META-ANALYSIS OF ENDOPHTHALMITIS
`AFTER INTRAVITREAL INJECTION OF
`ANTI–VASCULAR ENDOTHELIAL
`GROWTH FACTOR AGENTS
`Causative Organisms and Possible
`Prevention Strategies
`
`COLIN A. MCCANNEL, MD*†
`
`Purpose: To report the rates of endophthalmitis and the spectrum of causative
`organisms after intravitreal injection of anti–vascular endothelial growth factor agents and
`possible prevention strategies.
`Methods: Meta-analysis of the U.S. literature from 2005 to 2009 reporting endoph-
`thalmitis bacterial
`isolates after intravitreal
`injection of anti–vascular endothelial growth
`factor agents and comparison with reports of endophthalmitis bacterial
`isolates after
`intraocular surgery in the United States.
`Results: Endophthalmitis after intravitreal
`injection occurred in 52 of 105,536 injections
`(0.049%) (95% confidence interval [CI], 0.038–0.065%). Among 50 cases of endophthalmitis
`with bacterial culture isolates, 24 (48.0% [95% CI, 34.8–61.5%]) were culture negative and 26
`(52% [95% CI, 38.5–65.2%]) were culture positive. Among the 26 culture-positive isolates,
`causative organisms were coagulase-negative Staphylococcus in 17 cases (65.4% [95% CI,
`46.0–80.6%]), Streptococcus species in 8 cases (30.8% [95% CI, 16.5–50.2%]), and Bacillus
`cereus in 1 case (3.8% [95% CI, 0.9–19.0%]). Streptococcus species were significantly more
`frequent after intravitreal
`injection than after intraocular surgery in the Endophthalmitis
`Vitrectomy Study (29 of 226 isolates, 9.0% [95% CI, 6.3–12.6%], P = 0.005), a report on
`clear corneal cataract surgery endophthalmitis (6 of 73 isolates, 8.2% [95% CI, 3.9–16.8%], P =
`0.022), and a report on postvitrectomy endophthalmitis with no cases of Streptococcus species.
`Conclusion: Streptococcal isolates are approximately three times more frequent after
`intravitreal anti–vascular endothelial growth factor injection than after intraocular surgery.
`Strategies to consider minimizing oropharyngeal droplet transmission may include avoiding
`talking, coughing, and sneezing or wearing surgical masks.
`RETINA 31:654–661, 2011
`
`E ndophthalmitis after penetrating ocular proce-
`
`dures is a rare but devastating complication. The
`range of acute postoperative endophthalmitis in the
`United States has been reported to be 0.04% to
`0.076%.1–4 The most common causative organisms are
`coagulase-negative Staphylococcus species.
`Endophthalmitis after intravitreal injection of anti–
`vascular endothelial growth factor
`(VEGF) agents
`(pegaptanib, bevacizumab, and ranibizumab) is similarly
`rare. Reported endophthalmitis rates vary from 0.019%5
`to 0.54%.6 These rates are low despite the injections
`being performed in the office setting. To date, there have
`been no reports on the spectrum of causative organisms
`
`observed after endophthalmitis after anti-VEGF agent
`injection compared with those observed in acute post-
`operative endophthalmitis. This study describes a meta-
`analysis performed to determine the spectrum of
`causative organisms in endophthalmitis after intravitreal
`injection of anti-VEGF agents compared with those in the
`setting of acute postoperative endophthalmitis.
`
`Materials and Methods
`
`Using the National Library of Medicine PubMed
`interface (www.pubmed.gov), a literature search was
`
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`ENDOPHTHALMITIS AND INTRAVITREAL INJECTION  MCCANNEL
`
`655
`
`performed. All articles containing the keywords
`‘‘endophthalmitis’’ and ‘‘injection’’ during the years
`2005 to March 22, 2010, inclusive (Medline search
`date: March 22, 2010) were identified. Additionally,
`the articles were reviewed for references that might
`identify additional relevant studies, and these were
`also reviewed. Those articles in which the title
`suggested that
`the publication might contain in-
`formation on anti-VEGF agent injection endophthal-
`mitis were reviewed to assess whether the article met
`inclusion criteria. The inclusion criteria were three-
`fold. First, articles were required to report on
`endophthalmitis after
`intravitreal
`injection of an
`anti-VEGF agent. Second, articles were required to
`provide the endophthalmitis culture results, including
`bacterial species that were isolated (‘‘isolates’’).
