Overview

Most fungi causing orbital infections are ubiquitous aerobic organisms that are normal commensals of the respiratory, gastrointestinal (GI) and female genital tracts as well as in 25% of normal conjunctiva.¹ Fungal eye infections are rare in Western countries;² they are more frequently seen in tropical and subtropical regions.³ Local trauma (especially in hot and humid climates), contact lens wear and topical antibiotic or steroid treatment can all predispose to fungal infection³ as does immunocompromise, nonketotic diabetic ketoacidosis and contamination of distant indwelling devices (e.g. catheters and IV lines) via haematogenous spread.¹ Diagnosis is often difficult owing to the rarity of these infections and the fact that fungi may take weeks to culture and even longer for their sensitivity to antifungals to be determined.⁴ Clinical signs may also be relatively limited, initially at least.⁵ However, rapid diagnosis is the key to preventing the long-term ocular morbidity often associated with these infections.³

Ocular antifungals

There are three main classes of ocular antifungals:^2,6

• Polyenes, particularly amphotericin B 0.15%, and natamycin 1% which have a broad spectrum of activity.
• Azoles, as derivatives of imidazoles, which are useful in yeast infections, e.g. clotrimazole 1%, econazole 1%, itraconazole 1%, miconazole 1%.
• 5-fluorocytosine (flucytosine 1%), a synthetic fluorinated pyrimidine which is effective against yeasts.

Treatment tends to be long (in the order of weeks or months) and may involve topical ± systemic therapy depending on the nature of the infection and its severity. They may also be delivered into the vitreous. Typical topical antifungals include econazole 1% and amphotericin B 0.15% or 0.3%.⁴ Azoles are the preferred group of antifungals when deep-seated infection warrants systemic treatment.

Work is being done on developing new, more efficient antifungals but these new drugs remain at the experimental stage at the moment.^7,8

Indications¹

Fungal infections of the eye which may include orbital cellulitis, dacryocystitis, conjunctivitis, keratitis and endophthalmitis.⁹ Thus, they can work at a superficial level or penetrate deeply into the eye.¹⁰

Cautions and contra-indications

Previous anaphylactic reaction to amphotericin. Renal or hepatic impairment or haematological abnormalities should be excluded before starting these drugs (see 'Complications', below).

Initiation of treatment

• This is initiated by the ophthalmology team. The nature of fungal infections is such that many patients will already be under specialist care as symptoms will often have gone on for a length of time. A number patients will have been treated for a bacterial infection before a correct diagnosis is made.
• Samples such as corneal scrapes will have been obtained prior to initiation of therapy.
• Any steroid treatment needs to be discontinued.⁵
• Initially, treatment is intense (hourly drops) until the condition is controlled (days to a couple of weeks).
• Antifungal preparations for the eye are not generally available and have to be specifically made up for each patient.

Monitoring

This should be carried out by the ophthalmology team and, in addition to monitoring the infection itself, care should be taken to monitor the full blood count, and renal and hepatic functions, depending on which drug is being used (see 'Complications', below). Secondary effects of the infection will be monitored and treated (e.g. raised intraocular pressure).

Complications and reasons to discontinue drug

Complications from topical administration of these drugs are very rare but theoretically possible. The complications outlined below relate to systemic administration:

• Polyenes: anaphylactic reaction, renal tubular damage.
• Azoles: transient liver function abnormalities.
• 5-fluorocytosine: marrow aplasia.

There are reports of in vitro antifungal resistant organisms due to the frequent use of azoles, polyenes and 5-fluorocytosines.⁹ Work is being done particularly on newer azoles, should the resistance manifest itself clinically. There is also research into improved delivery systems to potentiate the effect of existing drugs and allow their more effective use.¹⁰

Document references

1. Forrester JV, Dick AD, McMenamin PG, Lee WR. The Eye: Basic Sciences in Practice (2nd ed.) 2002, WB Saunders
2. Manzouri B, Vafidis GC, Wyse RK; Pharmacotherapy of fungal eye infections. Expert Opin Pharmacother, 2001;2(11):1849-57
3. Tilak R, Singh A, Maurya OP, et al; Mycotic keratitis in India: a five-year retrospective study. J Infect Dev Ctries. 2010 Mar 29;4(3):171-4. [abstract]
4. Watson S, Ocular therapeutic case studies: Differential diagnosis and management of microbial keratitis; Association of Optometrists. 2002
5. Jackson TL. Moorfields Manual of Ophthalmology, Mosby (2008)
6. Elliott T, Hastings M, Desselberger U; Lecture Notes on Medical Microbiology, 3rd Ed, 1997 Blackwell Science
7. Kernt M, Kampik A; Intraocular caspofungin: in vitro safety profile for human ocular cells. Mycoses. 2010 Feb 19. [abstract]
8. Xu Y, Pang G, Zhao D, et al; In vitro activity of thimerosal against ocular pathogenic fungi. Antimicrob Agents Chemother. 2010 Jan;54(1):536-9. Epub 2009 Oct 19. [abstract]
9. Nayak N; Fungal infections of the eye--laboratory diagnosis and treatment. Nepal Med Coll J. 2008 Mar;10(1):48-63. [abstract]
10. Kaur IP, Rana C, Singh H; Development of effective ocular preparations of antifungal agents. J Ocul Pharmacol Ther. 2008 Oct;24(5):481-93. [abstract]
11. Denniston AKO, Murray PI. Oxford Handbook of Ophthalmology, OUP (2008)

Acknowledgements