The Effectiveness and Safety of Intravitreal Injections of Voriconazole in the Treatment of Fungal Endophthalmitis: A Systematic Review

Abstract

Background:

Fungus endophthalmitis is a rare and serious infection that is treated with systemic and topical antifungal drugs. There is no clear consensus on the treatment of fungal endophthalmitis with intravitreal injections (IVIs) of voriconazole. This systematic review aims to summarize the literature on IVIs of voriconazole for fungal endophthalmitis.

Methods:

We conducted a systematic review of the literature to determine the effectiveness and safety of IVIs of voriconazole in the treatment of fungal endophthalmitis. We searched databases such as PubMed and Embase using the following search terms “Endophthalmitis” AND “Intravitreal Injections” AND “Voriconazole” with date limits of January 1, 1900, to December 31, 2022. We included all reports on humans, which described clinical outcomes of IVIs of voriconazole in the treatment of fungal endophthalmitis, including randomized controlled trials (RCTs) and case series. A descriptive synthesis of the data was conducted with a pooling of data for interventions.

Results:

One RCT and 21 retrospective studies were analyzed in this review. In these reports, a wide range of heterogeneous treatment regimens was used, including IVI in combination with other drugs, systemic therapy in combination with other agents, and surgery. Combined with other treatments, intravitreal voriconazole results in a favorable anatomical and clinical cure that was well tolerated.

Conclusions:

Reports on IVIs of voriconazole for fungal endophthalmitis demonstrate a heterogeneous approach to treatment. Of these, IVIs of voriconazole in anatomical and clinical outcomes appeared to be highly effective, although more data on its safety are needed.

Background

Fungal endophthalmitis is a severe intraocular infectious disease caused by fungal infections, which, if left untreated, can lead to irreversible visual impairment and damage to intraocular structures. It is a rare yet significant cause of vision loss worldwide. Generally, fungal endophthalmitis can be categorized as either endogenous endophthalmitis, resulting from the hematogenous spread of bacteria, or exogenous endophthalmitis, caused by eye injuries, eye surgeries, corneal infections, and other factors.^1–4 Several studies have identified Candida, Aspergillus, and Fusarium species as the primary causes of fungal endophthalmitis.^5–8

Since its introduction in 2002, voriconazole has attracted attention due to its broad-spectrum antifungal activity, excellent ocular penetration, and favorable safety profile.⁹ These qualities make it an appealing choice for intravitreal injections (IVIs) in the treatment of fungal endophthalmitis. Voriconazole exhibits a broad antimicrobial spectrum, effectively covering the majority of fungal types causing endophthalmitis. in addition, it demonstrates good activity against amphotericin B-resistant Aspergillus soilis, Fusarium, and other fungi.⁶

The intraocular penetration of orally administered voriconazole was investigated in the noninflamed human eye. The study revealed concentrations of 1.13 ± 0.57 g/mL in the aqueous and 0.81 ± 0.31 g/mL in the vitreous.¹⁰ These intraocular levels are several times higher than the MIC90 values for the most common fungal organisms associated with endophthalmitis. Furthermore, 1 study showed that concentrations of up to 250 μg/mL of voriconazole did not exhibit significant toxicity in vitro on primary human retinal pigment epithelium cells and optic nerve head astrocytes.¹¹

The International Disease Society of America (IDSA) recommends the administration of voriconazole loading dose 400 mg (6 mg/kg) intravenous every 12 h for 2 doses and then 300 mg (4 mg/kg) intravenous or oral every 12 h, as well as intravitreal administration of 100 μg/0.1 mL of voriconazole for the treatment of Candida and Aspergillosis endophthalmitis, with strong recommendation and weak quality evidence.^12,13 However, the effectiveness of IDSA-recommended treatment for fungal infections caused by other species remains uncertain. Furthermore, no systematic review has been conducted thus far on the treatment of fungal endophthalmitis.

Designing a standardized treatment protocol for fungal endophthalmitis has proven challenging due to the diverse presentation, variable duration of symptoms, severity of the condition, and differences in fungal virulence. In light of voriconazole's wide-ranging antimicrobial efficacy, favorable intraocular permeability, and potential photoreceptor toxicity, a systematic review of the clinical outcomes of IVIs for treating fungal endophthalmitis was conducted. The goal was to synthesize the relevant literature on the subject.

