2025+国际共识指南：真菌性眼内炎的诊断和管理

Abstract

Fungal endophthalmitis represents one of the most challenging intraocular infections to diagnose and manage in ophthalmology.Despite advances in diagnostic techniques and treatment options, numerous controversies persist regarding optimal approaches to this sight-threatening condition. Due to the low incidence and significant variation in the severity and time of presentations, no large-scale randomized controlled trials have been done.Therefore, identify-ing controversies and deliberating the best approach to diagnosing and treating fungal endophthalmits by international experts would help establish consensus statements that can guide clinical practice. The Asia-Pacific Academy of Professors in Ophthalmology(AAPPO), Asia-Pacific Vitreo-Retina Society(APVRS), and Asia-Pacific Society of Ocular Inflammation and Infection(APSOII) saw this critical gap and formed an international panel of experts comprising 24 experts to establish 20 consensus statements. While there is consensus on the need for early diagnosis and prompt administration of antifun-gal therapy, there are conflicting views on the optimal diagnostic approach to be taken, the role and timing of performing vitrectomy, and the use of systemic antifungal agents. A particularly contested topic is the role of corticosteroids. In estab-lishing the 20 consensus statements, these thus serve as guidelines for diagnosing and managing fungal endophthalmitis.

Keywords Controversy,Consensus,AAPPO,APVRS,APSOII,Fungal endophthalmitis,Diagnosis, Management

*Correspondence:

Taraprasad Das

tpdbei@gmail.com; tpd@lvpei.org

Dennis S. C. Lam

dennisism@pierci.uhksz.org

Full list of author information is available at the end of the article

BMC

©The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedications waiver (http://creativecommons.org/licenses/by/4.0/).The Creative Commons Public Domain Dedications waiver (http://creativeco-

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Background

Globally, over 300 million people are affected by a severe fungal infection, and 25 million are at high risk of dying or losing their sight[1]. Two important ocular fungal infections are keratitis and endophthalmitis. The inci-dence of fungal endophthalmitis is higher in South Asia and Southeast Asia than in Europe and North America[2]. This has been noted to increase with the widespread use of immunosuppressive therapies and invasive pro-cedures. Without a global incidence report and a ran-domized clinical trial, there is no universally accepted diagnosis and management protocol for fungal endoph-thalmitis. Therefore, we took the opportunity to identify areas of controversy and establish consensus on diag-nosing and managing fungal endophthalmitis. The Asia-Pacific Vitreo-Retina Society(APVRS), the Academy of the Asia-Pacific Professors of Ophthalmology(AAPPO),and the Asia-Pacific Society of Ocular Inflammation and Infection(APSOII) have chosen“fungal endophthal-mitis” as one of the targeted topics for consensus and controversy for 2025 because of the reasons mentioned above. Two of this manuscript's senior authors(TD and DSCL) were appointed to coordinate this consensus project. This manuscript synthesizes evidence-based,real-world practice recommendations from leading global experts to guide diagnosing and managing fungal endophthalmitis.

Methodology

Further to appointing the two coordinators, the AAPPO, APVRS, and APOSII formed an international expert panel comprising 24 panelists from 12 countries/territories. A core group of three members(TD, DSCL,and NVR) was established to perform literature search and review on fungal endophthalmitis as well as pre-pare the first draft of the identified controversies and consensus developed with explanation and elaboration.These statements were organized into five categories:disease entity, clinical diagnosis, pathobiology includ-ing microbiology, treatment, and future development.Each panel member independently and anonymously reviewed each statement and provided comments to the core group. The core group then reviewed, evalu-ated the feedback and comments, revised, and sent out the second draft for further opinions. This process was repeated until the statements were finalized. Subse-quently, each panel member voted on each statement anonymously using a five-point Likert scale, rang-ing from‘strongly agree;‘agree;‘neutral’,‘disagree;’ to'strly disagree' A consensus was reached when at least 75% of the experts voted either'agree' or'strongly agree' for a statement.

# Controversies and consensus statements

Section 1. Disease entity

Fungal endophthalmitis accounts for approximately 15%-19% of all endophthalmitis globally. The incidence after an intraocular procedure(chiefly cataract surgery) is lesser in North America and Europe[3, 4] than in Asia[5, 6]. Fun-gal endophthalmitis is classified into exogenous and endog-enous. The incidence of these two forms varies based on multiple patient factors, including underlying health con-ditions and risk factors such as recent surgeries or intra-venous drug use. The reported incidence of postoperative,traumatic, and endogenous fungal endophthalmitis in India is 16.7%, 14.4%, and 18% of all endophthalmitis, respectively[7-9]. Fungal endophthalmitis, unless after trauma, usu-ally presents as delayed onset endophthalmitis[10, 11]. The time to the onset of symptoms is an important differentiat-ing feature. Acute bacterial endophthalmitis presents within days, and fungal endophthalmitis presents in weeks to months. It is usually indolent and may persist for a variable time. This contrasts with acute bacterial endophthalmitis,which presents as a single episode of severe inflammation[12, 13]. In addition to reduced vision, there would be a his-tory of intraocular surgery or trauma, invariably with veg-ative material(exogenous infection) or illness that also required intravenous fluid injection(endogenous infection).A history of long-time use of topical corticosteroids and/or broad-spectrum antibiotics to reduce recurrent and per-sistent redness and inflammation/infection is not uncom-mon. The inflammation typically worsens when steroids are tapered or discontinued. Outbreaks of fungal endophthal-mitis after cataract surgery were described previously[14].Traumatic fungal endophthalmitis often occurs after injury with vegetable matter, stone, or mud particles[13, 15]. The symptoms and signs develop earlier than post-procedure and endogenous endophthalmitis.

Patients with endogenous fungal endophthalmitis often present with underlying systemic disease(com-mon, diabetes mellitus), chronic infection(common,respiratory, and urinary tract infection), recent hos-pitalization(many times with an indwelling catheter),recent surgery(common, gastrointestinal, and colon),and immunosuppression(common, malignancy, immu-nodeficiency syndrome). A break in the blood-retinal barrier and a disrupted Bruch's membrane result in the spread of endogenous sources of fungal infection from chorio-capillaries into the vitreous. This results in acute suppurative inflammation of the vitreous. As a result, vit-ritis is the most consistent presentation in endogenous endophthalmitis, sometimes with characteristic lesions in the vitreous and/or retina. The most common sites of systemic infection are the liver(pyogenic liver abscess),lung(pneumonia),endocardium(infective endocarditis),

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and presumed cutaneous or pulmonary sources in intra-venous drug users[1]. Intravenous drug use increases the risk of endogenous fungal endophthalmitis. In the USA,Europe, and Australia, intravenous drug use-related endogenous fungal endophthalmitis is typically caused by Candida albicans[16-20].

Acute fungal endophthalmitis after cataract surgery is rare, but is a possibility. In an Indian study, nearly half to three-quarters of cases of fungal endophthalmitis were acute(time to onset of symptoms 30 days or less), and it was distributed nearly equally among three common fungi, Aspergillus, Candida, and Fusarium spp.[21].

The incidence of fungal endophthalmitis from large studies that analyzed at least 100 patients is listed in Table 1[21-28]. Aspergillus spp. and Candida spp.are the predominant causative fungi in exogenous and endogenous fungal endophthalmitis.

