Chapter 62
Ocular Pharmacology of Antifungal Drugs
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Fungi are complex biologic organisms. Unlike bacteria, they contain a nucleus, nucleolus, mitochondria, ribosomes, and centrioles. An important feature is the cell wall, which is composed principally of chitin and, in some instances, cellulose. Fungi exist in either a filamentous or yeast form, but certain fungi are dimorphic, depending on culture conditions.

The development of antifungal therapy has been a slow process. The complex structure of fungi has proved to be a formidable barrier to progress. Attention has focused on agents that would disrupt the cell wall or interfere with metabolic processes within the fungal cell. Although many different compounds with antifungal activity in vitro have been identified, the polyene antibiotics (most notably amphotericin B and natamycin) were the first to demonstrate effective clinical activity for ocular infections. With the discovery of the antifungal activity of the azole compounds, however, a whole new class of agents has slowly evolved. As a result, the future of antifungal therapy is considerably brighter now than it appeared to be a decade ago.

Little effort has been expended by drug companies to develop agents with pharmacologic profiles appropriate for the eye. This is despite the high prevalence of ocular fungal infections, particularly in tropical areas of the world, where the population is also the greatest. Instead, systemic preparations have been adapted by ophthalmologists for topical, subconjunctival, or intraocular use. In many instances, there is imperfect knowledge of the pharmacology of these agents, and what is known has been gleaned in great part from experimental studies in animals and experience in treating individual cases or small, uncontrolled case series.

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Polyene antibiotics, the first effective antifungal agents to be discovered, are produced by Streptomyces species.1 They share a common molecular structure, consisting of a conjugated double-bond system of variable size, which is linked to mycosamine, an amino acid sugar. The polyenes are classified according to the number of double bonds present. Their primary mode of action is to bind to ergosterol in the cell membrane, causing increased permeability and cell leakage. This general disruption of the cell membrane causes cell death.2,3 Although all polyenes, regardless of size, show this binding, the mechanism by which cell damage occurs differs depending on whether the polyene is large, with 35 or more carbon atoms (e.g., amphotericin B), or small, with less than 30 carbon atoms (e.g., natamycin). Large polyenes have the ability, because of size, to form channels in the cell wall; this allows for electrolyte movement and leads to potassium loss.3 Small polyenes are unable to span the width of the cell membrane; instead, they are believed to accumulate in the membrane, forming “blisters” that then disrupt the cell wall (Fig. 1).4 The polyenes bind only to the sterol-containing cell wall of eukaryotic cells and preferentially to ergosterol. It is this preferential affinity for ergosterol that makes the polyene attractive as an antifungal agent, because the fungal cell wall sterol is ergosterol. Cholesterol is the sterol in the human cell wall. Nonetheless, there is enough binding to cholesterol to create toxic side effects with these agents, whether used systemically or topically. There is also evidence that they can cause oxidative damage to the cells.3,5,6 Attempts to reduce toxicity by altering the chemistry of these compounds have so far been unsuccessful. In this chapter, only two polyenes will be considered: amphotericin B and natamycin. Nystatin, the first polyene to be discovered (in 1950), does not have any practical applications in ophthalmology.

Fig. 1. Comparison of the mechanisms of action of large and small polyenes. (Reprinted with permission from Forster RK: Fungal diseases. In Smolin G, Thoft RA (eds): The Cornea, p 235. Boston, Little, Brown & Co, 1987)


Amphotericin B (Fig. 2), produced by Streptomyces nodosus,1 was the first polyene shown to be effective in treating systemic mycoses.7 It is poorly soluble in water and has a tendency to degrade when exposed to light.8 In vivo, the rapid tissue binding of amphotericin B limits the actual amount of bioactive drug. In an attempt to increase solubility and drug bioavailability while limiting toxicity, several approaches have been tried, including methyl esterification and combination with liposomes and other vehicular compounds. Methyl esterification appeared promising initially because of enhanced solubility9; however, severe toxicity led to abandonment of this approach.10 Amphotericin B lipid complexes such as ABLC (Liposome Co., Princeton, NJ), Amphocil (Sequus Pharmaceuticals, Menlo Park, CA), and AmBisome (NeXstar Pharmaceuticals, Boulder, CO) are now available and we can expect new formulations of amphotericin B in other lipid vehicles. These promising new preparations eliminate the need for the deoxycholate solubilizer, the prime cause of eye pain and poor compliance when administered topically. Consequently, reduced toxicity allows the use of more drug both systemically and locally in the eye.3,11 A number of studies are under way with a variety of treatment modalities.12–14

Fig. 2. Structural formula of amphotericin B.

Amphotericin B (Fungizone, E.R. Squibb and Sons, Princeton, NJ) is available for intravenous use in 20-mL vials containing 50 mg of amphotericin B powder, 41 mg of sodium deoxycholate, and a sodium phosphate buffer. Before intravenous injection, the powder is reconstituted to a concentration of 5 mg/mL in 10 mL of distilled water.

