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

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 POE and is safe for patients with or without a perioperative capsular rupture. While these 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 relationship between the injection of cefuroxime and POE.

Although cataract surgery is highly effective and relatively safe, surgical complications are still a major source of morbidity as a result of the high case load and increasing number of cataract operations.¹ The 3 most severe complications are retinal detachment, with a 4-year cumulative risk of 0.99%,² cystoid macular edema (CME), with an incidence of 0.95%,³ and endophthalmitis.

In general, postoperative endophthalmitis (POE) appears unexpectedly and often results in severe visual impairment, with one-third of patients recovering 6/18 visual acuity or less.⁴ Risk factors for POE include older age (≥85 years), male sex, perioperative complications, and clear corneal incision.^5,6 The incidence of POE ranges from 0.04% to 0.8%^7-10 and has increased significantly from 2000 to 2003 (0.265%) compared with the previous decade (0.087% in the 1990s), probably because of a switch to clear corneal incisions.^7-10

Swedish ophthalmologists began routinely using intracameral injections of cefuroxime sodium as prophylaxis against POE in 2002 with very good results.¹¹ In a multicenter study of 13 698 patients conducted by the European Society of Cataract and Refractive Surgeons between 2003 and 2006, the use of intracameral injections of cefuroxime at the end of the surgery was found to be effective, reducing the incidence of POE 5-fold.¹²

Currently, there is no current single standard for the use of cefuroxime as prophylaxis against POE. The authors of a Cochrane database systematic review, published in 2013 and including 100 876 adults and 131 cases of endophthalmitis, recommended the use of intracameral injections of cefuroxime.¹³ The use of intracameral antibiotics in the United States is considered off-label and not yet approved by the US Food and Drug Administration.¹⁴ In a study conducted in California, 20.1% of surgeons used cefuroxime.⁹

Surgeons not using cefuroxime as prophylaxis against POE expressed concern about the risks induced by noncommercially prepared antibiotic preparations.¹⁵ More specifically, they mentioned reports of retinal toxicity as reflected by increased rates of CME occurring after a high dose of cefuroxime, with each case of retinal toxicity due to dilution errors in preparing the cefuroxime solution.^16-20

The main perioperative complication of cataract surgery is the capsular rupture of the lens that often results in outcomes of poor visual acuity²¹ and increases the risk of CME,²² as well as POE, 6-fold.¹⁰ When this event occurs, some surgeons are reluctant to inject an antibiotic into the eye because of the potential risk of CME.¹⁵ However, cefuroxime might be particularly useful after a capsular rupture because of the dramatically increased risk of POE as a result of the rupture.

The intracameral injection of cefuroxime at the conclusion of cataract surgery has been recommended by authorities in France since 2011,²³ and cefuroxime (Aprokam) has been approved since 2012 by the European Medicines Agency²⁴ and the French Agency of Drugs.²⁵ Thus, we are now in a position to assess the effect of cefuroxime on the incidence of POE in routine clinical practice.

The purpose of this study was to determine the evolution of the national incidence rate of POE in France between January 2010 and October 2014 and its associations with the intracameral injection of cefuroxime at the end of cataract surgery, together with other classical risk factors of POE. The secondary objective was to assess the retinal safety of this type of injection and its possible use in cases of a perioperative capsular rupture of the lens.

Box Section Ref ID

The study protocol was approved by the national health authority in France and by the ethics committee of the University Hospital of Montpellier, France. Informed consent was not provided because the data were deidentified.

The data for all patients 40 years of age or older who underwent cataract surgery in France (65 million inhabitants) between January 2010 and October 2014 were collected from the Programme de Médicalisation des Systèmes d'Information (PMSI) and from Extraction Recherches Analyses pour un Suivi Médico-Economique. Since 2004, the PMSI compiles discharge abstracts related to all admissions in the 1546 French health care facilities, public or private. The information in these abstracts covers both medical and administrative data. These data are anonymized with regard to the names of patients and physicians. Routinely collected medical data include the principal diagnosis, secondary diagnoses, and procedures performed. Diagnoses identified during the hospital stay are coded according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). This database was previously used in ophthalmology to assess the epidemiology and trends of cataract surgery in France,¹ the risk factors of pseudophakic retinal detachment,² and the characteristics of CME following cataract surgery.³