`Third, articles were required to report on patient
`populations in the United States, given the possible
`variation in procedures, settings, and bacterial colo-
`nization patterns elsewhere. Articles that fulfilled all
`inclusion criteria were included in the meta-analysis.
`Additionally, references in the selected articles and
`those of review articles on endophthalmitis were used
`to identify additional publications that might be
`eligible for inclusion. Any additional publications
`that met the inclusion criteria were also included in the
`meta-analysis. Articles that reported on endophthal-
`mitis rates but did not include the causative organism
`information or those that had no cases of endoph-
`thalmitis were excluded. A large series of endoph-
`thalmitis after surgery performed in the operating
`room that provided information on causative organ-
`isms, or isolates, from the United States were selected
`for comparison.
`Statistical analyses between the meta-analysis and
`the comparative postoperative studies were made
`using the chi-square test. A funnel plot was performed
`to assess systematic publication bias of the meta-
`analysis.
`
`From the *Jules Stein Eye Institute; and †Department of
`Ophthalmology, David Geffen School of Medicine, University of
`California, Los Angeles, Los Angeles, California.
`Funded in part by an unrestricted grant from the Research to
`Prevent Blindness and the Jules Stein Eye Institute, Los Angeles, CA.
`Parts of this work were presented at the 2010 Annual Meetings of
`the American Association of Retina Specialists, Vancouver, Canada,
`and the American Academy of Ophthalmology, Chicago, IL.
`The author has no proprietary interest
`in the subjects or
`technology discussed in this article.
`Reprint requests: Colin A. McCannel, MD, Jules Stein Eye
`Institute, University of California, Los Angeles, 100 Stein Plaza,
`Los Angeles, CA 90095; e mail: cmccannel@jsei.ucla.edu
`
`Results
`
`The initial PubMed search returned a total of
`432 articles. After additional inclusion of referenced
`articles, there were 24 articles that provided information
`on endophthalmitis and causative organisms after anti-
`VEGF agent injection. After all inclusion criteria were
`applied, there were 16 remaining articles that fulfilled
`all inclusion criteria. The relevant information from
`these articles is summarized in Table 1.5–20
`Studies reporting endophthalmitis and causative
`organisms after
`intravitreal
`injection outside the
`United States were reports by Aggio et al,21 Alkuraya
`et al,22 Artunay et al,23 and Yenerel et al,24 and Wu
`et al.25 A report by Lee et al26 was excluded because
`the authors convincingly tracked the occurrence of
`two cases of Serratia marcescens endophthalmitis to
`pharmacy contamination. In the VEGF Inhibition
`Study in Ocular Neovascularization (VISION) trial27,28
`publications, causative organisms of the 12 cases of
`endophthalmitis were not reported, and thus, these cases
`were not considered in the meta-analysis.
`A total of 54 cases of endophthalmitis were
`considered in the meta-analysis. The cumulative rate
`of endophthalmitis was determined to be 52 cases after
`105,536 injections (0.049%) (95% confidence interval
`[CI], 0.038–0.065%). Two case reports were not
`included in the rate calculation because no denominator
`was provided in the publications for these cases. A
`culture was obtained for 50 cases, 24 (48.0% [95% CI,
`34.8–61.5%]) of which were negative. Among the
`26 cultured endophthalmitis cases for which the isolates
`were reported, the most common causative organisms
`were
`coagulase-negative Staphylococcus
`species,
`which accounted for 17 of the 26 cases (65.4% [95%
`CI, 46.0–80.6%]). The second most common causative
`organisms were Streptococcus species (8 of 26 or
`30.8% [95% CI, 16.5–50.2%]). One case was caused by
`Bacillus cereus (30.8% [95% CI, 16.5–50.2%]).
