Structural and Functional Insight into Intracameral Cefuroxime Ocular Toxic Syndrome (ICOTS) in Eyes with Disrupted Intraocular Barrier

Intracameral injection of cefuroxime at the recommended dose of 1.0 mg in 0.1 ml solution has become a routine practice in Europe for the prophylaxis of postoperative endophthalmitis following cataract surgery. The European Society of Cataract and Refractive Surgeons (ESCRS) multicenter study demonstrated that intracameral cefuroxime significantly decreases the postoperative endophthalmitis rate after cataract surgery [1]. However, the effectiveness of this procedure remains a topic of debate [2, 3] and, additionally, its use remains off-label in the USA [4].

Cefuroxime retinal toxicity primarily manifests as extensive serous macular detachment. This condition can be differentiated from pseudophakic cystoid macular edema (Irvine-Gass Syndrome) based on the timing of onset and the imaging features [5]. The fluid typically resolves spontaneously within 1 or 2 weeks, leading to an apparently benign prognosis [6]. However, cases with poor visual outcomes have been reported [7, 8].

To our knowledge, no study has evaluated the characteristics of this condition using techniques other than optical coherence tomography (OCT) and fluorescein angiography during or after the acute phase of toxicity in eyes with a disrupted intraocular barrier. The aim of the study reported here was to provide new insights into intracameral cefuroxime ocular toxic syndrome (ICOTS) after cataract surgery using ultra-wide-field [9] OCT angiography (UWF-OCTA) combined with retinal electrophysiology and perimetry. We monitored and documented both acute and chronic functional and structural changes.

Considering the known effects of cefuroxime toxicity and their potential exacerbation in eyes with a disrupted intraocular barrier, which may facilitate drug penetration from the anterior chamber to the retina, we hypothesized that patients with a history of pars-plana vitrectomy (PPV) or anterior vitrectomy would exhibit prolonged structural and functional retinal changes following intracameral cefuroxime injection.

We present a retrospective case series involving four patients with no concomitant systemic diseases who experienced serous retinal detachments due to intracameral cefuroxime toxicity (administered at a standard dose of 1.0 mg/0.1 ml solution), which appeared the day after cataract surgery. All patients had a disrupted vitreous architecture representing a natural intraocular diffusion barrier between the anterior chamber and the retina. Patients underwent a complete ophthalmological evaluation, including best-corrected visual acuity (BCVA) assessment, 30–2 standard automated perimetry (Humphrey Field Analyzer; Carl Zeiss Meditec AG, Jena, Germany), multifocal electroretinography (ERG) using Retimax ointment (CSO, Florence, Italy), ultrasonography (Eye Cubed Ultrasound System; Ellex, Inc., Lumibird Medical, Cournon-d'Auvergne, France), spectral-domain OCT with Spectralis (Heidelberg Engineering, Heidelberg, Germany), and swept-source (SS) UWF-OCTA with VG200S (SVision Imaging, Henan, China). Functional and structural examinations performed were retrospectively evaluated at the preoperative visit (T0) and at 1 day (T1), 1 week (T2), 1 month (T3), 6 months (T4), and 1 year (T5) after cataract surgery.

The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study was approved by the Internal Review Board of the University of Tor Vergata (ethics approval ID: 263.22). Written informed consent was obtained from all participants for the use of the data and their publication.

Table 1 summarizes the demographic, clinical, functional, and structural characteristics of the patients included in the present study.

Cefuroxime retinal toxicity is a condition described in the literature following either erroneous high doses or standard doses of intracameral injection [10‐12]. We assume this condition is likely to be underestimated because an OCT examination is not routinely performed during the week following surgery when serous retinal detachments can be detected.

To the best of our knowledge, studies evaluating the safety of intracameral cefuroxime injection after cataract surgery, with or without perioperative capsular rupture, have examined the incidence of macular edema only after at least 2 weeks post-surgery, when the edematous phase of ICOTS has concluded [13, 14]. A potential explanation could be the confusion of the condition with pseudophakic macular edema, which is typically an inflammatory and non-toxic disease [5].

