 33), while Lyall and associates found 5.2 6 3.6 (1–15).16 The median time from injection to initial presentation was 4 (1–26) days, in accordance with other studies investigating endophthalmitis after IVT.19,20,29 The most common symptom of endophthalmitis was reduced vision, in accordance with the literature, whereas redness and pain were more frequent in our study.16 Bacterial identification was achieved in 43.4%, which is within the range of other series reporting identification between 30% and 60%.17,19,29 In our study, the positive rate of aqueous sampling (30%) was consistent with the literature, but the positive rate of vitreous sampling (81%) VOL. -, NO. -

was higher than in other reports.38 The majority of the organisms identified were gram-positive (91.3%), and coagulase-negative staphylococci were the most common organisms isolated. This is in accordance with other studies of endophthalmitis after IVT injection.5,6,39 We had only 1 case of Streptococcus, contrasting with other studies in which streptococcal species were in greater proportion after IVT injections.5,6,20,39 This low rate of oral pathogens may be related to the widespread use of face masks and more stringent aseptic techniques employed by retina specialists in France and recommended by the French Agency for the Safety of Health Products. In the current study, neither the time from injection to development of symptoms nor the clinical signs differentiated culture-positive from culture-negative endophthalmitis, as shown by some authors19 but refuted by other reports.16,40 Furthermore, there was no significant difference in the visual recovery rate between culture-positive and culture-negative cases, in accordance with Shah and associates.19 We acknowledge several limitations to this study. First, its retrospective design, with missing data and possible minor changes in injection protocols that may have occurred over the study period, weakens the conclusions. Second, the rate of endophthalmitis after IVT injections could be underestimated because it is possible, although unlikely, that a few cases were not reported. However, all endophthalmitis cases, whatever their cause, were managed in each center or at least in their referral surgical center. Third, the management of endophthalmitis after IVT injections was heterogeneous in the participating centers, especially in terms of corticosteroid use and initial vitrectomy. Fourth, although the value of systemic antibiotics in the management of endophthalmitis has not been shown in the literature, this is current practice in France. Fifth, taking into account both anti-VEGF agent and corticosteroid injections risks the inclusion of pseudoendophthalmitis related to corticosteroids. This condition has been well documented for triamcinolone but not for dexamethasone implants, which were used in 4 cases in our study. Moreover, 2 out of the 6 cases of endophthalmitis following triamcinolone IVT injections were culture positive. Actually, 2 studies have already reported on the rate of endophthalmitis after corticosteroid or anti-VEGF agent IVT injections in the same publication.13,18 Sixth, it was not possible to reliably consider the number of eyes treated using the conjunctival mould assist device. We only took into consideration the number of centers using this device, another limitation of our study. Seventh, the findings of this study apply for a given country with specific rules suited to the environment of IVT injections, namely asepsis and antisepsis. For instance, the use of a sterile drape, face mask, surgical hat, sterile gloves, and surgical gown are uncommon in the United States. Therefore, extrapolation to other countries with different techniques requires careful consideration.

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The strength of this study is its very large sample size—25 centers throughout France—with public and private practices studied over the same period of time, providing an assessment of real-life conditions close to current IVT injection practices. In conclusion, this nationwide retrospective study found an overall incidence of 0.021% endophthalmitis after

intravitreal injections of anti–vascular endothelial growth factor agents or corticosteroids. The endophthalmitis rate was higher with antibiotic prophylaxis or antiseptic use, as suggested in other series.20 The overall prognosis of these endophthalmitis cases was poor. Further studies to define specific guidelines for endophthalmitis management after intravitreal injections are warranted.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: Alain M. Bron: Board membership (Allergan, Bausch & Lomb, Horus, The´a); Catherine Creuzot-Garcher: Board membership (Alcon, Allergan, Bayer, Bausch & Lomb, Novartis, The´a). Funding support was received from the Ministry of Health (PHRC inter-re´gional), Dijon, France. The authors attest to their independence in reporting the study data and interpretation of the data. All authors attest that they meet the current ICMJE requirements to qualify as authors. Details of centers and the people who took part actively to this research are listed in Supplemental Material at www.ajo.com.

