Cefuroxime-Induced Toxic Maculopathy after Intracameral Injection of Standard Dose: A Case Report

Acute endophthalmitis after cataract surgery is a rare but highly severe, vision-threatening complication. The advent of intracameral antibiotics has contributed to a significant decrease in cases of postoperative endophthalmitis [1]. The ESCRS study suggested that intracameral cefuroxime reduced by 5-fold the risk of postoperative endophthalmitis [2]. However, drug preparation processes in the operating room can cause incorrect dilution and contamination errors. Simultaneously, increased dose has been associated with complications such as macular toxicity, blocked retinal vessels, endothelial toxicity, toxic endophthalmitis, and toxic anterior segment syndrome (TASS) [3].

Cefuroxime is a second-generation cephalosporin that is active against Gram-positive bacteria, most notably Staphylococcus aureus. It has specific activity against Haemophilus influenza and is less susceptible than the earlier cephalosporins to beta-lactamase inactivation [4]. The 2017 Cochrane review and meta-analysis concluded that the ESCRS study “provides the best evidence for antibiotic prophylaxis against post-cataract surgery endophthalmitis” [1]. Therefore, the 2006 ESCRS endophthalmitis prophylaxis study is considered one of the most influential studies in the past 20 years on cataract surgery. In 2012, the European Medicines Agency (EMA) licensed Aprokam (Laboratories Théa), the first intracameral cefuroxime formulation, and in 2013, it was effectively endorsed in the ESCRS Guidelines for Prevention and Treatment of Endophthalmitis. Despite its occurrence in Europe, the FED has not approved the intracameral use of cefuroxime [5].

The first case of a correct dose of cefuroxime-induced toxic maculopathy was presented in 2014 [6]. In this case, we report a case of macular deem with serous retinal detachment after an uneventful cataract operation using intracameral injection of correct doses of cefuroxime. We presume that the retina injury can be attributed to cefuroxime toxicity even with the use of a standard dose.

An 82-year-old man was scheduled to undergo cataract surgery in the right eye. His medical history showed high blood pressure, which was well controlled. Preoperative OCT of the right eye showed minimal dry AMD in the form of one isolated para-foveal drusen (shown in Fig. 1).

The best-corrected preoperative visual acuity (BCVA) of the right eye was 20/50, with no improvement with a pinhole. The cataract operation involved a 2.5 mm temporal clear cornea incision, standard cataract emulsification, and implantation of acrylic posterior chamber intraocular lens into the lens capsule. The operation was uneventful, was not laborious, had no complications, had no posterior-capsule rapture, and was performed by an experienced surgeon. At the end of the procedure, the patient received 0.1 mL of a 10 mg/mL solution of intracameral cefuroxime, as usual.

On the first postoperative day, the patient complained of visual reduction in the right eye. His BCVA was 20/200. His right eye was relatively calm, with mild corneal oedema and only a few cells (+1)floating in the anterior chamber. Intraocular pressure was 19 mm Hg, and the fundus was pale in the posterior pole. No other clinical signs were noted.

OCT demonstrated increased macular oedema with cystic spaces within the central macular area, locating at the outer retinal layers and providing a mixed clinical picture of schisis and serous retinal detachment. The central macular thickness was 628 micrometres (shown in Fig. 2).

The patient received hourly g. dexamethasone 0.1% for 4/7 and then 2 h for 3/7. He was also prescribed g. dorzolamide 2% BD for 1/52 and orally t. methylprednisolone 16 mg BD 3/7, 8 mg BD 3/7, and 4 mg BD for 3/7. Four days after the operation, there was an impressive reversal of macular thickening, and the foveal area had no serous detachment. The central macular thickness was 285 micrometres (shown in Fig. 3), and the BCVA was 6/6.

The steroid treatment by mouth was discontinued, and the patient continued his treatment with g. dexamethasone 0.1% QDS for 3/52 and BD for 2/52 and g. ketorolac 0.5% TDS for 6/52. The patient was examined 11 days postoperatively, and OCT confirmed a healthy central macular thickness (shown in Fig. 4, 5), while the BCVA remained 20/20. One month after surgery, the BCVA and OCT remained normal.

Toxic maculopathy may present either sporadically when the correct dosage is used or, more commonly, when an incorrect concentration of cefuroxime is used intracamerally. The recommended dosage is 1 mg cefuroxime/0.1 mL, and it is suggested to be safe up to 3 mg cefuroxime/0.1 mL [7].

Cystoid macular oedema (CME) is the primary cause of reduced vision after cataract surgery. A medical history of uveitis, diabetes mellitus with diabetic retinopathy, and intraoperative complications can increase the risk of CME after surgery [8]. Our case illustrates that toxic maculopathy may occur even in the absence of high risks and with an incorrect dose of cefuroxime.

The aetiology of CME after cataract surgery is not fully understood. In a study performed by Zuo et al. [9], the authors suggested that after the use of the correct dose, toxic maculopathy may have been caused by transient retinal pigment epithelium sodium-potassium pump dysfunction. In other studies, pathological vascular activity and haematological barriers disruption were also reported when an incorrect dose of intracameral cefuroxime was used [6].