Postoperative endophthalmitis was identified with the ICD-10 code H44.0 associated with medical care in the 6 weeks following cataract surgery. For each patient, the cataract surgery was identified by the PMSI code BFGA004, corresponding to a cataract extraction performed by phacoemulsification with intraocular lens implantation in a capsular bag, or by BFGA002, BFGA006, BFGA008, or BFGA009, corresponding to manual extracapsular extraction. A perioperative vitrectomy that was performed for a posterior capsular rupture was recorded with the code BGFA008 associated with the surgical care. The intracameral injection of cefuroxime was assessed with the code BELB001, which indicates an injection of an organic or inert substance in the anterior chamber of the eye.

Retinal safety was assessed by the risk of CME. As approved in a recent report,³ CME was tracked by acetazolamide prescription with the pharmaceutical Code Identifiant de Présentation 3400930305270 that includes all prescriptions outside the hospital. Acetazolamide is the first-line therapy recommended by the French Society of Ophthalmology for symptomatic CME with vision loss, along with topical nonsteroidal anti-inflammatory drugs and corticosteroids.³ To exclude patients receiving acetazolamide for a medical indication other than CME, such as for short-term increased intraocular pressure, we did not include patients who had received acetazolamide prior to surgery and only considered 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 probability of our including patients with CME for increased intraocular pressure in this study is low.

We assessed the incidence of POE within 6 weeks of surgery overall and by year. Comparisons between groups were made using the χ² test and the Cochran-Armitage test for trend. The Bonferroni correction was used to account for multiple comparisons.

Logistic regression was used to analyze the factors associated with POE, including cefuroxime use, age, sex, history of diabetes, anterior vitrectomy for posterior capsular rupture (the main perioperative complication), and surgical technique (extracapsular extraction). A crude odds ratio (OR) was calculated for each factor, and an adjusted OR (AOR) and an associated P value of .01 were then used to detect the independent relationship between each factor and the occurrence of POE after cataract surgery.

The assessment of CME was limited to a sample of 53 292 patients from Extraction Recherches Analyses pour un Suivi Médico-Economique between January 2012 and October 2014 from the Languedoc-Roussillon region (2.7 million inhabitants out of 65 million in France) because of the availability of pharmaceutical codes limited to this area. Logistic regression was used to analyze the risk factors associated with CME, including age, sex, cefuroxime use, history of diabetes, anterior vitrectomy for posterior capsular rupture, and surgical technique (extracapsular extraction), and to calculate crude ORs and AORs.

To assess the effect of cefuroxime on POE and its retinal safety in cases of capsular rupture during surgery, we computed a 4-class variable: (1) patients with a capsular rupture who did not receive an intracameral injection of cefuroxime, (2) patients with a capsular rupture who received an intracameral injection of cefuroxime, (3) patients without a capsular rupture who did not receive an injection of cefuroxime, and (4) patients without a capsular rupture who received an intracameral injection of cefuroxime. For patients who had both eyes operated on, POE or CME were recorded if they occurred after the first and/or the second cataract surgery. All analyses involved use of SAS version 9.4 (SAS Institute Inc) and were performed in the Department of Biostatistics, Epidemiology, and Clinical Research at the University of Montpellier, Montpellier, France.

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 the mean [SD] age was 73.9 [9.5] years) underwent cataract surgery; 1941 eyes (in 1941 patients) had a POE in the 6 weeks after cataract surgery, for an estimated individual risk of 0.08%. The median latency between cataract surgery and POE onset was 3 weeks (interquartile range, 2-5 weeks).

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]) (Table 1).

After adjustment for multiple factors, the risk of POE was associated with a vitrectomy for a perioperative capsular rupture (OR, 5.17 [95% CI, 3.54-7.55]), an extracapsular extraction (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 of cefuroxime (AOR, 0.61 [95% CI, 0.56-0.68]) (Table 2).

After adjustment for multiple factors, the risk of CME was lower in patients younger than 75 years of age than in patients 75 years of age or older (AOR, 0.76 [95% CI, 0.62-0.93]). Cystoid macular edema was associated with a vitrectomy for a perioperative capsular rupture (AOR, 8.89 [95% CI, 3.55-22.26]) and male sex (AOR, 1.27 [95% CI, 1.05-1.54]). An increased risk of CME with use of cefuroxime was not identified (AOR, 0.86 [95% CI, 0.71-1.05]) (Table 3).