Consensus Statement 1.1: Fungal infections of the eye occur less frequently than bacterial infections. It is usually a delayed presentation. [Consensus score: 100%(strongly agree:80%;agree:20%;neutral:0%;disagree:0%;strongly disagree 0%)].

Consensus Statement 1.2: Endogenous fungal endoph-thalitis is as common as exogenous endophthalmitis.The common systemic diseases are the liver, the lungs(pneumonia), and the endocardium.[Consensus score:50%(strongly agree: 15%; agree: 35%; neutral: 15%; disa-gree:35%; strongly disagree 0%)].

Consensus Statement 1.3: Acute fungal endophthal-mitis after an intraocular procedure is also a possibility.[Consensus score: 95% (strongly agree: 40%; agree: 55%;neutral: 5%; disagree: 0%; strongly disagree 0%)].

Consensus Statement 1.4: Traumatic fungal endoph-thalmitis usually results from vegetative matter or soil injuries and presents earlier than other forms of fungal endophthalmitis.[Consensus score: 100%(strongly agree: 70%;agree:30%;neutral:0%;disagree:0%;strongly disa-gree 0%].

Consensus Statement 1.5: Vitritis is the most consist-ent clinical presentation in endogenous fungal endoph-thalmitis and may be accompanied by characteristic vitreous or retinal lesions. [Consensus score: 90%(strongly agree: 55%; agree: 35%; neutral: 10%; disagree: 0%;strongly disagree 0%)].

Table 1 The incidence of fungal endophthalmitis has been reported in larger studies worldwide

||Authors|Period|Country|No. of eyes|Predominant fungal pathogen|Percentage of fungal endophthalitis| |---|---|---|---|---|---|---| |Exogenous||||||| ||Das et al.[21]|2005-2020|India|3830 Culture-proven|Aspergillus spp.39.0% Fusarium spp.15.9% Candida spp.15.1%|19.1% Postoperative:46.9% Traumatic 35.6% Endogenous:17.5 With IOFB: Fusarium spp.2.6% Without IOFB: Aspergillus spp.2.6% Fusarium spp.2.7% Candida spp.1.6% Mucor spp.1.6%| ||Yang et al.[22]|2013-2020|China|383 Culture-proven|Post-traumatic With IOFB: Aspergillus spp.2.6% Without IOFB: Aspergillus spp.2.6% Fusarium spp.2.7% Candida spp.1.6% Mucor spp.1.6%|With IOFB: 7.9% Without IOFB: 15.6%| ||Chakrabarti[23]|1992-2005|India|113 Culture-proven|Aspergillus spp.54.4% Candida 24.6% Melanized fungi 10.6%|Postoperative:46.9% Post-trauma 10.6%| |Endogenous|Schimel et al.[24]|2000-2011|USA|448 Culture-proven|Candida albicans 5.8% N/A|15.8% 12.4%| ||Chen et al.[25]|2005-2024|China|177|N/A|12.4%| ||Cho et al.[26]|2006-2013|USA, South Korea|174|Candida spp. 22.7% Aspergillus spp.3.1% :|| ||Dave et al.[27]|2006-2018|India|173 Culture-proven|Candida spp. 4.6% Aspergillus spp.4.0% Fusarium spp.1.7% Candida spp.19.1%|19.4% Korea:16.4% 19.1%| ||Kim et al.[28]|2006-2018|South Korea|152 Candidemia|Candida spp. 19.1%|19.1%|

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Section 2. Clinical diagnosis

The signs include variable degrees of lid edema, chronic conjunctival congestion, hypopyon, and intense vitris.Typical signs of fungal endophthalmitis include nodu-lar exudates over the iris and crystalline/intraocular lens(IOL) surface, vitreous exudates arranged like a string of pearls, and creamy white circumscribed cho-rioretinal lesions[29](Fig.1). Some prominent anterior and posterior segment signs of fungal endophthalmitis are listed hereunder(Table 2).

A history of using long-term topical corticosteroid and/or broad-spectrum antibiotic to reduce recurrent and persistent redness and inflammation is not uncom-mon. A relatively quiet-looking eye with mild vitreous haze in a patient on prolonged topical and systemic steroids after intraocular surgery should raise suspi-cion of fungal endophthalmitis. In post-cataract sur-gery endophthalmitis, the fungi may also be sequestered under the IOL/capsular bag, making it difficult to detect the fungi. Systemic investigations could be required;these include complete blood count, serum urea and electrolytes, liver function tests, peripheral blood cul-ture, sputum and urine culture, chest radiogram, liver ultrasonogram, and transthoracic echocardiogram. The treating clinician decides the quantum of investigations based on the precipitating event and clinical suspicions.

In children, fungal endophthalmitis occurs more often after trauma. The infecting fungi are no different,and treatment is like treating endophthalmitis in adults,except that the children may require vitrectomy more often, and one should exercise caution in systemic anti-fungal therapy.

Ultrasonography (B-scan) is an important ancillary test to aid the clinical diagnosis. It quantifies vitreous exudation and structural changes of the retina and cho-roid [30]. It is useful in eyes with severe vitreous opaci-ties, which limit the view of the retina. It also helps in making treatment decisions and prognosticating the treatment outcomes.

Consensus Statement 2.1: Posterior segment signs are more apparent than the anterior segment signs in fungal endophthalmitis.[Consensus score: 75% (strongly agree: 40%; agree: 35%; neutral: 20%; disagree: 5%;strongly disagree 0%)].

Consensus Statement 2.2: Systemic investigations are essential in all fungal endophthalmitis.[Consensus score: 75%(strongly agree: 50%; agree: 25%; neutral:20%; disagree: 5%; strongly disagree 0%)].

Section 3. Pathobiology

Pathology

Three key factors define the outcome of the infect-ing fungi: infectivity, pathogenicity, and virulence. The

primary fungal pathogens can cause disease in immuno-compromised patients. However, most pathogenic fungi are opportunistic and do not usually cause disease unless there are alterations in immune defenses. Infection occurs when fungi penetrate rate barriers (such as intact skin and mucous membrane linings) or breach the immuno-logical defense (such as the host's immunocompromised state or debilitating conditions). Fungi also gain access to the host tissues after penetrating trauma or inhalation.Exogenous endophthalmitis occurs when the mechani-cal barriers of the eye(eyelids, tear film, nonkeratinized squamous epithelium of conjunctiva and cornea) are breached by trauma, surgery, or the extension of fungal keratitis (including corneal perforation) [31, 32]. Endog-enous infection spreads from the choroidal capillaries to the vitreous through disrupted Bruch's membrane. The severity of the disease depends on the size of the inocu-lum, the magnitude of tissue destruction, the ability of the fungi to multiply in tissues, and the immunologic sta-tus of the host.

Microbiology

Common ocular pathogenic septate filamentous fungi are Aspergillus, Fusarium, and the common pathogenic yeast is Candida species. Aspergillosis occurs in people with chronic pulmonary diseases, organ transplants(liver, renal, and bone marrow), leukemia, and drug abuse. The fungus usually gains access to the eye as it spreads from the lungs to the choroid and invades the retinal and cho-roidal vessel walls. Fusarium endophthalmitis usually occurs as an extension of the nonhealing corneal ulcer (Fusarium keratitis is common) [31]. There was a higher incidence of Mucor infection in endogenous endophthal-mitis during the SARS-CoV-2 pandemic in India [33].Table 3 lists the common endophthalmitis-causing fungi and associated risk factors.