`In comparison, the causative organisms and their
`relative rates among the 3 largest studies of post-
`operative endophthalmitis with causative organisms
`after surgery in the operating room are summarized in
`Table 2.29–31 For comparison,
`isolates of normal
`conjunctival flora from patients about
`to undergo
`intravitreal injection for the first time are summarized
`in Table 3.32 Comparing the distribution of organisms
`in the meta-analysis with these postoperative reference
`studies, Streptococcus species were significantly more
`frequent after intravitreal
`injection than after in-
`traocular surgery in the Endophthalmitis Vitrectomy
`Study29,33 (29 of 323 isolates, 9.0%, P = 0.005),
`a recent report on post–clear corneal cataract surgery
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`656
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`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2011  VOLUME 31  NUMBER 4
`
`Table 1. Studies of Endophthalmitis After Anti-VEGF Agent Injection Included in the Meta-analysis
`
`Endophthalmitis
`
`Study
`
`Anti-VEGF Agent
`
`Injections
`
`Rosenfeld7 (MARINA)
`Heier8 (FOCUS)
`Heier9 (Phase I/II)
`Scott6 (DRCRnet)
`Kopel10
`Mason5
`Pili et al11
`
`Fintak et al12
`
`Brown et al13 (ANCHOR)†
`Diago et al14
`Bhavsar et al15 (DRCRnet)
`Lima et al16
`
`Klein et al17
`
`Bakri et al18
`Chen et al19
`Fong et al20
`
`Total
`Total by category
`
`Ranibizumab
`Ranibizumab
`Ranibizumab
`Bevacizumab
`Bevacizumab
`Bevacizumab
`Pegaptanib
`Bevacizumab
`Ranibizumab
`Bevacizumab
`Ranibizumab
`Ranibizumab
`
`Ranibizumab
`Bevacizumab
`Ranibizumab
`Pegaptanib
`Bevacizumab
`Ranibizumab
`Bevacizumab
`Pegaptanib
`Bevacizumab
`Ranibizumab
`All
`
`10,443
`1,544‡
`407
`185
`*
`5,223
`406
`3,501
`6,347
`12,585
`14,320
`3,125‡
`3,875
`3,226
`6,527
`2,416
`128
`8,039
`22,579
`208
`*
`324
`128
`105,536
`
`Cases
`
`5
`5
`1
`1
`1*
`1
`0
`1
`2
`3
`3
`3
`3
`3
`1
`2
`0
`5
`10
`1
`1*
`1
`1
`52 (+2*)
`
`Rate (%)
`
`0.048
`0.324
`0.246
`0.541
`NA
`0.019
`0.029
`
`0.024
`0.021
`0.096
`0.077
`0.093
`0.034
`
`0.049
`
`0.481
`NA
`0.442
`
`0.049*
`
`Non-Streptococcus
`Species
`
`Categories of
`Organism Identified
`
`Streptococcus
`Species
`
`No
`Isolate
`
`Study
`
`Coagulase-Negative
`Staphylococcus
`
`Bacillus
`cereus
`
`Streptococcus
`viridans
`
`Streptococcus
`salivarius
`
`Streptococcus
`mitis
`
`No Growth/
`‘‘Sterile’’
`
`Not
`Cultured
`
`Rosenfeld7 (MARINA)
`Heier8 (FOCUS)
`Heier9 (Phase I/II)
`Scott6 (DRCRnet)
`Kopel10
`Mason5
`Pili et al11
`
`Fintak et al12
`
`Brown et al13
`(ANCHOR)†
`Diago et al14
`Bhavsar et al15
`(DRCRnet)
`Lima et al16
`
`Klein et al17
`
`Bakri et al18
`Chen et al19
`
`—
`1
`1
`1
`—
`1
`—
`—
`—
`1
`—
`1
`
`2
`2
`
`1
`—
`1
`3
`—
`—
`
`—
`—
`—
`—
`1
`—
`—
`—
`—
`—
`—
`—
`
`—
`—
`
`—
`—
`—
`—
`—
`—
`—
`
`—
`—
`—
`—
`—
`—
`—
`—
`—
`2
`—
`—
`
`—
`1
`
`—
`1
`—
`1
`—
`—
`—
`
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`
`—
`—
`
`—
`—
`—
`1
`—
`—
`—
`
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`1
`—
`
`—
`—
`
`—
`—
`—
`—
`—
`—
`1
`
`4
`4
`—
`—
`—
`—
`—
`1
`2
`—
`2
`1
`
`1
`—
`
`1
`—
`—
`2
`5
`1
`—