Although intravenous amphotericin B has been used since its discovery for the treatment of ocular infections, its pharmacokinetic profile for ocular tissues is not particularly good. Its most useful application appears to be for the treatment of endogenous and exogenous endophthalmitis caused by Candida species. Levels achievable within the vitreous and posterior eye structures appear to be sufficient for these highly susceptible organisms, although not for other filamentous fungi. Concentrations of biologically active amphotericin B in the cornea and the anterior eye after intravenous administration have consistently been low.15–17

Topical Administration

Although there is no preparation of amphotericin B specifically designed for ophthalmic use, this agent has been used topically for the treatment of fungal keratitis since the late 1950s. Toxicity is a troublesome complication. Because of this problem, Wood and Williford18 evaluated amphotericin B (Fungizone) that had been diluted with distilled water to a concentration of 0.15% in a series of patients with mycotic keratitis. They demonstrated both efficacy and markedly reduced toxicity. In a further series, reduction of the concentration of amphotericin B to 0.05% virtually abolished toxic reactions. Animal studies likewise showed that concentrations as low as 0.03% were remarkably efficacious against susceptible Candida species.19,20 The use of topical concentrations greater than 0.15% has been reported, but this is not recommended because of toxicity; there is little evidence of superior efficacy in the higher concentrations. The topical preparation, when stored at 36°C, retains potency for 1 week. Care should be taken to handle the solution aseptically, because it does not contain a bacteriostatic agent.21

There have been numerous clinical and experimental studies of the efficacy of topical amphotericin B in concentrations ranging from 0.05% to 1%. The pharmacokinetic profile is not particularly good (Table 1). In particular, the corneal epithelium appears to be a powerful barrier to corneal penetration. This is an important issue because the epithelium may heal over fungal lesions in the cornea.22,23 In animal studies, topical amphotericin B 0.15% was virtually unable to penetrate the corneal stroma when the epithelium was intact. Removal of the epithelium was associated with greatly increased penetration, and the degree of penetration was found to be proportional to the size of the epithelial defect.24 Efficacy was also greatly enhanced in these models.


TABLE 1. Ocular Drug Concentrations of Polyenes*

Green et al15NZW rabbitsAmphotericin B1 mg/kgIntravenous—normal eyeBioassayNot done0 μg/mLNot detected
Green et al15NZW rabbitsAmphotericin B1 mg/kgIntravenous—inflamed corneaBioassayNot doneTraceTrace
Green et al15NZW rabbitsAmphotericin B1 mg/kgIntravenous—inflamed eyeBioassayNot done0.18 μg/mLTrace
Green et al15NZW rabbitsAmphotericin B150 μg/0.3 mLSubconjunctival—normal eyeBioassayNot doneTraceNot detected
Green et al15NZW rabbitsAmphotericin B150 μg/0.3 mLSubconjunctival—inflamed corneaBioassayNot doneTraceTrace
Green et al15NZW rabbitsAmphotericin B150 μg/0.3 mLSubconjunctival—inflamed eyeBioassayNot doneTraceTrace
Fisher et al16HumanAmphotericin B0.6 mg/kgIntravenousBioassayNot done0.24 μg/mL0.23 μg/mL
O'Day et al17HumanAmphotericin B15–50 mg/dayIntravenousBioassayNot done0.17 μg/mL0.17 μg/mL
O'Day et al23Dutch-belted rabbitsAmphotericin B0.15% 1 drop q 5 min × 13Topical—intact epitheliumRadioassay3.4 μg/g wet wt0.38 μg/mLNot done
O'Day et al23Dutch-belted rabbitsAmphotericin B0.15% 1 drop q 5 min × 13Topical—debrided epitheliumRadioassay33.5 μ/g wet wt2.7 μg/mLNot done
Schwartz et al28NZW rabbitsAmphotericin BShield soaked in 0.15%Collagen shield—debrided epitheliumHPLC17.5 μg/g wet wt0.3–0.5 μg/mLNot done
Schwartz et al28NZW rabbitsAmphotericin B0.15% 1 drop q 1 min × 5Topical—debrided epitheliumHPLC8.0 μg/g wet wt0.3–0.5 μg/mLNot done
O'Day et al30Dutch-belted rabbitsAmphotericin B1500 μg/0.3 mLSubconjunctival—intact epitheliumBioassay80.8 μg/g wet wt1 μg/mLNot done
O'Day et al30Dutch-belted rabbitsAmphotericin B1500 μg/0.3 mLSubconjunctival—debrided epitheliumBioassay90.1 μg/g wet wt0.4 μg/mLNot done
Ellison85NZW rabbitsNatamycin5 or 10 mg/kgIntravenousPhotometricNot done2–3 μg/mLNot done
O'Day et al25Dutch-belted rabbitsNatamycin5% 1 drop q 5 min × 13TopicalRadioassay2576 μg/g wet wt548 μg/mLNot done
Pleyer et al12NZW rabbitsLiposomal amphotericin B0.48% × 1 dropTopical—intact epitheliumHPLC1.2 μg/gNot doneNot done
Pleyer et al12NZW rabbitsAmphotericin B0.48% × 1 dropTopical—intact epitheliumHPLC19.0 μg/gNot doneNot done
Pleyer et al12NZW rabbitsLiposomal amphotericin B0.48% × 1 dropTopical—debrided epitheliumHPLC2.5 μg/gNot doneNot done
Pleyer et al12NZW rabbitsAmphotericin B0.48% × 1 dropTopical—debrided epitheliumHPLC52.5 μg/gNot doneNot done

NZW, New Zealand white, HPLC, high-performance liquid chromatography.
* Concentrations of polyene antifungal agents in ocular tissues that have been reported in the literature.
These data represent peak levels measured and are not comprehensive. Each cited work should be read in its entirety for complete understanding of the exact meaning of these excerpted values.