Histopathology of formalin-fixed tissue and micro-biology of ocular fluid are the two primary sources of laboratory confirmation. In histopathology, the inflam-matory cells are best seen by hematoxylin and eosin(H&E) stains. The fungal hyphae appear refractile to pale acidophilic filaments, thin or broad, septate or aseptate,and with or without branching. These hyphae are high-lighted by special stains like periodic acid Schiff (PAS)and gomori methenamine silver (GMS) (Fig. 2). The char-acterization of fungi on histopathology is limited; hence,further ancillary techniques or microbiological culture correlation are needed [36].

Microbiological confirmation of fungi includes direct microscopy and culture. Direct microscopy using lacto-phenol cotton blue (LCB) and calcofluor white (CFW) is quicker. The color changes with the special stains help:Blue with LCB and fluorescent with CFW. Sabouraud

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 Fig.1 Typical signs of fungal endophthalmitis. a(Left) String of pearls;(Middle) Pre-retinal deposits;(Right) Vitreous membranes.b(Top panel)Bilateral endogenous fungal endophthalmitis. Multiple subretinal/ chorioretinal infiltrates and vitreous opacities, more in the left eye than in the right eye.Blood,urine,and vitreous fluid had Candida albicans.(Bottom panel) Unilateral endogenous fungal endophthalmitis.(Left) Slit-lamp examination shows corneal edema and anterior chamber exudation. Fundus examination shows tree-branch-like vitreous condensations. Blood and vitreous grew Fusarium petroilphilum.(Adapted with permission from[29].) c Candida endophthalmitis.(Left) Fundus-vitritis; two raised chorioretinal fungal lesions protruding into the vitreous.(Right) B-scan further delineating the lesions penetrating the Bruch's membrane.(Adapted with permission from[57] CC-BY-NC)

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Table 2 Clinical features of fungal endophthalmitis

|Anterior segment|Posterior segment| |---|---| |1.Conjunctival congestion 2.Dry appearing hypopyon 3.Yellowwhite-white nularod exudates on the iris/lens surface 4.Yellowwhite-white infiltrates at the coroesclonal wound of cataract surgery|1.Vitritis 2.Vitreous membranes 3. A string of pearl arrangement of vitreous exudates 4.Creamy white, circumscribed chorioretinal lesions|

Table 3 Common ocular fungi and risk factors causing endophthalmitis.[21,34,35]

|Category|Fungi|Risk factors| |---|---|---| |Post-procedure|Aspergillus spp. Candida spp. Fusarium spp.|•Cataract surgery ●Intraocular injections ●Contaminated surgical supply ●Extension of fungal keratitis| |Post-traumatic|Fusarium spp. Aspergillus spp. Candida spp.|•Penetrating ocular trauma ●Vegetative matter injuries •Rural injuries| |Endogenous|Candida spp. Candida spp.|•Hematogenous spread from systemic fungemia ●Intravenous drug use| ||Histoplasma spp. Aspergillus spp.|•Immunosuppression|

dextrose agar(SDA) and potato dextrose agar (PDA) are selective media for fungi; SDA and PDA are incubated at 25°C for 2-4 weeks. The chocolate agar/blood agar/brain heart infusion broth could also be used. Fungi are slow-growing organisms; cultures may take up to two weeks(Fig.3).

<BeginOfPara>Minimum fungicidal concentration(MFC) in fun-gal infection is like minimum inhibitory concentration(MIC). MIC is the lowest concentration of an antimi-crobial agent that prevents≥95% of visible growth of a microorganism, usually bacteria. MFC is the lowest drug concentration that achieves≥98% killing of a particular fungus. While MIC remains the standard endpoint for susceptibility testing due to ease of use and clinical rel-evance in most settings, MFC has shown better correla-tion with clinical outcomes in severe fungal infections especially in immunocompromised hosts, deep-seated infections(e.g., meningitis, endophthalmitis), and where fungicidal action is preferred or critical [37].

Resistance to antifungal drugs occurs through sev-eral mechanisms. It includes(1) nonsynonymous point mutations within the gene encoding the target enzyme(leading to alteration in the amino acid sequence),(2)increased expression of the target enzyme through increased transcription of the gene encoding it,(3)decreased concentrations of the drug within the fungal cells due to drug efflux, and(4) changes in the biosyn-thetic pathway resulting in reduced production of the target of the antifungal agents[38-40]. Biofilm forma-tion is one of the major causes of resistance. The poten-tial to form biofilms has been demonstrated in some ocular fungi(such as Aspergillus fumigatus, Candida albicans, Fusarium solani, Cladosporium sphaerasper-mum, and Acremonium implicatum)[41,42].

In recent years, molecular microbiology techniques and technologies have significantly advanced for rapid detection of infection. These techniques are highly sensitive and specific enough to complement the con-ventional methods. The most widely used molecular techniques are the polymerase chain reaction (PCR)and real-time PCR. PCR detects the DNA of microor-ganisms in the intraocular fluids; the primers are either uniplex or multiplex for detecting a particular organ-ism or a group of organisms. Pan-fungal PCR is useful in diagnosing fungal endophthalmitis [43]. Next-gener-ation sequencing (NGS) is a high-throughput, culture-independent technique. It allows an unbiased approach to detecting pathogens. Targeted NGS provides bet-ter sensitivity and specificity. Studies in India have reported a large proportion of polymicrobial infections in culture-negative endophthalmitis [44,45]. Investiga-tors have shown similar results after targeted metagen-omics and Nanopore targeted sequencing (NTS). NGS

 Fig.2 Photomicrograph depicting inflammatory cells along with septate fungal filaments in the intraocular contents(red arrows).(a) H&E,(b) GMS and(c) PAS staining(400x). H&E, hematoxylin and eosin; GMS, gomori methenamine silver; PAS, periodic acid Schiff

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 Fig.3 Microbiology of common fungi causing endophthalmitis. a,b Microscopy-septate branching filaments(Gram stain 1000x); Fluorescent,septate, branching fungal filaments(CFW, 400x) in vitreous samples were later identified as Aspergillus spp.(Adapted with permission from [87]).c,d Aspergillus flavus.c Microscopy of culture-LPCB mount showing septate, hyaline hyphae with rough-walled conidiophores terminating in globose vesicles bearing phialides(400x).d The culture on SDA shows characteristic granular, yellow-green colonies,typical of A.flavus,after 5 days of incubation at 25°C.e,f Candida albicans.e Microscopy-Gram stain of culture showing Gram-positive, oval to budding yeast cells with pseudohypae(1000x).f CFW Microscopy-stain highlighting budding yeast cells and occasional germ tubes under fluorescence microscopy(400x).g,h Fusarium solani.g Microscopy of culture-LPCB mount showing hyaline, septate hyphae with abundant sickle-shaped macroconidia and a blunt apical cell(400x).h Culture on SDA incubated at 25-30°C showing fast-growing, cottonies with a white surface that later becomes pink to violet with a pale reverse.(this figure is contributed by Dr. Joveeta Joseph, original author). CFW,calcofluor white;LPCB,lactophenol cotton blue; SDA,sabouraud dextrose agar

can identify virulence-associated genes that could help identify resistant pathogens to guide medical therapy[46-48].