Methods

The study protocol was registered with PROSPERO (2022: CRD42022333837). The conduct and reporting of the study follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The objective of this review was to evaluate the effectiveness and safety of management strategies for IVI voriconazole for fungal endophthalmitis using available literature. The treatment of fungus endophthalmitis and the associated clinical outcomes have been examined. The primary outcome at the end of the follow-up period was effectiveness, which included favorable visual function outcomes with visual acuity ≥0.1; favorable anatomical outcomes with retinal attachment and no active inflammation; and favorable clinical outcomes with no eyeball atrophy, evisceration, enucleation, or death observed. Safety items included adverse reactions to the eye or system.

Study selection

Studies were considered eligible if they were peer-reviewed original research articles that encompassed patients diagnosed with fungal endophthalmitis. The clinical diagnosis was confirmed by analyzing the vitreous and/or aqueous using culture or polymerase chain reaction techniques. In addition, blood cultures can be employed for diagnosing endogenous endophthalmitis. The articles reported visual function outcomes, ocular anatomical outcomes, and infection control effects in patients who underwent IVIs of voriconazole. The studies included randomized controlled trials (RCTs), cohort studies, case series, and case reports. Conversely, studies that did not include patients treated with IVIs of voriconazole were excluded.

Data source and search strategy

The systematic review was conducted in accordance with the PRISMA guidelines. The following databases were searched: PubMed, Embase, Cochrane Library ClinicalTrials.gov, Chinese National Knowledge Infrastructure, and WanFang. The search terms used were as follows: “Endophthalmitis” AND “Intravitreal Injections” AND “Voriconazole’. The search was performed using a global data mining approach, with the date range set from January 1, 1900, to December 31, 2022.

Data extraction and risk of bias assessment

Two authors screened references and compiled articles based on the above criteria. Data extracted from each study included the name of the first author, study year, study location, sample size, types of infectious fungi, treatment regimens, and treatment outcome. Researchers evaluated the risk of bias in the included RCTs based on Cochrane risk-of-bias criteria and case series based on Joanna Briggs Institute (JBI) Critical Appraisal tools.^14,15 Disagreements were resolved by the third author.

Results

Study characteristics

As a result of our search, 936 titles were found after duplicates and non-human studies had been removed. Nine hundred fourteen of these studies met the exclusion criteria described above after screening their title, abstract, and full text. Ultimately, our analysis included 22 studies that investigated the clinical outcomes of intravitreal voriconazole treatment for fungal endophthalmitis, comprising 21 case series and one randomized open-label trial (Fig. 1).^16–37

FIG. 1.

Flow diagram of studies screened for inclusion.

A total of 160 eyes from 139 patients were included in the analysis (Table 2). Among these patients, various medical conditions were present, including diabetes mellitus, glaucoma, hepatitis C, post-lung transplants, bone marrow transplants, pre-B cell acute lymphoblastic leukemia, neutropenia, sub-Tenon's triamcinolone, presumed lung Aspergillosis, immunosuppressive prescriptions, drug addiction, intravenous infusions, peripherally inserted central catheters, and receiving monoclonal antibodies.

The infectious causes of fungal endophthalmitis reported in the studies included 30 cases related to penetrating trauma, 12 cases associated with keratitis, 26 cases following various surgical procedures, 50 cases of endogenous endophthalmitis, and 42 cases with unspecified causes of infection. In all these reports, the diagnosis of fungal endophthalmitis was established through microscopy, culture, and, in some cases, by polymerase chain reaction.

Methodological quality of included reviews

The quality of included reviews was deemed moderate based on the results using the Cochrane risk-of-bias criteria and the JBI Critical Appraisal Checklist for Systematic Reviews (see Table 1 for detailed assessment). In studies No. 1, 3, 7, 9, 12, and 17, all 10 questions on the checklist received a “yes” response. However, in some case series, several questions were rated as “unclear” or “no,” primarily due to the lack of clarity regarding the consecutiveness and completeness of cases included, as well as their demographic characteristics.

