The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection
The Role of Topical Antibiotic Prophylaxis toPrevent Endophthalmitis after IntravitrealInjection
Philip Storey, MD, Michael Dollin, John Pitcher, MD,Sahitya Reddy, Joseph Vojtko, James Vander, MD,Jason Hsu, Sunir J. Garg, MD,the Post-Injection Endophthalmitis Study Team
To compare the incidence of endophthalmitis after intravitreal injection with and without topical
postinjection antibiotic prophylaxis.
All patients treated with intravitreal injection of ranibizumab, bevacizumab, or aflibercept for
a variety of retinal vascular diseases at a single, large retina practice between January 1, 2009, and October 1,2012, were included.
The total numbers of patients and injections were determined from a review of billing code and
practice management records. Endophthalmitis cases were determined from billing records and from an infectionlog. All cases of endophthalmitis were confirmed with chart review. A 28-month period when topical antibioticswere prescribed after intravitreal injection was compared with a 9-month period when topical antibiotics were notprescribed. Patients treated during an 8-month transition period were excluded to allow for the conversion ofantibiotic prescription practices.
Incidence of endophthalmitis, visual acuity outcomes, and microbial spectrum.
During the study period, a total of 117 171 intravitreal injections were performed (57 654 injections
during the topical antibiotic period, 24 617 during the transition period, and 34 900 during the no-antibioticperiod), with a total of 44 cases of suspected endophthalmitis (0.038%; 1 in 2663 injections), 17 of whichshowed culture-positive results (0.015%; 1 in 6892 injections). During the 28-month topical antibiotic period,there were 28 cases of suspected endophthalmitis (0.049%; 1 in 2059 injections), 10 of which showed culture-positive results (0.017%; 1 in 5765 injections). During the 9-month no-antibiotic period, there were 11 cases ofsuspected endophthalmitis (0.032%; 1 in 3173 injections), 4 of which showed culture-positive results (0.011%; 1in 8725 injections). Topical antibiotic use was associated with a trend toward increased risk of suspectedendophthalmitis (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.77e3.10) and culture-positive endoph-thalmitis (OR, 1.51; 95% CI, 0.47e4.83).
The incidence of endophthalmitis after intravitreal injection is low. Using postinjection topical
antibiotic drops does not reduce the risk of endophthalmitis developing and is associated with a trend towardhigher incidence of endophthalmitis. Ophthalmology 2014;121:283-289 ª 2014 by the American Academy ofOphthalmology.
*Group members listed online in Appendix 1 (available at
The use of intravitreal injections for eye disease has increased
demonstrated a reduction in postprocedure or postinjection
dramatically because of the efficacy of several medications,
endophthalmitis through use of prophylactic antibiotic
including steroids and antievascular endothelial growth
drops.Recent evidence suggests that topical antibiotics
factor (VEGF) agents. Although uncommon, postinjection
may even be harmful by increasing antibiotic-resistant
endophthalmitis can cause significant ocular morbidity.