Consensus Statement 3.1: Fungal infection occurs more often in immunocompromised people.[Consensus score: 95%(strongly agree: 50%; agree: 45%; neutral: 5%;disagree:0%; strongly disagree 0%)].

Consensus Statement 3.2: Common ocular patho-genic septate filamentous fungi are Aspergillus, Fusar-ium, and the common pathogenic yeast is Candida.(Consensus score: 100% (strongly agree: 75%; agree:25%; neutral: 0%; disagree: 0%; strongly disagree 0%)].

Consensus Statement 3.3: The microbiology confir-mation of fungi includes direct microscopy and culture.[Consensus score: 100%(strongly agree: 75%; agree:25%; neutral: 0%; disagree: 0%; strongly disagree 0%)].

Consensus Statement 3.4: The MFC should be used in fungal infection.[Consensus score: 75%(strongly agree: 45%; agree: 30%; neutral: 20%; disagree: 0%;strongly disagree 5%)].

Consensus Statement 3.5: In all culture-negative endophthalmitis, molecular microbiology work-up, such as NGS, helps identify the infecting fungi.[Consensus score: 95%(strongly agree: 55%; agree: 40%; neutral: 5%;disagree: 0%; strongly disagree 0%)].

Section 4. Management

Vitrectomy is often required in infective fungal endoph-thalmitis for several reasons. It plays diagnostic, thera-peutic, and complication-management roles. It physically reduces infectious load (debris and fungal elements),inflammatory cells, necrotic tissue, and retina-damag-ing toxins. It helps drug penetration, prevents/mini-mizes structural damage, clears the media opacities,and helps restore vision. In a large Indian series of 730 culture-proven cases of fungal endophthalmitis, nearly all patients underwent vitrectomy[21]. Vitrectomy is also indicated for treating complications of fungal endoph-thalmitis, such as persistent vitreous opacities, epiretinal membrane, and retinal detachment [49].

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Patients with fungal endophthalmitis benefit from early vitrectomy.[50, 51]. Unlike the Endophthalmi-tis Vitrectomy Study recommendations for conserva-tive vitrectomy in bacterial endophthalmitis(i.e.,50%vitreous removal)[3], fungal infections often require more extensive vitreous clearance[52]. Where it is safe, induction of a limited posterior hyaloid separation over the posterior pole but staying short of the periph-ery can be attempted. In pseudophamic eyes, clearance of the anterior vitreous is required, as exudates often accumulate near the ciliary sulcus, and inadequate clearance can lead to persistent or recurrent inflamma-tion. Endoscopic vitrectomy or temporary keratopros-thesis can be considered when corneal opacity limits visualization[53]. Apparently, the anatomical and vis-ual outcomes are better after endoscopic vitrectomy in the required situation.

Antifungal agents are the backbone of treating fungal endophthalmitis. Only a few antifungal molecules are used in ocular infections. Intravitreal antifungal agents are the mainstay of treatment, though it is equally impor-tant to administer them through other routes, such as topical and systemic, to treat all potential reservoirs of infection, maximize antifungal efficacy, and reduce the risk of recurrence. In fungal endophthalmitis, the vitre-ous is primarily involved, but the fungi may also reside in other ocular sites such as the anterior chamber, cor-nea, behind the ciliary body, and in the pseudophakic eye, around the IOL. Intravitreal antifungal agents deliver high drug concentration directly into the vitreous, topi-cal agents treat infection in the anterior segment of the eye, and systemic antifungal potentials activate the intravitreal drug concentration while treating the extraocular foci, if any. Multimodal treatment ensures a synergistic effect,improving the chances of eliminating the infection. A combination of intracameral and intravitreal voricona-zole has been shown to be effective in managing fungal

<EndOfPara>endophthalmitis; it should be considered, given the pro-pensity of intra-capsular or peri-IOL sequestration [54].

Usually, more than one intravitreal injection is required. An Indian report of 730 culture-proven cases of fungal endophthalmitis that reported that all patients needed vitrectomy and an average of two intravitreal antifungal agents[21]. The International Committee of Intraocular Inflammation Society recommends intravitreal antifun-gals only for mild vitritis and a combination of intravit-real antifungals and vitrectomy for moderate to severe vitritis[55].

Table 4 enumerates the essential differences in manag-ing bacterial and fungal endophthalmitis. Systemic ther-apy, when begun after renal and liver function tests, must be continued for 4-6 weeks. A few studies have docu-mented a faster reduction of inflammation after explan-tation of the IOL and posterior capsule in recalcitrant pseudophacic fungal endophthalmitis[56-59].

Antifungal drugs

Five families of antifungals are extensively used to treat human fungal infections. The antifungal agents are dose-dependent, fungistatic, and fungicidal. The com-monly used antifungal agents are:(1) polyenes(ampho-tericin B);(2) azoles, such as imidazoles(miconazole,econazole, koconazole), and triazoles.(itraconazole,fluconazole, voriconazole, posaconazole);(3) echino-candins(casopfungin, micafungin, anidulafungin);(4)flucytosine, a pyrimidine analogue; and(5) allylamines(terbinafine). The three general mechanisms of action for antifungal agents are cell membrane disruption, cell division inhibition, and cell wall synthesis inhibition[60]. All these drugs inhibit the synthesis of or directly interact with ergosterol, the predominant component of the fungal cell membrane. The antifungal agents are usually fungistatic in the concentrations used in clini-cal practice but are fungicidal in higher concentrations.

Table 4 Essential differences in the management of bacterial and fungal post-cataract endophthalmitis

|Treatment modality|Post-cataract surgery bacterial endophthalmitis|Fungal endophthalmitis| |---|---|---| |Tap-Inj|Presenting vision $\geq$ HM|Not advised| |Vit-Inj|Presenting vision $\leq$ LP Extent: $50\%$ of vitreous|Used in most series of fungal endophthalmitis, irrespective of presenting vision| |Intravitreal injections|Combinatorial antibiotics; One against GPC, one against GNB Repeat: at $36-72~h$ , if needed|One antifungal agent Repeat intravitreal injection is nearly a rule| |Topical antimicrobials|Intensive|Intensive in post-procedural and post-traumatic cases| |Systemic antimicrobials|No added value|Always in endogenous cases; optional in others| |Corticosteroids|Intravitreal, topical, and systemic (based on institutional practice)|Intravitreal and systemic steroids are usually not used. Topical steroids could be used in some cases|

HM=hand motions; GNB=gram-negative bacilli; GPC=gram-positive coci; IOL= intraocular lens; LP=light perception; PVA=presenting visual acuity; Tap-Inj=vitreous tap(biopsy)+intravitreal injection; Vit-Injv=vitectomy(includes biopsy)+intravitreal injection

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The primary route of administration of these agents is intravitreal injection, often supplemented with sys-temic(more often) and topical therapy[61] (Table 5).

Candida species are generally susceptible to ampho-tericin B, fluconazole, and voriconazole. However, sys-temic amphotericin B achieves therapeutic intraocular concentrations in only a minority of cases, and it is typically reserved for azole-resistant infections. Flu-conazole is a reasonable first-line option for susceptible Candida infections, given its lower cost, widespread availability, lower hepatic toxicity, and lack of need for therapeutic drug monitoring. Conversely, voricona-zole has a broader spectrum, including activity against fluconazole-resistant species such as Candida glabrata and Candida krusei, and also covers filamentous fungi such as Aspergillus spp.[62-64].

