Effectiveness and Safety of an Intracameral Injection Of

Research

Original Investigation Effectiveness and Safety of an Intracameral Injection of Cefuroxime for the Prevention of Endophthalmitis After Cataract Surgery With or Without Perioperative Capsular Rupture

Vincent Daien, MD, PhD; Laurence Papinaud, MD; Mark C. Gillies, MBBS, PhD, FRANZCO; Caroline Domerg, MS; Nicolas Nagot, MD, PhD; Sandy Lacombe, MS; Jean Pierre Daures, MD, PhD; Isabelle Carriere, PhD; Max Villain, MD, PhD

IMPORTANCE Postoperative endophthalmitis (POE) often results in severe visual impairment. In clinical studies, an intracameral cefuroxime injection at the end of surgery was found to be effective at reducing the incidence of POE. Two important issues are the retinal safety of cefuroxime and its use for patients with perioperative capsular rupture where the risk of POE is dramatically increased.

OBJECTIVE To assess the effectiveness and retinal safety of an intracameral injection of cefuroxime sodium for the prevention of POE and its possible use in cases of a perioperative capsular rupture of the lens.

DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of patients 40 years of age or older who underwent cataract surgery at 1 of 1546 French health care facilities, public or private, and whose medical records were obtained from the national administrative database. Data analyses were performed between March and November 2015.

MAIN OUTCOMES AND MEASURES The effectiveness and safety of the prophylactic injection of cefuroxime as measured by the incidence of POE and cystoid macular edema.

RESULTS From January 2010 to October 2014, a total of 3 351 401 eyes of 2 434 008 patients 40 years of age or older (58.9% were women, and the mean [SD] age was 73.9 [9.5] years) underwent cataract surgery; 1941 patients (0.08%) developed POE during the 6 weeks after cataract surgery. The incidence of POE after cataract surgery decreased over the course of the study (0.11%, 0.09%, 0.08%, 0.06%, and 0.05% in 2010, 2011, 2012, 2013, and 2014, respectively [P = .001 for trend]) as the use of cefuroxime prophylactic injections increased (11.1%, 14.4%, 32.8%, 64.8%, and 79.1% in 2010, 2011, 2012, 2013, and 2014, respectively [P = .001 for trend]). After multivariate adjustment, the risk of POE was reduced with the use of cefuroxime (odds ratio, 0.61 [95% CI, 0.56-0.68]). The retinal safety of an injection of cefuroxime, which was assessed by multiadjusted odds of retinal cystoid macular edema, was not increased for patients receiving cefuroxime injections (odds ratio, 0.86 [95% CI, 0.71-1.05]). For patients with a perioperative capsular rupture of the lens (the major risk factor for POE), the incidence of POE was lower for those who received an injection of cefuroxime than for those who did not (0.37% vs 0.51%, respectively [P = .001]), whereas an increased risk of cystoid macular edema was not identified for those who received or did not receive an injection of cefuroxime (5.6% vs 7.3%, respectively [P = .12]).

CONCLUSIONS AND RELEVANCE These data suggest that, in routine practice, the intracameral injection of cefuroxime at the conclusion of cataract surgery is associated with a lower risk of Author Affiliations: Author POE and is safe for patients with or without a perioperative capsular rupture. While these affiliations are listed at the end of this article. data might be used to support the consideration of its routine use to prevent POE, in the absence of a randomized clinical trial, they cannot prove a direct cause-and-effect Corresponding Author: Vincent Daien, MD, PhD, Department of relationship between the injection of cefuroxime and POE. Ophthalmology, Hôpital Gui de Chauliac, CHU de Montpellier, 80, avenue Augustin Fliche, 34295 JAMA Ophthalmol. 2016;134(7):810-816. doi:10.1001/jamaophthalmol.2016.1351 Montpellier CEDEX 5, France Published online May 2, 2016. ([email protected]).