Table 1.

Assessment of the Risk of Bias in the Included Randomized Controlled Trials/Case Series

Study no.	Author (year)	I	II	III	IV	V	VI	VII
16	Li (2017)	?	?	−	−	+	−	?

Study no.	Author (year)	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10
1	Sen et al. (2021)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
2	Liu et al. (2020)	Y	Y	Y	Y	U	Y	Y	Y	Y	Y
3	Zhuang et al. (2020)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
4	Sen et al. (2006)	Y	Y	Y	U	U	Y	Y	Y	Y	Y
5	Sahu et al. (2021)	Y	Y	Y	U	U	Y	Y	Y	Y	Y
6	Scartozzi et al. (2011)	Y	Y	Y	U	U	Y	Y	Y	N	Y
7	Breit et al. (2005)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
8	Motukupally et al. (2015)	Y	Y	N	U	U	N	Y	Y	Y	Y
9	Tran et al. (2018)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
10	Vinekar et al. (2014)	Y	Y	Y	U	U	Y	Y	Y	Y	Y
11	Liu et al. (2014)	Y	Y	Y	U	U	Y	Y	Y	Y	Y
12	Moloney and Park (2013)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
13	Mithal et al. (2015)	Y	Y	Y	Y	Y	Y	Y	Y	N	Y
14	Bui and Carvounis (2016)	Y	Y	Y	U	U	Y	Y	Y	N	Y
15	Chen et al. (2020)	Y	Y	Y	U	U	Y	Y	Y	N	Y
17	Vasconcelos-Santos and Nehemy (2009)	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
18	Cakir et al. (2009)	Y	Y	Y	U	U	Y	Y	Y	N	Y
19	Lin et al. (2008)	Y	Y	Y	N	N	Y	Y	Y	Y	Y
20	Bienvenu et al. (2020)	Y	Y	Y	N	N	Y	Y	Y	Y	Y
21	Chen et al. (2007)	Y	Y	Y	N	N	Y	Y	Y	N	Y
22	Jain et al. (2007)	Y	Y	Y	U	U	Y	Y	Y	Y	Y

I: Random sequence generation (selection bias); II: Allocation concealment (selection bias); III: Blinding of participants and personnel (performance bias); IV: Blinding of outcome assessment (detection bias); V: Incomplete outcome data (attrition bias); VI: Selective reporting (reporting bias); VII: Other bias. Q1: Were there clear criteria for inclusion in the case series? Q2: Was the condition measured in a standard, reliable way for all participants included in the case series? Q3: Were valid methods used for identification of the condition for all participants included in the case series? Q4: Did the case series have consecutive inclusion of participants? Q5: Did the case series have complete inclusion of participants? Q6: Was there clear reporting of the demographics of participants in the study? Q7: Was there clear reporting of clinical information of participants? Q8: Were the outcomes or follow-up results of cases clearly reported? Q9: Was there clear reporting of the presenting site(s)/clinic(s) demographic information? Q10: Was statistical analysis appropriate?

+, low risk of bias; −, high risk of bias; ?, unclear risk of bias; N, no; U, unclear; Y, yes.

This review encompassed only one randomized trial, which carried a risk of bias, consequently impacting the confidence in the findings. The quality of the case series was assessed as moderate. Overall, the available data on IVIs of voriconazole for fungal endophthalmitis are associated with low certainty.

Types of endophthalmitis fungal infection

Out of 22 studies, 20 provided information on the type of fungal infection, while studies No. 11 and 12 did not specify this detail. The identified fungal species included Aspergillus, Fusarium, Candida, Scedosporium apiospermum, Dematiaceous fungi, Rhodotorula, Acremonium, Verticillium, Glomerella, and Unidentified mold (see Table 2 for details).

Table 2.