Systemic therapy remains the mainstay of treatment in endogenous fungal endophthalmitis. If diagnosed early, when lesions are confined to the choroid(i.e., flat choroiditis) and have not breached the outer blood-retinal barrier, intravitreal therapy is typically unnec-essary. However, adjunctive intravitreal antifungal therapy is warranted once lesions become raised(cho-rioretinitis) or involve the vitreous(endophthalmitis)[65].

Corticosteroids are not contraindicated in bacterial endophthalmitis. The Endophthalmitis Vitrectomy Study used oral prednisolone 30 mg twice daily, a day after the intravitreal antibiotics [3]. There are documented ben-efits of intravitreal dexamethasone in bacterial endoph-thalmitis [66-68]. But corticosteroids are not advised in fungal endophthalmitis for fear of worsening infection[30]. Intravitreal dexamethasone is generally not recom-mended in fungal endophthalmitis despite experimental and human studies of its possible benefits, as conflicting reports have also shown loss of eye when treated with intravitreal steroids[69-71].

While monotherapy(vitrectomy or intravitreal or sys-temic) might sometimes work, a combined therapy in fungal endophthalmitis is increasingly recognized as essential because of(1) poor ocular penetration of many systemic antifungals,(2) frequent biofilm formation on intraocular tissues of the IOL(pseudophakic eyes) that reduces the drug efficacy,(3) increasing drug resistance,and(4) the severe inflammatory load resulting in fungal biomass and toxic debris in the vitreous cavity. Some of the new antifungal agents to treat invasive and refractory fungal infections are olorofim and terbinafine. Olorofim is the orotomide class of antifungals for the treatment of invasive mold infections. It inhibits dihydroorotate

Table 5 Antifungal agents and routes of administration in endophthalmitis

|Antifungal agent|Class|Activity|Intravitreal(0.1 mL)|Intravitreal(0.1 mL)|Topical|Systemic(adult)|Systemic(adult)|Toxicity| |---|---|---|---|---|---|---|---|---| |Antifungal agent|Class|Activity|Dose|Preparation|Topical|Dose|Dose|Toxicity| |Molecule|Class|Activity|Dose|Preparation|$$\begin{array}{l}\text{Topical}\\ \end{array}$$|$$\begin{array}{l}\text{Systemic(adult)}\\ \end{array}$$|$$\text{Toxicity}$$|| |Amphotericin B|Polyene|Broad range|5μg|50 mg+10 mL DW Draw 0.1 mL+0.9 mL NS Inject 0.1mL|1.5 mg/mL (0.15%)|IV.0.5-1.0 mg/kg|Kidney|| |Caspofungin|Echinocandins|Aspergillus Candida|50μg|50 mg+10 mL DW Draw 0.1 mL+0.9 mL NS Inject 0.1mL|5 mg/mL 0.5% NS|IV.70 mg over 1 ha IV.50 mg over 1 hb|Liver|| |Ketoconazole|Imidazole|Aspergillus primarily|-|-|-|PO.200 mgq 12 h|Liver|| |Fluconazole|Imidazole|Candida primarily|100-200 ug|2 mg/mL(0.05- 0.1 mL)|2 mg/mL|PO.200-400 mg/day 0.2%|Liver|| |Micafungin|Echinocandins|Candida primarily|25μg|50 mg+20 mL DW Draw 0.1 mL+1.9 mL NS Inject 0.1mL|- (2.2%|IV.100 mg q 24 h infusion|Liver|| |Posaconazole|Triazole|Aspergillus Candida|100μg|300 mg+30 mL DW Draw 0.1 mL+0.9 mL NS Inject 0.1mL|- (2.15%)|PO.300 mgq 12 ha PO.300 mgq 24 h|Liver|| |Natamycin|Polyene|Broad range|-|-|50 mg/mL*-|-|-|| |Voriconazole|Triazole|Broad range|100μg|200 mg+20 mL DW Draw 0.1 mL+0.9 mL NS Inject 0.1mL|-|PO.200 mgq 12 h IV.6mg/kg 12 h IV.4mg/kg 12h|Liver||

DW=distilled water;NS=normal saline;IV=intravenous;PO=per os

${}^{a}$ represents loading dose; ${}^{b}$ represents maintenance dose; ${}^{*}$ represents commercially available

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dehydrogenase, a key enzyme in the biosynthesis of pyri-midines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B[72]. Terbinafine is an allylamine antifungal agent and acts by inhibiting squalene epoxidase (an enzyme in the fungal ergosterol biosynthesis pathway) [73]. These antifungals are spe-cifically useful in invasive filamentous fungal infection.These antifungals are currently reserved for refractory fungal infection and are often combined with intravitreal antifungal agents. Some of the examples are intravitreal voriconazole with systemic voriconazole+terbinafine, or systemic voriconazole+terbinafine+olorofim in Fusar-ium and Lomentospora infection [74, 75].

Treatment outcomes

Generally, the visual outcome of fungal endophthalmitis is not as good as that of bacterial endophthalmitis[21]. A study from India that analyzed 730 cases reported that at least 10% of eyes needed therapeutic keratoplasty,and up to 7% were eviscerated. After treatment, the final(best corrected) visual acuity was>20/400 in 30.5% of eyes,>20/40 in 7.9% of eyes, and 12%(n=88) of eyes lost light perception (Table 6). The outcomes could be better if the treatment is done sufficiently early and adequately.Some of the cases are illustrated in Figs. 4 and 5.

The recent identification of a novel fungal species, Can-dida auris, has developed into an international public health concern. Candida auris was first isolated in 2009 from the external ear canal of a 70-year-old patient from Japan[77]. Since then, infections due to Candida auris have been reported in over 40 countries, with mortality rates between 30 and 60%, largely secondary to significant and sometimes untreated drug resistance to all known antifungal classes of drugs [78]. In 2022, Breazzzano and colleagues described a case of endogenous pano-phthalmitis involving Candida auris in a 30 -year-old immunocompromised male. The patient underwent enu-cleation and ultimately died despite treatment with intra-vitreal and systemic antifungals [79]. Diagnostic methods employed by laboratories frequently misidentify Candida auris as other organisms, making diagnosis, manage-ment, and infection control efforts challenging [80].

 Fig.4 Treatment outcome in post-cataract and traumatic fungal endophthalmitis. a Post-cataract surgery endophthalmitis.At presentation, the eye was congested with corneal edema and a streak of hypopyon; the presenting vision was 20/100(Left).After three vitreous surgeries, intravitreal antifungals, and intraocular lens explant, the final vision was 20/50.(Right) Vitreous grew Aspergillus niger. b Traumatic endophthalmitis.The patient was earlier treated with lensectomy-vitrectomy and was referred for recurrent infection. At presentation, the eye was aphakic with yellow-white exudates behind the iris.(Left) The presenting vision was finger count at two meters. After two additional vitrectomies and 14 intravitreal antifungals, the final vision was 20/60.(Right) Vitreous grew Aspergillus flavus.(Adapted with permission from[88] CC-B-NC)

Consensus Statement 4.1: Early and complete vit-rectomy in fungal endophthalmitis results in a superior outcome.[Consensus score: 90% (strongly agree: 50%;agree: 40%; neutral: 10%; disagree: 0%; strongly disa-gree 0%)].

