The Role of Topical Antibiotic Prophylaxis to Prevent Endophthalmitis After Intravitreal Injection

The Role of Topical Antibiotic Prophylaxis to Prevent Endophthalmitis after Intravitreal Injection

Philip Storey, MD, MPH,1 Michael Dollin, MD,1 John Pitcher, MD,1 Sahitya Reddy, BA,2 Joseph Vojtko, BA,2 James Vander, MD,1 Jason Hsu, MD,1 Sunir J. Garg, MD,1for the Post-Injection Endophthalmitis Study Team*

Objective: To compare the incidence of endophthalmitis after intravitreal injection with and without topical postinjection antibiotic prophylaxis. Design: Retrospective case-control study. Participants: 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. Methods: 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 infection log. All cases of endophthalmitis were confirmed with chart review. A 28-month period when topical antibiotics were prescribed after intravitreal injection was compared with a 9-month period when topical antibiotics were not prescribed. Patients treated during an 8-month transition period were excluded to allow for the conversion of antibiotic prescription practices. Main Outcome Measures: Incidence of endophthalmitis, visual acuity outcomes, and microbial spectrum. Results: 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-antibiotic period), with a total of 44 cases of suspected endophthalmitis (0.038%; 1 in 2663 injections), 17 of which showed 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 of suspected endophthalmitis (0.032%; 1 in 3173 injections), 4 of which showed culture-positive results (0.011%; 1 in 8725 injections). Topical antibiotic use was associated with a trend toward increased risk of suspected endophthalmitis (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.77e3.10) and culture-positive endophthalmitis (OR, 1.51; 95% CI, 0.47e4.83). Conclusions: 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 toward higher incidence of endophthalmitis. Ophthalmology 2014;121:283-289 ª 2014 by the American Academy of Ophthalmology.

*Group members listed online in Appendix 1 (available at http://aaojournal.org).

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.4e6 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.1 bacterial strains7,8 and may increase the risk of endoph- Prophylactic measures, including the use of various topical thalmitis.9 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. Topical antibiotics long have been endophthalmitis incidence. Many physicians continue to the standard of care after ocular surgery, and this prescribe antibiotics after intravitreal injection.10 This study practice was carried over to ocular injections. Although evaluates the role of topical antibiotic prophylaxis after topical antibiotics reduce conjunctival bacterial growth2 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 with povidoneeiodine,3 no randomized trials have intravitreal injections to date.

2014 by the American Academy of Ophthalmology ISSN 0161-6420/14/$ - see front matter 283 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2013.08.037 Ophthalmology Volume 121, Number 1, January 2014

Methods Transition Period Overview Before May 2011, all patients were prescribed postinjection topical antibiotics 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; outcomes and bacterial spectrum. date of tap and injection; visual acuity before causative injection, at time of tap and injection, at 3 months after the procedure, and at 6 Outcomes months after the procedure; type of injection; lot number; under- lying diagnosis; culture results; and antibiotic resistance. The primary outcome was occurrence of endophthalmitis after intravitreal injection. Secondary outcomes were microbial spec- Inclusion and Exclusion Criteria trum and clinical outcomes including return to baseline visual acuity (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. fi hypopyon on initial presentation. Endophthalmitis results were Endophthalmitis was de ned 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 fl analyzed using Excel (Microsoft, Redmond, WA), and statistical with presumed in ammatory endophthalmitis treated primarily analysis was performed using GraphPad Software (GraphPad, La with topical steroids without tap-and-inject treatment were Jolla, CA). excluded from analysis. Injection Technique Results All injections were performed in office-based settings. Eyes were prepped in a standardized method with a topical nonviscous Effect of Antibiotics anesthetic, one topical antibiotic drop during the initial 28 months of the study period, topical 5% povidoneeiodine (Betadine 5%; 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, fl anesthetic and another drop of 5% povidoneeiodine before injec- and 1373 a ibercept) 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 and 5% povidoneeiodine. A sterile drape and eyelash preparation injections). Seventeen cases showed culture-positive results 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 injections for aflibercept. Overall rates of culture-positive endophthalmitis Endophthalmitis Treatment Protocol 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 the various agents. 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; Table 1). 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 was extended. aureus and Lactobacillus.

