Chapter 2

............................

Antifungal Agents

The antifungal agents used in ophthalmology can be divided into several groups on the basis of their chemical structure: (1) polyenes; (2) flucytosine, and (3) azoles. In addition, several antiseptic agents are used.

The ocular findings from animal studies are mainly presented in chapter 7 (see pp. 162–196).

2.1

Polyenes

Because of their toxicity, the polyene antibiotics natamycin (pimaricin) and nystatin are only used topically. They are not absorbed from the gut, however, and can thus be given orally in the treatment of fungal infections of the gastrointestinal mucosa. They are used as aerosols in the treatment of mucosal mycoses of the respiratory tract. In severe cases, amphotericin B may also be given by intravenous or intravitreous injection.

The polyene antibiotics are capable of penetrating ergosterol, a constituent of the plasma membranes of fungi, in such a way that hydrophilic pores develop [1]. This formation of ‘leaks’ explains the eYcacy of these agents against both resting and growing fungi [2–6].

2.1.1

Amphotericin B

Amphotericin B was developed as early as the 1950s from Streptomyces nodosus [3, 7] and still represents the antifungal agent of first choice [8, 9] and the standard against which new agents are measured [10, 11].

Systemic use of amphotericin B is associated with the major side eVect of nephrotoxicity, with reduced glomerular filtration, hypokalemia and acidosis [3, 8, 12, 13] Renal damage can be alleviated or even prevented by saline infusions [14] or parenteral administration of flucytosine [15]. Combination

27

with flucytosine allows the recommended dose (1 mg/kg body weight) to be reduced by 50%.

Amphotericin B may only be administered in 5% glucose solution, as the drug precipitates in physiological saline. A liposomal formulation has also been developed, and this is better tolerated and has more favorable pharmacokinetics than the original formulation [16–21]. Tolerability may also be improved by administration of amphotericin B in a fat emulsion [22–24]. The dose is 1 mg/kg body weight administered as a mixture of 2 mg of amphotericin B per 1 ml fat emulsion (Intralipid). However, in a randomized clinical study any reduction of side eVects could not be demonstrated [25], this formulation has not been registrated and pulmonary embolism may develop due to enlarged lipid particles [26]. Amphotericin B is well tolerated in colloidal dispersion in sodium cholesteryl sulphate without the risk of renal toxicity [27]. At present, however, it is not yet clear whether these new formulations of amphotericin B are equivalent to or better than the earlier simple amphotericin B preparations.

After systemic administration, amphotericin B penetrates the aqueous humor and to a certain extent the vitreous humor [28], where the concentration may exceed the minimum inhibitory concentration (MIC) for the pathogen [29, 30]. Systemic administration is usually advisable in endogenous endophthalmitis involving fungemia, in order to include any extraocular foci. In exogenous endophthalmitis, on the other hand, direct injection of amphotericin into the anterior chamber or the vitreous body is initially preferable to parenteral administration, because it achieves higher concentrations and avoids systemic side eVects. As a rule, a dose of 5–10 lg (maximum) is injected into the center of the vitreous cavity following pars plana vitrectomy [31–43], after which the electroretinogram may be temporarily reduced [42, 44]. The injection may be repeated, but candidal endophthalmitis has been successfully treated with a single dose of 5 lg without vitrectomy [45]. Measurements of drug clearance in rabbits showed that the half-lives in unmodified phakic eyes, Candida-infected eyes, aphakic eyes and aphakic vitrectomized eyes to be 9.1, 8.6, 4.7 and 1.4 days after a single intravitreous injection of 10 lg [44].

Instructions for the preparation of amphotericin solution for intraocular injection are given in table 2.1. Repeated injections (7.5 lg once daily) into the anterior chamber are well tolerated [46, 47]. A subconjunctival injection is possible [47, 48], but may result in the formation of nodules and yellowish discoloration [49].

Fungal infections of the cornea are treated with eye-drops (5 mg/ml) [50–65]. Twelve patients, 4 with Fusarium spp., responded successfully to amphotericin B at a concentration of only 0.15% [66]. Amphotericin has also been used in the form of an eye ointment [67, 68], but this may cause a burning sensation. Instructions for preparation of eye-drops and eye ointment are

Table 2.1. Preparation of amphotericin B for intraocular injection (75 lg/ml)

•Add 10 ml of water for injection to a bottle containing 50 mg of amphotericin B dry substance (Bristol-Myers Squibb); shake the bottle until the solution is clear (50 mg of amphotericin B)

•Take up 1 ml of the solution in a 10 ml syringe (5 mg of amphotericin B)

•Make up to 10 ml with water for injection, mix well, then discard the contents apart from 1 ml (0.5 mg of amphotericin B)

•Dilute this amount (500 lg) with water for injection to make 6.7 ml and shake well (74.62 lg of amphotericin B)

•Aspirate 0.1 ml of this mixture into an insulin syringe (7.5 lg of amphotericin B)

Table 2.2. Preparation of amphotericin B drops

0.5% (5 mg/ml) drops

•Add 10 ml water for injection to a bottle of 50 mg of amphotericin B dry substance (Bristol-Myers Squibb); shake the bottle until the solution is clear

•Remove some of the solution with a syringe and instill directly into the conjunctival sac

•The solution may be kept in a refrigerator for 1 week when using a sterile workbench

•If the mixture is to be transferred to eye-drop bottles, filter through a 0.2 lm poremesh as it is a colloidal suspension

0.15% drops

•Take 3 ml of the 0.5% solution and make up to 10 ml with water for injection

•Shake well

Table 2.3. Preparation of amphotericin B 0.5% ointment (5 mg/g)

•Add 3 ml water for injection to a bottle containing 50 mg of amphotericin B dry substance (Bristol-Myers Squibb); shake the bottle until the solution is clear

•Blend amphotericin B solution 1.5 ml, Eucerin anhydr. (sterile) 1.0 g, Bepanthen Augen-

salbe Ô (eye ointment) to 5.0 g using a sterile workbench

•The ointment may be in a refrigerator for 1 week

given in tables 2.2 and 2.3. With topical use, it must be remembered that amphotericin B does not penetrate the corneal epithelium, thus necessitating corneal abrasion (see chapter 7, p. 172).

The spectrum of activity of amphotericin B covers most fungi, including

C. albicans, most species of Aspergillus, H. capsulatum, Cryptococcus spp. and

Blastomyces spp. [3, 9]. Some isolates of C. albicans, however, have been found to be resistant in vitro (by MIC values) and in vivo [69]. Variable sensitivity has been shown by species of Curvularia, Alternaria, Wangiella and Clado-

sporium [9]. P. boydii is often resistant. S. brevicaulis proved susceptible to a combination of topical amphotericin B and chloramphenicol [70, 71]. Mixed results were reported for P. lilacinus [72, 73]. Despite sensitivity of the organisms, progressive inflammation developed in invasive A. fumigatus keratitis [74] and in F. solani keratitis [75], presumably due to insuYcient penetration.