When the epithelium is absent, amphotericin B also appears to pass through the cornea to the anterior chamber. Penetration of inflamed corneas is also good. Amphotericin B (0.15%) administered topically was present in the cornea and aqueous of rabbit eyes inflamed by the intrastromal injection of clove oil, even in the presence of an intact epithelium.

The high concentrations of drug are mitigated by a very low bioactivity due to tissue binding. In Dutch-belted rabbits, this bioactivity has been measured at 7% of total drug in the cornea and 5% of total drug in aqueous humor.23 In spite of this, a therapeutic concentration of drug is achievable in the cornea with intense topical therapy.

The optimal frequency for the topical administration of amphotericin B is unknown. However, animal studies suggest that an initial loading approach of one drop every 5 minutes for 1 hour leads to a rapid accumulation of drug within the cornea, with drug still detectable 24 hours after the last drop.25 In the clinical setting, a practical approach is to give one drop every half hour initially with a gradual reduction to six to eight drops per day. After the infection is under control, this can be further reduced to three to four drops daily.

In some studies, collagen shields impregnated with amphotericin B were applied directly to infected corneas as a means of enhancing drug levels.26–28 The pharmacologic advantage of this approach over less expensive topical therapy is uncertain. In one study, the use of topically applied liposome-encapsulated amphotericin B was not associated with significantly increased corneal drug concentration.12

Subconjunctival Administration

Subconjunctival injections of amphotericin B have been recommended for the treatment of fungal keratitis and scleritis. Experience with human cases29 and experimental studies in animals30 demonstrate the severe toxicity of this approach. Ulceration and necrosis of the conjunctiva may occur, with inflammation of the underlying sclera and ciliary body. This appears to be due to both the deoxycholate salt that is used as an emulsifying agent and the amphotericin B itself.30 The injections are also associated with severe pain. Studies in animal models suggest that the amount of drug that enters the cornea, anterior chamber, or vitreous cavity is negligible (see Table 1).31 This form of therapy is no longer recommended.

Intracameral Administration

With knowledge of the limited efficacy of systemic and topical amphotericin B in severe intraocular infections, clinicians have advocated the use of intravitreal injections of amphotericin B. There is good evidence that the intravitreal injection of 5 μg of amphotericin B can be efficacious in the treatment of Candida sp. infections,32,33 alone or in combination with systemic amphotericin B or other drugs. The toxicity of intravitreal amphotericin B in a single injection appears to be low and within the acceptable range.33–35 Repeated injections do carry an increased risk of toxicity, although a number of cases have been reported in which repeated injections in these concentrations led to no aftereffects in the eye.36–39 For cases in which there is evidence of anterior endophthalmitis due to progression of infection from the cornea into the anterior chamber, amphotericin B can be irrigated into the anterior chamber.40 Our experience using this drug in concentrations of 5 μg/mL is largely limited to cases at surgery when the chamber is irrigated before penetrating keratoplasty is performed. Injection of liposomal amphotericin B has the theoretic potential to increase the half-life while reducing toxic side effects.11

Susceptibility of Organisms to Amphotericin B

It is generally accepted that amphotericin B is most effective against yeasts, particularly Candida and Cryptococcus species. It appears much less useful for the treatment of filamentous fungus infections. This experience with systemic mycoses is confirmed mostly in the treatment of ocular mycoses. Although clinical and experimental evidence suggests that Candida albicans keratitis is very susceptible to topically applied amphotericin B in concentrations of 0.03% to 0.15%, and that Candida endophthalmitis can be effectively treated by intraocular and/or systemic amphotericin B, there is little evidence that endophthalmitis due to filamentous organisms can be treated by this route. Amphotericin B does exert some antifungal activity against Aspergillus, but experience in saving eyes with Aspergillus endophthalmitis has been disappointing.41,42


The other important polyene for use in ocular disease is natamycin (Fig. 3). This tetraene polyene is the only antifungal agent commercially available in the United States for use as an ophthalmic preparation. It is marketed by Alcon Laboratories as a 5% suspension (Natacyn). It can be stored at room temperature or refrigerated, but it should not be frozen or exposed to light or high temperatures.

Fig. 3. Structural formula of natamycin.

Natamycin was discovered in 1958. It is arguably the most important and valuable antifungal agent for ophthalmic use discovered to date. Because of its physical characteristics, natamycin is extremely difficult to study. Much of what is known about the drug has been learned, therefore, from clinical experience. However, some laboratory work does provide information about its pharmacokinetics and pharmacology (see Table 1). Natacyn is available in volumes of 15 mL, stored in glass bottles. As is the case with most polyenes, natamycin is insoluble in water, and the commercial preparation is a microfine suspension that must be shaken well before each use. After topical administration, the drug often adheres to the area of corneal ulceration and may be seen in the fornices.