`
`1
`—
`—
`—
`—
`—
`—
`—
`—
`—
`—
`1
`
`—
`—
`
`—
`—
`—
`—
`2
`—
`—
`
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`ENDOPHTHALMITIS AND INTRAVITREAL INJECTION  MCCANNEL
`
`657
`
`Table 1. (continued )
`Categories of
`Organism Identified
`
`Non-Streptococcus
`Species
`
`Streptococcus
`Species
`
`No
`Isolate
`
`Coagulase-Negative
`Staphylococcus
`
`Bacillus
`cereus
`
`Streptococcus
`viridans
`
`Streptococcus
`salivarius
`
`Streptococcus
`mitis
`
`No Growth/
`‘‘Sterile’’
`
`Not
`Cultured
`
`1
`1
`17
`18
`
`—
`—
`1
`8
`
`—
`—
`5
`28
`
`—
`—
`1
`
`—
`—
`2
`
`—
`—
`24
`
`—
`—
`4
`
`Study
`
`Fong et al20
`
`Total
`Total by category
`
`*Case reports that did not indicate among how many injections the infection occurred; these cases were excluded in the
`endophthalmitis rate calculation.
`†A small number of study centers were located outside the United States.
`‡The number of injections is not reported and estimated from the publication’s methods and number of enrollees.
`The table summarizes the studies’ endophthalmitis rate stratified by anti-VEGF agent, and overall, and indicates the specific isolates
`when available. Three larger groups are summarized: that is, non-Streptococcus species organisms, Streptococcus species organisms,
`and no isolate. MARINA, Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-
`Related Macular Degeneration; FOCUS, RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety; DRCRnet,
`Diabetic Retinopathy Clinical Research Network; ANCHOR, Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal
`Neovascularization in Age-Related Macular Degeneration; NA, not applicable.
`
`endophthalmitis30 (6 of 73 isolates, 8.2%, P = 0.022),
`and a report on postvitrectomy endophthalmitis31 with
`no cases of Streptococcus species. The report on
`normal conjunctival flora preinjection also indicated
`fewer Streptococcus species (9 of 129 isolates, 7%,
`P = 0.0016).
`A funnel plot estimating endophthalmitis rates
`against the number of injections reported in each
`study is shown in Figure 1.34 Among 4 small studies
`with the number of injections ,2,000,
`there was
`a wide spread of overestimates of endophthalmitis
`rates, ranging from 0.24% to 0.55%. Among large
`studies with the number of injections ranging from
`3,125 to 30,746, the estimated rate of endophthalmitis
`ranged from 0.02% to 0.1%. Therefore, there may be
`‘‘small study effects’’ overestimating the endophthal-
`mitis rate, and it
`is unlikely that a systematic
`publication bias exists for reported rates of endoph-
`thalmitis after intravitreal anti-VEGF injections.
`
`Discussion
`
`This meta-analysis of endophthalmitis after intra-
`vitreal anti-VEGF injections found a significantly
`greater
`rate of endophthalmitis cases caused by
`Streptococcus species than has been reported for
`postoperative endophthalmitis. Streptococcus species,
`which comprise at least 41% culturable adult salivary
`flora,35,36 are thought to contaminate operative fields
`by aerosolization or droplet spread37–41 and may be
`related to the difference in causative organisms in
`these 2 settings.
