Retinal toxicity secondary to subconjunctival cefuroxime following pars plana vitrectomy: A case report and literature review

Purpose To present a case of inadvertent retinal toxicity induced by a standard dose of subconjunctival cefuroxime after epiretinal membrane surgery. Narrative review of cefuroxime overdose or toxicity after intraocular surgery was carried out to describe characteristics of cefuroxime toxicity and their relationship to visual outcome. Observations A 64-year-old man underwent pars plana vitrectomy (PPV) with epiretinal membrane peel and received a standard dose of subconjunctival cefuroxime as endophthalmitis prophylaxis. At two weeks, visual acuity measured counting fingers, and fundus examination showed haemorrhages and cotton wool spots. Fluorescein angiography confirmed widespread ischaemia involving the macula. Subsequent litigation ruled that inadvertent cefuroxime toxicity after an accidental penetration of sclera was the likely aetiology. Conclusions and importance In addition to inadvertent overdose due to dilution errors, accidental scleral penetration is another mechanism for drug toxicity following subconjunctival cefuroxime injection. Literature review revealed broadly different manifestations of cefuroxime retinal toxicity. This case highlights the need to consider severe cefuroxime toxicity in patients presenting with unexplained post-PPV visual loss.


Introduction
Antibiotics are routinely administered during intraocular surgery as prophylaxis against post-operative endophthalmitis. Previous case reports described retinal toxicity of varying severity after intracameral cefuroxime use in cataract surgery; this ranges from transient retinal oedema to severe haemorrhagic retinal infarction and optic atrophy. [1][2][3][4][5][6][7][8] A case series of 152 patients undergoing combined phacovitrectomy did not report any toxicity with intracameral cefuroxime. 9 In vitreoretinal surgery, a more commonly used route of antibiotic delivery is via the subconjunctival space. Here, we report a case of retinal toxicity in a patient receiving subconjunctival cefuroxime 125 mg after pars plana vitrectomy (PPV).

Case report
A 64-year-old man with a preoperative best corrected visual acuity (BCVA) of 6/9 underwent epiretinal membrane (ERM) surgery in the left eye (LE) under general anaesthesia at a different institution. There was no significant past medical history or previous ocular surgery. PPV using 23-gauge sclerotomies with routine ERM peel and a fluid fill was performed. At the end of the procedure, subconjunctival cefuroxime (125 mg in 1 ml) was given for endophthalmitis prophylaxis, although volume delivered was not documented. The procedure was reported to be technically uneventful, although it was immediately complicated by inferior subconjunctival haemorrhage and a vitreous cavity haemorrhage was noted on the following day.
BCVA declined to finger counting at day one and this persisted despite resolution of vitreous haemorrhage. The intraocular pressure (IOP) at day two was 14 mmHg. At two weeks post-surgery, the patient sought a second opinion with our service. Slit lamp examination revealed subconjunctival haemorrhage, clear cornea, IOP 11 mmHg, deep and quiet anterior chamber, clear lens and no vitreous inflammation. Fundus examination showed macular fold. In addition, there were widespread deep retinal haemorrhages and cotton wool spots more prominent in the midperipheral and peripapillary areas. There was no vascular tortuosity and the optic disc was not swollen. Fundus fluorescein angiogram showed widespread leakage and ischaemia (Fig. 1). BCVA worsened to light perception due to the maculopathy, and a macula involving retinal detachment subsequently developed within four months of the original procedure.
He underwent PPV with silicon oil tamponade, subsequent retinectomy due to proliferative vitreoretinopathy and lastly, a silicon oil removal. There were no pre-operative or intra-operative findings such as a retinal tear, needle marks on the retinal pigment epithelium or choroid, or choroidal haemorrhage which might have confirmed scleral penetration by the subconjunctival injection during the initial vitrectomy. Despite a flat retina, in the absence of tamponade, the LE BCVA did not improve. The retina at five-year follow-up was largely white and ischaemic, with only a small island of healthy retina. Final visual acuity measured light perception.
A litigation was raised against the surgeon who performed the ERM peel procedure. As clinical features resembled severe cefuroxime toxicity, the court ruled that an accidental penetration of the sclera during subconjunctival injection was the likely aetiology. Another potential mechanism considered was increased intraocular exposure to cefuroxime through a leaking sclerotomy.

Discussion
Our case identifies accidental penetration of sclera as a potential mechanism of cefuroxime toxicity after subconjunctival administration following PPV. Other factors that may theoretically increase the risk of toxicity include small eyes, sclerotomy leak and the use of intraocular tamponade. 10 This case highlights the need to consider cefuroxime toxicity in patients presenting with unexplained post-PPV visual loss.
Cases with good visual outcomes displayed early transient serous macular detachment (SMD) associated with intraretinal oedema predominantly in the outer nuclear layers. 1,[3][4][5][11][12][13][14][15]17 This developed rapidly (within 24 hours) but quickly resolved within one to two weeks without treatment. One case series attributed this to the practice of inflating clear corneal incisions with cefuroxime/balance salt solution (BSS) mixture. 11 Ellipsoid layer disruption was an observed feature in one case series involving six patients with variable visual outcomes (ranging from 6/12 to 6/60), but was not reported in other cases. 4 Our case is in keeping with the more severe manifestations of cefuroxime toxicity. This is in contrast with the only other report of subconjunctival cefuroxime retinal toxicity following a dose of 31.25mg. 15 In this case, the patient experienced SMD and macular oedema which resolved by day six. This may suggest variability and risk of toxic intraocular concentrations after subconjunctival cefuroxime injection and, as illustrated by our case, its potential to reach a toxic level after an accidental scleral penetration. Other factors affecting intraocular drug concentration after subconjunctival delivery include volume injected and in the context of PPV, the presence of sclerotomy leak, intraocular tamponade and ocular size. 10 This may support using commercially prepared intracameral cefuroxime formulations as endophthalmitis prophylaxis for pars plana vitrectomy to provide a more consistent intraocular concentration with a lower risk of toxicity. It is important though to note that intracameral cefuroxime does carry a risk of toxicity if a dilution error occurs.

Patient consent
Consent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.

Funding
This study was funded by Eyehope (UK registered charity 1119866).

Authorship
All authors attest that they meet the current ICMJE criteria for Authorship.

Declaration of competing interest
The following authors have no financial disclosures: AR, JN, TW.