The incidence of POE in each of the 4 groups of patients (with or without a capsular rupture and with or without a cefuroxime injection) is shown in Figure 1. For patients with a capsular rupture, the incidence of POE was lower when they received an injection of cefuroxime than when they did not (0.37% vs 0.51%, respectively [P = .001]).

The incidence of CME in each of the 4 groups of patients is shown in Figure 2. For eyes without a capsular rupture, the effect of the use or nonuse of cefuroxime on the incidence of CME was not identified (0.72% vs 0.84%, respectively [P = .80]), nor was an effect identified for eyes with a capsular rupture (5.6% vs 7.3%, respectively [P = .12]).

By using data from the PMSI program, an exhaustive national database containing medical records from the 1546 public or private health care facilities in France, we observed a reduction in the rate of POE by 50% over 5 years while the use of cefuroxime increased from 11% to 79% over the same period. In this work, we also provide a hierarchy of risk factors for the onset of POE: a perioperative capsular rupture, an extracapsular extraction, nonuse of cefuroxime, and male sex. The injection of cefuroxime decreased the risk of POE for patients with or without a capsular rupture and was not associated with an increased incidence of postoperative CME in a subgroup of 53 292 patients.

Although rare, cases of POE will increase with the increasing number of cataract operations engendered by demographic changes. In a recent observational study conducted in the United States among 204 515 participants between 2005 and 2012, the incidence of POE was 0.07%, with a decreasing incidence over time, to 0.05% in the 2011-2012 period.⁹ In our 4.8-year study among the general population in France, we found an estimated risk of POE of 0.08% and a decreased incidence of POE between 2010 and 2014 (0.11% and 0.05%, respectively). The prophylactic use of an intracameral injection of cefuroxime may have contributed to this favorable evolution in the incidence of POE in France because the incidence of other factors related to antisepsis or phacoemulsification did not significantly change during this period. Furthermore, in a recent study conducted by Herrinton et al,⁹ a topical antibiotic was not shown to add to the effectiveness of an intracameral regimen.

A 2014 online survey of the American Society of Cataract and Refractive Surgery members indicated that 47% of US ophthalmologists used cefuroxime.¹⁵ In the 2014 European observatory of cataract practice, 82% of surgeons said it was important to have a commercially available broad-spectrum antibiotic licensed for direct intracameral injection, and 42% cited medicolegal protection as the reason.²⁶ To date, cefuroxime is still not approved by the US Food and Drug Administration for this indication. In France, the use of cefuroxime was relatively low in 2010 and 2011 (11.1% and 14.4% respectively), then increased up to 79.1% in 2014, probably owing to recommendations in government health agency guidelines in 2011²³ and the commercial labeling of cefuroxime in 2012.²⁵

A perioperative posterior capsular rupture is a common complication of cataract surgery and one of the most significant risk factors for POE. A capsular rupture was reported to increase the risk of POE by 6-fold in a recent meta-analysis.²⁷ In the present study, the risk of POE after cataract surgery increased 5-fold with a posterior capsular rupture. The increased risk of endophthalmitis associated with a capsular rupture suggests that bacteria may be eliminated less efficiently from the vitreous cavity than from the anterior chamber.

With the progress made in the technique of cataract surgery, the use of extracapsular extraction is decreasing over time and is reserved for patients with particularly dense and hard crystalline lenses. We found extracapsular extraction to be a risk factor of POE after cataract extraction, with a 2-fold increased risk of POE, which was consistent with previous studies.²⁷

Pooled estimates from 3 multicenter, prospective, randomized controlled clinical studies concluded that not using cefuroxime increased the odds of POE by 5-fold.²⁷ In the present study, cefuroxime use was associated with a decreased risk of POE by 39%. The measured difference (5-fold vs 39%) may relate to a host of different issues, including the fact that prospective trials often have inclusion and exclusion criteria optimized to demonstrate a difference and that trolling big data is a powerful but decidedly imprecise (and at times even inaccurate) method for measuring outcomes.

