Table 2.

Pharmacological therapy available for the treatment of ocular fungal infections, presented by its spectrum of activity, routes of administration (including off-label use) and the associated unwanted effects and/or toxicity

Antifungal agent	Activity spectrum	Administration routes	Undesirable effects/toxicity	References
Anfotericin B	Broad spectrum of activity, is active against most fungi, with potent antifungal activity against Candida and Aspergillus species, but moderate to weak activity against Fusarium and Scedosporium species1,2,3	Intravenous, topical, intrastromal, intracameral, intravitreal, collagen lens1,5,7,14	Intraocular injections (> 1% w/v) are associated with adverse effects such as retinal toxicity, loss of retinal ganglion cells, vitreous inflammation, corneal edema, neovascularization, and corneal inflammation1 Cataract, hyphema, iritis and corneal edema3 Intravenous can lead to dose-dependent nephrotoxicity1,7 Headaches, chills, fever, and anorexia are common, other adverse side effects include mild anemia, nausea, vomiting, gastrointestinal cramps and diarrhea, and local thrombophlebitis at the infusion site7 Intravitreal injections can have highly destructive effects, leading to retinal necrosis and detachment7 Amphotericin B is a safe antifungal for use during pregnancy, labeled as a Category B drug by the FDA3	1. Patil and Majumdar (2017) 2. Lakhani et al. (2019) 3. Sahay et al. (2019) 4. Kaur and Kakkar (2010) 5. Thomas and Kaliamurthy (2013) 6. Mahmoudi et al. (2018) 7. Thomas (2003a) 8. Mills et al. (2020) 9. Guest et al. (2018) 10. Sng et al. (2021) 11. Srinivasan (2004) 12. Armstrong (2000) 13. Czakó et al. (2019) 14. Kalkanci and Ozdek (2010) 15. Von Jagow et al. (2020) 16. Mochizuki et al. (2013)
Natamycin	Broad spectrum of activity but is limited to filamentous fungi, such as Fusarium and Aspergillus species, Acremonium, Alternaria, Cephalosporium, Colletotrichum, Curvularia, Lasiodiplodia, Scedosporium, Trichophyton and Penicillium. Only moderate to weak activity against yeast fungi (Candida species)2,3,4	Topical, 5% ophthalmic suspension1,4,5	Prolonged use may be associated with some local symptoms of discomfort, such as mild irritation, redness, foreign body sensation, stinging, burning sensation, and tearing. Adherence of particles from the natamycin suspension to the area of epithelial ulceration as well as the fornix and eyelid margins is a common problem3
Voriconazole	Broader spectrum of activity, potent antifungal action against Candida and Aspergillus species (even those known to be resistant to amphotericin B, fluconazole, and itraconazole), Scedosporium, Fusarium, Paecilomyces, Cryptococcus, and dimorphic fungal pathogens. Activity against Mucorales is minimal5,6	Intrastromal, intracameral, intravitreal, oral, intravenous, topical5,1,6,2	Adverse effects associated with the use of oral voriconazole include visual disturbances, changes in color vision, and photophobia. Rarely, transient visual hallucinations or confusion may occur. Rashes, hepatotoxicity, electrocardiographic changes, and fluoride-associated bone toxicity may also be seen. Topical use may cause periocular contact dermatitis. It is an FDA-labeled category D antifungal and is contraindicated during pregnancy as it is teratogenic and results in skeletal and visceral abnormalities3 Intracameral administration it represents the spread of infection (invasiveness), intraocular inflammation, lenticular damage, glaucoma, hyphema, and potential endothelial damage3
Fluconazole	Active against Candida species (except Candida krusei and C. glabrata may have low susceptibility) and Aspergillus, with resistance by other filamentous fungi, such as Fusarium spp., Scedosporium spp., and Mucorales, a narrow spectrum compared to other triazoles3,5,6	Topical, oral systemic5,2	Subconjunctival injection of fluconazole has been investigated3,5,2 Low toxicity2 Common systemic adverse effects include gastritis, headache, and rash. In some cases, thrombocytopenia, Stevens-Johnson Syndrome, and hepatotoxicity may occur. Labeled a Category D drug by the FDA for use during pregnancy and therefore should not be used in these cases3
Ketoconazole	Broader spectrum of activity3,7 Antifungal activity limited to some filamentous, yeast (including Candida spp.), dimorphic fungi, and dermatophytes1,3	Oral, topical, systemic subconjunctival1,3,4	The main adverse effect of its oral use is hepatotoxicity, gynecomastia, hyperglycemia, menstrual changes, hypertension, decreased libido, oligospermia, anaphylaxis, adrenal insufficiency, anorexia, hyperlipidemia, increased appetite, insomnia, nervousness may also be reported, headache, dizziness, paresthesia, drowsiness, photochemical toxicity, and orthostatic hypotension1,3 Other adverse effects include gastrointestinal disturbances like vomiting, diarrhea, nausea, constipation, abdominal pain, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration, hepatitis, and jaundice. Skin and subcutaneous tissue disorders include erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus, alopecia, xeroderma, malaise, peripheral edema, pyrexia, chills, and decreased platelet counts.1,3 It has been shown to be teratogenic in animal studies at high doses and has been labeled a Category C drug for use in pregnancy by the FDA3
Itraconazole	Activity against most Candida species, and several Aspergillus species, minimal or negligible activity against Fusarium and Mucorales species1,3	Systemic, oral, topical, intravitreal, subconjunctival injections1,3,5	Subconjunctival injections, some studies have reported the occurrence of retinal necrosis1 Oral administration, the most common complaints are gastrointestinal disturbances, rash, and headache, less frequently hypertriglyceridemia, hypokalemia, edema, decreased libido, and gynecomastia are observed1,3,7 Hepatotoxicity and liver failure are also among the most common adverse effects and are serious. It has been labeled Category C by the FDA for use in pregnant women as it is teratogenic3
Pozaconazole	Potent broad-spectrum activity against most Candida species (even fluconazole-resistant isolates), Fusarium, Aspergillus, and Mucorales3,8	Oral, intravenous, topical3,8	Fever, diarrhea, nausea, vomiting, and headache. In addition, hypokalemia, rash, thrombocytopenia, abdominal pain, elevated liver enzyme levels, and hepatocellular damage may be observed. Good long-term tolerability. Classified in Category C by the FDA for use during pregnancy as it is teratogenic3
Miconazole	Variable activity against filamentous fungal species, potent activity against Aspergillus species, and weak activity against Fusarium species.2 Appears to be important in the treatment of Scedosporium apiospermum keratitis5	Intravenous, oral, topical, subconjunctival2,4,5,7	–
Isavuconazole	Broader spectrum of activity, Candida spp., Aspergillus fumigatus9,10	Oral, intravenous9,10	–
Equinocandinal (caspofungin, micafungin, anidulafungin)	Narrow antifungal spectrum, fungicidal activity against Candida spp. and fungistatic for Aspergillus spp., are not active against Fusarium species, but are active against other clinically relevant species3,11	Intravenous, topical, intravitreal injection, topical, intravitreal1,3,8,15,16	Systemic echinocandins are generally well tolerated with few adverse effects, which include headache, gastrointestinal upset, elevated liver enzyme (aminotransferase) levels, and mild infusion reaction3
Flucytosine	Narrow spectrum of activity, is more effective against the genus Candida and some filamentous fungi, limited activity against Aspergillus spp., whereas Fusarium species are resistant to this drug3,12	Topical, systemic3,5,12	–
Polyhexamethylene biguanide	General environmental biocide, showing good in vitro activity against fungi7,13	Topical7,13	–