TASS is a rare but severe anterior segment inflammation that usually occurs within the first 48 h after anterior segment surgery [10]. Because of the acute presentation of this condition, we considered differentiating between cefuroxime toxicity and TASS. In our case, there were no specific signs of inflammation in the anterior chamber, while there was evident CME with serous detachment in the macular area on the OCT. This clinical appearance differentiated the complication we noticed in our case with the TASS, where anterior segment signs are vigorous and evident in the early postoperative days. Irvine-Gass syndrome was also excluded. First, on the basis that it was noted on the first post-operative day, the Irvine-Gass syndrome is presented later, usually between the fourth and sixth week post-operatively. Second, because in cefuroxime-induced toxic maculopathy, the macular oedema takes the form of large retinal serous detachment with a schisis-like appearance of the outer nuclear layers while it appears within the retinal layers in Irvine-Gass syndrome [6]. In addition, hypotonus maculopathy, vein occlusion, and vitreomacular traction were excluded based on clinical assessment and OCT findings.

There are several reports of toxic maculopathy following the use of an increased dose (more than 50 mg/mL) of intracameral cefuroxime [7]. The intracameral use of 1 mg/0.1 mL of cefuroxime has been found to be safe for the macula area [11] and is effective in reducing the risk of endophthalmitis by 5 times [12]. There are several reports, such as the one that we present here, in which the authors observed toxic maculopathy after the intracameral injection of a correct dose [13]. However, Gupta et al. [11] reported no evidence of increased macular toxicity secondary to using 1 mg/0.1 mL of intracameral cefuroxime.

When the macular toxicity is related to an increased concentration of the cefuroxime, then the postoperative inflammation may share some characteristics with TASS: it begins within 24 h after surgery, it is associated with fibrin formation and corneal oedema, and it improves with topical steroid treatment. However, in the case of an increased concentration of cefuroxime, the inflammation is not restricted to the anterior segment, which argues in favour of a diagnosis of mild toxic endophthalmitis rather than TASS [6, 14]. After intracameral injection of a high dose of cefuroxime, toxic implications have been observed in the retina, with transient or permanent macular changes evidenced on OCT as well as to the optic nerve as optic neuropathy with RAPD and defects in colour perception. These defects may permanently affect visual function [3]. The treatment of cefuroxime-toxic maculopathy is the same as in the case of a standard dose or increased dose and involves NSAID and steroid drops. However, the recovery time is shorter when a standard cefuroxime dose is used [13], compared to longer periods when a high dose of cefuroxime is used [3].

The importance of correct preparation of the intracameral injection of cefuroxime needs to be emphasized. The licensed intracameral cefuroxime is available in Europe as “APROCAM” as a sterile powder of 50 mg [15]. Before injection, the powder was dissolved to 5 mL of sodium chloride 9 mg/mL (0.9%). And again, it should be diluted in 1/10, taking 0.1 mL of this solution and 0.9 mL of normal saline 0.9% to produce 1 mg/0.1 mL cefuroxime solution. Due to human errors, incorrect dilutions, such as tenfold of the correct concentration, may be used, resulting in a potential toxic effect on the macula. To secure the administration of the accurate dosage, licensed intracameral cefuroxime may be provided in a smaller dose and ideally in a quantity that will require only one dilution for the correct concentration: for example, a vial of 10 mg of sterile powder of cefuroxime, which will be diluted with 1 mL of NaCl 0.9%.

The patient was concerned about significant reduction in his vision in the first postoperative day and asked for an immediate appointment. The patient understood the explanation he received, showed trust in his surgeon, and was fully compliant with the treatment. After his quick recovery, he was happy, relieved, and remained thankful and reassured.

Surgeons should be aware of toxic maculopathy in cases of reduced vision during the first few days after uncomplicated cataract surgery. Standard anti-inflammatory treatment is effective and ensures good functional visual acuity. Macular toxicity is more frequent and may have a more severe clinical appearance when cefuroxime concentration is high. Despite the severity of early clinical findings, the resolution of toxic maculopathy is complete and occurs within a few days. It is usually longer when the concentration of cefuroxime is high and can result in some degree of permanent damage to the outer retina. The correct dilution of cefuroxime is of utmost importance, and ways of securing the correct concentration need to be re-considered. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543837).

This study protocol was reviewed and approved by the Athenian Clinic Clinical Ethics Committee on the 9th of October 2024. A written informed consent was obtained from the patient for publication of the clinical details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

M.E.P.: substantial contributions to the acquisition, analysis, or interpretation of data for the work; drafting the work or reviewing it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. S.B.: substantial contributions to the conception or design of the work and the acquisition, analysis, and interpretation of data for the work; reviewing the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work. E.P.P.: substantial contributions to the design of the work and analysis and interpretation of data for the work; drafting the work or reviewing it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work. T.R.: substantial contributions to the analysis and the interpretation of data for the work; reviewing the work critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work.

All data generated or analysed during this study are included in this article and its online supplementary material. Further enquiries can be directed at the corresponding author.