Consensus Statement 4.2: Treatment with antifun-gal agents is required via all routes-intravitreal, topical,and systemic.[Consensus score: 85%(strongly agree: 55%;agree: 30%; neutral: 10%; disagree: 5%; strongly disagree 0%)].

Consensus Statement 4.3: The IOL and posterior cap-sule explanation may be considered in recalcitrant pseu-dophakic fungal endophthalmitis.[Consensus score: 90%$(\text{strongly agree:}60\%$; agree:}30\%$; neutral: 10\%$; disagree:0\%$; strongly disagree 0\%$].

Table 6 Comparative treatment outcome of fungal and bacterial endophthalmitis in Indian studies. [21,27,76]

|Vision after treatment|Postoperative|Postoperative|Post-trauma|Post-trauma|Endogenous|Endogenous| |---|---|---|---|---|---|---| |treatment|Fungal [21] n=342|Bacterial[68] n=206|Fungal [21] n=260|Bacterial[68] n=182|Fungal [21] n=128|Bacterial [27] n=173| |≥20/400 (%)|37.4|60.9|38.4|63.9|59.4|26.0| |≥20/40(%)|7.3|19.5|7.3|29.6|10.9|11.0| |No light perception (%)|13.7|7.0|6.9|7.4|18.0|29.0|

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 Fig.5 Treatment outcome in endogenous fungal endophthalmits.to A an 80-year-old patient presented with light perception vision in the right eye. Vitreous tap was negative for organisms and growth.Subsequent pars plana vitrectomy with sub-retinal exudate biopsy confirmed a Candida albicans infection, presumably secondary to antecedent colonoscopy. In addition to diagnostic and therapeutic vitrectomy, the patient was treated with intravital and systemic voriconazole, resulting in the resolution of subretinal exudate but minimal improvement in vision (hand movements at 50 cm). b A 72-year-old male on steroids for chronic obstructive pulmonary disease was referred from a tertiary referral hospital, where he had been admitted for the management of presumed endogenous endophthalmits.The presenting vision was light perception. Previous pulmonary imaging revealed right upper lobe masses; bronchoscopy excluded malignancy and mycobacterial infection, though cultures were negative. Initial plans piana vitrectomy and vitreous microscopy,culture, and polymerase chain reaction were negative. A sub-retinal biopsy following pars plana vitrectomy (right and left eyes, 1 week following surgery in the right eye) confirmed Scedosporium apiospermum infection. This was managed with intravitreal and systemic voriconazole. The patient subsequently demonstrated resolution of infection but developed a retinal detachment under oil with no improvement in vision

Consensus Statement 4:4. Intravitreal dexamethasone can be administered in fungal endophthalmitis.[Consen-sus score: 25% (strongly agree: 0%; agree: 25%; neutral:40%; disagree: 20%; strongly disagree 15%)].

<BeginOfPara>Consensus Statement 4.5: Systemic antifungal therapy should be initiated after baseline renal and liver func-tion assessment and continued for 4-6 weeks.[Consensus score: 85%(strongly agree: 35%; agree: 50%; neutral: 15%;disagree: 0%; strongly disagree 0%)].

Section 5. Future developments

Indiscriminate use of antifungal agents and widespread agricultural antifungal exposure have resulted in resist-ance to one or more antifungal agents. The three prin-cipal concerns in antifungal therapy are: (1) physicians have less opportunity to switch therapy because suscep-tibility tests are not done routinely; (2) there is a limited choice of antifungal drugs; (3) there are no well-defined endpoints.

Globally, the antifungal stewardship (AFS) has not received as much attention as antimicrobial steward-ship. AFS is a coordinated effort within a healthcare set-ting to optimize the use of antifungal agents. It aims to improve patient outcomes, minimize adverse effects and reduce the risk of resistance. It calls for responsible use of antifungal molecules so that the most effective treatment can be administered while preserving the effectiveness of these medicines for future use. The Mycoses Study Group has made several recommendations for AFS, including engaging the management leadership group, increasing the accountability and responsibility of the health per-sonnel, providing education and practical training, moni-toring and surveillance, reporting, and feedback [81, 82].

Traditional culture takes longer, sometimes up to two weeks, for the fungi to grow. This eventually delays the diagnosis and treatment. Several newer avenues are now available commercially or are being experimented in dif-ferent laboratories to expedite the detection of fungi.Some of these are inflammatory markers and newer molecular techniques. Some of these are described below.

Inflammatory markers

Galactomannan (GM) and 1,3 $\beta$ -D-glucan (BDG) bio-markers have been successfully used to diagnose invasive fungal endophthalitis using commercial ELISA Kits.1,3-BDG is a major polysaccharide cell wall component in many fungal species, including Candida and Asper-gillus spp. An elevated BDG level in the vitreous fluid of patients with endogenous fungal endophthalmitis has been reported; it could be more sensitive [83].

GM is a cell wall component of Aspergillus spp. mainly.Its detection via enzyme immunoassay is part of the diag-nostic criteria for invasive aspergillosis. A recent report has explored its use in diagnosing A. fumigatus in the vitreous sample and recommended its assay when the standard mycology is negative [84]. The data from India confirms significantly higher levels of vitreous GM in patients with culture-proven fungal infections than in patients with non-infectious retinal disorders. These tests could be considered in conjunction with clinical and routine microbiological tests. The added advantage is the speed-the results of these tests are available within

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2-3 h compared to several days of conventional culture[85].

Molecular methods

The molecular microbiology methods, in addition to PCR, real-time PCR, and NGS, are matrix-assisted laser desorption/ionization-time of flight(MALDI-TOF),and peptide nucleic acid fluorescence in situ hybridiza-tion [44-48]. Recently, a rapid molecular diagnostic tool,RID-Myc assay, using CRISPR-Cas 12a technology, has been described; it is not yet commercially available [86].

Negative culture is a common limitation of the conven-tional microbiology workup of fungal endophthalmitis.Due to delayed presentation, the classic clinical charac-teristics could be masked. This could be resolved using molecular techniques, including PCR, Sanger sequenc-ing, and targeted NGS[87]. NGS allows for unbiased,high-throughput detection of microbial DNA directly from intraocular specimens such as vitreous or aqueous humor. This culture-independent method can identify a broad range of pathogens including rare or fastidious fungi by analyzing genetic material even when organ-isms are nonviable or present in low abundance. As tech-nology becomes more accessible and rapid, NGS has the potential to complement or even surpass standard diagnostics in complex or refractory cases of infectious endophthalmitis.

Consensus Statement 5.1: Antifungal stewardship should be considered. [Consensus score: 95% (strongly agree: 60%; agree: 35%; neutral: 5%; disagree: 0%; strongly disagree 0%)].

Consensus Statement 5.2: Rapid diagnosis is required to institute early treatment. Fungal biomarkers like 1,3β-D-glucan and galactomanannare valueable adjuncts for the early diagnosis of fungal endophthalmitis.[Consensus score: 90%(strongly agree: 25%; agree: 65%; neutral: 10%;disagree: 0%; strongly disagree 0%)].