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lthough cataract surgery is highly effective and relatively safe, surgical complications are still a major Key Points source of morbidity as a result of the high case load and A Question Is the intracameral injection of cefuroxime at the end 1 increasing number of cataract operations. The 3 most severe of cataract surgery with or without perioperative capsular rupture complications are retinal detachment, with a 4-year cumula- effective and safe? tive risk of 0.99%,2 cystoid macular edema (CME), with an in- Findings In this population-based cohort study, the risk of cidence of 0.95%,3 and endophthalmitis. postoperative endophthalmitis was reduced with the use of In general, postoperative endophthalmitis (POE) appears cefuroxime. The risk of cystoid macular edema was not increased unexpectedly and often results in severe visual impairment, for patients receiving an injection of cefuroxime. with one-third of patients recovering 6/18 visual acuity or less.4 Meaning This study suggests that an intracameral injection of Risk factors for POE include older age (≥85 years), male sex, cefuroxime is associated with a lower risk of postoperative 5,6 perioperative complications, and clear corneal incision. The endophthalmitis, but the design precludes evaluation of a incidence of POE ranges from 0.04% to 0.8%7-10 and has in- cause-and-effect relationship between the injection of cefuroxime creased significantly from 2000 to 2003 (0.265%) compared and postoperative endophthalmitis. with the previous decade (0.087% in the 1990s), probably because of a switch to clear corneal incisions.7-10 ary 2010 and October 2014 and its associations with the in- Swedish ophthalmologists began routinely using intra- tracameral injection of cefuroxime at the end of cataract sur- cameral injections of cefuroxime sodium as prophylaxis against gery, together with other classical risk factors of POE. The POE in 2002 with very good results.11 In a multicenter study secondary objective was to assess the retinal safety of this type of 13 698 patients conducted by the European Society of Cata- of injection and its possible use in cases of a perioperative cap- ract and Refractive Surgeons between 2003 and 2006, the use sular rupture of the lens. of intracameral injections of cefuroxime at the end of the surgery was found to be effective, reducing the incidence of POE 5-fold.12 Methods Currently, there is no current single standard for the use of cefuroxime as prophylaxis against POE. The authors of a The study protocol was approved by the national health au- Cochrane database systematic review, published in 2013 and thority in France and by the ethics committee of the Univer- including 100 876 adults and 131 cases of endophthalmitis, rec- sity Hospital of Montpellier, France. Informed consent was not ommended the use of intracameral injections of cefuroxime.13 provided because the data were deidentified. The use of intracameral antibiotics in the United States is considered off-label and not yet approved by the US Food and Drug Population-Based Cohort Study Administration.14 In a study conducted in California, 20.1% of Data Source surgeons used cefuroxime.9 The data for all patients 40 years of age or older who under- Surgeons not using cefuroxime as prophylaxis against POE went cataract surgery in France (65 million inhabitants) be- expressed concern about the risks induced by noncommer- tween January 2010 and October 2014 were collected from the cially prepared antibiotic preparations.15 More specifically, they Programme de Médicalisation des Systèmes d'Information mentioned reports of retinal toxicity as reflected by in- (PMSI) and from Extraction Recherches Analyses pour un Suivi creased rates of CME occurring after a high dose of cefurox- Médico-Economique. Since 2004, the PMSI compiles dis- ime, with each case of retinal toxicity due to dilution errors in charge abstracts related to all admissions in the 1546 French preparing the cefuroxime solution.16-20 health care facilities, public or private. The information in these The main perioperative complication of cataract surgery abstracts covers both medical and administrative data. These is the capsular rupture of the lens that often results in out- data are anonymized with regard to the names of patients and comes of poor visual acuity21 and increases the risk of CME,22 physicians. Routinely collected medical data include the prin- as well as POE, 6-fold.10 When this event occurs, some sur- cipal diagnosis, secondary diagnoses, and procedures per- geons are reluctant to inject an antibiotic into the eye formed. Diagnoses identified during the hospital stay are coded because of the potential risk of CME.15 However, cefuroxime according to the International Statistical Classification of Dis- might be particularly useful after a capsular rupture because eases and Related Health Problems, Tenth Revision (ICD-10). This of the dramatically increased risk of POE as a result of the database was previously used in ophthalmology to assess the rupture. epidemiology and trends of cataract surgery in France,1 the risk The intracameral injection of cefuroxime at the conclu- factors of pseudophakic retinal detachment,2 and the charac- sion of cataract surgery has been recommended by authori- teristics of CME following cataract surgery.3 ties in France since 2011,23 and cefuroxime (Aprokam) has been approved since 2012 by the European Medicines Agency24 and Data Extraction the French Agency of Drugs.25 Thus, we are now in a position Postoperative endophthalmitis was identified with the ICD-10 to assess the effect of cefuroxime on the incidence of POE in code H44.0 associated with medical care in the 6 weeks fol- routine clinical practice. lowing cataract surgery. For each patient, the cataract sur- The purpose of this study was to determine the evolution gery was identified by the PMSI code BFGA004, correspond- of the national incidence rate of POE in France between Janu- ing to a cataract extraction performed by phacoemulsification

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Table 1. Incidence of Acute Endophthalmitis and Data on Injections of Cefuroxime Between January 2010 and October 2014 in France

Cataract No. (%) of Patients Who Received No./Total No. (%) of Patients Year Operations, No. Cefuroxime Injectiona With Acute Endophthalmitisa 2010 659 397 73 325 (11.12) 546/496 363 (0.11) 2011 687 403 98 986 (14.40) 467/518 889 (0.09) 2012 716 008 234 707 (32.78) 406/507 500 (0.08) 2013 732 939 474 725 (64.77) 304/506 667 (0.06) 2014 555 654 439 633 (79.12) 218/436 000 (0.05) (9 mo only) a P = .001 for trend.