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13. Chen E, Lin MY, Cox J, Brown DM. Endophthalmitis after intravitreal injection: the importance of viridans streptococci. Retina 2011;31(8):1525–1533. 14. Fintak DR, Shah GK, Blinder KJ, et al. Incidence of endophthalmitis related to intravitreal injection of bevacizumab and ranibizumab. Retina 2008;28(10):1395–1399. 15. Klein KS, Walsh MK, Hassan TS, et al. Endophthalmitis after anti-VEGF injections. Ophthalmology 2009;116(6):1225. 16. Lyall DA, Tey A, Foot B, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond) 2012;26(12):1517–1526. 17. Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, et al. Endophthalmitis after intravitreal anti-vascular endothelial growth factor antagonists: a six-year experience at a university referral center. Retina 2011;31(4):662–668. 18. Nentwich MM, Yactayo-Miranda Y, Schwarzbach F, Wolf A, Kampik A. Mino de Kaspar H. Endophthalmitis after intravitreal injection: decreasing incidence and clinical outcome-8year results from a tertiary ophthalmic referral center. Retina 2014;34(5):943–950. 19. Shah CP, Garg SJ, Vander JF, Brown GC, Kaiser RS, Haller JA. Outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmology 2011;118(10):2028–2034. 20. Storey P, Dollin M, Pitcher J, et al. The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection. Ophthalmology 2014;121(1):283–289. 21. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009;116(1):57–65. 22. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal specialists in the United States. Am J Ophthalmol 2011;151(2):329–332. 23. Abell RG, Kerr NM, Allen P, Vote BJ. Intravitreal injections: is there benefit for a theatre setting? Br J Ophthalmol 2012; 96(12):1474–1478. 24. de Caro JJ, Ta CN, Ho HK, et al. Bacterial contamination of ocular surface and needles in patients undergoing intravitreal injections. Retina 2008;28(6):877–883. 25. Bhavsar AR, Googe JM Jr, Stockdale CR, et al. Risk of endophthalmitis after intravitreal drug injection when

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34. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular agerelated macular degeneration. N Engl J Med 2004; 351(27):2805–2816. 35. Labetoulle M, Frau E, Offret H, Nordmann P, Naas T. Nonpreserved 1% lidocaine solution has less antibacterial properties than currently available anaesthetic eye-drops. Curr Eye Res 2002;25(2):91–97. 36. Tanner J, Swarbrook S, Stuart J. Surgical hand antisepsis to reduce surgical site infection. Cochrane Database Syst Rev 2008;(1):CD004288. 37. Ratnarajan G, Nath R, Appaswamy S, Watson SL. Intravitreal injections using a novel conjunctival mould: a comparison with a conventional technique. Br J Ophthalmol 2013; 97(4):395–397. 38. Chiquet C, Cornut PL, Benito Y, et al. Eubacterial PCR for bacterial detection and identification in 100 acute postcataract surgery endophthalmitis. Invest Ophthalmol Vis Sci 2008; 49(5):1971–1978. 39. Simunovic MP, Rush RB, Hunyor AP, Chang AA. Endophthalmitis following intravitreal injection versus endophthalmitis following cataract surgery: clinical features, causative organisms and post-treatment outcomes. Br J Ophthalmol 2012;96(6):862–866. 40. Mezad-Koursh D, Goldstein M, Heilwail G, ZayitSoudry S, Loewenstein A, Barak A. Clinical characteristics of endophthalmitis after an injection of intravitreal antivascular endothelial growth factor. Retina 2010;30(7): 1051–1057.

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UNIVERSITY HOSPITALS:

SUPPLEMENTAL MATERIAL
PRIVATE PRACTICE CENTERS:

Laurent Berthon (Centre d’exploration re´tinienne Kle´ber, Lyon), Quaranta-El Maftouhi and Amina Bakhti (Centre ophtalmologique Rabelais, Lyon), John Conrath (Clinique Monticelli, Marseille), Yannick Le Mer (Fondation Ophtalmologique Adolphe de Rothschild, Paris), Christiane Besse Ramahefasolo (Centre Rennes-Arras, Paris), Florence Coscas and Catherine Franc¸ais (Centre ophtalmologique de l’Ode´on, Paris), Typhaine Grenet and Salomon Yves Cohen (Centre ophtalmologique d’imagerie et de laser, Paris), Joe¨l Uzzan (Clinique Mathilde, Rouen), Sam Razavi (Clinique Saint-Gatien, Tours).

9.e1

Maher Saleh and Bernard Delbosc (Besanc¸on), Gilles Chaine, Franck Fajnkuchen and Audrey Giocanti (Bobigny), Marie-Noe¨lle Delyfer and Jean-Franc¸ois Korobelnik (Bordeaux), Giuseppe Querques, Olivier Chevreaud and Eric Souied (Cre´teil), Ce´cile Musson and Christophe Chiquet (Grenoble), Vincent Fortoul and Laurent Kodjikian (Hoˆpital de la Croix Rousse, Lyon), Morgane Straub and Carole Burillon (Centre hospitalier, Lyon-Sud), Jean-Paul Berrod (Nancy), Ste´phanie Baillif (Nice), Jean-Franc¸ois Girmens (Centre hospitalier national d’ophtalmologie des Quinze-Vingts, Paris), Julien Pe´rol (Hoˆpital Lariboisie`re, Paris), Nicolas Leveziel and Miche`le Boissonnot (Poitiers), Marc Muraine (Rouen), David Gaucher (Strasbourg), Marie-Laure Le Lez and Pierre-Jean Pisella (Tours).

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