`
`Staphylococcal organisms (coagulase-negative Staphy-
`lococcus, Staphylococcus aureus, and methicillin-resistant
`S. aureus) occur rather uniformly at rates of approximately
`70% to 80% across all studies (Tables 1–3), including the
`current meta-analysis of anti-VEGF injections (Table 1).
`However, the rate of Streptococcus species as a causative
`organism of postoperative endophthalmitis or preexisting
`colonization of the conjunctiva is in the range of 0% to 9%
`(Tables 2 and 3), which contrasts dramatically with the
`30.2% rate of streptococcal endophthalmitis after intra-
`vitreal injection (Table 1) found in the meta-analysis. This
`three to four times higher rate of endophthalmitis from
`Streptococcus species suggests that
`the spectrum of
`organisms is different than in the operating room setting
`and that Streptococcus species are more common
`causatives of endophthalmitis after intravitreal injection.
`A review of the ophthalmic literature indicates no
`explanation for the different streptococcal endoph-
`thalmitis rates after intravitreal anti-VEGF agents
`compared with the postoperative setting. However,
`there is compelling evidence that aerosol contamina-
`tion of the surgical field by respiratory flora may be
`contributory. Dural puncture (i.e., lumbar puncture for
`spinal anesthesia) is a procedure similar to intravitreal
`injection in that it involves needle penetration into
`a nutrient-rich body cavity in a nonoperating room
`setting. The rate of postdural puncture meningitis is
`low (0.2–1.8/10,000)42–44 compared with that of
`postintravitreal injection endophthalmitis (4.9/10,000
`in this meta-analysis).
`the factors that have been
`A closer
`look at
`determined to increase the risk of postdural puncture
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`meningitis may help ophthalmologists further reduce
`the risk of endophthalmitis after intravitreal injections.
`McLure et al40 and Phillips et al45 in similar studies
`investigated whether wearing soft pleated face masks
`affects agar dish contamination. These reports de-
`termined that the absence of a surgical mask was
`associated with a statistically significant increase in
`colonies per exposed plate. They recovered a-hemo-
`lytic Streptococci, nonhemolytic Streptococci, and
`coagulase-negative Staphylococci.40
`O’Kelly and Marsh39 and Phillips et al45 in similar
`studies investigated the effect of talking and wearing
`a face mask on agar plate contamination to assess
`procedure infection risk. In these studies, there was
`a significant
`increase in colony counts when not
`wearing a mask and talking compared with not talking
`or wearing a mask. Furthermore, O’Kelly and Marsh39
`suggest
`that not
`talking is nearly as effective as
`wearing a face mask in preventing agar plate
`contamination and thus reducing procedure infection
`risk from respiratory tract flora.
`Another procedure that is similar to an intravitreal
`injection is intraarticular injection. A recent report by
`Reeves and Hovart46 implicates the absence of a face
`mask as the likely cause of infection with a-hemolytic
`Streptococcus after an intraarticular knee injection. In
`this report, infection risk in a retrospective series of
`injections is associated with talking when no mask was
`worn.46
`There is also direct evidence that respiratory droplet
`transmission from the health care provider may be the
`source of procedure-related infection. Using molecu-
`lar techniques, causative organism of meningitis cases
`after dural puncture procedures was indistinguishable
`from those
`recovered
`from the
`procedurist’s
`mouth.37,41,47 Sheretz et al38 describe an outbreak of
`5 cases of methicillin-resistant S. aureus infections, 5
`cases of pneumonia, 1 case of bacteremia, and an
`additional 3 cases of colonization with methicillin-
`resistant S. aureus over a 3-week period. Investigation
`traced the probable source of
`the outbreak to
`a physician colonized with the same organism, and
`that during the outbreak, he had a viral upper
`respiratory infection (URI). Further investigation also
`showed that while this individual had very little
`‘‘bacterial shedding’’ when not experiencing a viral
`URI, he did shed a large amount of bacteria when
`purposely reinfected with a rhinovirus (Type 39). This
`observation suggests that viral URI increases bacterial
`shedding. A surgical mask was able to minimize
`dispersal of bacteria during the study of the URI
`episode.38
`lend critical evidence that
`These publications
`supports droplet or aerosol transmission of infections
`
`Thetabesummarzesthreerepresentatvestudesofpostoperatveendophthamts.Theastcoumnsummarzesthesoatesfromthecurrentmeta-anayssforcomparson.