Pharmacokinetics and Pharmacology

Natamycin is easily absorbed into the cornea; however, it exhibits a high degree of binding in tissue, which severely limits its bioactivity.25 In addition, the corneal epithelium is a substantial barrier to corneal penetration. These characteristics account for the poor pharmacokinetic profile of this drug. However, extensive clinical experience with several fungi,43,44 in addition to laboratory studies,22,45–47 supports its value as an effective antifungal agent. In experimental pharmacokinetic studies using radiolabeled natamycin, high concentrations of the agent were detected in the cornea by radioassay after intensive topical administration. High levels were also detected in the aqueous.25 Because of tissue binding, only 2% of this drug is bioactive. The relatively high total corneal drug levels achievable by intensive administration assure that adequate therapeutic levels in the cornea are available. In experimental studies, it has been demonstrated that removal of the corneal epithelium dramatically increases penetration and efficacy.22,46,47

Topical Administration

As with amphotericin B, an initial loading approach is recommended. This consists of the administration of one drop every half hour with a gradual reduction to six to eight times and then three to four times a day. No other routes of administration are practical with this drug.


Topical natamycin 5% suspension is well tolerated in the cornea. Corneal toxicity does occur, however, with prolonged use, usually in the form of a punctate keratitis. Diffuse conjunctival inflammation is also seen, and a consistent low-grade inflammation has been reported.21,48 In an animal model, natamycin did not retard the healing of corneal epithelial defects.49 Natamycin has been shown to be most effective against the filamentous fungi, especially Fusarium and Aspergillus infections,43,48 which are the most common causes of fungal keratitis worldwide. Numerous clinical series in the United States and elsewhere have established the primacy of natamycin in the treatment of fungal infections caused by filamentous fungi; however, it is less effective against yeast infections.21 It should be noted, however, that treatment failures presumably due to organism resistance occur in both Fusarium and Aspergillus keratitis as well as with other organisms. Large series of cases describing therapy for filamentous fungi other than Fusarium or Aspergillus are lacking.

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A new era in antifungal therapy began in the mid 1960s with the discovery of the antifungal properties of the antiprotozoan azole compounds. In the succeeding 30 years, the list of these agents with antifungal activity has slowly but steadily grown. There are two major types of azoles used in ophthalmology. Imidazoles, the first to be discovered, are five-membered ring structures containing two nitrogen atoms. A complex side chain is attached to one of the nitrogen atoms (Fig. 4). The triazoles, developed more recently, contain three nitrogen atoms in a five-membered ring (Fig. 5). Several of these, such as thiobendazole and econazole, had only brief periods of use and will not be discussed here. The remainder of this section focuses on the imidazoles (miconazole, ketoconazole, and clotrimazole) and the triazoles (fluconazole and itraconazole).

Fig. 4. Structural formula of imidazole.

Fig. 5. Structural formula of triazole.

The mode of action of the azoles as a group is to inhibit ergosterol synthesis in the fungal cell wall. This leads to the accumulation of 14-methylated ergosterol precursors. As a result, the cell membrane is destabilized, cell growth is inhibited, and ultimately the cell dies.50,51 The unsubstituted nitrogen in the azole moiety binds to cytochrome P-450,51,52 but there is varying affinity for fungal and human cytochrome P-450 enzymes among the azoles so far developed. The triazoles (fluconazole and itraconazole), the latest compounds to be clinically applicable, are distinguished by their relatively high affinity for fungal cytochrome P-450 enzymes as compared with their affinity for human cytochrome P-450 enzymes.51 This differential affinity reduces the severity of certain side effects while increasing the likelihood of antifungal activity, which makes them attractive compounds for clinical use. Although inhibition of ergosterol synthesis is the principal mode of action of these compounds, there is some evidence, based on an additive or synergistic effect of amphotericin B, for other cellular or biologic actions harmful to fungi.53,54 The azoles are fungistatic compounds at the concentrations likely to be achieved within tissues. Frank fungicidal activity can be observed at higher concentrations in vitro; this appears to be due to direct membrane damage to the cell wall that is unrelated to inhibition of ergosterol synthesis.55 This fungicidal effect is thought to be dependent on the growth phase of the susceptible organism, and it is observed with some, but not all, azoles.


These compounds have two nitrogens in the azole ring.


Miconazole is a phenethyl imidazole that was first synthesized in Belgium in 1969 (Fig. 6). In addition to its antifungal activities, it has some activity against gram-positive bacteria.55

Fig. 6. Structural formula of miconazole.

PHARMACOKINETICS AND PHARMACOLOGY. Miconazole can be administered by topical, subconjunctival, intravitreal, and intravenous routes. Experimental data from rabbits suggest that both topical and subconjunctival administration produce high concentrations in the cornea and aqueous (Table 2). Other experimental studies suggest that levels achieved in the cornea by subconjunctival administration may be extremely transient.31 Levels can also be detected in the aqueous humor when the drug is administered intravenously. Intravenous administration has led to successful treatment in some reported cases.55 The intravenous preparation of 1% miconazole and the 2% miconazole nitrate cream (Monistat) can be administered topically. Miconazole has poor pharmacokinetics when administered topically. The corneal epithelium represents a substantial barrier to penetration. If the corneal epithelium is removed, the drug easily enters the cornea.56 As with other antifungal agents, an initial loading dose approach is recommended because of the poor pharmacokinetics. Miconazole exhibits high tissue binding, so only about 30% of the drug present in tissue is thought to be bioactive.50


