Endophthalmitis After lntravitrea l Injections:
`Incidence, Presentation, M anagement, and
`Visual Outcome
`
`DENIS DOSSARPS, ALAIN M. BRON, PHILIPPE KOEHRER, LUDWIG S. AHO-GLELE, AND
`CATHERINE CREUZOT-GARCHER, FOR THE FRCR NET (FRENCH RETI NA SPECIALISTS NEn
`
`• PURPOSE: T o report the inciden ce and characteristics
`of endophthalmitis after intravitreal injections of anti(cid:173)
`vascular endothelial growth factor agents or corticoste(cid:173)
`roids and to describe the clinical and bacteriologic
`characteristics, managemen t, and outcome of these eyes
`with acute endophthalmitis in France.
`• DESIGN: Retrospective, nationwide multicenter case
`series.
`• METHODS: From January 2, 2008 to June 30, 20 13, a
`total of 3 16 576 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 pa(cid:173)
`tients treated for endophthalmitis after injection during
`the same time period. The main outcome measures were
`the incidence of clinical endophthalmitis and visual acu(cid:173)
`ity 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 inter(cid:173)
`val [Cl], 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 identifi(cid:173)
`cation was achieved in 43.4%. T he most frequent patho(cid:173)
`gens were gram-positive bacteria (91.3%), including
`coagulase-negative Staphylococcus in 78.3%. Neither the
`interval between injection and presentation for endophthal(cid:173)
`mitis nor the clinical sign~ differentiated culture-positive
`from culture-negative cases. In multivariate analysis, the
`u~e of a disposable conjunctival mould assist device and
`the use of prophylaxis with an antibiotic or antiseptic
`were significantly associated with an increased incidence
`.001). The majority of patients
`of endophthalmitis (P
`had worse visual acuity after 3 month~ of follow-up when
`compared with acuity before endophthalmitis.
`
`IAJO.coml
`,_ _ _ _, Supplemental Material available at AJO.com.
`Accepted for publication Apr IO, 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 !NRA, 6265 C NRS, Burgundy University
`(A.M.B., C.C.G.), Dijon, France.
`Inquiries co Catherine Creuzoc-Garcher, Service d'Ophcalmologie,
`CHU Dijon, 14 Rue Paul Gaffarel, 21079 Dijon, France; e-mail:
`catherine.creuzot-garche.@chu-dij on.fr
`
`• CONCLUSIONS: The incidence of presumed endophthal(cid:173)
`mitis after intravitreal injections of anti-vascular endothe(cid:173)
`lial growth factors or corticosteroids was low and the
`prognosis poor. Prevention and management remain
`challenging. It remains to be determined whether the find(cid:173)
`ings of this study are relevant for other countries using
`(Am J
`different techniques for intravitreal injections.
`Ophthalmol 20 15 ;160 (1 ):17-25. © 20 15 by Elsevier
`Inc. All rights reserved. )
`
`T HE NUMBER O F IN1RAVITREAL (!VT) INJECTIO NS 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 endophthalmit is, retinal detach(cid:173)
`ment, and cataract.2 Infectious endophthalmit is is one of
`the most feared complicat ions after IVT injections because
`of its poor prognosis. In the literature, the incidence of
`endophthalmit is 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 inject ions, respect ively.5•6 Although the
`risk
`is
`low,
`infect ious 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 inci(cid:173)
`dence of presumed endophthalmitis after IVT injections
`
`0002-9394/$36.00
`http://dx.doi.org/10. 1016/j.ajo.2015.04.013
`
`© 2015 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
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`

`

`centers
`ophthalmic
`nationwide
`25
`in
`performed
`throughout France and, second, to describe the prophylac-
`tic 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 prac-
`tice 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 in-
`jection 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), triamcino-
`lone acetonide (4 mg/0.1 mL; Kenacort; Bristol-Myers
`Squibb, New York, New York, USA), and the dexametha-
`sone 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 intra-
`ocular inflammation occurring within 4 weeks after IVT in-
`jection and requiring intravitreal antibiotics. In each center,
`the cases of endophthalmitis during the same time period
`were identified by searching the operative code for endoph-
`thalmitis 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 num-
`ber of injections preceding endophthalmitis; and the reason
`for performing IVT injection. Finally, the management of
`the endophthalmitis, namely intravitreal antibiotic injec-
`tion, 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
`
`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 fenes-
`trated 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 de-
`vice (InVitria; FCI Ophthalmics, Pembroke, Massachu-
`setts, USA) without a lid speculum was used. Each
`ophthalmologist administered anti-VEGF agents or ste-
`roids 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 tele-
`phone 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% picloxy-
`dine (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 sta-
`tistical 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 endoph-
`thalmitis, 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
`
`18
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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
`
`Centers, Number (%)
`
`Univariate Analysis, P
`
`Multivariate Analysis, P
`
`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
`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.