with intraocular lens implantation in a capsular bag, or by of pharmaceutical codes limited to this area. Logistic regres- BFGA002, BFGA006, BFGA008, or BFGA009, correspond- sion was used to analyze the risk factors associated with CME, ing to manual extracapsular extraction. A perioperative vi- including age, sex, cefuroxime use, history of diabetes, ante- trectomy that was performed for a posterior capsular rupture rior vitrectomy for posterior capsular rupture, and surgical was recorded with the code BGFA008 associated with the sur- technique (extracapsular extraction), and to calculate crude gical care. The intracameral injection of cefuroxime was as- ORs and AORs. sessed with the code BELB001, which indicates an injection To assess the effect of cefuroxime on POE and its retinal of an organic or inert substance in the anterior chamber of safety in cases of capsular rupture during surgery, we com- the eye. puted a 4-class variable: (1) patients with a capsular rupture Retinal safety was assessed by the risk of CME. As ap- who did not receive an intracameral injection of cefuroxime, proved in a recent report,3 CME was tracked by acetazol- (2) patients with a capsular rupture who received an intracam- amide prescription with the pharmaceutical Code Identifiant eral injection of cefuroxime, (3) patients without a capsular rup- de Présentation 3400930305270 that includes all prescrip- ture who did not receive an injection of cefuroxime, and tions outside the hospital. Acetazolamide is the first-line (4) patients without a capsular rupture who received an intra- therapy recommended by the French Society of Ophthalmol- cameral injection of cefuroxime. For patients who had both ogy for symptomatic CME with vision loss, along with topical eyes operated on, POE or CME were recorded if they occurred nonsteroidal anti-inflammatory drugs and corticosteroids.3 To after the first and/or the second cataract surgery. All analyses exclude patients receiving acetazolamide for a medical indi- involved use of SAS version 9.4 (SAS Institute Inc) and were cation other than CME, such as for short-term increased in- performed in the Department of Biostatistics, Epidemiology, traocular pressure, we did not include patients who had re- and Clinical Research at the University of Montpellier, Mont- ceived acetazolamide prior to surgery and only considered pellier, France. patients after a 2-week washout period without acetazolamide after cataract surgery. While an increase in intraocular pressure can occur in the first days after cataract surgery, the Results probability of our including patients with CME for increased intraocular pressure in this study is low. Over the 4.8 years of the study, 3 351 401 eyes of 2 434 008 patients 40 years of age or older (58.9% were women, and Statistical Analysis the mean [SD] age was 73.9 [9.5] years) underwent cataract We assessed the incidence of POE within 6 weeks of surgery surgery; 1941 eyes (in 1941 patients) had a POE in the 6 overall and by year. Comparisons between groups were made weeks after cataract surgery, for an estimated individual using the χ2 test and the Cochran-Armitage test for trend. The risk of 0.08%. The median latency between cataract Bonferroni correction was used to account for multiple surgery and POE onset was 3 weeks (interquartile range, comparisons. 2-5 weeks). Logistic regression was used to analyze the factors associated with POE, including cefuroxime use, age, sex, history Evolution of the Incidence of POE and the Use of Cefuroxime of diabetes, anterior vitrectomy for posterior capsular rup- Between 2010 and October 2014 ture (the main perioperative complication), and surgical tech- The incidence of POE after cataract surgery decreased over the nique (extracapsular extraction). A crude odds ratio (OR) was course of the study (0.11%, 0.09%, 0.08%, 0.06%, and 0.05% calculated for each factor, and an adjusted OR (AOR) and an in 2010, 2011, 2012, 2013, and 2014, respectively [P = .001 for associated P value of .01 were then used to detect the inde- trend]) as the use of cefuroxime prophylactic injections in- pendent relationship between each factor and the occur- creased (11.1%, 14.4%, 32.8%, 64.8%, and 79.1% in 2010, 2011, rence of POE after cataract surgery. 2012, 2013, and 2014, respectively [P = .001 for trend]) (Table 1). The assessment of CME was limited to a sample of 53 292 patients from Extraction Recherches Analyses pour un Suivi Risk Factors of POE After Cataract Surgery Médico-Economique between January 2012 and October 2014 After adjustment for multiple factors, the risk of POE was as- from the Languedoc-Roussillon region (2.7 million inhabi- sociated with a vitrectomy for a perioperative capsular rup- tants out of 65 million in France) because of the availability ture (OR, 5.17 [95% CI, 3.54-7.55]), an extracapsular extrac-

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Table 2. Incidence and Risk Factors of POE Among 2 434 008 Patients Who Underwent Cataract Surgery in France Between January 2010 and October 2014