TABLE 2. Ocular Drug Levels of Imidazoles*

Foster and Stefanyszyn56NZW rabbitsMiconazole1% 1 drop q 15 min × 8Topical—intact epitheliumBioassay10 μg/g dry wt0.6 μg/mLNot detectable
Foster and Stefanyszyn56NZW rabbitsMiconazole1% 1 drop q 15 min × 8Topical—debrided epitheliumBioassay93.3 μg/g dry wt4.6 μg/mLNot detectable
Foster and Stefanyszyn56NZW rabbitsMiconazole10 mg in 1 mLSubconjunctival—intact epitheliumBioassay13.4 μg/g dry wt4.9 μg/mL1.35 μg/mL
Foster and Stefanyszyn56NZW rabbitsMiconazole10 mg in 1 mLSubconjunctival—debrided epitheliumBioassay35.9 μg/g dry wt10.2 μg/mL0.25 μg/mL
Foster and Stefanyszyn56NZW rabbitsMiconazole30 mg/kgIntravenousBioassayNot detectable7.8 μg/mLNot detectable
O'Day et al17HumanKetoconazole600 mg qidPer osBioassayNot done0.35 μg/mL0.71 μg/mL
Savani et al58NZW rabbitsKetoconazole80 mg/kg × 1Intravenous, normal eyeBioassay0.7 μg/g wet wt7.4 μg/mLNot done
Savani et al58NZW rabbitsKetoconazole80 mg/kg × 1Intravenous, inflamed eyeBioassay1.4 μg/g wet wt33.6 μg/mL16.4 μg/mL
Grossman and Lee86Pigmented rabbitsKetoconazole100 μg/mL × 0.5 mLTranssceral iontophoresisBioassayNot done10.2 μg/mL0.1 μg/mL
Grossman and Lee86Pigmented rabbitsKetoconazole100 μg/mL × 0.5 mLTranscorneal iontophoresisBioassay7.7 μg/g wet wt1.4 μg/mLNot done
Grossman and Lee86Pigmented rabbitsKetoconazole100 μg/mL × 0.5 mLSubconjunctivalBioassay5.9 μg/g wet wt0.8 μg/mL0.7 μg/mL
Hemady et al57NZW rabbitsKetoconazole1% 1 drop q 15 min × 8Topical—intact epitheliumBioassay52 μg/g dry wt32.5 μg/mLNot detectable
Hemady et al57NZW rabbitsKetoconazole1% 1 drop q 15 min × 8Topical—debrided epitheliumBioassay1391 μg/g dry wt46.3 μg/mL9.2 μg/mL
Hemady et al57NZW rabbitsKetoconazole10 mg in 1 mLSubconjunctival—intact epitheliumBioassay263 μg/g dry wt25.1 μg/mLNot detectable
Hemady et al57NZW rabbitsKetoconazole10 mg in 1 mLSubconjunctival—debrided epitheliumBioassay830 μg/g dry wt28 μg/mL1.7 μg/mL
Hemady et al57NZW rabbitsKetoconazole200 mg × 1Per osBioassay67 μg/g dry wt1.6 μg/mLNot detectable

NZW, New Zealand White.
* Concentrations of imidazole antifungal agents in ocular tissues that have been reported in the literature.
These data represent peak levels measured and are not comprehensive. Each cited work should be read in its entirety for complete understanding of the exact meaning of these excerpted values.


TOXICITY. Topical miconazole 1% exhibits minimal toxicity that is characterized by conjunctival injection and punctate corneal epithelial erosions. Animal studies suggest that the rate of healing of epithelial defects is not retarded by topical administration of the drug.49 Subconjunctival administration is generally well tolerated. Systemic administration of miconazole has been successful in a few reported cases, but this form of therapy has been superseded by the triazoles, which have greatly improved pharmacokinetics.


Ketoconazole (Fig. 7) is available as 200-mg tablets (Nizoral, Janssen Pharmaceutical, Titusville, NJ) to be taken once daily. There is no commercial preparation of ketoconazole for topical use in the eye. Rabbit studies have used ketoconazole powder that was dissolved in dilute hydrochloric acid (0.1N) and then further diluted with water to concentrations of 1% to 5%.

Fig. 7. Structural formula of ketoconazole.

Ketoconazole was developed subsequent to miconazole and has an improved pharmacokinetic profile. Like miconazole, it inhibits ergosterol synthesis in vivo. Water solubility and systemic absorption are better than those of miconazole. The tissue binding of ketoconazole is similar to that of miconazole.

PHARMACOKINETICS AND PHARMACOLOGY. Good total drug levels in the cornea have been reported when ketoconazole is administered topically (see Table 2); however, the corneal epithelium is a barrier to penetration.57 The amount of this drug that is biologically active is unknown; however, ketoconazole, like most imidazoles, exhibits a high degree of protein binding. High levels in the aqueous and cornea have been reported after oral administration of a dose of 80 mg/kg daily.58 The evidence regarding levels after subconjunctival injection is conflicting, with some studies finding high levels and others suggesting little or no penetration of bioactive drug (see Table 2).31,57

EFFICACY AND SPECTRUM OF ACTIVITY. Ketoconazole has a wide spectrum of activity in vitro. Clinically, it has been shown to be effective against systemic Candida infections. There are some reports suggesting its value against Aspergillus, Fusarium, and Curvularia ocular infections.55 However, in the laboratory, the efficacy of ketoconazole for the treatment of these infections has not been demonstrated.