Consensus Statement 5.3: Advanced molecular diag-nostics such as PCR, NGS, and MALDI-TOF should be considered in suspected fungal endophthalmitis, especially when conventional microbiological methods are inconclu-sive.[Consensus score: 100% (strongly agree: 65%; agree:35%; neutral: 0%; disagree: 0%; strongly disagree 0%)].

Results of voting and discussion

Table 7 provides a summary of the key consensus state-ments along with the corresponding voting results.

Fungal infections of the eye are less frequent than bac-terial infections, but they are more serious. At the same time, research on fungal infections is generally less exten-sive than research on bacterial infections. There are sev-eral reasons, including(1) it was always considered a niche problem(occurring in immunocompromised and

transplant recipients) and never perceived as a public health problem(for example, tuberculosis or plague),(2)more challenging to diagnose that could result in under-reporting and hence does not attract the funding agen-cies as they do not view a priority disease due to low incidence reports,(3) the fungi being eukaryotic organ-isms like human cells makes it harder to develop anti-fungal drugs that are effective against fungi but not toxic to humans(unlike bacteria, prokaryotic microorgan-isms, are biologically more distinct from humans, mak-ing selective targeting easier), and(4) low levels of public and institutional awareness. Hence, there are fewer large studies and no randomized clinical trials for fungal endophthalmitis. This communication collated the avail-able literature and surveyed twenty-four world experts to create a consensus and understand the controversies in managing fungal endophthalmitis. In 18 of 20(90%)statements, there was good agreement(>75%‘agree’ to'strgly agree'); this included epidemiology, the clinical signs, pathobiology, management, and future develop-ments. In two statements, there were fewer agreements(<75%); these included(1) the relative incidence of exogenous and endogenous endophthalmitis and(2) the utility of intravitreal dexamethasone.(see Table 7) The following could be explanations for these varied opin-ions.(1) Given that exogenous (after intraocular proce-dures and trauma) fungal endophthalmitis is more often reported from Asia, and endogenous fungal endoph-thalmitis is more often reported from Europe, North America, and Oceania, the opinion on the frequency and the signs is bound to vary.(2) The corticosteroids suppress the immune response, which can worsen the fungal infection by reducing the host immune response.Intravitreal corticosteroid(Consensus Statement 4.4)also attracted three'strongly disagree' answers. While it still does not have universal acceptance, in selected and carefully monitored situations, corticosteroids might be considered adjunctively after antifungal therapy is estab-lished and fungal infection is possibly controlled. The other'strongly disagree' answer was to the routine MFC test(Consensus Statement 3.4). However, the MFC test should be a standard microbiology work-up, considering growing resistance to commonly used antifungal agents.There are 1.5 to 5 million species of fungi that can grow almost anywhere e.g., in water, soil, plants, and animals.

There are 1.5 to 5 million species of fungi that can grow almost anywhere e.g., in water, soil, plants, and animals.The primary pathogenic fungi usually have an environ-mental reservoir[88]. Opportunistic pathogens take advantage of debilitated or immunocompromised hosts to cause infection. Unlike fungal keratitis[89], the global burden of fungal endophthalmitis is not reported. Assess-ment of the worldwide burden and epidemiologic trends is critical to prioritizing prevention strategies, diagnos-tic modalities, and therapeutic interventions. However,

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Table 7 Results of the voting on the consensus statements of fungal endophthalmitis

|Section|Consensus statement|C score(%)|Strongly agree(%)|Agree(%)|Neutral(%)|Disagree (%)|Strongly disagree (%)| |---|---|---|---|---|---|---|---| |1. Disease entity|||||||| |1.1|Fungal infections of the eye occur less frequently than bacterial infections. It is usually a delayed presentation|100|80|20|0|0|0| |1.2|Endogenous fungal endophthalmitis is as common as exog-enous endophthalmitis.The common systemic diseases are the liver, the lungs (pneumonia), and the endocardium|50|15|35|15|35|0| |1.3|Acute fungal endophthalmitis after an intraocular procedure is also a possibility|95|40|55|5|0|0| |1.4|Traumatic fungal endophthalmits usually results from vegeta-tive matter or soil injuries and presents earlier than other forms of fungal endophthalmits|100|70|30|0|0|0| |1.5|Vitritis is the most consistent clinical presentation in endogenous fungal endophthalmits and may be accompanied by characteris-tic vitreous or retinal lesions|90|55|35|10|0|0| |2.Clinical diagnosis|||||||| |2.1|Posterior segment signs are more apparent than the anterior segment signs in fungal endophthalmitis|75|40|35|20|5.0|0| |2.2|Systemic investigations are essential in all fungal endophthalmits 75|50|25|20|20|5|0| |3.Pathobi biology|||||||| |3.1|Fungal infection occurs more often in immunocompromised people|95|50|45|5|0|0| |3.2|Common ocular pathogenic septate filamentous fungi are Asper-gillus, Fusarium, and the common pathogenic yeast is Candida|100|75|25|0|0|0| |3.3|The microbiology confirmation of fungi includes direct micros copy and culture|100|75|25|0|0|0| |3.4|The minimum fungicidal concentration should be used in fungal infection|75|45|30|20|0|5| |3.5|In all culture-negative endophthalmitis, molecular microbiology work-up, such as NGS, helps identify the infecting fungi|95|55|40|5|0|0| |4. Management|||||||| |4.1|Early and complete vitrectomy in fungal endophthalmits results in a superior outcome|90|50|40|10|0|0| |4.2|Treatment with antifungal agents is required via all routes-intra- vitreal, topical, and systemic|85|55|30|10|5|0| |4.3|The intraocular lens and posterior capsule explanational may be considered in recalcitrant pseudophamic fungal endophthalmits|90|60|30|10|0|0| |4.4|Intravitreal dexamethasone can be administered in fungal endophthalmitis endophthalmitis.|25|0|25|40|20|15| |4.5|Systemic antifungal therapy should be initiated after baseline renal and liver function assessment and continued for 4-6 weeks|85|35|50|15|0|0| |5. Future developments|||||||| |5.1|Antifungal stewardship should be considered|95|60|35|5|0|0| |5.2|Rapid diagnosis is required to institute early treatment. Fungal biomarkers like 1,3 β-D-glucan and galactomanann are valuable adjuncts for the early diagnosis of fungal endophthalmits|90|25|65|10|0|0| |5.3|Advanced molecular diagnostics such as PCR,NGS, and MALDI-TOF should be considered in suspected fungal endophthalmits, especially when conventional microbiological methods are inconclusive|100|65|35|0|0|0|

Consensus score(C score) was defined as the value of the summation of the 'strongly agree', and 'agree' percentages; C score≥75% was considered 'consensus achieved'; and C score<75% was 'consensus not reached'. Only two statements were 'consensus not achieved' (unbold and underlined). Bold indicates statements which were ‘consensus achieved’

PCR=polymerase chain reaction; NGS=next-generation sequencing; MALDI-TOF=matrix-assisted laser desorption/ionization-time of flight

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quantifying the global burden of fungal endophthalmitis has several challenges, as has already been stated. Given the low incidence and regional variations, there is no well-defined protocol for diagnosing and treating fungal endophthalmitis. A randomized clinical trial is not feasi-ble for fungal endophthalmitis. Analyzing real-world data and sourcing real-world evidence is one modality to cre-ate an appropriate management strategy [90,91].