bacterial strainsand may increase the risk of endoph-
Prophylactic measures, including the use of various topical
thalmitis.The previous studies were relatively small and may
antibiotics, have been used to reduce the incidence of
not have been powered adequately to detect a difference in
endophthalmitis incidence. Many physicians continue to
the standard of care after ocular surgery, and this
prescribe antibiotics after intravitreal injecThis study
practice was carried over to ocular injections. Although
evaluates the role of topical antibiotic prophylaxis after
topical antibiotics reduce conjunctival bacterial growth
intravitreal injection of anti-VEGF agents as well as the
and may have a possible synergistic effect when combined
microbial spectrum after injection in the largest series of
Ó 2014 by the American Academy of Ophthalmology
Before May 2011, all patients were prescribed postinjection topicalantibiotics to use 4 times daily for 4 days. As early as June 2011,
This single-center retrospective, comparative, case-control study
some physicians stopped using antibiotic prophylaxis, and on
was approved by the Wills Eye Institute Institutional Review
September 1, 2011, retinal physicians practicing at Wills Eye
Board. As part of an ongoing infection surveillance program, the
Institute adopted a practice-wide policy stopping use of post-
authors prospectively recorded endophthalmitis cases occurring
injection topical antibiotics. We considered May 1, 2011, through
after intravitreal injection secondary to intravitreal injection of
December 31, 2011, to be a transition period during which
bevacizumab (Genentech, South San Francisco, CA), ranibizumab
physicians and patients changed prophylaxis strategies. A review
(Genentech), triamcinolone, or aflibercept (Regeneron, Tarrytown,
of all endophthalmitis cases confirmed that all patients from
NY). The endophthalmitis log and billing records were used to
January 1, 2009, through April 30, 2011, received postinjection
identify retrospectively all cases of endophthalmitis treated with
antibiotics, whereas all patients from January 1, 2012, through
vitreous tap and injection between January 1, 2009, and October 1,
October 1, 2012, did not receive postinjection antibiotics. We did
2012, at a single retina practice. The total number of intravitreal
not include injections or endophthalmitis cases during the transi-
injections performed during the period was determined from billing
tion period in our analysis of endophthalmitis incidence. We did,
data. Charts of all patients who were treated for endophthalmitis
however, include transition period cases in our analysis of visual
were reviewed. Recorded data included date of causative injection;
date of tap and injection; visual acuity before causative injection, attime of tap and injection, at 3 months after the procedure, and at 6
months after the procedure; type of injection; lot number; under-lying diagnosis; culture results; and antibiotic resistance.
The primary outcome was occurrence of endophthalmitis afterintravitreal injection. Secondary outcomes were microbial spec-
trum and clinical outcomes including return to baseline visualacuity (plus or minus 2 lines of Snellen acuity), final visual acuity
All eyes with presumed infectious endophthalmitis following
of counting fingers or worse, and the presence of pain, vitreitis, or
intravitreal injection of an anti-VEGF medication were included.
hypopyon on initial presentation. Endophthalmitis results were
Endophthalmitis was defined as any case in which clinical suspi-
considered culture positive if there were positive gram stain or
cion was high enough to warrant tap and inject (typically decreased
positive growth results on culture plates. Clinical variables were
visual acuity, pain, !2þ anterior chamber cell, and vitreitis). Eyes
analyzed using Excel (Microsoft, Redmond, WA), and statistical
with presumed inflammatory endophthalmitis treated primarily
analysis was performed using GraphPad Software (GraphPad, La
with topical steroids without tap-and-inject treatment were
All injections were performed in office-based settings. Eyes wereprepped in a standardized method with a topical nonviscous
anesthetic, one topical antibiotic drop during the initial 28 monthsof the study period, topical 5% povidone
Between January 1, 2009, and October 1, 2012, a total of 117 171
Alcon Labs, Fort Worth, TX), followed by another drop of topical
intravitreal injections (71 791 ranibizumab, 44 007 bevacizumab,
anesthetic and another drop of 5% povidone
and 1373 aflibercept) were performed, and a total of 44 patients
tion. Rarely, a subconjunctival 2% lidocaine injection was
with suspected endophthalmitis after intravitreal injection under-
administered before the second administration of topical anesthetic
went vitreous tap with antibiotic injection (0.038%; 1 in 2663
injections). Seventeen cases showed culture-positive results
eiodine. A sterile drape and eyelash preparation
were not used. Injection with a 30- or 31-gauge needle was per-
(0.015%; 1 in 6892 injections). Overall rates of suspected
formed 3.5 to 4.0 mm from the limbus. Physicians individually
endophthalmitis were 24 in 71 791 injections for ranibizumab
determined use of a bladed lid speculum, conjunctival displace-
(0.033%; 1 in 2991 injections); 20 in 44 007 injections for bev-
ment before injection, and superior versus inferior injection site.