Summary of Included Review Characteristics

Study no.	Country	Study design (eyes)	Cause of infection					Comorbidities	Organism				Initial visual acuity
Study no.	Country	Study design (eyes)	EE	KA	PT	Pos	NM	Comorbidities	Aspergillus	Fusarium	Candida	Others fungus	Initial visual acuity
1	India	Case series (n = 14)	11	3				—	5 A. niger, 2 A. terreus, 2 A. nidulans, 1 A. flavus	1	2 C. albicans	1 Dematiaceous fungus	<0.112, >0.282^a
2	China	Case series (n = 19)		7	10	2		—	4 A. flavus, 5 A. fumigatus	4 F. moniliforme, 2 F. oxysporum, 1 F. solani	2 C. albicans	1 Rhodotorula sp.	<0.117, >0.281, uncooperative 1
3	China	Case series (n = 15)			15			—	10	1		3 Unidentified mold, 1 Dematiaceous mold	<0.115
4	India	Case series (n = 5)	2			3		—	2 A. niger, 1 A. flavus	1		1 S. apiospermum	<0.15
5	India	Case series (n = 4)	4					Diabetes 1, Monoclonal antibody therapy 2, immunosuppressive Rx 1, Presumed lung Aspergillosis 1, post-COVID-19 recovered 4	2 A. fumigatus, 2 A. niger				<0.14
6	United States	Case series (n = 2)	2					Sub-Tenon's triamcinolone 1			2 C. parapsilosis		>0.282^a
7	United States	Case series (n = 1)	1					T cell lymphoma			1 C. albicans		5/200
8	India	Case series (n = 4)	2		2			—			4		<0.14
9	United States	Case series (n = 1)				1		—			1 C. albicans		—
10	India	Case series (n = 1)				1		None			1 C. glabrata		CF 1
11	China	Case series (n = 6)					6	—	—	—	—	—	<0.15, 0.151
12	Australia	Case series (n = 5)	5					IVDU 3, PICC 2, hepatitis C 2	—	—	—	—	<0.11, 0.14
13	India	Case series (n = 12)			2	10		—	8 A. terreus, 2 A. flavus				<0.112
14	United States	Case series (n = 5)	2	2		1		—		2		2 S. apiospermum, 1 Glomerella sp.	<0.14, 1.01
15	China	Case series (n = 4)	3		1			Bone marrow transplantation 2		2	2 C. albicans		<0.12, 0.11, >0.281
16	China	Randomized open-label trial (n = 36)
		Study group					18		18 A. fumigatus				≤0.118
		Control group					18		18 A. fumigatus				≤0.116, >0.12
17	Brazil	Case series (n = 4)				4		Diabetes 2	1			1 Acremonium sp., 1 Penicillium sp., 1 Verticillium sp.	<0.11, 0.1–0.282, >0.11
18	Turkey	Case series (n = 8)	7			1		Glaucoma3, diabetes 2		8			<0.14, 0.1–0.281, >0.283
19	United States	Case series (n = 3)				3		—	1 A. flavus		2		—
20	France	Case series (n = 7)	7					Drug addiction 3, immunosuppressive Rx 2			4 C. albicans, 3 C. tropicalis		<0.14, 0.1–0.282, >0.281^a
21	Australia	Case series (n = 2)	2					Post-lung transplant 2, immunosuppressive Rx 2				2 S. apiospermum	0.1–0.282
22	United States	Case series (n = 2)	2					Pre-B cell acute LL 1, neutropenia 1				2 S. apiospermum	<0.11, >0.281

Best-corrected visual acuity.

A., Aspergillus; C., Candida; CF, count fingers; EE, endogenous endophthalmitis; F., Fusarium; IVDU, intravenous drug use; KA, keratitis associated; LL, lymphoblastic leukemia; NM, not mentioned; PICC, peripherally inserted central catheter; Pos, postoperative; PT, penetrating trauma; S., Scedosporium.

Treatment of IVI voriconazole for fungal endophthalmitis

In all eyes included in the study, intravitreal voriconazole was administered, except for the control group in one RCT (Table 3). With the exception of study No. 15, which did not specify combination pharmacotherapy, all studies utilized systemic antifungal treatments such as voriconazole, amphotericin B, fluconazole, itraconazole, and caspofungin. Other drug treatments included topical and systemic antibiotics, as well as IVIs of amphotericin B and antibiotics. Surgical interventions comprised pars plana vitrectomy, intraocular lens explantation, lensectomy, iridectomy, silicone oil usage, capsulectomy, endolaser coagulation, and anterior chamber washing.