Patients, No. Odds Ratio (95% CI) Incidence Characteristic No POE POEof POE, % P Valuea Crude Adjustedb Overall 2 432 067 1941 0.08 Age, y <75 1 247 900 1030 0.08 1 [Reference] 1 [Reference] .12 ≥75 1 184 167 911 0.08 0.93 (0.85-1.02) 0.95 (0.87-1.04) Sex Female 1 431 866 960 0.07 1 [Reference] 1 [Reference] <.001 Male 1 000 201 981 0.10 1.46 (1.34-1.60) 1.45 (1.33-1.60) Cefuroxime use No 1 477 765 1393 0.09 1 [Reference] 1 [Reference] <.001 Yes 954 302 548 0.06 0.61 (0.55-0.67) 0.61 (0.56-0.68) History of diabetes No 2 271 826 1845 0.08 1 [Reference] 1 [Reference] .004 Yes 160 241 96 0.06 0.74 (0.60-0.90) 0.71 (0.58-0.87) Surgical technique Phacoemulsification 2 422 117 1921 0.08 1 [Reference] 1 [Reference] <.001 ≥1 Extracapsular extraction 9950 20 0.20 2.54 (1.63-2.94) 2.00 (1.28-3.13) Vitrectomy for perioperative capsular rupture No 2 426 080 1913 0.08 1 [Reference] 1 [Reference] <.001 Yes 5987 28 0.47 5.96 (4.10-8.66) 5.17 (3.54-7.55) Abbreviation: POE, postoperative endophthalmitis. a Comparisons were corrected for multiple testing using the Bonferroni method. b Adjusted for age, sex, cefuroxime use, history of diabetes, and anterior vitrectomy for posterior capsular rupture.

tion (AOR, 2.00 [95%, CI 1.28-3.13]), and male sex (AOR, 1.45 [95% CI, 1.33-1.60]). The risk of POE was reduced with the use Discussion of cefuroxime (AOR, 0.61 [95% CI, 0.56-0.68]) (Table 2). By using data from the PMSI program, an exhaustive Risk Factors of Postoperative CME After Cataract Surgery national database containing medical records from the 1546 After adjustment for multiple factors, the risk of CME was lower public or private health care facilities in France, we in patients younger than 75 years of age than in patients 75 years observed a reduction in the rate of POE by 50% over 5 of age or older (AOR, 0.76 [95% CI, 0.62-0.93]). Cystoid macu- years while the use of cefuroxime increased from 11% to lar edema was associated with a vitrectomy for a periopera- 79% over the same period. In this work, we also provide a tive capsular rupture (AOR, 8.89 [95% CI, 3.55-22.26]) and male hierarchy of risk factors for the onset of POE: a periopera- sex (AOR, 1.27 [95% CI, 1.05-1.54]). An increased risk of CME tive capsular rupture, an extracapsular extraction, nonuse with use of cefuroxime was not identified (AOR, 0.86 [95% CI, of cefuroxime, and male sex. The injection of cefuroxime 0.71-1.05]) (Table 3). decreased the risk of POE for patients with or without a capsular rupture and was not associated with an increased Effectiveness and Safety of Cefuroxime for Patients incidence of postoperative CME in a subgroup of 53 292 With a Perioperative Capsular Rupture patients. The incidence of POE in each of the 4 groups of patients (with or without a capsular rupture and with or without a cefurox- Evolution of the Incidence of POE Between January 2010 ime injection) is shown in Figure 1. For patients with a capsu- and October 2014 lar rupture, the incidence of POE was lower when they re- Although rare, cases of POE will increase with the increas- ceived an injection of cefuroxime than when they did not ing number of cataract operations engendered by demo- (0.37% vs 0.51%, respectively [P = .001]). graphic changes. In a recent observational study conducted The incidence of CME in each of the 4 groups of patients in the United States among 204 515 participants between is shown in Figure 2. For eyes without a capsular rupture, the 2005 and 2012, the incidence of POE was 0.07%, with a effect of the use or nonuse of cefuroxime on the incidence of decreasing incidence over time, to 0.05% in the 2011-2012 CME was not identified (0.72% vs 0.84%, respectively period.9 In our 4.8-year study among the general population [P = .80]), nor was an effect identified for eyes with a capsu- in France, we found an estimated risk of POE of 0.08% and lar rupture (5.6% vs 7.3%, respectively [P = .12]). a decreased incidence of POE between 2010 and 2014

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Table 3. Incidence and Risk Factors of Postoperative CME Among 53 292 Patients Who Underwent Cataract Surgery in the Languedoc-Roussillon Region of France Between January 2012 and October 2014