acizumab (0.045%; 1 in 2200 injections); and 0 in 1373 injectionsfor aflibercept. Overall rates of culture-positive endophthalmitis
were 12 in 71 791 for ranibizumab (0.017%; 1 in 5983 injections),5 in 44 007 for bevacizumab (0.011%; 1 in 8801 injections), and
All eyes with presumed infectious endophthalmitis immediately
0 in 1373 for aflibercept. There was no statistically significant
underwent a pars plana vitreous tap using a 25- or 27-gauge needle
difference in suspected or culture-positive endophthalmitis among
with attempted aspiration and subsequent injection of intravitreal
antibiotics. If the physician was unable to obtain vitreous fluid, an
During the 28-month period when postinjection topical antibi-
aqueous tap was performed. Patients received intravitreal vanco-
otics were prescribed, 57 654 injections (36 781 ranibizumab,
mycin (1 mg/0.1 ml) and ceftazidime (2 mg/0.1 ml). Intravitreal
20 873 bevacizumab, and 0 aflibercept) were administered and 28
amikacin (400 mg/0.1 ml) was substituted for ceftazidime for
cases of suspected endophthalmitis occurred (0.049%; 1 in 2059
patients with penicillin allergy. Subsequent intravitreal antibiotics
injections), 10 of which showed culture-positive results (0.017%; 1
were modified based on culture sensitivities. Patients variably were
in 5765 injections; Twenty-four eyes received anti-VEGF
prescribed atropine sulfate 1% drops twice daily as well as fortified
injection for neovascular age-related macular degeneration (AMD)
vancomycin (25 mg/ml), fortified tobramycin (15 mg/ml), and
and 4 received injection for macular edema secondary to retina
prednisolone acetate 1% drops every hour. Patients were followed
vein occlusion. Causative organisms included 4 cases of Strepto-
up daily until evidence of clinical improvement was apparent. At
coccus viridans, 2 cases of Enterococcus, 2 cases of coagulase-
that point, the drops were tapered slowly and the follow-up interval
negative Staphylococcus, and 1 case each of Staphylococcus
Storey et al Antibiotics to Prevent Endophthalmitis
Table 1. Suspected Endophthalmitis Cases and Antibiotic Prophylaxis Strategies
During the 8-month transition period, 24 617 injections (14 178
eyes vs. 13/13 no postintravitreal injection antibiotic eyes;
ranibizumab, 10 437 bevacizumab, and 2 aflibercept) were per-
P ¼ 1.0), vitreitis (23/31 postintravitreal injection antibiotic eyes
formed. Five cases of suspected endophthalmitis occurred
vs. 7/13 no postintravitreal injection antibiotic eyes; P ¼ 0.29), and
(0.020%; 1 in 4923), and 3 showed culture-positive results
hypopyon (24/31 postintravitreal injection antibiotic eyes vs. 7/13
(0.012%; 1 in 8206 injections). The 3 cases in which topical
no postintravitreal injection antibiotic eyes; P ¼ 0.16). Clinical
antibiotics were used all grew coagulase-negative Staphylococcus.
presentation of patients with culture-positive endophthalmitis did
No growth was found in the 2 cases in which no topical antibiotics
not differ with the use of topical antibiotics: all patients had
were prescribed. Three patients were being treated for neovascular
decreased vision and most reported pain (11/13 postintravitreal
AMD, whereas 2 patients received treatment for diabetic macular
injection antibiotic eyes vs. 4/4 no postintravitreal injection anti-
biotic eyes; P ¼ 1.0), vitreitis (12/13 postintravitreal injection
During the 9-month period in which postinjection antibiotics
antibiotic eyes vs. 3/4 no postintravitreal injection antibiotic eyes;
were not prescribed, 34 900 injections (20 832 ranibizumab, 12 697
P ¼ 0.43), and hypopyon (11/13 postintravitreal injection antibi-
bevacizumab, and 1371 aflibercept) were administered and 11
otic eyes vs. 3/4 no postintravitreal injection antibiotic eyes;
cases of suspected endophthalmitis occurred (0.032%; 1 in 3173
P ¼ 1.0). We found no statistically significant differences in
injections), 4 of which showed culture-positive results (0.011%; 1
clinical presentation between culture-positive versus culture-
in 8725 injections; All 11 cases of suspected
endophthalmitis received anti-VEGF injection for neovascularAMD. Causative organisms included 2 cases of S. viridans, 1 case
of S. aureus, and 1 case of nonspeciated gram-positive cocci ongram stain.