284 Storey et al Antibiotics to Prevent Endophthalmitis

Table 1. Suspected Endophthalmitis Cases and Antibiotic Prophylaxis Strategies

Prophylactic Topical Antibiotics No Prophylactic Antibiotics Intravitreal Medication Injections Cases (Incidence) Injections Cases (Incidence) Odds Ratio (95% Conﬁdence Interval) Ranibizumab 36 781 16 (0.044%) 20 832 7 (0.034%) 1.29 (0.53e3.15) Bevacizumab 20 873 12 (0.057%) 12 697 4 (0.032%) 1.83 (0.59e5.66) Aﬂibercept 0 0 1371 0 d Total 57 654 28 (0.049%) 34 900 11 (0.032%) 1.54 (0.77e3.10)

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- edema. 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; Table 1). All 11 cases of suspected negative cases. endophthalmitis received anti-VEGF injection for neovascular AMD. Causative organisms included 2 cases of S. viridans, 1 case of S. aureus, and 1 case of nonspeciated gram-positive cocci on Visual Outcomes gram 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 fi e thalmitis (odds ratio, 1.54; 95% con dence interval, 0.77 3.10; visual acuity (2 lines of visual acuity) by 3 months after injection. Table 1) and culture-positive endophthalmitis (odds ratio, 1.51; Four additional cases returned to baseline visual acuity by 6 fi e 95% con dence interval, 0.47 4.83; Table 2). months. We found that use of postinjection topical antibiotics did not affect return to baseline visual acuity at 6 months (16/29 Clinical Outcomes postintravitreal injection antibiotic eyes vs. 8/13 no postintravitreal injection 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 Tables 3 and 4, and most reported pain (29/31 postintravitreal injection antibiotic respectively.

Table 2. Culture-Positive Endophthalmitis Cases and Antibiotic Prophylaxis Strategies

Prophylactic Topical Antibiotics No Prophylactic Antibiotics Intravitreal Medication Injections Cases (Incidence) Injections Cases (Incidence) Odds Ratio (95% Conﬁdence Interval) Ranibizumab 36 781 8 (0.022%) 20 832 3 (0.014%) 1.51 (0.40e5.69) Bevacizumab 20 873 2 (0.010%) 12 697 1 (0.0079%) 1.22 (0.11e13.4) Aﬂibercept 0 0 1371 0 d Total 57 654 10 (0.017%) 34 900 4 (0.011%) 1.51 (0.47e4.83)

285 Ophthalmology Volume 121, Number 1, January 2014

Table 3. Visual Acuity Outcomes for Culture-Positive Cases

Visual Acuity Postinjection Topical At 3 Months after At 6 Months after Patient No. Agent Antibiotics Used At Injection At Presentation Endophthalmitis Endophthalmitis Culture Results 1 Ranibizumab Yes 20/300 HM NLP NLP Streptococcus viridans 2 Bevacizumab Yes 20/200 HM 20/200 CF Coagulase- negative staphylococcus 3 Ranibizumab Yes 20/100 NLP NLP NLP Enterococcus faecalis 4 Ranibizumab Yes 20/200 LP 20/400 20/400 Enterococcus faecalis 5 Ranibizumab Yes 20/200 HM CF 20/400 Staphylococcus aureus 6 Ranibizumab Yes 20/40 20/400 CF CF Streptococcus mitis 7 Ranibizumab Yes 20/40 CF CF HM Streptococcus veridans 8 Ranibizumab Yes 20/200 HM LP HM Streptococcus mitis 9 Bevacizumab Yes 20/100 HM Lost to follow-up Lost to follow-up Lactobacillus 10 Ranibizumab Yes 20/30 HM 20/80 20/60 Coagulase- negative staphylococcus 11 Ranibizumab Yes (transition 20/30 HM HM 20/50 Coagulase- negative period) staphylococcus 12 Bevacizumab Yes (transition 20/20 HM 20/70 20/40 Coagulase- negative period) staphylococcus 13 Bevacizumab Yes (transition 20/40 HM 20/50 HM Coagulase- negative period) staphylococcus 14 Bevacizumab No 20/80 HM NLP NLP Streptococcus salivarius 15 Ranibizumab No CF LP LP LP Streptococcus sanguis 16 Ranibizumab No 20/20 HM 20/70 20/50 Nondifferentiated gram-positive cocci 17 Ranibizumab No 20/40 HM CF CF Staphylococcus aureus

CF ¼ counting ﬁngers; HM ¼ hand movements; LP ¼ light perception; NLP ¼ no light perception.