Table 3.

Outcome Data for Interventions

Study no.	IVI vori	Other medication treatment regimen			Operation treatment regimen	Duration of follow-up (months)	Final visual acuity	Clinical outcome	Visual function cure (%)	Anatomical cure (%)	Clinical cure (%)
Study no.	IVI vori	Total	Topical	IVI	Operation treatment regimen	Duration of follow-up (months)	Final visual acuity	Clinical outcome	Visual function cure (%)	Anatomical cure (%)	Clinical cure (%)
1	+	Antifungals + antibiotics 14, steroids 7	Antifungal 14		IOL explantation 4, SFIOL 3, PK 1, PPV 12, PPV 3	7.0 ± 7.9	<0.19, >0.281, 0.1 to 0.284^a	—	35.7	100	100
2	+	AmB, Flu, Vori, Itra	Itra, AmB, Flu, natamycin, Vori	AmB	PPV 14, IVI 16, LE 6, PK 7	25.0 ± 17.0	<0.111. ≥0.1 to ≤0.285, evisceration 2, Uncooperative 1	Evisceration 2	26.3	89.5	89.5
3	+			Ceftaz + norvancomycin 9	PPV + LE 15, IE 2, SO 9	—	<0.112, ≥0.1 to ≤0.283	—	20	100	100
4	+	Flu 5	Vori 5	AmB 5	IOL explantation 3, AC cleaning 1, LE 1, AC tap fluid 1	—	<0.13, 0.1 to 0.282	RA 3, RD 2, infections resolved 5	40	60	100
5	+	Glucocorticoids 4	antibiotics 2, Vori 1	antibiotics 1	PPV + SO 3, VL 1	53.0 ± 23.9	<0.14	RD 1, central scarring 1	0	75	100
6	+	Vori 1, Vanco 1, Ceftaz 1, Triamcinolone 1, AmB 1, Flu 1			PPV	11.5	>0.282^a	Infections resolved 2, Ocular hypertension and cystoid macular 1	100	100	100
7	+	Vori 1, caspofungin 1			—	—	20/1001	Infection resolved, retina remained attached	—	—	—
8	+	Vori 2	Vori 1, AmB 1, natamycin 1	AmB 1	PPV, IOL explantation, AC washing, VL 1	40 ± 2.1	0.21, <0.13	Infections resolved 2, infections Improved 1	25	100	100
9	+	AmB			PPV, AC washing, IOL explantation, TAP V/C	99.6	0.21	IOL/open posterior capsule	—	—	—
10	+	Vori		AmB	PK, PPV	11	CF 1	Anatomical cure: +, visual cure: −	—	—	—
11	+			AmB 1	PK 1, PPV 5	—	Evisceration 1, <0.13, 0.11, 0.21	—	33.3	83.3	100
12	+	Flu 3, Vori 2		AmB 3	PPV 5	11	<0.11, >0.284	—	80	100	100
13	+			AmB 12	PPV 12	3.3	<0.18, 0.1 to 0.282, >0.282	Corneal scarring 5, CD 7, hypotony 5, vitreous opacities 4, RD 1	33.3	41.7	100
14	+	Vori 5, posaconazole 1	Vori 1, natamycin 1	AmB 2	PPV 5, SO 2, PPL 3, AC washing 1, IOL explantation 1	8.6 ± 3.0	<0.11, ≥0.45	IOL 1, inflammation resolved 4, ocular hypotension 1, keratoplasty 1	100	100	100
15	+	—	—	—	Lens excision 2, PPV 4, EC 2, SO 3	2.75 ± 1.3	0.11	Clinical outcome favorable 2, PVR occurred 1, retinal detachment 1	25	75	100
16
Study group	+	Vori	Atropine		—	0.83	≤0.116, >0.12	Improved (P < 0.05) compared to the control group in corneal opacity, aqueous flare, and vitreous opacity	11.1	100	100
Control group	−	Vori	Atropine		—	0.83	≤0.116, >0.12	—	11.1	100	100
17	+	Vori 4		AmB 1	PPV + capsulectomy 4; IOL explantation 3	7.25	<0.12, 0.282	RD 2, ocular hypotension and optic disk was pale 1	50	50	100
18	+	Vori 8, Itra 8	AmB 8	AmB 8	PPV 8, IOL and capsule explantation 7, AC membrane removal 1, SOT 8	5.7 ± 0.7	<0.15, 0.1 to 0.283, >0.281	Corneal opacity 3, evisceration 1, SO present 6, secondary ERM and ME 1	50	100	100
19	+	Flu	Natamycin		AC washing+PPV 3, IOL explantation 1	4.7 ± 1.5	0.1 to 0.281, >0.282^a	Improvement in intraocular inflammation and preservation of globe anatomy 3	100	100	100
20	+	Vori 5, flucytosine 2, caspofungin 1		AmB 1	PPV 5	16	0.1 to 0.282, >0.285^a	Cataract 2, death 2	100	42.9	42.9
21	+	Vori, AmB, Terb		Vanco+Ceftaz	PPV 2	19.5	—	Enucleation 2	0	0	0.00
22	+	Vori, antibiotic		AmB	PPV 2, SOT 2	—	—	Enucleation and death from sepsis 1, infections resolved and retinal detachment 1	0	0	50