`
`.242
`.079
`
`.412
`
`.174
`
`.011
`
`.548
`
`.180
`
`.844
`
`.645
`
`.534
`.021
`
`ND
`ND
`
`ND
`
`ND
`
`.001
`
`ND
`
`ND
`
`ND
`
`ND
`
`ND
`.001
`
`24 (96.0)
`10 (40.0)
`
`4 (16.0)
`
`22 (88.0)
`
`4 (16.0)
`
`3 (12.0)
`
`7 (28.0)
`
`10 (40.0)
`
`11 (44.0)
`
`2 (8.0)
`2 (8.0)
`
`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, Col-
`lege Station, Texas, USA) and R software version 3,
`‘‘meta’’ and ‘‘metaphor’’ packages (R Foundation for Statis-
`tical 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 percent-
`ages. Ninety-five percent confidence intervals (95% CI)
`were estimated using the binomial exact method. Qualita-
`tive variables were compared using the x2 or Fisher exact
`test. Continuous variables were compared using nonpara-
`metric 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
`
`for random effects meta-analysis was used in the presence
`of heterogeneity.11 An influential analysis of the random-
`effects model was performed. The Clopper-Pearson confi-
`dence 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 signifi-
`cance 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 cen-
`ter was 8390 (680 39 857), for a total of 316 576 IVT in-
`jections. 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
`
`VOL. 160, NO. 1
`
`ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTIONS
`
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`TABLE 2. Demographics, Management, Bacteriology and
`Visual Outcome of Suspected Endophthalmitis Cases
`(N 60) After Intravitreal Injections, in 25 French Centers
`
`TABLE 2. Demographics, Management, Bacteriology and
`Visual Outcome of Suspected Endophthalmitis Cases
`(N 60) After Intravitreal Injections, in 25 French Centers
`(Continued )
`
`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)
`
`36 (60.0)
`
`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
`
`2.0 (0.9 3.0)
`
`0.7 (0.6 1.3)
`
`Visual acuity, 8 days after
`endophthalmitis
`Visual acuity, 1 month after
`endophthalmitis
`Visual acuity, 3 months after
`endophthalmitis
`LogMAR ¼ logarithm of the minimal angle of resolution.
`Values are displayed as median (range)
`for continuous
`variables and number (%) for categorical variables.
`aVancomycin 1 mg and ceftazidime 2.25 mg.
`bFive patients had both aqueous and vitreous sampling.
`cFor visual outcome, values are displayed as median
`(25th percentile 75th percentile).
`
`0.7 (0.4 1.0)
`
`in each center was 1 (0 12). Taking into account the great
`heterogeneity of the number of injections among partici-
`pating 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 het-
`erogeneity 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).
` INTRAVITREAL INJECTION PROCEDURE: 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 (P¼ .011 and P¼ .021, respec-
`tively). In multivariate analysis, use of a disposable conjunc-
`tival 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 pre-
`sentation 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 intravi-
`treal 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
`
`Visual Acuity Loss (N 36)
`
`Visual Acuity Recovery (N 24)
`
`P
`
`Age (y)
`Diabetes
`Indication, AMD
`Agent, anti VEGF
`Number of intravitreal injections before
`endophthalmitis
`Days to presentation
`3 (1 26)
`Vision loss
`36 (100.0)
`Pain
`33 (91.7)
`Redness
`35 (97.2)
`Hypopyon
`25 (69.4)
`Vitritis
`36 (100.0)
`Second intravitreal injection of antibiotics
`21 (58.3)
`Intravitreal injection of betamethasone
`11 (30.6)
`Topical fortified antibiotics
`13 (36.1)
`Systemic corticosteroids
`13 (36.1)
`Subconjunctival injections of betamethasone
`24 (66.7)
`Early pars plana vitrectomy
`3 (8.3)
`Bacterial identification (culture positive)a
`11 (34.4)
`Baseline visual acuity limited to light perception
`9 (25.0)
`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 vari
`ables; the level of statistical significance was set at P < .05.