Mean follow-up for all suspected endophthalmitis cases was 20.7
Compared with the period in which no antibiotics were used,
months. Two of 44 patients (1 culture positive, 1 culture negative)
the use of postinjection topical antibiotics was associated with
had follow-up of less than 1 month and were excluded from visual
a trend toward increased incidence of both suspected endoph-
outcome analysis. Most eyes (54.8%; 23/42) returned to baseline
thalmitis (odds ratio, 1.54; 95% confidence interval, 0.77e3.10;
visual acuity (Æ2 lines of visual acuity) by 3 months after injection.
and culture-positive endophthalmitis (odds ratio, 1.51;
Four additional cases returned to baseline visual acuity by 6
months. We found that use of postinjection topical antibiotics didnot affect return to baseline visual acuity at 6 months (16/29
postintravitreal injection antibiotic eyes vs. 8/13 no postintravitrealinjection antibiotic eyes; P ¼ 0.75). There was also no difference
Overall, patients with presumed endophthalmitis reported pain,
between the 2 groups in the proportion of patients with visual
redness, or decreased vision an average of 3.7 days after injection
acuity of counting fingers or worse at 6 months (11/29 post-
(range, 1e11 days). Patients prescribed topical antibiotics sought
intravitreal injection antibiotic eyes vs. 6/13 no postintravitreal
treatment an average of 3.7 days after injection versus an average
injection antibiotic eyes up; P ¼ 0.74).
of 3.5 days for patients not prescribed antibiotics (P ¼ 0.82).
Visual acuity outcomes were significantly worse for culture-
Regardless of antibiotic prophylaxis strategy, culture-positive cases
positive cases compared with culture-negative cases, regardless
sought treatment an average of 3.6 days after injection, compared
of topical antibiotic use. At 6 months, only 18.8% of culture-
with 3.7 days for culture-negative cases (P ¼ 0.84). One culture-
positive cases (3/16) returned to baseline visual acuity compared
negative case was excluded from analysis because the patient’s
with 80.8% (21/26) of culture-negative cases (P < 0.001). At 6
nursing home delayed seeking care until 17 days after injection.
months, 62.5% of culture-positive cases (10/16) had vision of
Postinjection antibiotic use did not alter the clinical presentation
counting fingers or worse compared with 26.9% (7/26) of culture-
of patients with suspected or culture-positive endophthalmitis. For
negative cases (P ¼ 0.029). Visual outcomes of culture-positive
suspected endophthalmitis cases, all patients had decreased vision
and culture-negative cases are displayed in
and most reported pain (29/31 postintravitreal injection antibiotic
Table 2. Culture-Positive Endophthalmitis Cases and Antibiotic Prophylaxis Strategies
Table 3. Visual Acuity Outcomes for Culture-Positive Cases
CF ¼ counting fingers; HM ¼ hand movements; LP ¼ light perception; NLP ¼ no light perception.
antibiotics vs. 2/5266 or 0.038% no antibiotics; P ¼ 0.32). However, the study’s sample size was small, leading some
In this single-center, retrospective, case-control study, we
investigators to state that “the conclusions may be the result
compared endophthalmitis incidence during a 28-month
period when topical antibiotics were prescribed with
Given the increasing number of studies suggesting that
that during a 9-month period when no antibiotics were
topical antibiotics after intravitreal injection do not prevent
prescribed, separated by an 8-month transition period as
endophthalmitis, some investigators believe that there is no
providers and patients altered prophylaxis practices. We
need for topical antibiotic use after intravitreal injection.
found that postinjection topical antibiotics did not decrease
In 2012, the American Academy of Ophthalmology joined
endophthalmitis incidence and that the clinical presentation
the Choosing Wisely campaign initiated by the American
and visual outcomes of patients with suspected endoph-
Board of Internal Medicine Foundation to create a list of
thalmitis were similar regardless of whether postinjection
Five Things Physicians and Patients Should Question.The
topical antibiotics were used initially.
Previous studies comparing topical antibiotics prescribed
routinely providing antibiotics before or after intravitreal
for several days after injection with no topical antibiotics
injections” as a possible intervention to eliminate
have not found statistically significant differences in
unnecessary costsHowever, there are variable data on
endophthalmitis rates, although all had relatively small
the usefulness of postinjection antibiotics to prevent
sample sizes. Bhatt et concluded that there was
endophthalmitis, and therefore no current guidelines
no difference in rates of suspected endophthalmitis with
recommending for or against their use.
