Role of Intrastromal Injections in Fungal Keratitis
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Treatment of fungal ulcers is one of the most challenging tasks. The incidence of fungal keratitis is more in developing countries as compared to developed countries with Aspergillus being the most common species isolated worldwide. As fungal ulcers are deep and involve the deep stroma, a direct drug delivery system in the form of intrastromal injections are helpful in the management of these deep recalcitrant fungal ulcers. Commonly used antifungal drugs for intrastromal injections include voriconazole, amphotericin B ,fluconazole and natamycin.
The various antifungal drugs used in cases of fungal keratitis fall in the following categories
a) Large polyenes
Nystatin, amphotericin B
b) Small polyenes
2 ) Azoles
a) Imidazoles Miconazole,ketoconazole,clotrimazole
b) Triazoles Fluconazole,itraconazole
3 ) Pyrimidines
This class of antifungal agents includes amphotericin B, nystatin and natamycin . Nystatin has not been used to treat eye infections for several decades due to its low tissue penetration, toxicity, and reports of resistance. Amphotericin B and natamycin have been used intrastromally in the management of recalcitrant fungal keratitis.
Azoles act on fungal cytochrome P450 enzymes by blocking the synthesis of ergosterol in the plasma membrane, thus inhibiting fungal growth. Azoles are divided into two major classes - imidazoles were the first to be introduced, followed by triazoles. Both have similar antifungal spectra, but triazoles have the advantages of being metabolised more slowly and exerting less influence on the metabolism of steroids in humans . These drugs are metabolised primarily in the liver, therefore control of liver enzymes is recommended. They have teratogenic activity (class C) and should not be used during pregnancy. The imidazoles used more often include miconazole ,econazole and ketoconazole. Among the first-generation triazoles, the most commonly used are itraconazole and fluconazole. Second-generation triazoles were introduced into clinical practice in the past decade and include voriconazole and posaconazole .
Pyrimidines are represented by 5-fluorocytosine (5-FC) or flucytosine, which is the only antifungal agent with intracellular action. After being absorbed by the fungus it is converted into 5-fluorouracil which is a powerful antimetabolite and acts by inhibiting the synthesis of DNA. Its use in eye infections is restricted due to its narrow antifungal spectrum and low penetration into ocular tissues.
Commonly used Intrastromal Antifungal Drugs
AMB belongs to the family of polyene macrolide antibiotics and was the first broad-spectrum antifungal agent to be discovered. Isolated in the 1950s, AMB is produced by the actinomycete Streptomyces nodosus and became popular after approval by the FDA in the 1960s due to its great efficiency in controlling disseminated fungal infections.(1)
Mechanism of action
AMB acts by increasing cell permeability through the formation of pores in the fungal cell membrane by binding to ergosterol and by promoting oxidative action on cells,thus altering their metabolic functions.
Amphotericin derives its name from its amphoteric properties and is effective in both extremes of acidic and basic Ph .It has low water solubility and needs to be diluted in deoxycholate for administration. It is photo- and thermosensitive and should be storedin a dark and refrigerated place (2-8°C). (1,2)
AMB acts on both yeasts and filamentous fungi. It has an excellent spectrum, being effective against Candida., Aspergillus sp,Penicillium marneffei and to a lesser extent, against Fusarium species. (1)
Intrastromal injections of amphotericin B in humans have not shown any toxicity however in animal models concentration of amphotericin B above 20ug/0.1 ml caused corneal edema,epithelial erosions and neovascularisation.(3)
Mechanism of Action
Voriconazole acts by inhibiting the synthesis of ergosterol and much more effective than 1st generation triazoles.
Effective in the treatment of keratitis by Candida,Aspergillus, Fusarium,Scedosporium and Paecilomyces (4,5)
Its advantages compared to polyenes include its greater stability to light and temperature, remaining effective for up to 30days (6,7).
Preparation of intrastromal drug concentration
Intrastromal dose of Amphotericin B is 5-10ug/0.1 ml.
Preparation of intrastromal Amphotericin B is done by reconstituting 50mg powder of Amphotericin B in 10ml dextrose 5% to give concentration of 5mg/ml and 500 ug/0.1ml Further this concentration is diluted with 9.9 ml dextrose 5% in a tuberculin syringe to give concentration of 500ug/10 ml and 50ug/ml and 5 ug/0.1 ml.
Dose of Intrastromal Voriconazole is 50 ug/ 0.1 ml and is prepared by adding 19 ml distilled water in 200 mg powder of voriconzole to get 20 ml drug (10mg in 1 ml) 1 ml of drug is taken and 9 ml distilled water is added to get 10 mg in 10 ml . .05 ml of this solution contains 50 ug or 0.1 ml of this solution contains 100 ug.
Technique of giving intrastromal Injection
Intrastromal injections can be giveb under topical anaesthesia or peribulbar anaesthesia under full aseptic conditions, the preloaded drug should be administered under operating microscope. The bevel down, the needle is inserted obliquely from the uninvolved area to just reach the abscess at mid-stromal level which is the intended area of drug deposition . The drug then is injected and the amount of hydration of the cornea is used as a guide to assess the area covered. Once the desired amount of hydration is achieved, the plunger is withdrawn slightly to ensure discontinuation of the capillary column and thus prevent back-leakage of the drug. Five divided doses are given around the abscess to form a deposit of the drug around the circumference of the lesion. This is done in a way that a centripetally directed progressive wave of fluid appears to encompass the abscess along each meridian. Circumferential injection will ensure the formation of a barrage of intrastromal drug around the entire abscess. (8)
1) Direct drug delivery.
2) Overcomes the problem of poor penetration of drugs .
3) Intrastromal drug which is injected acts like a depot causing slow release of drug.
Thus, intrastomal injections are safe and effective way for the treatment of deep and recalcitrant fungal ulcers although this novel way of treatment needs to be studied more before it is adapted as a standard procedure.
1) Bennett J. Agentes antimicrobianos, agentes antifúngicos. In: Brunton L, editor. Goodman & Gilman: as bases farmacológicas da terapêutica. 11a ed. Rio de Janeiro: McGraw-Hill; c2007. p. 1103-17.
2) Oliveira PR, Resende SM, Oliveira FC, Oliveira AC. Ceratite fúngica. Arq Bras Oftalmol. 2001;64(1):75-9.
3) Qu L, Li L, Xie H. Curr Eye Res. 2014 Apr;39(4):340-7.
4) Anderson KL, Mitra S, Salouti R, Pham TA, Taylor HR. Fungal keratitis caused by Paecilomyces lilacinus associated with a retained intracorneal hair. Cornea. 2004;23(5):516-21.
5) Bunya VY, Hammersmith KM, Rapuano CJ, Ayres BD, Cohen EJ. Topical and oral voriconazole in the treatment of fungal keratitis. Am J Ophthalmol. 2007;143(1):151-3.
6) Al-Badriyeh D, Neoh CF, Stewart K, Kong DC. Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis. ClinOphthalmol. 2010;4:391-405.
7) Dupuis A, Tournier N, Le Moal G, Venisse N. Preparation and stability of voriconazole eye drop solution. Antimicrob Agents Chemother. 2009;53(2):798-9.
8) Sharma N, Agarwal P, Sinha R, Titiyal J.S., VelpandianT, Vajpayee R, Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series Br J Ophthalmol 2011;95:1735-1737 doi:10.1136