Discussion 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 11 compared endophthalmitis incidence during a 28-month of a random sampling error.” 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 11,12 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 13 thalmitis were similar regardless of whether postinjection Five Things Physicians and Patients Should Question. The topical antibiotics were used initially. American Academy of Ophthalmology listed “[not] 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 14 have not found statistically significant differences in unnecessary costs. However, there are variable data on endophthalmitis rates, although all had relatively small the usefulness of postinjection antibiotics to prevent sample sizes. Bhatt et al4 concluded that there was endophthalmitis, and therefore no current guidelines no difference in rates of suspected endophthalmitis with recommending for or against their use. or without topical antibiotics (5/2287 or 0.22% 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 9 0.90). Cheung et al9 concluded that the overall rate of the finding of Cheung et al of greater incidence of intravitreal injection-related endophthalmitis is greater with endophthalmitis with the use of topical 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 lower endophthalmitis rates compared with patients 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

286 Storey et al Antibiotics to Prevent Endophthalmitis

Table 4. Visual Acuity Outcomes for Culture-Negative Cases

Visual Acuity Postinjection Topical At 3 Months At 6 Months after Patient No. Agent Antibiotics Used At Injection At Presentation after Endophthalmitis Endophthalmitis 18 Bevacizumab Yes 20/100 CF 20/80 20/200 19 Bevacizumab Yes 20/70 HM CF 20/70 20 Ranibizumab Yes 20/50 HM 20/100 20/100 21 Bevacizumab Yes 20/70 HM 20/100 20/50 22 Bevacizumab Yes 20/200 HM CF CF 23 Bevacizumab Yes 20/200 HM 20/400 20/200 24 Bevacizumab Yes 20/200 HM 20/300 20/200 25 Bevacizumab Yes 20/30 20/250 20/30 20/30 26 Ranibizumab Yes 20/30 20/400 20/50 20/60 27 Bevacizumab Yes 20/30 HM 20/30 20/30 28 Bevacizumab Yes CF CF CF CF 29 Ranibizumab Yes 20/200 HM Lost to follow-up Lost to follow-up 30 Ranibizumab Yes 20/400 CF 20/400 20/400 31 Ranibizumab Yes 20/40 LP CF CF 32 Ranibizumab Yes 20/60 HM 20/100 20/100 33 Bevacizumab Yes 20/30 CF 20/30 20/40 34 Ranibizumab Yes 20/60 20/200 20/60 20/30 35 Ranibizumab Yes 20/125 HM LP NLP 36 Bevacizumab No (transition period) CF CF 20/60 20/60 37 Bevacizumab No (transition period) CF CF 20/400 20/400 38 Bevacizumab No 20/100 20/200 20/50 20/60 39 Ranibizumab No 20/40 CF 20/70 20/70 40 Ranibizumab No 20/400 CF CF CF 41 Bevacizumab No 20/40 CF 20/40 CF 42 Bevacizumab No 20/40 CF CF 20/60 43 Ranibizumab No 20/50 20/80 20/50 20/30 44 Ranibizumab No CF HM CF CF

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 al8 showed that formed in the office, often with no masking of the physi- repeated use of topical fluoroquinolone drops after 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 al15 demonstrated 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.21 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 isolates,16,17 and 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 sensitive strains.18 strategies such as wearing protective masks during Several recent studies have found that organisms typi- intravitreal procedures. 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 procedures.1,7,19 Our 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 procedures.20 For 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