Our study aimed to evaluate the effect of prophylactic
with antibiotics vs. 5/2480 or 0.20% no antibiotics; P ¼
antibiotics in the largest series to date. Our study confirmed
0.90). Cheung et alconcluded that the overall rate of
the finding of Cheung et alof greater incidence of
intravitreal injection-related endophthalmitis is greater with
the use of topical antibiotics compared with no antibiotics
antibioticsdalthough neither study found the increased
(5/8259 or 0.061% with 5 days of antibiotics vs. 2/5266 or
risk to be statistically significant. Although our infection
0.038% with no antibiotics; P ¼ 0.57). Cheung et al also
rates were lower, we found a similarly sized increased risk
concluded that if only culture-positive endophthalmitis
of endophthalmitis with the use of topical antibiotics
cases were considered, the use of topical antibiotics showed
(odds ratio, 1.54 in the current study vs. 1.59 in the study
by Cheung et al). In contrast to Cheung et al, we found
receiving no antibiotics (1/8259 or 0.012% with 5 days of
that topical antibiotics also were associated with a trend
Storey et al Antibiotics to Prevent Endophthalmitis
Table 4. Visual Acuity Outcomes for Culture-Negative Cases
CF ¼ counting fingers; HM ¼ hand movements; LP ¼ light perception; NLP ¼ no light perception.
toward increased risk of culture-positive endophthalmitis.
There has been much speculation concerning the potential
We found no difference in rates of suspected or culture-
increased association of intravitreal injections with oral
positive endophthalmitis between anti-VEGF agents.
flora. Oropharyngeal droplet transmission may be the cause
Several possibilities may explain the trend toward
of this increased risk of Streptococcus infection after
increased endophthalmitis rates with topical antibiotic use.
injection. One difference between intravitreal injections and
Several studies have shown that topical antibiotics lead to an
other ocular procedures is that injections often are per-
increase in resistant organisms. Milder et showed that
formed in the office, often with no masking of the physi-
cian, patient, or technician. In contrast, all persons in the
intravitreal injection resulted in a significantly increased
operating room are masked and the patient is draped. A
rate of bacterial resistance (63.6%) compared with control
recent study found that rates of postintravitreal injection
eyes (32.1%). Kim et aldemonstrated substantial
endophthalmitis were lower when the procedure was per-
levels of resistance to third- and fourth-generation fluo-
formed in the operating room as compared with in
roquinolones as well as multidrug resistance in patients
the office.One suggested strategy to reduce droplet
treated with topical antibiotics after multiple intravitreal
transmission is talking cessation. However, this has the
injections. Cultures from eyes with endophthalmitis have
inherent limitation of prohibiting communication between
shown a higher incidence of antibiotic resistance among
the physician and patient during the procedure and could
bacterial isoland resistant bacterial strains have
increase the potential for incorrect site procedures. Our
been found to cause more severe ocular inflammation than
study was not designed to evaluate the role of other
Several recent studies have found that organisms typi-
cally associated with oral flora are more prevalent with
Strengths of this study include the large number of
endophthalmitis occurring after intravitreal injection than
intravitreal injections performed by a single retina group
after other vitreoretinal pOur study also
over a fairly short period. A potential limitation of this
found that oropharyngeal organisms were more common
study is its retrospective, case-control nature. However,
after intravitreal injection than in reports of other eye
identification of endophthalmitis cases did not depend on
proceduFor the 17 culture-positive cases of endoph-
physician recall. All cases were identified using a combi-
thalmitis, 6 cases grew Streptococcus species (35.3%).
nation of a prospective endophthalmitis log, as well as
from billing records and chart review of all patients treated
intravitreal triamcinolone injection in the DRCRnet and
for endophthalmitis resulting from any cause during
SCORE clinical trials. Am J Ophthalmol 2007;144:454–6.