TOXICITY. Systemically administered ketoconazole appears to be relatively safe, although hepatotoxicity has been reported.21 Toxicity is usually reversible with cessation of the drug, but recovery may be slow. Rarely, deaths have been reported. Topical preparations of ketoconazole are well tolerated. The 1% ketoconazole preparation does not retard the closure of epithelial defects in the rabbit cornea.49 Ketoconazole may have its greatest use as an adjunctive therapy systemically in the treatment of severe anterior segment fungal infections.


Clotrimazole (Fig. 8), a chlorinated trityl imidazole, was synthesized in 1967 by Bayer Laboratories in Germany. Its potential as an antifungal agent was quickly recognized.59–61

Fig. 8. Structural formula of clotrimazole.

PHARMACOKINETICS AND PHARMACOLOGY. Clotrimazole is poorly soluble in water and cannot be administered parenterally. When given by mouth, it is rapidly absorbed, and satisfactory blood levels are maintained from the beginning of treatment. Clotrimazole, however, induces microsomal enzyme oxidation, so these levels are difficult to maintain.55

A topical ophthalmic preparation of clotrimazole can be made with 1% clotrimazole in peanut oil.44 Lotrimin cream (1%), a dermatologic preparation containing 1% clotrimazole, can be applied to the eye and is well tolerated.55 This must be carefully distinguished from the dermatologic lotion, which contains alcohols that are harmful to the cornea.

EFFICACY AND SPECTRUM OF ACTIVITY. Clotrimazole in vitro has been shown to have broad-spectrum antifungal activity and has been considered useful in the treatment of Aspergillus infections in vivo.55 However, clotrimazole is a fungistatic drug and, in practice, its potential has not been realized. Clotrimazole has been largely superseded by the newer azole compounds.

TOXICITY. With systemic administration, hepatotoxicity, nausea, and diarrhea have been reported. Topical clotrimazole, either as a 1% preparation in peanut oil or as the dermatologic cream, has been well tolerated in humans. However, ocular irritation and punctate keratopathy have been reported after long-term use.55 The safety and efficacy of subconjunctival and intracameral clotrimazole have not been thoroughly evaluated.


These compounds have three nitrogens in the azole ring. The triazoles were developed as a result of experience with the early imidazoles. The two compounds available are fluconazole (Diflucan) and itraconazole (Sporanox). These compounds differ considerably in their physicochemical properties. Whereas previous azole compounds have been distinguished by their lack of water solubility and high protein binding, fluconazole is water soluble and has a low binding to protein. Itraconazole, although somewhat similar to the imidazoles because of its insolubility in water and its high protein binding, is thought to have considerable tissue penetration.


Fluconazole (Fig. 9) is the first antifungal agent to have both a good pharmacokinetic profile when administered systemically and a low incidence of systemic side effects.58,62 The agent is potentially useful for ocular infections when administered topically, subconjunctivally, intravitreally, and systemically. Fluconazole is rapidly distributed in high concentrations throughout the total body water, including the eye (Table 3).58,62–64 The drug has a terminal half-life of 24 hours, and studies in rabbits have revealed excellent uptake and persistence in all ocular tissues and fluids (Fig. 10).58,62,65

Fig. 9. Structural formula of fluconazole.


TABLE 3. Ocular Drug Concentrations of Triazoles*

Savani et al58NZW rabbitsFluconazole80 mg/kgIntravenous—normal eyeBioassay2.1 μg/g wet wt21.9 μg/mL16 μg/mL
Savani et al58NZW rabbitsFluconazole80 mg/kgIntravenous—inflamed eyeBioassay6.2 μg/g wet wt50.2 μg/mL21.5 μg/mL
O'Day et al62Dutch-belted rabbitsFluconazole10 mg/kgPer osHPLC5.8 μg/g wet wt4.2 μg/mL4.4 μg/mL
O'Day et al62Dutch-belted rabbitsFluconazole20 mg/kgPer osHPLC13.3 μg/g wet wt7.4 μg/mL9.8 mg/mL
Abe and Ishikawi87HumanFluconazole200 mgPer os—inflamed eye Not done5.3 μg/mLNot done
Abe and Ishikawi87HumanFluconazole200 mg/day × 11Per os—inflamed eye Not done12.6 μg/mL10.5 μg/mL
Urbak and Degn64HumanFluconazole400 mg/day × 6.5 weeksPer osNot givenNot doneNot done15 μg/mL
Aust et al63HumanFluconazole200 mg 0.5–8 hours before assayPer osHPLCNot done3.7 μg/mLNot done
Savani et al58NZW rabbitsItraconazole80 mg/kgPer os—normal eyeBioassay0.03 μg/g wet wtNot detectableNot detectable
Savani et al58NZW rabbitsItraconazole80 mg/kgPer os—inflamed eyeBioassay0.05 μg/g wet wt0.92 μg/mL0.22 μg/mL
O'Day et al88Dutch-belted rabbitsSaperconazole0.25% 1 drop q 5 min × 13Topical—intact epitheliumHPLC6.2 μg/g wet wt0.24 μg/mLNot done
O'Day et al88Dutch-belted rabbitsSaperconazole0.25% 1 drop q 5 min × 13Topical—debrided epitheliumHPLC76.2 μg/g wet wt4.0 μg/mLNot done
O'Day et al88Dutch-belted rabbitsSaperconazole0.25% × 0.3 mLSubconjunctival—intact epitheliumHPLC12.9 μg/g wt wt1.0 μg/mLNot done
O'Day et al88Dutch-belted rabbitsSaperconazole0.25% × 0.3 mLSubconjunctival—debrided epitheliumHPLC93.4 μg/g wet wt3.1 μg/mLNot done
O'Day et al88Dutch-belted rabbitsSaperconazole10 mg/kg × 1Per osHPLCNot doneNot detectable<0.01 μg/mL
O'Day et al88Dutch-belted rabbitsSaperconazole0.25% 1 drop q 5 min × 13Topical—debrided epitheliumBioassay15.7 μg/g wet wtNot doneNot done