Patients, No. Odds Ratio (95% CI) Incidence of Characteristic No CME CMECME, % P Valuea Crude Adjustedb Overall 52 882 410 0.78 Age, y <75 29 305 254 0.87 1 [Reference] 1 [Reference] .008 ≥75 23 577 156 0.66 0.77 (0.63-0.95) 0.76 (0.62-0.93) Sex Female 31 422 216 0.69 1 [Reference] 1 [Reference] .006 Male 21 460 194 0.90 1.32 (1.08-1.59) 1.27 (1.05-1.54) Cefuroxime use No 19 738 170 0.86 1 [Reference] 1 [Reference] .08 Yes 33 144 240 0.72 0.84 (0.69-1.02) 0.86 (0.71-1.05) History of diabetes No 51 020 396 0.78 1 [Reference] 1 [Reference] .91 Yes 1862 14 0.75 0.97 (0.57-1.66) 0.89 (0.52-1.53) Vitrectomy for perioperative capsular rupture No 52 814 405 0.77 1 [Reference] 1 [Reference] <.001 Yes 68 5 7.35 9.59 (3.85-23.90) 8.89 (3.55-22.26) Surgical technique Phacoemulsification 52 759 410 0.78 1 [Reference] 1 [Reference] .002 ≥1 Extracapsular extraction 119 4 3.36 4.33 (1.59-11.77) 3.38 (1.21-9.52) Abbreviation: CME, cystoid macula edema. a Comparisons were corrected for multiple testing using the Bonferroni method. b Adjusted for age, sex, cefuroxime use, history of diabetes, and anterior vitrectomy for posterior capsular rupture.

Figure 1. Incidence of Postoperative Endophthalmitis (POE) Figure 2. Incidence of Postoperative Cystoid Macular Edema (CME) Among 2 434 008 Patients With or Without a Capsular Rupture Among 53 292 Patients With or Without a Capsular Rupture and With or Without an Injection of Cefuroxime and With or Without an Injection of Cefuroxime

4115 Patients (0.17%) with capsular rupture 55 Patients (0.10%) with capsular rupture who did not receive cefuroxime who did not receive cefuroxime P <.001 P = .12 1887 Patients (0.08%) with capsular rupture 18 Patients (0.03%) with capsular rupture who received cefuroxime who received cefuroxime

1 475 054 Patients (60.60%) without capsular 33 366 Patients (62.61%) without capsular rupture who did not receive cefuroxime rupture who received cefuroxime P <.001 P = .80 952 952 Patients (39.15%) without capsular 19 853 Patients (37.25%) without capsular rupture who received cefuroxime rupture who did not receive cefuroxime

0 0.1 0.2 0.3 0.4 0.5 0.6 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 Incidence of POE, % Incidence of Postoperative CME, %

For patients with a perioperative capsular rupture of the lens, the incidence of For eyes without a capsular rupture, the effect of the use or nonuse of POE was lower for those who received an injection of cefuroxime than for cefuroxime on the incidence of CME was not identified (0.72% vs 0.84%, those who did not (0.37% vs 0.51%, respectively [P = .001]). Comparisons respectively [P = .80]), nor was an effect identified for eyes with a capsular were corrected for multiple testing using the Bonferroni method. rupture (5.6% vs 7.3%, respectively [P = .12]). Comparisons were corrected for Overall P < .001. multiple testing using the Bonferroni method. Overall P < .001.

(0.11% and 0.05%, respectively). The prophylactic use of an Increased Use of Intracameral Injections of Cefuroxime intracameral injection of cefuroxime may have contributed Between January 2010 and October 2014 to this favorable evolution in the incidence of POE in France A 2014 online survey of the American Society of Cataract and because the incidence of other factors related to antisepsis Refractive Surgery members indicated that 47% of US oph- or phacoemulsification did not significantly change during thalmologists used cefuroxime.15 In the 2014 European ob- this period. Furthermore, in a recent study conducted by servatory of cataract practice, 82% of surgeons said it was im- Herrinton et al,9 a topical antibiotic was not shown to add to portant to have a commercially available broad-spectrum the effectiveness of an intracameral regimen. antibiotic licensed for direct intracameral injection, and 42%