the study period. Adherence to antibiotic drop use after
6. Bhavsar AR, Googe JM Jr, Stockdale CR, et al. Diabetic
injection was not assessed during the period when antibi-
Retinopathy Clinical Research Network. Risk of endoph-
otics were prescribed. If antibiotics do increase rates of
topical antibiotics are not required: the Diabetic Retinop-
endophthalmitis, nonadherence to topical antibiotics would
tend to underestimate the incidence of endophthalmitis in
triamcinolone clinical trials. Arch Ophthalmol 2009;127:
the antibiotic use group. Conversely, some patients could
have continued to use antibiotic drops even after being
7. Kim SJ, Toma HS. Antimicrobial resistance and ophthalmic
instructed not to do so. An 8-month transition period was
antibiotics: 1-year results of a longitudinal controlled study of
included in the study design to limit this potential source of
patients undergoing intravitreal injections. Arch Ophthalmol
endophthalmitis and sought treatment elsewhere, but given
8. Milder E, Vander J, Shah C, Garg S. Changes in antibiotic
the tertiary care nature of our practice, this is less likely,
resistance patterns of conjunctival flora due to repeated use of
and we know of no instances in which this occurred.
topical antibiotics after intravitreal injection. Ophthalmology2012;119:1420–4.
Finally, retina specialists involved in the study knew that
9. Cheung CS, Wong AW, Lui A, et al. Incidence of endoph-
topical antibiotic prophylaxis was discontinued at a specific
thalmitis and use of antibiotic prophylaxis after intravitreal
time. It is possible that physicians increased precautions
injections. Ophthalmology 2012;119:1609–14.
(e.g., extra povidoneeiodine, refraining from talking,
10. Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal
change in speculum use) after topical antibiotic use was
injection techniques among retinal specialists in the United
discontinued. However, no retina specialists reported
States. Am J Ophthalmol 2011;151:329–32.
increasing their customary precautions after stopping
11. Kulkarni AA, Altaweel MM, Tewari A. Comment on: Cheung
prophylactic antibiotic use. Furthermore, physicians were
CS, Wong AW, Lui A, et al. Incidence of endophthalmitis and
unaware that a study would evaluate the effect of
use of antibiotic prophylaxis after intravitreal injections.
prophylactic antibiotics, making an unmasking bias less
Ophthalmology 2012;119:1609e14. In: American Societyof Retina Specialists October Literature Roundup. April 2012.
Although the probability of developing endophthalmitis
after intravitreal injection is low, treatment of AMD, retinal
vein occlusions, and diabetic macular edema can require
12. Chen RW, Rachitskaya A, Scott IU, Flynn HW. Is the use of
years of repeated injections. Consequently, ophthalmolo-
topical antibiotics for intravitreal injections the standard of
gists have attempted to prevent infection through a number
care or are we better off without antibiotics? JAMA Oph-
of measures, including prophylactic topical antibiotics. Our
study adds to the current body of literature indicating that
13. Cassel CK, Guest JA. Choosing wisely: helping physicians
postinjection topical antibiotics do not decrease rates of
and patients make smart decisions about their care. JAMA
endophthalmitis. Given evidence suggesting potential harm
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of topical antibiotics and a potential increase in endoph-
wisely: five ideas that physicians and patients can discuss.
thalmitis rates with their use, we recommend against the
routine use of topical antibiotics after intravitreal injection.
15. Kim SJ, Toma HS, Midha NK, et al. Antibiotic Resistance of
Conjunctiva and Nasopharynx Evaluation Study: a prospective
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16. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone
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Storey et al Antibiotics to Prevent Endophthalmitis
Presented at: Wills Eye Hospital Annual Conference, 2013; Retina Society
Annual Meeting, 2013; and as a poster at: Association for Research in
Vision and Ophthalmology Annual Meeting, 2013; and American Academy
of Ophthalmology Annual Meeting, November 2013, New Orleans, LA.
1 The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, The
Retina Service of Wills Eye Hospital, Thomas Jefferson University, Phil-
The author(s) have no proprietary or commercial interest in any materials
2 Department of Ophthalmology, Thomas Jefferson University, Phila-
Sunir J. Garg, MD, Mid Atlantic Retina, The Retina Service of Wills Eye
Hospital, Thomas Jefferson University, 840 Walnut Street, Suite 1020,
available online in appendix 1 All members of the
PIE Study Team are from The Retina Service of Wills Eye Hospital,MidAtlantic Retina, Thomas Jefferson University, Philadelphia, PA.
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