2.1.2

Natamycin (Pimaricin)

This substance was isolated in 1955 from Streptomyces spp. that were found in the vicinity of Pietermaritzburg, Natal, South Africa. The name pimaricin is derived from that of the town, and the names natamycin and S. natalensis from that of the province from which the species was obtained [76]. The antibiotic is available as a suspension in concentrations of 1–5% and is well tolerated. In assessing the reports in the literature, it has to be borne in mind that in the USA and the UK, the 5% solution is used almost exclusively. In central Europe, on the other hand, natamycin is so far available for ophthalmological use only in the form of a 1% eye ointment.

Natamycin was very eVective in vitro against C. albicans, A. fumigatus and F. solani [77, 78]. Its activity against Fusarium spp., in particular, was clearly greater than that of the azole derivatives [79]. Natamycin 5% is being used clinically with good results in keratomycoses, especially if these are still superficial [40, 58, 62, 80–89]. In keratitis caused by Fusarium spp. or Aspergillus spp., natamycin is superior to amphotericin B, while amphotericin is more eVective in candidal keratomycosis [81, 84, 90].

Natamycin 2.5% in combination with miconazole has been successfully used in corneal infections caused by Paecilomyces spp. [91], though the fungus was said to be sensitive only to miconazole [92]. Natamycin 1% has also been prescribed [93, 94] sometimes in combination with nystatin [56, 95–97]. There are no reports of unequivocal eVects, as in the case of the 5% concentration.

Experimental studies of natamycin are described in chapter 7 (see p. 173 and 179).

2.1.3

Nystatin

Nystatin has been applied topically to the eye in a concentration of 100,000 IU [98]. A suspension is prepared from the pure substance with sterile, isotonic phosphate buVer solution (table 2.4). Nystatin is well tolerated [99].

Table 2.4. Preparation of nystatin drops (100,000 IU/ml)

•To prepare the buVer solution, mix 20 ml of sodium dihydrogen phosphate solution (8.0 g NaH2PO4 /1,000 ml H2O) with 80 ml disodium hydrogen phosphate solution (9.47 g Na2HPO4 /1,000 ml H2O) and, after addition of 0.44 g sodium chloride sterilize by autoclave

•Shake the contents of a bottle of pure substance (Candio-Hermal Ô, Hermal) with 5 ml of the isotonic, isohydric phosphate buVer solution described

•This preparation is a suspension and should be shaken before use

•The pure substance can also be used to prepare an ointment (100,000 IU nystatin/g ointment)

Nystatin has been prescribed for candidal keratomycoses [51, 62, 100–103] as well as for those caused by Aspergillus spp. [52, 104–107]. In one study, nystatin (drops and 5000 IU subconjunctivally) was used in keratomycoses that had been confirmed by culturing but were not described in detail. It proved successful in 53% of 30 cases, compared with 75% of 20 patients treated with amphotericin [99]. In another group in this study, 34% of 35 patients were cured with 2% miconazole.

Nystatin is not a first-line drug, as other agents are more eVective; however, it may serve as an alternative in some cases.

2.2

Flucytosine

Flucytosine (5-fluorocytosine, 5-FC) is derived from a fluorinated pyrimidine derivative, which is converted by fungi into 5-fluorouracile [57, 108]. Its toxic eVects are due to its antimetabolite activity. Thrombocytopenia is a known adverse eVect of flucytosine. A dose of 160 mg/kg body weight is recommended for systemic administration. Flucytosine is eVective against C. albicans [77, 109] and Cryptococcus spp. [5]. The development of resistance cannot, however, be ruled out [110, 111].

Oral administration of flucytosine, alone or in combination with amphotericin, has often been used or recommended in fungemia with or without fungal endophthalmitis [6, 8, 34, 40, 42, 75, 112–128]. A 1.5% concentration of flucytosine may be applied topically to the eye [55, 129]. Oral doses of flucytosine, as well as topical applications as 1% drops, have been successfully used in candidal keratitis [57, 108, 130]. The treatment should be continued for a period of 12–32 weeks [57]. A keratomycosis caused by A. alternata

Table 2.5. Use of flucytosine 1% drops

•A dose of the infusion solution (Ancothil Ô, Roche) (2.5 g/250 ml) may be aspirated directly into a sterile syringe and instilled into the conjunctival sac

•The solution must be stored at 15–23 ºC to avoid conversion to 5-fluorouracil (not visible)

Table 2.6. Preparation of clotrimazole 1% oily drops

•Dissolve the drug (US Ph. 21, obtainable from various suppliers) in sterile oil in a waterbath under aseptic conditions in the proportions clotrimazole, 0.1 g, and castor oil, 10.0 g

•Filter the solution through a 0.2-lm filter into sterile eye-drop bottles

cleared up completely in response to oral flucytosine plus topical application of natamycin and thimerosal [131]. Topical flucytosine has also been used in fungal blepharoconjunctivitis [130].

The use of flucytosine eye-drops is described in table 2.5.

2.3

Azoles

The antifungal agents of this drug category are chemically derived from the imidazole ring and are usually substituted in the 2 position. They have a broad spectrum of activity which includes dermatophytes, e.g. Trichophyton, Microsporon and Epidermophyton, as well as other pathogens such as Candida spp. and Cryptococcus spp. Some azoles were inactive in vitro against Fusarium spp. [79], though their use has been reported to be successful after several weeks in vivo [132, 133]. A general overview has been published by [134–137], respectively. Development of resistance has occurred and must be taken into account [137].

2.3.1

Clotrimazole

Clotrimazole (1-(a-2-chlorotrityl)imidazole) was one of the first azoles in clinical use. It can be used as a 1% concentration in castor oil or as an ointment (tables 2.6, 2.7). The use of polyethylene glycols or cremophor as vehicles

Table 2.7. Preparation of clotrimazole 1% ointment

•Dissolve clotrimazole (as in table 2.6) in sterile oil with heating and mix with white soft paraYn

•The proportions are clotrimazole, 0.1 g, arachis oil (sterile), 5.0 g, white soft paraYn for ophthalmic use, 10.0 g

causes epithelial damage [138]. Complete healing was recorded in several cases of A. fumigatus keratitis [58, 139] and in keratomycoses caused by Candida spp. [58] or by Penicillium spp. [140, 141]. In 1 case each of infection with

Monosporium apiospermum, P. rugulosum and A. ianus, as well as 2 cases of

T. famata, the lesions healed completely after treatment with clotrimazole as single agent for 3–8 weeks [140]. The same treatment was successfully used in keratomycosis caused by (1 case each) A. fumigatus, P. rugulosum and Cladosporium sp. [141]. Clotrimazole also proved eVective against S. brevicaulis in vitro [266].

Clotrimazole has also been prescribed for topical application in combination with oral ketoconazole [142]. The risk of resistant fungal strains must, however, be taken into account [110], and for this reason clotrimazole is now generally considered to be a secondor third-line drug.

2.3.2

Miconazole

Miconazole was usually instilled into the eye in a 1% solution, but could also be administered by subconjunctival injection (5–10 mg) [40, 143] or systemically (20 mg/kg). Miconazole had also been given by intravitreous injection [143]. Resistance did occur [34, 110], but the in vitro eYcacy of miconazole exceeded that of natamycin and nystatin [83].