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cited medicolegal protection as the reason.26 To date, cefu- approved since 2012 by the European Medicines Agency,24 and roxime is still not approved by the US Food and Drug Admin- this commercial preparation effectively obviates the risk of di- istration for this indication. In France, the use of cefuroxime lution errors due to ad hoc formulations.25 was relatively low in 2010 and 2011 (11.1% and 14.4% respec- Another question relates to retinal safety with the use of tively), then increased up to 79.1% in 2014, probably owing to intracameral cefuroxime in cases of perioperative capsular rup- recommendations in government health agency guidelines in ture where the risk of POE and CME is dramatically increased.10 201123 and the commercial labeling of cefuroxime in 2012.25 In a study of 62 patients, the use of intracameral cefuroxime was not associated with increased macular thickness 4 to 6 Risk Factors of POE After Cataract Surgery weeks postoperatively compared with patients not receiving A perioperative posterior capsular rupture is a common com- cefuroxime.30 In the present big-data analysis, the incidence plication of cataract surgery and one of the most significant of CME did not differ between patients who received and pa- risk factors for POE. A capsular rupture was reported to in- tients who did not receive cefuroxime and between patients crease the risk of POE by 6-fold in a recent meta-analysis.27 In with and patients without a capsular rupture. the present study, the risk of POE after cataract surgery in- Javitt31 highlights that a major barrier to the adoption of increased 5-fold with a posterior capsular rupture. The intracameral antibiotics in the United State is the absence of a US creased risk of endophthalmitis associated with a capsular rup- Food and Drug Administration–approved intracameral antibi- ture suggests that bacteria may be eliminated less efficiently otic preparation. This type of approval would require a cost- from the vitreous cavity than from the anterior chamber. effective preparation and arguments for the safety of intracam- With the progress made in the technique of cataract sur- eral antibiotics. The present safety analysis could support future gery, the use of extracapsular extraction is decreasing over time recommendations of intracameral cefuroxime use for patient and is reserved for patients with particularly dense and hard crys- with or without a perioperative capsular rupture of the lens. talline lenses. We found extracapsular extraction to be a risk factor of POE after cataract extraction, with a 2-fold increased risk Strengths and Limitations of POE, which was consistent with previous studies.27 The strengths of the study are the sample size and the exhaus- Pooled estimates from 3 multicenter, prospective, ran- tive national recruitment, with the inclusion of all health care domized controlled clinical studies concluded that not using facilities, public or private, and all patients across the coun- cefuroxime increased the odds of POE by 5-fold.27 In the pre- try who underwent cataract surgery (as opposed to single- sent study, cefuroxime use was associated with a decreased institute reports). Other factors related to antisepsis or the risk of POE by 39%. The measured difference (5-fold vs 39%) phacoemulsification technique may have affected the final rate may relate to a host of different issues, including the fact that of endophthalmitis. These include surgical experience, smaller prospective trials often have inclusion and exclusion criteria incisions, and the use of injectable instead of foldable intra- optimized to demonstrate a difference and that trolling big data ocular lenses, which may have had more contact with the peri- is a powerful but decidedly imprecise (and at times even in- ocular area. However, no substantial changes in the surgical accurate) method for measuring outcomes. procedure are known to have occurred during this short study Consistent with previous reports, we found that male sex period (2010-2014), except for the introduction and general- was associated with an increased risk of POE, but we did not ization of cefuroxime. Cases of CME were analyzed in a lim- confirm that older age is associated with an increased risk of ited percentage of patients in only 1 region (53 292 patients). POE.27 Several studies have reported increased rates of eye The cross-sectional design of this study only allows one trauma among men that may increase the incidence of POE.28 to evaluate associations. The design does not allow one to The decreased risk of POE in patients with diabetes in our study evaluate whether there is a cause-and-effect relationship be- is probably related to the French recommendation of an oral tween the injection of cefuroxime and POE. 500-mg dose of levofloxacin the day before and 2 to 4 hours before cataract surgery for patients with diabetes.23 Conclusions Retinal Safety of Intracameral Injection of Cefuroxime In a rabbit model, 1 mg of cefuroxime administered intravit- These data suggest that, in routine practice, the intracameral really was not toxic to the retina, whereas 10 mg of cefurox- injection of cefuroxime at the conclusion of cataract surgery ime induced structural damage.29 Some surgeons stopped is associated with a lower risk of POE and is safe for patients using cefuroxime as a result of case reports of macular edema with or without a perioperative capsular rupture. This study after an overdose of intracameral cefuroxime,16-20 despite the does not support the proposition that cefuroxime should be fact that these cases were the result of dilution errors. In Eu- withheld in cases of perioperative capsule rupture lest it pre- rope, but not in United States, cefuroxime (Aprokam) has been cipitates CME.

ARTICLE INFORMATION Published Online: May 2, 2016. Department of Ophthalmology, University of Submitted for Publication: January 20, 2016; final doi:10.1001/jamaophthalmol.2016.1351. Montpellier, Montpellier, France (Daien, Carriere, revision received April 4, 2016; accepted April 5, Author Affiliations: Department of Villain); Inserm, Montpellier, France (Daien, 2016. Ophthalmology, Hôpital Gui de Chauliac, CHU de Carriere); Echelon Régional du Service Médical du Montpellier, Montpellier, France (Daien, Villain); Languedoc–Roussillon, Biostatistics Department,