287 Ophthalmology Volume 121, Number 1, January 2014 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 thalmitis after intravitreal drug injection when topical antibiotics are not required: the Diabetic Retinop- endophthalmitis, nonadherence to topical antibiotics would athy Clinical Research Network laser-ranibizumab- tend to underestimate the incidence of endophthalmitis in triamcinolone clinical trials. Arch Ophthalmol 2009;127: the antibiotic use group. Conversely, some patients could 1581–3. 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 bias. Additionally, a patient could have developed 2011;129:1180–8. endophthalmitis and sought treatment elsewhere, but given 8. Milder E, Vander J, Shah C, Garg S. Changes in antibiotic fl the tertiary care nature of our practice, this is less likely, resistance patterns of conjunctival ora due to repeated use of and we know of no instances in which this occurred. topical antibiotics after intravitreal injection. Ophthalmology 2012;119:1420–4. Finally, retina specialists involved in the study knew that fi 9. Cheung CS, Wong AW, Lui A, et al. Incidence of endoph- topical antibiotic prophylaxis was discontinued at a speci c 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 use of antibiotic prophylaxis after intravitreal injections. unaware that a study would evaluate the effect of e prophylactic antibiotics, making an unmasking bias less Ophthalmology 2012;119:1609 14. In: American Society of Retina Specialists October Literature Roundup. April 2012. likely. Available at: http://www.asrs.org/patients/retina-news/literature- Although the probability of developing endophthalmitis roundup/91/october-literature-roundup. Accessed August 18, after intravitreal injection is low, treatment of AMD, retinal 2013. 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 thalmol 2013;131:840–2. study adds to the current body of literature indicating that 13. Cassel CK, Guest JA. Choosing wisely: helping physicians and patients make smart decisions about their care. JAMA postinjection topical antibiotics do not decrease rates of – endophthalmitis. Given evidence suggesting potential harm 2012;307:1801 2. 14. Parke DW II, Coleman AL, Rich WL III, Lum F. Choosing 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 Ophthalmology 2013;120:443–4. 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 References study of patients undergoing intravitreal injections. Ophthal- mology 2010;117:2372–8. 16. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone 1. Shah CP, Garg SJ, Vander JF, et al. Post-Injection Endoph- resistance in staphylococcal endophthalmitis isolates. Arch thalmitis (PIE) Study Team. Outcomes and risk factors Ophthalmol 2006;124:479–83. associated with endophthalmitis after intravitreal injection of 17. Yin VT, Weisbrod DJ, Eng KT, et al. Antibiotic resistance of anti-vascular endothelial growth factor agents. Ophthalmology ocular surface flora with repeated use of a topical antibiotic 2011;118:2028–34. after intravitreal injection. JAMA Ophthalmol 2013;131: 2. Moss JM, Sanislo SR, Ta CN. A prospective randomized 456–61. evaluation of topical gatifloxacin on conjunctival flora in 18. Hooper DC. Fluoroquinolone resistance among gram-positive patients undergoing intravitreal injections. Ophthalmology cocci. Lancet Infect Dis 2002;2:530–8. 2009;116:1498–501. 19. McCannel CA. Meta-analysis of endophthalmitis after intra- 3. Ta CN, Egbert PR, Singh K, et al. 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288 Storey et al Antibiotics to Prevent Endophthalmitis Footnotes and Financial Disclosures

Originally received: May 29, 2013. Presented at: Wills Eye Hospital Annual Conference, 2013; Retina Society Final revision: August 24, 2013. Annual Meeting, 2013; and as a poster at: Association for Research in Accepted: August 27, 2013. Vision and Ophthalmology Annual Meeting, 2013; and American Academy Available online: October 21, 2013. Manuscript no. 2013-861. of Ophthalmology Annual Meeting, November 2013, New Orleans, LA. 1 The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, The Financial Disclosure(s): Retina Service of Wills Eye Hospital, Thomas Jefferson University, Phil- The author(s) have no proprietary or commercial interest in any materials adelphia, Pennsylvania. discussed in this article. 2 Department of Ophthalmology, Thomas Jefferson University, Phila- Correspondence: delphia, Pennsylvania. Sunir J. Garg, MD, Mid Atlantic Retina, The Retina Service of Wills Eye *A full listing of The Post-Injection Endophthalmitis (PIE) Study Team is Hospital, Thomas Jefferson University, 840 Walnut Street, Suite 1020, available online in appendix 1 (http://aaojournal.org). All members of the Philadelphia, PA 19107. E-mail: [email protected]. PIE Study Team are from The Retina Service of Wills Eye Hospital, MidAtlantic Retina, Thomas Jefferson University, Philadelphia, PA.

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