Best-corrected visual acuity.

+, positive; −, negative; AC, anterior chamber; AmB, Amphotericin B; CD, choroidal detachment; Ceftaz, ceftazidime; CF, count fingers; EC, endolaser coagulation; ERM, epiretinal membrane; Flu, fluconazole; IVI, intravitreal injection; IE, iridectomy; IOL, intraocular lens; Itra, itraconazole; LE, lensectomy; ME, macular edema; PK, penetrating keratoplasty; PPL, pars plana lensectomy; PPV, pars plana vitrectomy; PVR, proliferative vitreoretinopathy; RA, retina attached; RD, retina detached; SFIOL, scleral-fixated intraocular lens; SO, silicone oil; SOT, silicone oil tamponade; TAP, tap and inject; Terb, terbinafine; Vanco, vancomycin; VL, vitreous lavage; Vori, voriconazole.

Effectiveness and safety

Regarding the functional outcome, the clinical results ranged from 0% to 100% for studies where the visual acuity was ≥0.1. Notably, study No. 5, 21, and 22 reported a functional outcome of 0.0%, primarily comprising patients with endogenous fungal endophthalmitis treated with immunosuppressive drugs for lung transplantation, leukemia, monoclonal antibody therapy, and immunoglobulin therapy. Several factors, including medical history, concurrent medications, and fungal infections, might contribute to the unfavorable visual acuity prognosis.

In terms of anatomical and clinical outcomes, most eyes demonstrated retinal attachment and no active inflammation at the end of the follow-up period. However, study No. 21 and 22 presented poor ocular anatomy and clinical outcomes, with 2 eyes requiring enucleation, 1 eye experiencing retinal detachment, and 1 patient succumbing to the infection. No correlation was observed between the cause of infection and the anatomical outcome.

The studies included in this review did not report any adverse effect associated with intravitreal voriconazole, either on the eye or the overall system.

Discussion

To the best of our knowledge, this is the first systematic review assessing the effectiveness and safety of IVIs of voriconazole in treating fungal endophthalmitis, comprising 22 studies and 139 patients. Despite heterogeneity in data quality and a limited number of patients with fungal endophthalmitis, the findings of this systematic review can be summarized as follows: (1) In terms of functional outcomes, clinical results varied from 0% to 100% for studies involving patients with visual acuity ≥0.1. Notably, patients receiving immunosuppressive drugs exhibited poorer visual acuity outcomes. (2) Regarding anatomical and clinical outcomes, the majority of eyes demonstrated retinal attachment and an absence of active inflammation at the end of the follow-up period. (3) IVI treatment was found to be safe and well tolerated, with no reported case of serious adverse drug reaction.