`aDone in 53 patients.
`
`.131
`.999
`.391
`.501
`.279
`
`.957
`.059
`.422
`.999
`.590
`.400
`.793
`.773
`.410
`.999
`.788
`.247
`.157
`.765
`
`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)
`
`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)
`
`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 base-
`line VA limited to light perception (LP), 5 patients under-
`went 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 char-
`acteristics 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-
`
`statistically
`jections before endophthalmitis was not
`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 major-
`ity 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 count-
`fingers 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 multivar-
`iate analysis (Table 3; only univariate analysis is displayed).
`During the follow-up, 1 case of phthisis occurred 105 days af-
`ter the presentation with endophthalmitis. After endoph-
`thalmitis, corticosteroid or anti-VEGF IVT injections to
`treat initial macular disease were restarted in 37 of 60 pa-
`tients (61.7%) after a median time of 113 (25 770) days.
`
`VOL. 160, NO. 1
`
`ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTIONS
`
`21
`
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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
`
`Study, Publication Year
`
`Treatment(s)
`
`Injections (n)
`
`Cases (n)
`
`Rate (%) (95% CI)
`
`Endophthalmitis
`
`Current study, 2015
`A, C
`316 576
`Fileta et al,5 2014a
`A
`350 535
`McCannel,6 2011a
`A
`105 536
`Lyall et al,16 2012
`A
`186 972
`Storey et al,20 2014
`A
`117 171
`Moshfeghi et al,17 2011
`A
`60 322
`Day et al,4 2011
`A
`40 903
`Casparis et al,12 2014
`A
`40 011
`Chen et al,13 2011
`A, C
`33 580
`Klein et al,15 2009
`A
`30 736
`Shah et al,19 2011
`A
`27 736
`Fintak et al,14 2008
`A
`26 905
`Nentwich et al,18 2014
`A, C
`20 179
`Brynskov et al,3 2014
`A
`20 293
`A ¼ anti vascular endothelial growth factor agents; C ¼ corticosteroids.
`aMeta analysis.
`
`65
`197
`52
`47
`44
`12
`38
`3
`13
`15
`23
`6
`6
`0
`
`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)
`
`DISCUSSION
`
`THIS STUDY IS THE LARGEST SINGLE RETROSPECTIVE STUDY
`evaluating the incidence of endophthalmitis after IVT in-
`jections, 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 endophthalmi-
`tis rates following anti-VEGF injections was the meta-
`analysis 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 retrospec-
`tive 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 statis-
`tical analysis (such as inverse variance weighting). The au-
`thors 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 micro-
`biological data, unlike the analysis of Fileta and associates.5
`
`Considering the 0.021% overall incidence of the present
`study calculated simply from the number of endophthalmi-
`tis occurrences among the 316 576 injections, the inci-
`dence 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 AN-
`CHOR studies, which reported an endophthalmitis rate
`of 0.05%.7,21
`This difference may be attributable to the injection con-
`ditions. In most published reports, clinicians did not wear a
`face mask, they did not use a sterile drape to cover the pa-
`tient’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 endophthal-
`mitis 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 multi-
`ple sources of contamination. The main sources of ocular
`contamination are pathogens of the lid margin and con-
`junctiva with a possible inoculation into the vitreous cavity
`
`22
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`AMERICAN JOURNAL OF OPHTHALMOLOGY
`
`JULY 2015
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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 povidone-
`iodine, the benefit of antibiotics in preventing endophthal-
`mitis 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 world-
`wide, 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 Prod-
`ucts, 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 eye-
`lashes, 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 viola-
`tions, the most common being failure to use an eyelid spec-
`ulum.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 sur-
`geon, 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 investi-
`gating 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 be-
`tween 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%)
`
`was higher than in other reports.38 The majority of the or-
`ganisms
`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 au-
`thors19 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 surgi-
`cal center. Third, the management of endophthalmitis af-
`ter IVT injections was heterogeneous in the participating
`centers, especially in terms of corticosteroid use