Consistent with previous reports, we found that male sex was associated with an increased risk of POE, but we did not confirm that older age is associated with an increased risk of POE.²⁷ Several studies have reported increased rates of eye trauma among men that may increase the incidence of POE.²⁸ The decreased risk of POE in patients with diabetes in our study is probably related to the French recommendation of an oral 500-mg dose of levofloxacin the day before and 2 to 4 hours before cataract surgery for patients with diabetes.²³

In a rabbit model, 1 mg of cefuroxime administered intravitreally was not toxic to the retina, whereas 10 mg of cefuroxime induced structural damage.²⁹ Some surgeons stopped using cefuroxime as a result of case reports of macular edema after an overdose of intracameral cefuroxime,^16-20 despite the fact that these cases were the result of dilution errors. In Europe, but not in United States, cefuroxime (Aprokam) has been approved since 2012 by the European Medicines Agency,²⁴ and this commercial preparation effectively obviates the risk of dilution errors due to ad hoc formulations.²⁵

Another question relates to retinal safety with the use of intracameral cefuroxime in cases of perioperative capsular rupture where the risk of POE and CME is dramatically increased.¹⁰ In a study of 62 patients, the use of intracameral cefuroxime was not associated with increased macular thickness 4 to 6 weeks postoperatively compared with patients not receiving cefuroxime.³⁰ In the present big-data analysis, the incidence of CME did not differ between patients who received and patients who did not receive cefuroxime and between patients with and patients without a capsular rupture.

Javitt³¹ highlights that a major barrier to the adoption of intracameral antibiotics in the United State is the absence of a US Food and Drug Administration–approved intracameral antibiotic preparation. This type of approval would require a cost-effective preparation and arguments for the safety of intracameral antibiotics. The present safety analysis could support future recommendations of intracameral cefuroxime use for patient with or without a perioperative capsular rupture of the lens.

The strengths of the study are the sample size and the exhaustive national recruitment, with the inclusion of all health care facilities, public or private, and all patients across the country who underwent cataract surgery (as opposed to single-institute reports). Other factors related to antisepsis or the phacoemulsification technique may have affected the final rate of endophthalmitis. These include surgical experience, smaller incisions, and the use of injectable instead of foldable intraocular lenses, which may have had more contact with the periocular area. However, no substantial changes in the surgical procedure are known to have occurred during this short study period (2010-2014), except for the introduction and generalization of cefuroxime. Cases of CME were analyzed in a limited percentage of patients in only 1 region (53 292 patients).

The cross-sectional design of this study only allows one to evaluate associations. The design does not allow one to evaluate whether there is a cause-and-effect relationship between the injection of cefuroxime and POE.

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 POE and is safe for patients with or without a perioperative capsular rupture. This study does not support the proposition that cefuroxime should be withheld in cases of perioperative capsule rupture lest it precipitates CME.

Submitted for Publication: January 20, 2016; final revision received April 4, 2016; accepted April 5, 2016.

Corresponding Author: Vincent Daien, MD, PhD, Department of Ophthalmology, Hôpital Gui de Chauliac, CHU de Montpellier, 80, avenue Augustin Fliche, 34295 Montpellier CEDEX 5, France (vincent.daien@gmail.com).

Published Online: May 2, 2016. doi:10.1001/jamaophthalmol.2016.1351.

Author Contributions: Drs Daien and Papinaud had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Daien, Gillies, Daures, Carriere, Villain.

Acquisition, analysis, or interpretation of data: Daien, Papinaud, Gillies, Domerg, Nagot, Lacombe, Daures.

Drafting of the manuscript: Daien, Papinaud, Gillies, Domerg, Daures, Villain.

Critical revision of the manuscript for important intellectual content: Daien, Gillies, Nagot, Lacombe, Carriere.

Statistical analysis: Daien, Papinaud, Domerg, Lacombe, Daures.

Obtained funding: Daien, Lacombe.

Administrative, technical, or material support: Papinaud, Domerg, Nagot.

Study supervision: Gillies, Carriere, Villain.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and Dr Gillies reports having received grants and personal fees from and been on the advisory boards of Novartis, Bayer, and Allergan. No other disclosures are reported.

Funding/Support: This study was supported by the University Hospital Montpellier France, Appel d’Offre Interne 2015, for biostatistical analysis.

Role of the Funder/Sponsor: The funder/sponsor had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.