The clinical use of topical miconazole was successful in keratomycoses caused by Aspergillus spp. [57, 132, 144] or by Cryptococcus sp. [145], as well as in combination with oral ketoconazole, 200 mg/day, against Drechslera spp. and Curvularia spp. [132]. In an open prospective study, 1% miconazole was successful in 55 of 85 patients (64.7%) with a mean healing time of 22 days [146]. EYcacy was most pronounced against Candida spp. (4 of 5), followed by Aspergillus spp. (14 of 20) and Fusarium spp. (3 of 6). A 2% miconazole ointment had also been prescribed [99, 147]. Miconazole appears to be the only eVective agent against P. lilacinus [91, 92]. Topical as well as systemic miconazole was eVective against S. brevicaulis keratitis [148]. Intraocular blas-

tomycosis cleared up only when subconjunctival miconazole, 5 mg/0.5 ml, was added to the treatment with intravenous amphotericin B [149]. On the other hand, a case of keratitis caused by P. boydii failed to respond even to 1,200 mg 3 times daily in combination with hourly applications of 1% miconazole and 2 further subconjunctival injections of miconazole, resulting in the loss of the eye. The organism was sensitive to the drug (MIC 0.5 mg/l) [150].

Systemic doses of miconazole were used with good results in Botyrodiplodia theobromae keratitis [151], and in Aspergillus keratitis [152], as well as in orbital abscess caused by P. boydii [153]. The compound was also eVective in C. albicans endophthalmitis [32, 122] and in postoperative Aspergillus endophthalmitis [154]. On the other hand, endophthalmitis resulting from coccidioidomycosis worsened during treatment with miconazole, but improved when this was replaced by amphotericin B [155].

It had been recommended to administer an antihistamine before parenteral administration. The adverse eVects were probably attributable to the vehicle, Cremophor EL [156] and consisted of nausea, pruritus, cardiac dysrhythmia and, in some cases, phlebitis [157, 158].

Systemic miconazole has failed to fulfil the original expectations [159]. Meanwhile the manufacturer has discontinued the production of the intravenous solution with the result that topical ophthalmic use with this formulation is no longer possible.

2.3.3

Ketoconazole

This imidazole derivative has been prescribed for topical as well as systemic use (200–400 mg daily). A general overview is provided by [160]. Apart from nausea and vomiting, liver damage may result from systemic administration [161]. The adverse eVects are dose related [8, 129].

Oral doses of ketoconazole have proved especially eVective in keratomycosis due to Fusarium spp. [133], particularly in combination with topical miconazole [132]. A case of Botyrodiplodia keratitis that had failed to respond to ketoconazole cleared up when miconazole was given intravenously [162]. In a study involving 30 cases of keratomycoses (including 11 Aspergillus, 6 Fusarium and 3 Curvularia), ketoconazole was given orally in doses of 600 mg/ day, 400 mg/day or 200 mg/day for 5 days each; it proved very eVective in 20 cases, and no adverse eVects were reported [266]. Oral ketoconazole was eVective in a case of Candida endophthalmitis involving the anterior sections of the eye which had failed to respond to natamycin [163]. It was ineVective, however, in experimental Aspergillus keratitis [164].

Table 2.8. Preparation of ketoconazole 2% oily drops (20 mg/ml)

•Dissolve 1 tablet (200 mg) of ketoconazole (Nizoral Ô, Janssen) in 10 ml of castor oil using a mortar and pestle

•Shake well, do not filter, and do not freeze

Following diagnostic and therapeutic vitrectomy the intravitreous concentration of ketoconazole 8 h after an oral dose of 600 mg was shown to be 0.92 mg/l, which was above the MIC for the oVending organism C. parapsilosis [165]. It has accordingly been recommended that systemic ketoconazole is used in the treatment of fungal endophthalmitis [40], particularly as it has no serious side eVects [165, 166]. It has been claimed that a combination with intravitreous amphotericin B [165] or with oral flucytosine [115, 267] was beneficial in candidal deep mycosis. On the other hand, microbiologists warn against the combination of ketoconazole and amphotericin B, because Candida spp. resistant to ketoconazole but sensitive to amphotericin B developed resistance in vitro to the latter antifungal agent [166].

As with miconazole, ketoconazole has failed to fulfil early expectations of eYcacy in invasive mycoses and has been largely superseded by itraconazole and fluconazole [159].

It has been recommended that eye-drops are prepared by pulverising a 200-mg tablet and adding 10 ml of sterile saline solution [167] or 5 ml of 4.5% boric acid solution with 5 ml hydroxypropylmethylcellulose [168]. This results in a solution of low pH, however, so it is preferable to suspend the lipophilic ketoconazole in castor oil or ground-nut oil (table 2.8). Ketoconazole 2% eyedrops have been found eVective against Aspergillus spp., F. solani and Alternaria spp. [168], as well as in combination with oral ketoconazole, 200 mg/day, against Penicillium spp. [167].

2.3.4

Itraconazole

Itraconazole has proved very eVective in systemic Aspergillus infections [169–174]. The MICs are favorable even in infections with problem organisms, e.g. C. glabrata, C. krusei and C. neoformans. Itraconazole is particularly eVective in infections with dermatophytes; the only gaps in the spectrum are Fusarium spp. [79, 170] and Zygomyces spp. [175]. Itraconazole is regarded as the treatment of choice in histoplasmosis [176]. In cryptococcosis it is recommended as a good alternative to the standard combination of amphoter-

icin B and flucytosine [177]. After administration of a mean itraconazole dose of 5.1 mg/kg body weight/day, serum levels varied widely in the same individual and between diVerent individuals (range 117–1127 mg/ml) [171]. Absorption of orally administered itraconazole capsules can be increased in patients with achlorhydria or otherwise reduced gastric acidity by concurrent ingestion of a cola beverage (pH 2.5) [178]. Drinking cola is not necessary if itraconazole is taken in liquid form due to the low pH of the solution.

Itraconazole, 200 mg/day orally, was used in 40 cases of keratomycosis (19 caused by F. solani and 15 by Aspergillus spp). The Aspergillus infections responded particularly well to the treatment [179, 180]. Similar results were obtained in a patient with Aspergillus keratitis who was treated with itraconazole, 400 mg/day, plus topical amphotericin B [181]. In a case of keratomycosis caused by S. brevicaulis, the fungus was resistant to amphotericin B but sensitive to itraconazole [182]; however, despite a dose of 200 mg twice daily, the case required penetrating keratoplasty. In a case of scleritis caused by A. flavus, itraconazole finally induced resolution after the condition had failed to respond to oral ketoconazole and topical amphotericin B [183]. P. boydii , on the other hand, proved resistant (MIC?50 mg/l) [150]. Corneal penetration of topical itraconazole has been studied in the rabbit [184].

2.3.5

Fluconazole

This triazole antifungal drug, which has been available since the mid1980s, is suitable for systemic (200–400 mg/day) as well as topical use. It is marked by low plasma protein binding and good pharmacokinetics [135, 185–187]. Experimental studies have shown that after systemic administration fluconazole penetrates the eye [188, 189] and the cerebrospinal fluid [161, 190, 191]. The concentration in the aqueous humor of patients 2 h after an oral dose of 200 mg were 2–7 and 5.4 lg/ml (mean, 3.7×2.17 lg/ml), measured by high-performance liquid chromatography [192]. In 1 case of P. boydii endophthalmitis, the drug concentration in the vitreous humor was 55% of the plasma level [193]. Following oral doses of 400 mg/day, concentrations of fluconazole were 15 lg/ml in the vitreous humour and 19 lg/ml in the plasma [194].