The current consensus, derived from expert clinical experience and a review of available literature, aimed to address the main hurdles ophthalmologists face in diag-nosing and managing this vision-threatening condition.This guideline emphasizes the importance of clinical suspicion following intraocular surgery, trauma, and in immunosuppressed people. The panel recommends com-bining direct microscopy, culture, and molecular tech-niques in culture-negative cases. The limited availability of effective antifungal agents with good intraocular pen-etration and safety profiles further complicates the treat-ment of fungal endophthalmitis. The panel supports the early use of intravitreal antifungals. The higher frequency of Candida species in endogenous endophthalmitis and Aspergillus species in exogenous endophthalmitis

calls for different antifungal strategies. See Fig. 6 for a suggested treatment strategy for fungal endophthalmitis.

Conclusion

Fungal endophthalmitis remains a formidable diagnostic and therapeutic challenge in ophthalmology. It is primar-ily due to its insidious onset, limited diagnostic tools,and the complex nature of fungal pathogens. There is a clear consensus that exogenous infection occurs in tropi-cal and subtropical climates, that endogenous infection occurs after systemic infection in immunocompromised people and drug users, and that early recognition, micro-biological confirmation, and early appropriate antifungal therapy result in better diagnosis. A significant area of controversy is corticosteroid therapy. Corticosteroids in fungal infections are not considered for fear of the risk of immune suppression and exacerbation of fungal pro-liferation, yet some clinicians argue for their cautious use in select cases to mitigate damaging inflammatory responses once the fungal infection is controlled. Newer diagnostic techniques[86] and newer antifungal agents[72-75] hold promise. While a randomized clinical trial is the ideal solution, a more nuanced understanding of

 Fig.6 Suggested management algorithm of fungal endophthalmitis

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the disease spectrum, multidisciplinary research, and real-world evidence are critical.

Abbreviations

|AAPPO|Asia-Pacific Academy of Professors in Ophthalmology| |---|---| |AFS|Antifungal stewardship| |APSOII|Asia-Pacific Society of Ocular Inflammation and Infection| |APVRS|Asia-Pacific Vitre-retina Society| |BDG|β-D-glucan| |CFW|Calcofluor white| |GM|Galactomannan| |GMS|Gomori methemamine silver| |H&E|Hematoxylin and eosin| |IOFB|Intraocular foreign body| |OIFB|Intraocular lens| |LCB|Lactophenol cotton blue| |MALDI-TOF|Matrix-assisted laser desorption/ionization-time of flight| |MFC|Minimum fungicidal concentration| |MIC|Minimum inhibitory concentration| |NGS|Next-generation sequencing| |PAS|Periodic acid Schiff| |PCR|Polymerase chain reaction| |PDA|Potato dextrose agar| |SDA|Sabouraud dextrose agar|

Acknowledgements

Not applicable.

Author contributions

TD and DSCL conceptualized the study design and developed the methodol-ogy.TD wrote the original draft.TD,DSCL,and NVR analyzed and interpreted the data. All authors contributed to the review of the manuscript and consen-sus statements, voted on the consensus, revised and edited the manuscript. All authors read and approved the final version of the manuscript.

Funding

This study was supported by Ms. May Lam Research and Education Fund of The Primaria International Eye Research Institute(PIER) of The Chinese Univer-sity of Hong Kong(Shenzhen).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

Department of Vitreoretinal Services,Shantilal Shanghvi Eye Institute,Mumbai, India.2AnBajaj Retina Institute,Srimati Kanuri Santhamma Center for Vitreoretinal Diseases,LV Prasad Eye Institute,Hyderabad,Telangana,India.3The Primaria International Eye Research Institute(PIER),The Chinese University of Hong Kong(Shenzhen), Longxiang Boulevard,Longgang District,Shenzhen 2001,China.4Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock,AR,USA.Sydney Retina Clinic,Sydney Eye Hospital,University of Sydney,Sydney,NSW,Australia.6Institute for Research in Ophthalmology, Foundation for Oph-thalmology Development, Poznan, 2o. Department of Ophthalmol-ogy,Pitie-Salpetriere University Hospital,Sorbonne University,Paris,France.8Department of Ophthalmology,Linkou Main Branch,Chang Gung Memorial

Hospital,Taoyuan,Taiwan,China.9Department of Ophthalmology,Chang Gung Memorial Hospital,Keelung,Taiwan,China.10Department of Ophthal-mology,Bascom Palmer Eye Institute,University of Miami,�Miami,FL,USA.11Department of Ophthalmology,Kim's Eye Hospital,Youngdeungpo-Gu,Seoul,South Korea.12J-CREST(Japan Clinical Retina Study Group),Kagoshima,Japan.13Department of Ophthalmology,Hyogo Medical University,Nishi-nomiya,Japan.14Department of Ophthalmology,Tianjin Medical University General Hospital,Tianjin,China.15Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma,Tianjin Medical University,Tianjin,China.16School of Medicine,Nankai University,Tianjin,China.17Jhaveri Micro-biology Centre,Brien Holden Eye Research Center,Lv Prasad Eye Institute,Hyderabad,Telangana,India.18 College of Medicine,Chang Gung University,Taoyuan,Taiwan,China.19Department of Ophthalmology and Visual Sciences,The Chinese University of Hong Kong,Hong Kong,China.20Department of Ophthalmology and Visual Sciences,The Prince of Wales Hospital, Hong Kong,China.21 Hong Kong Eye Hospital, Hong Kong,China.22 Department of Ophthalmology and Visual Sciences, Lam Kin Chung.Jet King-Shing Ho Glauca Treatment and Research Center,The Chinese University of Hong Kong,Hong Kong,China.23Hong Kong Hub of Pediatric Excellence,The Chinese University of Hong Kong,Hong Kong,China.24State Key Laboratory of Ophthalmology,Guangdong Provincial Key Laboratory of Ophthalmol-ogy Visual Science,Zhongshan Ophthalmic Center,Sun Yat-Sen University,Guangzhou,China.25Save Sight Institute, Sydney Eye Hospital Campus,Sydney,NSW,Australia.26Sydney Eye Hospital, Sydney,NSW, Australia.27Retina Division,Department of Ophthalmology,Faculty of Medicine,Rajvithi Hospital,Rangsit University,Bangkok,Thailand.28Department of Ophthalmology,Caritas Medical Center, Hong Kong,China.29National Healthcare Group Eye Institute,Tan Tock Seng Hospital,Singapore,30Yong Loo Lin School of Medicine, National University of Singapore,Singapore,Singapore,Singapore,31Lee Kong Chian School of Medicine, Nanyang Technological University,Singapore,Singapore.32Singapore Eye Research Institute,Singapore,Singapore,33Duke-NUS Medical School,Singapore,Singapore.34 Beijing Tongren Eye Center,Beijing Tongren Hospital,Beijing Ophthalmology and Visual Science Key Lab,Beijing Institute of Ophthalmology,Capital Medical University,Beijing,China.C-MER Dennis Lam Parters Eye Center, c-International Care Group,Hong Kong,China.36Department of Ophthalmology,Chang Gung Memorial Hospital,Xiamen,China.37The C-MER (Shenzhen) Dennis Lam Eye Hospital,Shenzhen,China.38Eye Department,C+ Health CKJ (Shenzhen) Hospital,Luohu,Shenzhen,China.

Received:4 June 2025 Accepted:18 September 2025

Published online: 13 October 2025

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