NZW, New Zealand white, HPLC, high-performance liquid chromatography.
* Concentrations of triazole antifungal agents in ocular tissues that have been reported in the literature.
These data represent peak levels measured and are not comprehensive. Each cited work should read in its entirety for complete understanding of the exact meaning of these excerpted values.


Fig. 10. Fluconazole concentrations in cornea and serum after 1, 3, or 5 days' administration of 35 mg/kg/day of drug given as a single dose every 24 hours or divided and given every 12 hours. Values represent trough levels. (Reprinted with permission from O'Day, DM, Foulds G, Williams TE et al: Ocular uptake of fluconazole following oral administration. Arch Ophthalmol 108(7):1006, 1990)

TOPICAL ADMINISTRATION. Fluconazole is readily soluble in water, and although the intravenous preparation can be administrated topically at a dose of 2 mg/mL, studies of efficacy have yielded conflicting results with susceptible organisms. In our laboratory, topical amphotericin B appears far superior to fluconazole for Candida infections. Comparative studies of the efficacy of fluconazole in the treatment of infections caused by other filamentous fungi have not yet been reported.

SUBCONJUNCTIVAL ADMINISTRATION. After subconjunctival injection, fluconazole is rapidly cleared from the cornea and aqueous, so therapeutic levels will not likely be achieved.31

INTRACAMERAL ADMINISTRATION. Fluconazole has been injected into the vitreous of rabbits at a dose of 100 μg in a concentration of 1000 μg/mL. At this dosage, it appears nontoxic.66

SYSTEMIC ADMINISTRATION. The most important potential application of fluconazole in ophthalmology is systemic use in the treatment of Candida endophthalmitis in combination with or as a replacement for amphotericin B.67 Animal studies and clinical experience provide strong support for the efficacy of fluconazole in treating these infections.17,58,68 Pharmacologic studies in rabbits show that oral administration of 35 mg/kg/day, as either a single or divided dose, can provide good uptake of fluconazole into the cornea62 (see Fig. 10) and other ocular tissues. Both animal and clinical studies suggest that oral fluconazole in a dose of 200 to 600 mg per day alone may be efficacious in the treatment of Candida endophthalmitis.64,67,69,70 The treatment of endogenous Candida infections has not been well studied, but in a recent review of an uncontrolled case series and 21 additional cases in the literature, there is substantial evidence of the benefit of fluconazole treatment.70 In addition, controlled trials of fluconazole prophylaxis in patients susceptible to disseminated Candida infections lend further support to the value of this drug.71–73 The value of systemic fluconazole in intraocular infections caused by filamentous infections is uncertain. Clinical evidence for efficacy against Aspergillus infections is lacking, despite encouraging findings in an animal model.65 Oral fluconazole is used for the prophylaxis of systemic fungal infections, including the aspergilloses. There is evidence, as yet unconfirmed, that the agent may be efficacious at much higher doses (e.g., 2000 mg per day).51 There is no evidence available for the treatment of other filamentous fungi, although anecdotal reports of cases of post-traumatic fungal infections are supportive.

In view of the low toxicity and good pharmacokinetic profile of fluconazole, further research seems worthwhile so that its applicability, particularly with much higher doses of the drug, can be refined.


Itraconazole (Fig. 11), in contrast to fluconazole, exhibits poor water solubility and high protein binding (99%).50,51 These characteristics appear to make it less attractive than fluconazole, but its spectrum of activity in some respects surpasses that of fluconazole. Despite the apparent indifferent pharmacokinetic profile in the eye (see Table 3), the drug is well distributed in lipid-rich tissues in the body. Recent studies with a cyclodextrin-incorporated preparation suggest that dramatically improved drug concentrations may be achievable.74,75 The lack of an intravenous preparation is a considerable drawback, because effective oral absorption depends on the presence of food in the stomach and a low pH.51 One of the metabolites of itraconazole may also have antifungal effects.51

Fig. 11. Structural formula of itraconazole.