Although the in vitro activity of fluconazole is little if any better than that of other imidazole derivatives [195, 196], the in vivo results are far more favorable [197–200], so that fluconazole, with its low incidence of side eVects, is now regarded as a drug of choice for susceptible organisms [11, 159, 177, 201–203]. Sensitive pathogens include in particular C. albicans and Crypto-

Table 2.9. Use of fluconazole 0.2% drops (2 mg/ml)

•Aspirate a dose of the infusion solution Diflucan Ô (100 mg of fluconazole/50 ml) into a syringe under sterile conditions and instill directly into the conjunctival sac

•Diflucan may also be transferred, under sterile conditions, to eye-drop bottles; store in a refrigerator

coccus spp. Another major use is in the prevention of invasive candidiasis [201]. In a study comparing the eYcacy of fluconazole and amphotericin B plus flucytosine in 40 surgical patients with systemic candidiasis, the median elimination time of the pathogens was 8.5 days in the fluconazole group and 5.5 days in the combination group. Side eVects necessitating a change of therapy occurred twice in the combination group. The cure rates did not diVer between the 2 regimens [10].

Following widespread use of fluconazole, drug resistance is developing, particularly in non-C. albicans species [204, 205]. In addition, fluconazole is not suYciently active against Aspergillus spp. Interactions with other drugs and hormones are considerably less marked than those of ketoconazole, however, and in addition the compound causes few adverse eVects and is well tolerated [187].

Systemic fluconazole has been successfully used in Candida endophthalmitis [126, 194, 206–218]. Oral fluconazole has also been used successfully in Cryptococcus laurenti endophthalmitis [219].

Fluconazole 0.2% eye-drops (table 2.9) are well tolerated [Behrens-Bau- mann 1990, unpubl.data]. The use of an ophthalmic gel is recommended at night (table 2.10). Due to its good water solubility, fluconazole penetrates well into the deep corneal stroma and into the aqueous humor. Experimental data (pharmacokinetics, keratomycoses and endophthalmitis) are described in chapter 7.

2.3.6

Econazole, Voriconazole and Other Azole Antifungal Agents

2.3.6.1

Econazole

Econazole has been recommended as 1% eye-drops or ointment for the treatment of keratomycoses caused by Fusarium spp., Penicillium spp. or Aspergillus spp. [57, 220]. It shows marked activity in vitro against C. albicans and

Table 2.10. Preparation of fluconazole 0.2% gel

•The proportions are hypromellose (Methocel Ô E 4 M premium), 0.3 g, Diflucan i.v. solution to 10.0 g

•Transfer the Diflucan under sterile conditions to a 50-ml bottle and heat to about 50 ºC

•Mix with Methocel and shake well

•Allow the gel to cool in a refrigerator before transferring it to sterile eye-ointment tubes

•Store in the refrigerator no longer than 3 days

is the most eVective of the azoles against Fusarium spp., though it is less potent than natamycin [79]. In vivo, however, it was ineVective in 2 cases of Fusarium keratitis [221].

2.3.6.2

Voriconazole

Voriconazole (UL-109,496), a novel broad-spectrum azole, has been shown to be eVective in vitro against filamentous and dimorphic fungi including Aspergillus spp., Fusarium spp., P. boydii , Rhizopus spp., S. schenckii , B. dermatitis, Histoplasma spp., Paecilomyces spp., C. parapsiloris, C. krusei and C. albicans. The MIC values were similar to or lower than those of itraconazole or amphotericin B [222]. These results were confirmed by other studies including C. glabrata and C. krusei , which are inherently resistant to fluconazole [223, 224]. The drug was highly eVective after oral administration in systemic cryptococcosis as well as in aspergillosis and candidiasis in guinea pigs [225–229]. In man, voriconazole had good activity in chronic invasive aspergillosis, against acute invasive aspergillosis and in oropharyngeal candidiasis [229–231]. Visual disturbances (enhanced brightness of light or blurred vision) have been reported but were fully reversible, sometimes with continuing administration of the study drug [229–231].

2.3.6.3

Saperconazole and Thiabendazole

Saperconazole is highly eVective against Aspergillus spp. in vitro as well as against C. albicans [79, 232]. The pharmacokinetics after topical, subconjunctival and oral administration have been investigated in rabbits. Peak levels following subconjunctival injection in normal corneas (12.91×2.02 lg/g) were

approximately twofold greater than those following sustained topical administration (6.19×0.16 lg/g) and in debrided corneas were one-third higher than those following topical therapy in nondebrided corneas. Clearance was almost complete by 8 h. Levels following oral administration were low and probably subtherapeutic in all ocular tissues that were evaluated [233]. One case of Fusarium keratitis failed to respond to saperconazole [221]. Thiabendazole [57, 77, 234, 235] is no longer used.

2.4

Miscellaneous Antifungal Agents

A history of antifungal agents used in the past is provided by Gale [236]. These agents include silver sulphadiazine 1% [237], potassium iodide 1 g/ml [129, 238–240], and cycloheximide 0.02% [241]. Phenylmercury nitrate, 2 mg/ 100 ml, was used in vitro as a fungicide against Aspergillus spp., Scedosporium spp. and C. albicans [242].

Antiseptic agents have also been investigated (chlorhexidine, povidoneiodine, propamidine and polyhexamethylene biguanide) [243]. Chlorhexidine and povidone-iodine were the most eVective in vitro, but in a small in vivo pilot study, chlorhexidine gave better results than povidone-iodine. In another study chlorhexidine gluconate 0.2% was significantly superior over natamycin in a masked randomized clinical trial with 60 patients [244]. This conclusion has been confirmed recently [245].

Terbinafine is one of a new generation of antifungal drugs that is eVective in the treatment of dermatophyte infections. It is an allyl amine that inhibits the enzyme squalene epoxidase in fungal cell membranes. Terbinafine proved successful in 5 nonimmunocompromised cases of bronchopulmonary aspergillosis, in contrast with amphotericin B, itraconazole, and miconazole [246]. A case of pulmonary P. boydii infection refractory to itraconazole also responded to oral terbinafine [246]. White spots on the retina of monkeys and dyschromatopsia in one patient have been reported as side eVects [247].

Benomyl (methyl-1-butylcarbomoyl)-1-benzimidazole carbamate, is a fungicide that is widely used on many commercial food crops and ornamental plants. The compound has produced ocular and craniocerebral malformations, including retinal dysplasia, cataracts, microphthalmia and anopthalmia [248].

Pradimicins, a novel class of broad-spectrum antifungal compounds, are currently undergoing preclinical and phase I clinical trials. The pramidicin BMS-181184 has in vitro antifungal activity against Candida spp., C. neoformans, Aspergillus spp. and zygomycetes, whereas Fusarium spp. are comparatively resistant [249].

Table 2.11. Recommended drugs for fungal infections of the eye

2.5

Recommended Drugs for Fungal Infections

The drugs currently recommended for use against various fungal infections are shown in table 2.11. These recommendations are based on the current literature as cited.