`
`1•
`
`I
`
`—
`
`3.2–52.6%])
`[95%CI,
`
`1(14.3%
`
`4.8–18.5%])
`[95%CI,
`
`7(9.6%
`
`3.8–9.0%])
`[95%CI,
`
`19(5.9%
`
`Speces
`
`Gram-Negatve
`
`0.9–19.0%])
`[95%CI,
`
`16.5–50.2%])
`[95%CI,
`
`1(3.8%
`
`8(30.8%
`
`—
`
`3.0–15.1%])
`[95%CI,
`
`—
`
`3.9–16.8%])
`[95%CI,
`
`5(6.8%
`
`6(8.2%
`
`3.3–8.3%])
`[95%CI,
`
`17(5.3%
`
`Organsms
`
`Gram-Postve
`Msceaneous
`
`6.3–12.6%])
`[95%CI,
`
`29(9.0%
`
`—
`
`—
`
`3.0–15.1%])
`[95%CI,
`
`5(6.8%
`
`7.1–13.7%])
`[95%CI,
`
`32(9.9%
`
`46.0–80.6%])
`[95%CI,
`17(65.4%
`
`47.4–96.8%])
`[95%CI,
`
`6(85.7%
`
`57.1–78.0%])
`[95%CI,
`50(68.5%
`
`64.8–74.7%])
`[95%CI,
`
`26
`
`7
`
`73
`
`226(70%
`
`323
`
`settngmeta-anayss(currentstudy)
`ntheoffice
`afterntravtreanjecton
`
`Acuteendophthamts
`
`20-gaugevtrectomy31
`endophthamtsafter25-or
`
`Acutepostoperatve
`
`corneacataractsurgery30
`endophthamtsaftercear
`
`Acutepostoperatve
`
`VtrectomyStudy)29
`(Endophthamts
`endophthamts
`
`Acutepostoperatve
`
`Speces
`
`aureus
`
`Staphyococcus
`
`Isoates
`
`Streptococcus
`
`Staphylococcus
`
`Coaguase-Negatve
`
`Tabe2.RepresentatveStudesofPostoperatveEndophthamtsandtheReportedIsoates
`
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`ENDOPHTHALMITIS AND INTRAVITREAL INJECTION  MCCANNEL
`
`659
`
`Table 3. Conjunctival Flora Reported Recently
`
`Isolate
`Total
`
`Coagulase-Negative
`Staphylococcus
`
`Staphylococcus
`aureus
`
`Streptococcus
`Species
`
`Miscellaneous
`Gram-Positive
`Organisms
`
`Gram-Negative
`Organisms
`
`Conjunctival
`isolates32
`
`129
`
`98 (76%
`[95% CI,
`67.9–82.5%])
`
`9 (7%
`[95% CI,
`3.8–12.7%])
`
`9 (7%
`[95% CI,
`3.8–12.7%])
`
`6 (4.7%
`[95% CI,
`2.2–9.8%])
`
`8 (6.2%
`[95% CI,
`3.2–11.8%])
`
`Isolates in a recent study of conjunctival isolates in a patient population about to undergo intravitreal injection in the United States.
`
`by aerosolized bacteria from the oropharyngeal tract.
`Endophthalmitis is usually thought to originate from
`the patients’ flora.48 The causative
`organisms of
`organisms of endophthalmitis among several post-
`operative studies and a study of conjunctival isolates
`support
`the assumption that organisms from the
`patients’ flora caused endophthalmitis (Tables 2 and
`3). However, the same pattern does not hold for the
`causative organisms after intravitreal injection of anti-
`VEGF agents where this meta-analysis found a sub-
`stantially greater percentage of Streptococcus species.
