Commentary: Endophthalmitis following intravitreal injection of dexamethasone implant.

Intravitreal dexamethasone implant (DEX; Ozurdex; Allergan, Inc, Irvine, CA) is an efficacious treatment in the management of macular edema due to diabetes, retinal vein occlusions, and posterior uveitis. Its safety and efficacy has been demonstrated by randomized trials such as GENEVA and MEAD study.[12]

Endophthalmitis is a rare but serious ophthalmic complication following injection and intravitreal injection of steroid having 6.92-fold more propensity to cause endophthalmitis when compared with anti-VEGF (0.13% vs 0.019%). There are two hypothesis: first, larger bore of needle used for steroid injection (30 or 32 G for anti-VEGF agents, 27 or 25 G for triamcinolone, and 22 G for the DEX) may facilitate bacterial penetration and second, immunosuppression may cause endophthalmitis with a relatively lower bacterial load.[3] Endophthalmitis rate following DEX range from 0% to 1.3% with 0% in GENEVA study and 1.3% in HURON study. There are few case reports on endophthalmitis following DEX injection.

A PubMed-based search shows report of 11 eyes of endophthalmitis following DEX, the largest case series describing five such cases out of which three were DEX coadministered with bevacizumab.[4] Table 1 illustrates the 11 published cases of endophthalmitis following DEX with isolation of coagulase negative Staphylococcus (CONS) in 5 eyes, Alloiococcus otitidis in one and four eyes with no bacterial growth. Among 5 CONS cases, Species identification was done in 3 cases which showed Staphylococcus epidermidis (n = 2), Staphylococcus lugdunensis (n = 1), while in other 2 cases, species identification was not done. There were no details available in two eyes. Mean duration of presentation was 4.67 days (median: 3; range: 2–15 days). In 6 out of 10 eyes, implant was removed along with vitrectomy. Visual outcome ranged from counting fingers to 6/7.5, but majority had moderate recovery.

Table 1

Summary of characteristics and treatment outcomes of endophthalmitis following DEX injection

Study	Year	No. of cases	Sl no.	Onset in days	Vision presentation	Organism isolated	Treatment	DEX removal	PPV done in days	Final vision
Yorgun et al.[5]	2014	1	1	2	HM	Negative	PPV + IVAB	Yes	1	6/7.5
Mahalingam et al.[6]	2017	1	2	3	PL	CONS (not typed)	PPV + IVAB	Yes	1	6/36
Marchino et al.[7]	2013	1	3	2	PL	Alliococcus otitidis	IVAB PPV	Yes	7	CF
Lowder et al.[8]	2011	1	4	NA	NA	Negative	NA	NA	NA	NA
Boyer et al.[2]	2014	1	NA	NA	NA	NA	NA	NA	NA	NA
Goel et al.[9]	2017	1	5	15	CF	CONS (not typed)	IVAB PPV	Yes	2	6/18
Esen et al.[10]	2015	2	6	3	HM	Negative	IVAB	No	-	6/60
			7	3	HM	Negative	IVAB	No	-	6/36
Salceanu et al.[11]	2019	1	8	4	CF	Staphylococcus lugdunensis	IVAB PPV	Yes	1	6/36
Stem et al.[4]*	2017	2	9	NA	6/240	Staphylococcus epidermidis	IVAB	No	-	6/15
			10	NA	HM	Staphylococcus epidermidis	PPV	Yes	NA	6/240

DEX=Dexamethasone implant, PPV=Pars Plana vitrectomy, IVAB=Intravitreal antibiotics, NA=Not available, CONS=Coagulase negative Staphylococcus, HM=Hand motion, CF=Counting fingers, PL=Perception of light. *Three eyes with coadministered DEX and bevacizumab not included