The agent has undergone considerable study in vitro and in animal models, but reliable clinical experience is sparse. It is approved for the treatment of histoplasmosis, blastomycosis, aspergillosis, and onychomycosis.51 The recommended dose is 200 mg twice a day, but higher dosing regimens have been used with only mild side effects. However, the advantage of increasing the dose remains uncertain. An important possible application for the use of itraconazole, and one especially relevant to ophthalmology, is the treatment of Aspergillus infections. Clinical experience with systemic Aspergillus infections suggests that the drug is highly effective. Its advantage compared with amphotericin B, however, has yet to be established. Current thinking about the treatment of systemic infections is to continue to use amphotericin B as the initial drug of choice unless toxicity develops. Combination therapy, however, may be advantageous. In the eye, experience with this drug has been limited. There are no studies of its use as a topical preparation; however, animal studies with the subconjunctival injection of itraconazole suggest that persistent therapeutic levels in the cornea are achievable.31 Treatment studies in a rabbit model of Aspergillus keratitis have also demonstrated efficacy after subconjunctival injection.76 There are no studies of the treatment of other infections, and studies of topical therapy are not available.

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FLUCYTOSINEThe antifungal properties of flucytosine (5-fluorocytosine), a fluorinated pyrimidine (Fig. 12), were Üxnfirst described in 1963.77 The compound was synthesized in 1957 with the intent to use it in the treatment of leukemia.

Fig. 12. Structural formula of flucytosine.

Pharmacology and Pharmacokinetics

Flucytosine is transported across the fungal cell wall by a permease. Within the cell, the agent is deaminated to fluorouracil. This thymidine analogue then blocks further fungal thymidine synthesis.7 The enzyme that is responsible for the transportation of flucytosine across the cell wall is a specific permease produced by certain fungi. Mammalian cells normally are unable to metabolize flucytosine, so it does not inhibit metabolic processes within mammalian cells. The drug is taken by mouth and is well absorbed in the gastrointestinal tract. Therapeutic levels within the eye can be achieved after a dose of 50 to 150 mg/kg/day in divided doses (Table 4). The compound is moderately soluble in water.


TABLE 4. Ocular Concentrations of Flucytosine*

Walsh et al89NZW rabbitsFlucytosine250 mg/3 kg rabbitPer osBioassayNot done15.6 μg/mL10.3 mg/mL
Walsh et al89NZW rabbitsFlucytosine2.5 mg/0.5 mLSubconjunctivalBioassayNot done23.5 μg/mLNot detectable
O'Day et al17HumanFlucytosine1.5 g q 6 hPer osBioassayNot doneNot detectable22.2 μg/mL

NZW, New Zealand white.
*Concentrations of flucytosine in ocular tissues that have been reported in the literature. These data represent peak levels measured and are not comprehensive. Each cited work should be read in its entirety for complete understanding of the exact meaning of these excerpted values.


A topical solution of 1% flucytosine has been used with success in treating corneal infections.78 This preparation can be made by dissolving the contents of a capsule containing the compound in artificial tears. In experimental studies of Candida keratitis ranking the efficacy of a variety of antifungal agents, 1% flucytosine was found to rank behind amphotericin B and natamycin but was superior to miconazole.46 Although flucytosine has been advocated for use as a subconjunctival injection, the efficacy of this therapy remains to be established.

Efficacy and Spectrum of Activity

Flucytosine is effective against Candida, but resistance can be induced by therapy.79 Also, some fungi lack the specific permease to transport the drug into the cell and are thus resistant to flucytosine.80 To avoid induced resistance, it is recommended that flucytosine not be used alone in the treatment of fungal infections.


Flucytosine taken by mouth is well tolerated, but mild gastrointestinal symptoms, including nausea, vomiting, and diarrhea, may occur. Hepatotoxicity can also develop. Within the gastrointestinal tract, flucytosine is metabolized by bacteria to fluorouracil and can produce bone marrow toxicity. Fortunately, the toxic effects of flucytosine are reversible when the drug is stopped. Because flucytosine is excreted by the kidneys, it should be used with caution in patients with renal failure.21 The topical preparation is well tolerated. There is no evidence of impaired wound healing with topical administration.49

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An enhanced understanding of the cell biology of fungi is leading to the identification and synthesis of agents designed for a specific antifungal activity. The fungal cell wall has long been an obvious target for antifungal agents. Its major structural components are chitin and beta-glucans, and there is intense interest in a variety of compounds that inhibit their synthesis and regulation. Other compounds have been identified that complex with mannoproteins in the cell wall, thereby causing leakage of intracellular potassium.81 Other promising avenues of investigation involve pathways leading to the synthesis of ergosterol, phospholipids, and sphingolipids in the plasma cell membrane. The discovery that the amino acid analogue cispentacin interferes with the biosynthesis of nonmammalian sulfur-containing amino acids that are present in fungi has sparked interest in other amino acid analogues.81

A radically different approach focuses on those factors that determine an organism's virulence, defined as its unique ability to survive and grow in the host.81 Such factors are under genetic control, and this control is likely to be complex. Nonetheless, gradual elucidation of the molecular basis of fungal virulence will open up new avenues for treatment in which the targets are the virulence genes. One agent, azoxybacilin, has already been identified with gene-inhibitory activity.82–84

After a period of seeming stagnation in the development of antifungal agents over the last decade, the field is moving rapidly, taking advantage of fundamental discoveries in molecular biology. We can expect in the next few years that these new approaches will produce new agents for the therapy of fungal infection. Their application to the field of ocular fungal disease offers fascinating opportunities.

Supported in part by an unrestricted grant from Research to Prevent Blindness.
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