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Montpellier, France (Papinaud, Domerg); The Save 6. Hatch WV, Cernat G, Wong D, Devenyi R, cefuroxime during phacoemulsification surgery. Sight Institute, Sydney Medical School, University Bell CM. Risk factors for acute endophthalmitis JAMA Ophthalmol. 2015;133(10):1194-1197. of Sydney, Sydney, New South Wales, Australia after cataract surgery: a population-based study. 20. Delyfer MN, Rougier MB, Leoni S, et al. Ocular (Gillies); Department of Medical Information, Ophthalmology. 2009;116(3):425-430. toxicity after intracameral injection of very high Montpellier University Hospital, Montpellier, France 7. Miller JJ, Scott IU, Flynn HW Jr, Smiddy WE, doses of cefuroxime during cataract surgery. (Nagot); Department of Biostatistics, Epidemiology, Newton J, Miller D. Acute-onset endophthalmitis J Cataract Refract Surg. 2011;37(2):271-278. and Clinical Research, University of Montpellier, after cataract surgery (2000-2004): incidence, Montpellier, France (Lacombe, Daures). 21. Konstantopoulos A, Yadegarfar G, clinical settings, and visual acuity outcomes after Madhusudhana K, et al. Prognostic factors that Author Contributions: Drs Daien and Papinaud treatment. Am J Ophthalmol. 2005;139(6):983-987. determine visual outcome following cataract had full access to all the data in the study and take 8. Lalwani GA, Flynn HW Jr, Scott IU, et al. surgery complicated by vitreous loss. Eur J responsibility for the integrity of the data and the Acute-onset endophthalmitis after clear corneal Ophthalmol. 2009;19(2):247-253. accuracy of the data analysis. cataract surgery (1996-2005): clinical features, Study concept and design: Daien, Gillies, Daures, 22. Onal S, Gozum N, Gucukoglu A. Visual results causative organisms, and visual acuity outcomes. and complications of posterior chamber intraocular Carriere, Villain. Ophthalmology. 2008;115(3):473-476. Acquisition, analysis, or interpretation of data: lens implantation after capsular tear during Daien, Papinaud, Gillies, Domerg, Nagot, Lacombe, 9. Herrinton LJ, Shorstein NH, Paschal JF, et al. phacoemulsification. Ophthalmic Surg Lasers Imaging. Daures. Comparative effectiveness of antibiotic prophylaxis 2004;35(3):219-224. Drafting of the manuscript: Daien, Papinaud, Gillies, in cataract surgery. Ophthalmology. 2016;123(2): 23. Agence Française de Sécurité Sanitaire des Domerg, Daures, Villain. 287-294. produits de Santé (AFSSAPS). Antibioprophylaxie Critical revision of the manuscript for important 10. Taban M, Behrens A, Newcomb RL, et al. Acute en chirurgie oculaire: recommandations. Version intellectual content: Daien, Gillies, Nagot, Lacombe, endophthalmitis following cataract surgery: actualisée en mai 2011. http://www.ansm.sante.fr Carriere. a systematic review of the literature. Arch /var/ansm_site/storage/original/application Statistical analysis: Daien, Papinaud, Domerg, Ophthalmol. 2005;123(5):613-620. /dca8b90118e3928c0a640f6779dcd3a9.pdf. Lacombe, Daures. 11. Montan PG, Wejde G, Koranyi G, Rylander M. Accessed April 11, 2016. Obtained funding: Daien, Lacombe. Prophylactic intracameral cefuroxime: efficacy in 24. European Medicines Agency; Procedure Administrative, technical, or material support: preventing endophthalmitis after cataract surgery. Management Committees Support. List of Papinaud, Domerg, Nagot. J Cataract Refract Surg. 2002;28(6):977-981. nationally authorised medicinal products. Active Study supervision: Gillies, Carriere, Villain. 12. Barry P, Seal DV, Gettinby G, Lees F, Peterson M, substance: cefuroxime sodium (for intracameral Conflict of Interest Disclosures: All authors have Revie CW; ESCRS Endophthalmitis Study Group. use). Procedure no.: PSUSA/00010206/201411/ completedandsubmittedtheICMJEFormforDisclosure ESCRS study of prophylaxis of postoperative http://www.ema.europa.eu/docs/en_GB/document of Potential Conflicts of Interest, and Dr Gillies reports endophthalmitis after cataract surgery: preliminary _library/Other/2015/07/WC500189762.pdf Dated havingreceivedgrantsandpersonalfeesfromandbeen report of principal results from a European June 11, 2015. Accessed April 6, 2016. ontheadvisoryboardsofNovartis,Bayer,andAllergan. multicenter study. J Cataract Refract Surg. 2006;32 25. Agence Nationale de Sécurité du Médicament No other disclosures are reported. (3):407-410. (ANSM). APROKAM 50 mg, poudre pour solution Funding/Support: This study was supported by the 13. Gower EW, Lindsley K, Nanji AA, Leyngold I, injectable. ANSM website. http://ansm.sante.fr