References

1Campbell, G.D., Using amphotericin B. Intern. Med., 1982. 3: p. 95–102.

2Forster, R.K., Fungal diseases. 1983: Little, Brown.

3Gallis, H.A., R.H. Drew and W.W. Pickard, Amphotericin B. 30 years of clinical experience. Rev. Infect. Dis., 1990. 12: p. 308–329.

4Hamilton-Miller, J.M.T., Fungal sterols and the mode of action of the polyene antibiotics. Adv. Appl. Microbiol., 1974. 17: p. 109–134.

5Kobayashi, G.S. and G. MedoV, Antifungal agents. Recent developements. Ann. Rev. Microbiol., 1977. 31: p. 291–308.

6MedoV, G. and G.S. Kobayashi, Strategies in the treatment of systemic fungal infections. New Engl. J. Med., 1980. 302: p. 145–155.

7Newcomer, V.D., T.H. Sternberg, E.T. Wright and R.M. Reisner, Infectious diseases: Current states of amphotericin B in the treatment of the systemic fungus infections. J. Chronic Dis., 1959. 9:

p.353–374.

8Walsh, T.J., Recent advances in the treatment of systemic fungal infections. Meth. Find. Exptl. Clin. Pharmacol., 1987. 9: p. 769–778.

9Walsh, T.J. and A. Pizzo, Treatment of systemic fungal infections. Recent progress and current problems. Eur. Clin. Microbiol. Infect. Dis., 1988. 7: p. 460–475.

10Kujath, P., K. Lerch, P. Kochendo¨rfer and C. Boos, Comparative study of the eYcacy of fluconazole versus amphotericin B/flucytosine in surgical patients with systemic mycoses. Infect, 1993. 21:

p.376–82.

11Saag, M., W. Powderly, G. Cloud, P. Robinson, M. Grieco, U. Toazon, J. Fisher, N. Hyslop, J. Jacobson, R. Hafner and W. Dismukes, Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. New Engl. J. Med., 1992. 326:

p.83–89.

12Fisher, M.A., G.H. Talbot, G. Maislin, M.A.B.P.M. Keon, K.P. Tynan and B.L. Strom, Risk factors for amphotericin-B associated nephrotoxicity. Am. J. Med., 1989. 87: p. 547–552.

13Maddux, M.S. and S.L. Barriere, A review of complications of amphotericin B therapy. Recommendations for prevention and management. Drug. Intell. Clin. Pharm., 1980. 14: p. 177–181.

14Branch, R.A., Prevention of amphotericin B induced renal impairment. Arch. Intern. Med., 1988.

148:p. 2389–2394.

15Heidemann, H.T. and K.H. Brune, Verhinderung der Amphotericin-B-Nephrotoxizita¨t durch parenteral verabreichtes Flucytosin. Therapiewoche, 1987. 37: p. 4158–4166.

16Kirsh, R., R. Goldstein, J. TarloV, D. Parris, J. Hook, N. Hanna, P. Bugelski and G. Poste, An emulsion formulation of amphotericin B improves the therapeutic index when treating systemic murine candidiasis. J. Infect. Dis., 1988. 158: p. 1065–1070.

17Bo¨hme, A. and D. Hoelzer, Liposomal amphotricin B as early empiric antimycotic therapy of pneumonia in granulocytopenic patients. Mycoses, 1996. 39: p. 419–426.

18Adler-Moore, J.P. and R.T. ProYtt, Entwicklung, Charakterisierung, Wirksamkeit und Wirkungsmodus von Ambisome, einer unilamellaren Liposom-Formulierung von Amphotericin B. J. Liposom. Res., 1993. 3: p. 429–450.

19Heinemann, V., B. Kahny, A. Debus, K. Wachholz and U. Jehn, Pharmacokinetics of liposomal amphotericin B (AmBisome) versus other lipid-based formulations. Bone Marrow Transplant, 1994. Suppl. 5: p. S8–S9.

20Anaissie, E., V. Paetznick, R. ProYtt, J. Adler-Moore and G.P. Bodey, Comparison of the vitro antifungal activity of free and liposome-encapsulated amphotericin B. Eur. J. Clin. Microbiol. Infect. Dis., 1991. 10: p. 665–668.

21Tollemar, J. and O. Ringden, Early pharmacokinetic and clinical results from a noncomparative multicentre trial of amphotericin B encapsulated in a small unilamellar liposome (AmBisome). Drug. Invest., 1992. 4: p. 232–238.

22Chavanet, P.Y., I. Garry, N. Charlier, D. Caillot, J.P. Kistermann, M. D’Athis and H. Portier, Trial of glucose versus fat emulsion in preparation of amphotericin for use in HIV infected patients with candidiasis. Br. Med. J., 1992. 305: p. 921–925.

23Moreau, P., N. Milpied, N. Fayette, J. Ramee and J. Harousseau, Reduced renal toxicity and improved clinical tolerance of amphotericin B mixed with intralipid compared with conventional amphotericin B in neutropenic patients. J. Antimicrob. Chemother., 1992. 30: p. 535–541.

24Caillot, D., O. Casasnovas, E. Solary, P. Chavanet, B. Bonnotte, G. Reny, F. Entezam, J. Lopez,

A.Bonnin and H. Guy, EYcacy and tolerance of an amphotericin B lipid (Intralipid) emulsion in the treatment of candidaemia in neutropenic patients. J. Antimicrob. Chemother., 1993. 31: p. 161–169.

25Scho¨Vski, P., R. Wunder, D. Petersen, G. Schumann, B.S.U. Hertenstein, A. Ganser and M. Freund, Aphotericin B in intralipid. No evidence of improved toxicity profile, results of a randomized phase II-trial in neutropenic patients. Proc. Intersec. Conf. Antimicrobial., 1996. 36: p. 287.

26Ranchere, J., J. Latour, C. Fuhrmann, C. Lagallarde and F. Loreuil, Amphotericin B intralipid formulation. Stability and particle size. J. Anti. Chemoth., 1996. 37: p. 1165–1169.

27Herbrecht, R., Safety of amphotericin B colloidal dispersion. Eur. J. Clin. Microbiol. Infect. Dis., 1997. 16: p. 74–80.

28Fisher, J.F., A.T. Taylor, J. Clark and R. Rao, Penetration of amphotericin B into the human eye.

J.Infect. Dis., 1983. 147: p. 164.

29O’Day, D.M., W.S. Head, R.D. Robinson and W.H. Stern, Intraocular penetration of systemically administered antifungal agents. Curr. Eye. Res., 1985. 4: p. 131–134.

30Neppert, B., R. GuthoV and H.T. Heidemann, Endogene Candida-Endophthalmitis bei einem Drogenabha¨ngigen. intraveno¨se Therapie mit liposomal verkapseltem Amphotericin B. Klin. Mbl. Augenheilk., 1992. 201: p. 122–124.

31AVelt, J.C., H.W. Flynn, R.K. Forster, S. Mandelbaum, J.G. Clarkson and G.D. Jarns, Microbial endophthalmitis resulting from ocular trauma. Ophthalmology, 1987. 94: p. 407–413.