In this review, intravitreal voriconazole showed favorable anatomical and clinical outcomes in fungal endophthalmitis. Voriconazole has demonstrated efficacy against common fungi in endophthalmitis and exhibits excellent intraocular penetration.¹⁰ The drug's concentration between 0.05 and 2 μg/mL can effectively inhibit most fungal strains.^38,39 The species of fungal endophthalmitis infections is associated with the cause of infection, the geographical environment, and the patient's immune function. Candida is often the causative agent of endogenous fungal endophthalmitis, while disseminated Fusarium infections are observed in patients with compromised immune function.⁴⁰ In temperate climates, most cases of exogenous fungal endophthalmitis are caused by C. albicans. On the other hand, mold-induced endophthalmitis is more prevalent in tropical regions, where Fusarium and Aspergillus are the predominant culprits.^41,42

Apart from the prevalent fungal species in endophthalmitis mentioned above, this review also includes less common fungal species such as Scedosporium apiospermum and dematiaceous fungi. This review considers the culture results of the included literature as indicative of the actual species responsible for the intraocular fungal infection, rather than as contaminants.^29,43–47 Furthermore, some studies have demonstrated the effectiveness of intravitreal voriconazole for other fungal endophthalmitis, such as those caused by Cryptococcus neoformans, Histoplasma, and Coccidioides, which were not included in this review.^48–50

This study did not observe any evidence of systemic or intraocular toxicity related to voriconazole, especially concerning the retina. One study found that the use of intravitreal voriconazole up to 25 μg/mL did not cause any electroretinographic change or histologic abnormality in rodent retinas.⁵¹

Considering voriconazole as initial empiric therapy is recommended due to its broad-spectrum antifungal activity, favorable safety profile, and established efficacy against a wide range of fungal pathogens. It is advisable to retain tissue specimens to identify the type of fungal infection, and treatment can be adjusted, if necessary, based on fungal species or susceptibility results. For Zygomycetes without the antifungal activity of voriconazole, such as Mucormycosis and Absidia, other drugs with antifungal activity are recommended.^52,53

The outcome of visual function in fungal endophthalmitis varied significantly among the 21 studies reviewed. This variation could be attributed to several factors, including the limited number of participants in the studies, varying severity of eye infections and injuries, diverse species of fungi, the presence of different comorbidities in patients, and the utilization of multiple treatment approaches.^7,54,55 A systematic review found no significant difference between groups regarding clinical ocular outcomes for exogenous and endogenous endophthalmitis.⁵⁶ A retrospective study revealed that the clinical outcome of fungal endophthalmitis is generally influenced by the fungal species; infection with mold species was associated with worse visual acuity and a higher enucleation rate on final follow-up compared to infection with yeast species.⁵⁷ In addition, some patients in this study had endophthalmitis combined with both bacterial and fungal infections, which results in the final outcome that ocular inflammation is also influenced by antibacterial treatment.

Except for one RCT, the remaining 21 studies were retrospective case series, which may be susceptible to publication bias. In addition, the treatment regimens' significant heterogeneities hampers data synthesis and the comparison of treatment effectiveness. As a severe intraocular condition that can cause disability, this study is unable to distinguish between voriconazole monotherapy and combination therapy due to the variety of treatment regimens, which may include combination therapy with multiple medications, surgical intervention, and other approaches. Given that the majority of these data originate from nonrandomized studies, the overall quality of evidence is considered to be low.

Conclusion

Due to the rarity of fungal endophthalmitis and resource limitations, conducting an RCT in patients with this condition is not feasible. In this context, a systematic analysis is likely to be valuable in defining the treatment approach for fungal endophthalmitis. The findings from this study indicate that the majority of patients with fungal endophthalmitis demonstrated stable or improved clinical outcomes following IVI of voriconazole, with improvements observed in visual acuity, infection resolution, and retinal conditions.

Footnotes

Acknowledgment

The authors are thankful for the help from the staff in the Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University.

Authors' Contributions

Conceptualization: Y.X., X.W., and Z.J.; methodology: Y.X., X.W., and Z.J.; investigation: Y.X.; data curation: Y.X., X.W., and Z.J.; writing—original draft preparation: Y.X.; writing—review and editing: Y.X., X.W., and Z.J.; supervision: G.L. and C.Z. All authors have read and agreed to the published version of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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