`The limitations of this study include the retrospec-
`tive nature of the data considered in the meta-analysis,
`which may introduce bias. It is possible that not all
`cases of endophthalmitis were reported. In addition,
`meta-analyses are inherently subject to publication
`bias resulting from the possible lack of publications
`with negative findings (no reports of endophthalmitis)
`or possible lack of a broader experience because of
`limitations on total number of studies published on any
`one topic. Therefore, the rate of endophthalmitis and/
`
`or causative organism may be less accurate. Further-
`more, the speculation that aerosolized droplet con-
`tamination may be in part responsible for the relatively
`high rate of streptococcal endophthalmitis is supported
`by the literature on postdural puncture and intra-
`articular injections because no direct evidence from
`the ophthalmic literature exists.
`to be gained from
`There is valuable insight
`knowledge reported in the nonophthalmic literature
`regarding droplet transmission as a possible source of
`some cases of endophthalmitis,37–41,46 particularly that
`caused by potentially devastating Streptococcus
`species. Droplet or aerosol
`transmission may be
`enhanced by talking, coughing, or sneezing, and
`bacterial shedding may be exacerbated by URI.38
`Avoiding talking or wearing a face mask to minimize
`infection risk with intravitreal
`injections must be
`considered to mitigate the risk of droplet or aerosol
`transmission. Although published consensus state-
`ments on proper technique for intravitreal injections
`have not included the recommendation to wear a face
`
`35,000
`
`30,000
`
`Fig. 1. Funnel plot analysis
`to assess publication bias is
`shown.
`
`"' 25,000
`= =
`.: u
`..... = -.... = I,,,
`Q; 20,000
`!3 = z
`
`Q; 15,000
`.&;
`
`10,000
`
`5,000
`
`0
`
`0
`0.0%
`
`0.1%
`
`In
`
`0.4%
`0.3%
`0.2%
`Incidence of Endophthalmitis (%)
`
`0.5%
`
`0.6%
`
`Novartis Exhibit 2314.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`660
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES  2011  VOLUME 31  NUMBER 4
`
`mask,49,50
`the growing experience with cases of
`endophthalmitis and the presented evidence for oral
`flora as causative organisms for streptococcal endoph-
`thalmitis provide a strong case for wearing masks or at
`least eliminating talking during intravitreal injections.
`The Centers for Disease Control and Prevention’s
`Healthcare Infection Control Practices Advisory
`Committee issued recommendations in 2005 that for
`dural puncture procedures, a face mask should be
`worn.51
`In summary, this meta-analysis suggests that upper
`respiratory tract organisms are causative of endoph-
`thalmitis at a three to four times greater rate after
`intravitreal injection than after postcataract surgery or
`postvitrectomy cases of endophthalmitis. Thus,
`it
`seems
`likely that
`in at
`least
`some cases,
`the
`transmission of the organisms occurs by aerosolized
`upper respiratory tract organisms that contaminate the
`sterile injection field or the injection needle. Those
`performing intraocular
`injections should consider
`taking precautions against droplet contamination,
`such as not talking, talking with the mouth turned
`away from the field, or wearing a mask, especially if
`experiencing an URI, during intravitreal
`injection
`procedures. Such measures may help further reduce
`the already low rate of endophthalmitis after intra-
`vitreal injection. Further research to clarify the role of
`saliva droplet contamination in causing streptococcal
`endophthalmitis is warranted.
`
`Key words: bevacizumab, endophthalmitis, en-
`dophthalmitis pathogens, intravitreal injections, in-
`traocular
`injection,
`pegaptanib,
`ranibizumab,
`streptococcus endophthalmitis.
`
`Acknowledgments
`
`The author thanks Fei Yu, PhD, Research Scientist/
`Senior Statistician, Department of Biostatistics,
`UCLA School of Public Health, for his valuable and
`important contributions to this article.
`
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`
`Novartis Exhibit 2314.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`ENDOPHTHALMITIS AND INTRAVITREAL INJECTION  MCCANNEL
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