Endophthalmitis following intravitreal injections are caused by organisms of conjunctival and skin flora. CONS are the major group of organisms responsible for such infections. Several subspecies, such as S. lugdunensis isolated, show high virulence and rapid destructive properties. The organism form characteristic “Biofilm” around host tissue or prosthetic surfaces, hence has been implicated in systemic infections, such as endocarditis, bone and joint infections, and skin and soft tissue infections. Bacterial biofilms exhibit high levels of resistance and evasion from host immune defenses makes them difficulty to treat; these biolfilms or glycocalyx also interfere with the phagocytosis activity of neutrophils and play a role in bacterial colonization. The present issue of the journal has a publication on S. lugdunensis endophthalmitis following DEX injection highlighting the efficacy of the organism to grow on implants and prosthesis.[11] The recent alerts issued by FDA on increased silicone content in the Ozurdex injection and its temporary withdrawal from the market further raise the question of the facilitation of bacterial growth on silicone and thereby increasing the risk of endophthalmitis.

Suppurative keratitis and postoperative endophthalmitis are entities described in the eye.[12] Chiquet et al. studied this organism in postcataract surgery endophthalmitis and observed mean duration of presentation to be 7.4 days (median: 7; range: 5–12 days). Among five patients who developed endophthalmitis, four required Pars plana vitrectomy and three (60%) of them developed retinal detachment and ended up in less than ambulatory vision.[13] A case series of three S. lugdnensis endophthalmitis following intravitreal anti-VEGF injections has been described with poor visual outcomes.[14] Summary of S. lugdunensis endophthalmitis characteristics and outcome are briefed in Table 2. The organism is coagulase negative and is sometimes difficult to differentiate from Staphylococcus aureus; it presents with similar aggressive infections and bacterial endocarditis. It has an aggressive clinical course with retinal detachment in many patients warranting an early vitrectomy and poor visual outcome.

Table 2

Staphylococcus lugdunensis endophthalmitis: characteristics and outcome of published studies

Study	Year	No. of cases	Sl no.	Onset (in days)	Initial vision	Cause	Treatment	Timing of surgery (in days)	Vision outcome
Chiquet et al.[13]	2007	5	1	7	HM	Cat, PCR	IVAB, PPV	5	6/12
			2	6	PL	Cat, PCR	IVAB, PPV	17	HM (R.D)
			3	5	PL	Cat, PCIOL	IVAB, PPV	4	NLP (R.D)
			4	12	6/30	Cat, PCIOL	IVAB	-	6/6
			5	7	HM	Cat, PCIOL	IVAB, PPV	5	CF (R.D)
Kejbou et al.[14]	2014	3	1	2	PL	Lucentis	PPV+IVAB	1	HM
			2	3	6/60	Lucentis	IVAB	-	6/60
			3	2	6/60	Avastin	IVAB, PPV	2	6/30

Cat, PCR=Cataract extraction with posterior capsular rent, Cat, PCIOL=Cataract extraction with posterior chamber intraocular lens, PPV=Pars Plana vitrectomy, IVAB=Intravitreal antibiotics, R.D=Retinal detachment

There are no evidence-based guidelines for management of DEX-related endophthalmitis, although they all present with severe vitritis and require aggressive management. There are hypotheses suggesting that implant may act as permanent reservoir of bacteria by protecting them from host immune response; hence, early vitrectomy with implant removal is recommended in most studies (6/10), although few cases were managed with intravitreal antibiotics alone [Table 1]. It is much more obviated in S. lugdunensis endophthalmitis, since its peculiar feature of biofilm formation might cause further difficulty for antibiotics to penetrate. Most of the infections are Gram-positive cocci with majority being CONS and subtyping of the organism is important as S. lugdunensis differs significantly from S. epidermidis in terms of virulence and aggressive clinical course.[12]

CONS are the skin and conjunctival flora and are most common organisms causing endophthalmitis following Ozurdex injections. Hence, breach in aseptic precautions prior to intravitreal injections would become the major factor to look upon. A periocular scrub using 10% povidone iodine and 5% povidone iodine in conjunctival cul-de-sac for adequate contact time should be followed stringently. Any intraocular injection procedure should follow standard precaution of not touching the eye-lids, lashes, or periocular skin before injection to avoid endophthalmitis.

Prompt reporting of cases should be encouraged to add upon to the literature to frame evidence-based guidelines in management of endophthalmitis.