University Hospital Montpellier France, Appel McDonnell PJ. Perioperative antibiotics for /Activites/Autorisations-temporaires-d-utilisation d’Offre Interne 2015, for biostatistical analysis. prevention of acute endophthalmitis after cataract -ATU/ATU-de-cohorte-arretees/Liste-des-ATU-de Role of the Funder/Sponsor: The funder/sponsor surgery. Cochrane Database Syst Rev. 2013;7: -cohorte-arretees/APROKAM-50-mg-poudre-pour had no role in the design and conduct of the study; CD006364. -solution-injectable. Accessed April 6, 2016. collection, management, analysis, or interpretation 14. Ndegwa S, Cimon K, Severn M. Intracameral 26. European Society of Cataract & Refractive of the data; preparation, review, or approval of the antibiotics for the prevention of endophthalmitis Surgeons (ESCRS). XXXII Congress of the ESCRS. manuscript; and decision to submit the manuscript post-cataract surgery: review of clinical and 13-17 September 2014, Excel, London, UK. Posters: for publication. cost-effectiveness and guideline. Ottawa, Canada: European observatory of cataract practice: Canadian Agency for Drugs and Technologies in infectious post-operative Endophthalmitis REFERENCES Health; 2010. Rapid response report: Prophylaxis in 2014. ESCRS website. http://www 1. Daien V, Le Pape A, Heve D, Carriere I, Villain M. peer-reviewed summary with critical appraisal. .escrs.org/istanbul2015/programme/posters-details Incidence and characteristics of cataract surgery in https://www.cadth.ca/media/pdf/M0019 .asp?id=22529. Accessed April 6, 2016. France from 2009 to 2012: a national population _Intracameral_Antiobiotics_L3_e.pdf. Published 27. Cao H, Zhang L, Li L, Lo S. Risk factors for acute study. Ophthalmology. 2015;122(8):1633-1638. October 2010. Accessed May 4, 2011. endophthalmitis following cataract surgery: 2. Daien V, Le Pape A, Heve D, Carriere I, Villain M. 15. Chang DF, Braga-Mele R, Henderson BA, a systematic review and meta-analysis. PLoS One. Incidence, risk factors, and impact of age on retinal Mamalis N, Vasavada A; ASCRS Cataract Clinical 2013;8(8):e71731. detachment after cataract surgery in France: Committee. Antibiotic prophylaxis of postoperative 28. Endophthalmitis Study Group, European a national population study. Ophthalmology.2015; endophthalmitis after cataract surgery: results of Society of Cataract & Refractive Surgeons. 122(11):2179-2185. the 2014 ASCRS member survey. J Cataract Refract Prophylaxis of postoperative endophthalmitis 3. Daien V, Papinaud L, Domerg C, Lacombe S, Surg. 2015;41(6):1300-1305. following cataract surgery: results of the ESCRS Daures JP, Villain M. Incidence and characteristics 16. Buyukyildiz HZ, Gulkilik G, Kumcuoglu YZ. multicenter study and identification of risk factors. of cystoid macular edema after cataract surgery. Early serous macular detachment after J Cataract Refract Surg. 2007;33(6):978-988. Ophthalmology. 2016;123(3):663-664. phacoemulsification surgery. J Cataract Refract Surg. 29. Shahar J, Zemel E, Perlman I, Loewenstein A. 4. Ng JQ, Morlet N, Pearman JW, et al; Team 2010;36(11):1999-2002. Physiological and toxicological effects of EPSWA. Management and outcomes of 17. Le Dû B, Pierre-Kahn V. Early macular edema cefuroxime on the albino rabbit retina. Invest postoperative endophthalmitis since the after phacoemulsification and suspected overdose Ophthalmol Vis Sci. 2012;53(2):906-914. endophthalmitis vitrectomy study: the of cefuroxime: report of six cases [in French]. JFr 30. Gupta MS, McKee HDR, Saldaña M, Stewart Endophthalmitis Population Study of Western Ophtalmol. 2014;37(3):202-210. OG. Macular thickness after cataract surgery with Australia (EPSWA)'s fifth report. Ophthalmology. 18. Qureshi F, Clark D. Macular infarction after intracameral cefuroxime. J Cataract Refract Surg. 2005;112(7):1199-1206. inadvertent intracameral cefuroxime. J Cataract 2005;31(6):1163-1166. 5. Lundström M, Wejde G, Stenevi U, Thorburn W, Refract Surg. 2011;37(6):1168-1169. 31. Javitt JC. Intracameral antibiotics reduce the Montan P. Endophthalmitis after cataract surgery: 19. Wong DC, Waxman MD, Herrinton LJ, Shorstein risk of endophthalmitis after cataract surgery: does a nationwide prospective study evaluating NH. Transient macular edema after intracameral the preponderance of the evidence mandate a incidence in relation to incision type and location. injection of a moderately elevated dose of global change in practice? Ophthalmology. 2016;123 Ophthalmology. 2007;114(5):866-870. (2):226-231.

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