32Gallo, J., J. Playfair, J. Gregory-Roberts, H. Grunstein, P. Clifton-Bligh and F. Billson, Fungal endophthalmitis in narcotic abusers. Med. J. Austr., 1985. 142: p. 386–388.

33Gilbert, C.M. and M.A. Novak, Successful treatment of postoperative Candida endophthalmitis in an eye with intraocular lens implant. Am. J. Ophthal., 1984. 97: p. 593–595.

34Hammer, M.E., S. Harding and P. Wynn, Post-traumatic fungal endophthalmitis caused by Exophiala jeanselmei . Ann. Ophthal., 1983. 15: p. 853–855.

35Ho, P.C., F.I. Tolentino and A.S. Baker, Successful treatment of exogenous aspergillus endophthalmitis. A case report. Br. J. Ophthal., 1984. 68: p. 412–415.

36Lance, S.E., T.R. Friberg and R.P. Kowalski, Aspergillus flavus endophthalmitis and retinitis in an intravenous drug abuser. Ophthalmology, 1988. 95: p. 947–949.

37Malton, M.L., J.S. RinkoV, B.S. Doft and J.S. Kennerdell, Cryptococcal endophthalmitis associated with acute psychosis and exudative retinal detachment. Am. J. Ophthal., 1987. 104: p. 438– 439.

38Perraut Jr, L.E., L.E. Perraut, B. Bleiman and J. Lyons, Successful treatment of Candida albicans endophthalmitis with intravitreal amphotericin B. Arch. Ophthal., 1981. 99: p. 1565–1567.

39Peyman, G.A., C.P. Carroll and M. Raichand, Prevention and Management of Traumatic Endophthalmitis. Ophthalmology, 1980. 87: p. 320–324.

40Pflugfelder, S.C., H.W. Flynn, T.A. Zwickey, R.K. Forster, A. Tsiligianni, W.W. Culbertson and

S.Mandelbaum, Exogenous Fungal Endophthalmitis. Ophthalmol, 1988. 95: p. 19–30.

41Pulido, J.S., R. Folberg, K.D. Carter and P. Coonan, Histoplasma capsulatum endophthalmitis after cataract extraction. Ophthalmology, 1990. 97: p. 217–220.

42Rowsey, J.J., T.E. Acers, D.L. Smith, J.A. Mohr, D.L. Newsom and J. Rodriguez, Fusarium oxysporum endophthalmitis. Arch. Ophthal., 1979. 97: p. 103–105.

43Stransky, T.J., Postoperative endophthalmitis secondary to Candida parapsilosis: a case treated by vitrectomy and intravitreous therapy. Retina, 1981. 1: p. 179–185.

44Doft, B.H., J. Weiskopf, I. Nilsson-Ehle and L.B. Wingard, Amphotericin clearance in vitrectomized versus nonvitrectomized eyes. Ophthalmol., 1985. 92: p. 1601–1605.

45Stern, G.A., C.L. Fetkenhour and R.B. O’Grady, Intravitreal amphotericin B treatment of candida endophthalmitis. Arch. Ophthal., 1977. 95: p. 89–93.

46Behrens-Baumann, W., R. Ru¨chel, O. Zimmermann and M. Vogel, Candida tropicalis endophthalmitis following penetrating keratoplasty. Br. J. Ophthal., 1991. 75: p. 565.

47Chapman, F., K. Orr, W. Armitage and D. Cottrell, Candida glabrata endophthalmitis following penetrating keratoplasty. Br. J. Ophthalmol., 1998. 82: p. 712–713.

48Zadok, D. and J. Karpuch, Treatment of multiple corneal abscesses with fluconazole. Clin. Infect. Dis., 1994. 18: p. 482–484.

49Bell, R.W. and J.P. Ritchey, Subconjunctival nodules after amphotericin B injection. Medical therapy for Aspergillus corneal ulcer. Arch. Ophthal., 1973. 90: p. 402–404.

50Anderson, B.A. and E.W. Chick, Mycokeratitis: Treatment of fungal corneal ulcers with amphotericin B and mechanical debridement. South. Med. J., 1963. 56: p. 270–274.

51Bo¨ke, W. and H. Thiel, Zur konservativen Therapie der Hypopyonkeratitis und des Hornhautabszesses. Klin. Monatsbl. Augenheilkd., 1973. 163: p. 125–131.

52Chin, G.N., R.A. Hyndiuk, G.P. Kwasny and R.O. Schultz, Keratomycosis in Wisconsin. Am. J. Ophthal., 1975. 79: p. 121–125.

53Fine, B.S., Mycotic keratitis. 1965: Butterworths.

54Forster, R.K., G. Rebell and L.A. Wilson, Dematiaceous fungal keratitis. Clinical isolates and management. Br. J. Ophthal., 1975. 59: p. 372–376.

55Francois, J. and M. Rijsselaere, Keratomycoses. Ophthalmologica, 1979. 179: p. 32–41.

56Hamann, K.U., Exogene keratitis durch Chromomykose. Klin. Mbl. Augenheilk., 1977. 170: p. 89–94.

57Jones, B.R., Principles in the management of oculomycosis. Trans. Am. Acad. Ophthal. Otolaryng., 1975. 79: p. 15–53.

58Jones, D.B., Opportunistic fungal infections in ophthalmology. Fungal keratitis. 1975: Charles Thomas.

59Marchlewitz, M., Amphotericin B-Behandlung einer Keratomykose, verursacht durch Aspergillus fumigatus. Klin. Mbl. Augenheilk., 1965. 146: p. 146–147.

60Matsumoto, T. and N. Soejima, Keratomycosis. Mykosen, 1976. 19: p. 217–222.

61Ozawa, K. and H. Tuchihiru, Successful treatment of keratomycosis due to Scopulariopsis brevicaulis by topical amphotericin-B. Report of a case. Jap. J. Clin. Ophthal., 1985. 39: p. 1289–1292.

62Polack, F.M., H.E. Kaufman and E. Newmark, Keratomycosis. Arch. Ophthal., 1971. 85: p. 410–416.

63Schubert, E., Pilzinfektionen des Auges. Klin. Mbl. Augenheilk., 1970. 156: p. 391–394.

64Teoh, G.H., C.S. Yow and T.S. Soo-Hoo, Fungal keratitis. A case report of Aspergillus infection of the cornea. Singapore Med. J., 1982. 23: p. 42–45.

65Viallefont, H., C. Boudet, R.M. Philippot and J. Costeau, Aspergillose corne´enne. Essai de traitement par amphote´ricine B. Bull. Soc. Ophthal. Fr., 1964. 64: p. 658–660.

66Wood, T.O. and W. Williford, Treatment of keratomycosis with amphotericin B 0.15%. Am. J. Ophthal., 1976. 81: p. 847–849.

67Chaddah, M.R. and D.C. Agarwal, Treatment of keratomycosis with amphotericin B ointment. Ind. J. Ophthal., 1978. 26: p. 9–11.

68Hirose, H., H. Terasaki, S. Awaya and T. Yasuma, Treatment of fungal corneal ulcers with amphotericin B ointment. Am. J. Ophthalmol., 1997. 124: p. 836–38.

69O’Day, D.M., W.A. Ray, R.D. Robinson, W.S. Head and T.E. Williams, DiVerencez in response in vitro to amphotericin B among Candida albicans strains. Invest. Ophthalmol. Vis. Sci., 1991. 32:

p.1569–1572.