In 2018, the Royal College of Ophthalmology issued a safety alert regarding intracameral cefuroxime in which it recommended avoiding this drug whose summary of product characteristics specifically warns against its intraocular use [15]. Moreover, a recent pharmacovigilance study emphasized the need for caution regarding ocular toxicity when cefuroxime is administered intraocularly [16].

We evaluated four patients diagnosed with ICOTS using both structural and functional methods, even after fluid resolution. This approach helped us identify additional aspects of the disease.

The UWF-OCT examination revealed that both the posterior pole and the mid-periphery of the retina were affected (Fig. 1). During the acute phase, we also detected SS-OCT hyperreflective foci in the vitreous chamber that were not visible on ultrasonography (Fig. 2). These foci partially persisted until 1 year after surgery. In two patients, the resolution of the macular serous retinal detachment led to visible structural OCT damage of the outer retina, which is likely to be permanent (Fig. 3). UWF-OCTA revealed an increase in SVD in the posterior pole and mid-periphery during the acute phase, while at the resolution of subretinal fluid, SVD decreased; it was only partially restored but did not return to preoperative values after 12 months. The deep vascular complex, choriocapillaris, and choroidal circulations did not appear to be damaged. Vascular involvement included not only the macular region but also the retinal mid-periphery (Fig. 4). Multifocal ERGs, after the loss observed at T1-T2, showed a gradual recovery of the foveal response amplitude at T3-T5 (Fig. 5).

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Our results are consistent with the hypothesis that intracameral cefuroxime at the standard dose can cause retinal toxicity in eyes with a disrupted intraocular barrier. The observed serous retinal detachments and persistent functional alterations support the hypothesis that cefuroxime may penetrate the posterior segment in such cases, leading to transient but potentially irreversible retinal changes. The structural, vascular, and electrophysiological findings further suggest that the drug affects retinal structure and function beyond the acute phase.

It has been shown that intravitreal cefuroxime induces toxic damage to the inner retina and vascular cells and provokes an inflammatory response in endothelial cells [17]. A retrospective study found that over two-thirds of vitrectomized eyes receiving BSS perfusion solution containing cefuroxime sodium (1 mg/ml) developed macular edema [18].

Three of our patients had previously undergone PPV, and one had experienced intraoperative posterior capsule rupture requiring anterior vitrectomy. These procedures could be considered potential risk factors. PPV or anterior vitrectomy may increase the risk of ICOTS by disrupting the vitreous architecture and facilitating drug penetration from the anterior chamber to the retina. Of note, the most severe documented cases in the literature, contributing to a poor visual prognosis, were associated with posterior capsule rupture and anterior vitrectomy, which is consistent with our hypothesis [7, 8].

We suggest evaluating whether to revise the informed consent form to inform patients of the possible risks of ICOTS when administering this antibiotic prophylaxis, particularly if a known risk factor is present. Our findings support the value of performing an OCT examination on the day after surgery if there is a discrepancy between the ophthalmoscopic appearance of the anterior segment of the eye (clear ocular media) and the patient's BCVA. UWF-OCTA can be useful for assessing retinal vascular involvement in a condition that causes exudative retinal detachments in both the macula and peripheral retina. Multifocal ERG may also contribute to the functional evaluation of acute cefuroxime retinal toxicity.

The limitations of the present study include its retrospective design, small sample size, lack of a control group, and relatively short follow-up period. Future long-term prospective case–control studies with larger populations will be essential to determine whether cefuroxime toxicity could lead to irreversible structural and functional damage.

This study provides new information regarding retinal toxicity following standard-dose intracameral cefuroxime injection during cataract surgery. The drug's toxicity may cause persistent retinal changes even after serous retinal detachments have resolved, with functional and structural alterations that may continue for at least 1 year after surgery. Eyes that have undergone PPV or anterior vitrectomy may be at a higher risk of developing ICOTS. Ophthalmologists should be aware of this potential risk and consider informing patients about the possibility of ICOTS in these situations.