70Sekhon, A.S., Sensitivity of Scopulariopsis brevicaulis to some antimicrobial agents. Mycopathologia, 1975. 57: p. 177–179.

71Lotery, A.J., J.R. Kerr and B.A. Page, Fungal keratitis caused by Scopulariopsis brevicaulis. Successful treatment with topical amphotericin B and chloramphenical without the need for surgical debridement. Br. J. Ophthalmol., 1994. 78: p. 730–731.

72Miller, G.R., G. Rebell and R.C. Magoon, Intravitreal antimycotic therapy and the cure of mycotic endophthalmitis caused by a Paecilomyces lilacinus contaminated pseudophakos. Ophthalmic Surg., 1978. 9: p. 54–63.

73Minogue, M.J., T.J. Playfair, J.C. Gregory-Roberts and L.P. Robinson, Cure of paecilomyces endophthalmitis with multiple intravitreal injections of amphotericin B. Arch. Ophthalmol., 1989. 107:

p.1281.

74Searl, S.S., I.J. Udell, A. Sadun, N.E. Hyslop, D.M. Albert and K.R. Kenyon, Aspergillus keratitis with intraocular invasion. Ophthalmology, 1981. 88: p. 1244–1250.

75Savir, H., E. Henig and N. Lehrer, Exogenous mycotic infections of the eye adnexa. Ann. Ophthalmol., 1978. 10: p. 1013–1018.

76Raab, W., Pimaricin, ein Antibioticum gegen Pilze und Trichomonaden. Arzneim.-Forsch., 1967.

17:p. 538.

77Clayton, Y.M., Antifungal drugs for oculomycosis. II. Sensitivity of certain ocular fungi to antifungal drugs. Trans. Ophthal. Soc. U.K., 1970. 89: p. 837–844.

78Stern, G.A., In vitro antibiotic synergism against ocular fungal isolate. Am. J. Ophthal., 1978. 86: p. 359–367.

79Robinson, N., R. Penland and S.M. Osato, Comparative eYcacy of new azole antifungal agents against human ocular isolates. Invest. Ophthalmol. Vis. Sci., 1990. 31 Suppl: p. 451.

80Forster, R.K. and G. Rebell, The diagnosis and management of keratomycoses. I. Cause and diagnosis. II. Medical and surgical management. Arch. Ophthal., 1975. 93: p. I 975–978 II 1134–1136.

81Jones, D.B., R. Sexton and G. Rebell, Mycotic keratitis in South-Florida. A review of thirty nine cases. Trans. Ophthal. Soc. U.K., 1969. 89: p. 781–797.

82Jones, D.B., R.K. Forster and G. Rebell, Fusarium solani keratitis treated with natamycin pimaricin. Arch. Ophthal., 1972. 88: p. 147–154.

83Luque, A.G., R. Nanni and B.J. de Bracalenti, Mycotic keratitis caused by Curvularia lunata var. aeria. Mycopathologia, 1986. 93: p. 9–12.

84Malik, S.R.K. and S. Mitter, Medical treatment in keratomycosis. Indian J. Ophthal., 1979. 27: p. 190–192.

85Mitsui, Y., S. Kitano, Y. Uchida, N. Tanaka, S. Kobayashi, H. Tokuda, M. Ooishi, K. Shimada, J. Hara and H. Shiota, Clinical evaluation of pimaricin in the treatment of mycotic infections of the cornea. Nippon Ganka Gakkai Zasshi, 1982. 86: p. 2213–2223.

86Newmark, E., A.C. Ellison and H.E. Kaufman, Pimaricin therapy of cephalosporium and fusarium keratitis. Am. J. Ophthal., 1970. 69: p. 458–466.

87Newmark, E., H.E. Kaufman, F.M. Polack and A.C. Ellison, Clinical experience with pimaricin therapy in fungal keratitis. South. Med. J., 1971. 64: p. 935–941.

88O’Day, D.M., T.E. Moore and S.B. Aronson, Deep fungal corneal abscess. Combined corticosteroid therapy. Arch. Ophthalmol., 1971. 86: p. 414–419.

89Rosa, R.H., D. Miller and E.C. Alfonso, The changing spectrum of fungal keratitis in South Florida. Ophthalmol., 1994. 101: p. 1005–1013.

90Johns, K. and D.M. O’Day, Pharmacologic management of keratomycoses. Surv. Ophthalmol., 1988. 33: p. 178–188.

91Minogue, M.J., I.C. Francis, P. Quatermass, M.B. Kappagoda, R. Bradbury, R.S. Walls and P.I. Motum, Successful treatment of fungal keratitis caused by Paecilomyces liiacinus. Am. J. Ophthal., 1984. 98: p. 626–627.

92Kozarsky, A.M., R.D. Stulting, G.O. Waring, F.M. Cornell, L.A. Wilson and H.D. Cavanach, Penetrating keratoplasty for exogenous Paecilomyces keratitis followed by postoperative endophthalmitis. Am. J. Ophthal., 1984. 98: p. 552–557.

93Cuendet, J.F. and A. Nouri, Traitement local en ophtalmologie par un nouvel antibiotique fungicide, la ‘pimaricine’. Ophthalmologica (Basel), 1963. 145: p. 297–300.

94De Rooy, A.J.P.M., Pimaricin, a new fungistatic. Ophthalmologica (Basel), 1961. 141: p. 489.

95Dieckhues, B., Die Behandlung der Keratomykose mit Nystatin und Pimaricin. Klin. Mbl. Augenheilk., 1966. 148: p. 895–896.

96Hollwich, F. and B. Dieckhues, Die Keratomykose-eine Spa¨tkomplikation der Hornhautentzu¨ndung. Klin. Mbl. Augenheilk., 1970. 156: p. 395–401.

97Qadripur, S.A. and P.F. Krauss, Mykotisch ulcero¨se keratitis durch Aspergillus fumigatus. Mykosen, 1972. 15: p. 483–489.

98Suie, T. and W.H. Havener, Mycology of the eye. A review. Am. J. Ophthal., 1963. 56: p. 63–77.

99Reddy, P.R., P.S. Reddy, A.R. Reddy and N.K. Saboo, A comparative evaluation of nystatin, amphotericin B and miconazole in keratomycosis. Ind. J. Ophthal., 1982. 30: p. 249–250.

100Jelenkiewicz, J., A case of corneal candidiasis. Klin. Oczna, 1965. 35: p. 447–449.

101Neustein, I., P.P. Bonomo and R.B. Mattos Jr, EVect of nystatin in corneal infection by Candida albicans. Arq. Bras. Oftalmol., 1971. 34: p. 40–42.

102Roberts, S.S., Nystatin in monilia keratoconjunctivitis. Am. J. Ophthal., 1957. 44: p. 108–109.

103Rosen, R. and A.H. Friedman, Successfully treated postoperative Candida parakrusei endophthalmitis. Amer. J. Ophthal., 1973. 76: p. 574.

104Abboud, I.A. and L.S. Hanna, Ocular fungus. Report of two cases. Br. J. Ophthal., 1970. 54: p. 477–483.

105Casero, L., Queratomicosis, su aumento en los ultimos anos y su tratamiento con los nuevos antibioticos antifungosos. Arch. Soc. Oftalmol. Hispano-Americana, 1962. 1: p. 293–300.

106McGrand, J.C., Keratomycosis due to Aspergillus fumigatus cured by nystatin. Trans. Ophthal. Soc. U.K., 1970. 89: p. 799–802.

107Prasad, S. and H.V. Nema, Mycotic infections of cornea. (Drug sensitivity study). Ind. J. Ophthal., 1982. 30: p. 81–85.

108Richards, A.B., B.R. Jones, J. Whitwell and Y.M. Clayton, Corneal and intra-ocular infection by Candida albicans treated with 5-fluorocytosine. Trans. Ophthal. Soc. U.K., 1970. 89: p. 867–885.

109Segal, E., A. Romano, E. Eylan and R. Stein, Experimental and clinical studies of 5-fluorocytosine activity in Candida ocular infections. I. In vitro activity of 5-fluorocytosine on Candida species isolated from ocular infections. Chemotherapy, 1975. 21: p. 358–366.

110Dermoumi, H., Antimykotika – Empfindlichkeit bei klinisch bedeutsamen Hefen und Schimmelpilzen im Hemmhoftest. Mykosen, 1982. 25: p. 109–117.

111Normark, S. and J. Scho¨nebeck, In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrob. Agents Chemother., 1972. 2: p. 114–121.

112Brod, R.D., H.W. Flynn, J.G. Clarkson, S.C. Pflugfelder, W.W. Culbertson and D. Miller, Endogenous Candida endophthalmitis. Ophthalmology, 1990. 97: p. 666–674.

113Carney, M.D., J.L. Combs and W. Waschler, Cryptococcal choroiditis. Retina, 1990. 10: p. 27–32.

114Doft, B.H., J.G. Clarkson, G. Rebell and R.K. Forster, Endogenous Aspergillus endophthalmitis in drug abusers. Arch. Ophthal., 1980. 98: p. 859–862.

115Francis, P. and T.J. Walsh, Evolving role of flucytosine in immunocompromised patients: New insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis 1992;15:1003–1018.

116Edwards Jr, J.E., R.I. Lehrer, E.R. Stiehm, T.J. Fischer and L.S. Young, Severe candidal infections. Clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann. Int. Med., 1978. 89: p. 91–106.

117Firkin, F.C., Therapy of deep-seated fungal infections with 5-fluorocytosine. Aust. N.Z. J. Med., 1974. 4: p. 462–467.

118Greene, W.H. and P.H. Wiernik, Candida endophthalmitis. Am. J. Ophthal., 1972. 74: p. 1100–1104.

119Hanish, S.J., J.C. Perlmutter and C. Boucher, Exogenous Aspergillus endophthalmitis. Ann. Ophthal., 1984. 16: p. 417–419.

120Hiss, P.W., J.A. Shields and J.J. Augsburger, Solitary retinovitreal abscess as the initial manifestation of cryptococcosis. Ophthalmology, 1988. 95: p. 162–165.

121Holland, G., Endogenous Candida endophthalmitis. Ophthalmol., 1990. 97: p. 672–674.

122Keller, F., W. Waller and M. Augst, Problematik und Therapie von Organund Systemmykosen unter besonderer Beru¨cksichtigung einer Augenmykose. Mykosen, 1981. 24: p. 5–16.

123Kinyoun, J.L., Treatment of Candida endophthalmitis. Retina, 1982. 2: p. 215–222.

124Martenet, A.C. and H. Wildberger, Die Soorendophthalmitis und ihre Behandlung. Klin. Mbl. Augenheilk., 1976. 168: p. 137–140.

125Meyers, B.R., T.W. Liebermann and A.P. Ferry, Candida endophthalmitis complicating candidemia. Ann. Intern Med., 1973. 79: p. 647–653.

126Schrader, W., Endogene Candidaendophthalmitis: Fru¨hzeitige Diagnose und fru¨hzeitige Vitrektomie verbessern die Prognose. Fortschr. Ophthal., 1990. 87: p. 331–335.

127Shields, I.A., D.M. Wright, J.J. Augsburger and M. Wolkowicz, Cryptococcal chorioretinitis. Am. J. Ophthal., 1980. 89: p. 210–218.

128Sorrell, T., C. Dunlop, P. Collignon and J. Harding, Exogenous ocular candidiasis associated with intravenous heroin abuse. Br. J. Ophthalmol., 1984. 68: p. 841–845.

129Cohen, J., Antifungal chemotherapy. Lancet, 1982: p. 532–537.

130Romano, A., E. Segal, E. Eylan and R. Stein, Treatment of external ocular Candida infections with 5-fluorocytosine. Ophthalmologica (Basel), 1976. 172: p. 282–286.

131Graf, K., U¨ ber einen Fall von Keratomycosis der menschlichen Hornhaut, hervorgerufen durch Candida albicans. Klin. Mbl. Augenheilkd., 1963. 142: p. 579–581.

132Fitzsimons, R. and A.L. Peters, Miconazole and ketoconazole as a satisfactory first-line treatment for keratomycosis. Am. J. Ophthal., 1986. 101: p. 605–608.

133Ishibashi, Y., Oral ketoconazole therapy for keratomycosis. Am. J. Ophthal., 1983. 95: p. 342–345.

134Raab, W., Mykosebehandlung mit Imidazolderivaten. 1978: Springer Verlag.

135Fromtling, R.A., Overview of medically important antifungal azole derivative. Clin. Microbiol. Rev., 1988. 1: p. 187–217.

136Graybill, J.R., New antifungal agents. Eur. J. Clin. Microbiol. Infect. Dis., 1989. 8: p. 402–421.

137Denning, D.W., Azole resistance in Candida. Eur. J. Clin. Microbiol. Infect. Dis., 1997. 16: p. 261– 280.

138Gilbert, M.L., M.S. Osato and K.R. Wilhelmus, Ocular toxicity of topical clotrimazole preparations.

J.Tox. Cut. Ocul. Tox., 1987. 6: p. 3–7.

139Jones, B.R. and A.B. Richards, Clotrimazole in the treatment of ocular infection by Aspergillus fumigatus. Postgraduate Med. J., 1974(July Suppl.): p. 39–45.

140Neuhann, T., Clotrimazol in der Behandlung von Keratomykosen. Klin. Mbl. Augenheilk., 1976.

169:p. 459–462.

141Swietliczkowa, I., E. Szusterowska-Martinowa and W. Braciak, Clinical evaluation of 1% cloteimazol ointment in the treatment of corneal mycoses. Klin. Oczna, 1984. 86: p. 221–223.

142Darcis-Dubois, C. and J.F. Weekers, Keratomycose. Diagnose und Therapie. Contactologia, 1985.

7:p. 175–176.

143Forster, R., Endophthalmitis. Duane‘s Clinical Ophthalmology, ed. W. Tasman and E. Jaeger. Vol. 4. 1992: Lippincott Company Philadelphia. p. 1–21.

144Foster, C.S., Miconazole therapy for keratomycosis. Am. J. Ophthal., 1981. 91: p. 622–629.

145Perry, H.D. and E.D. Dounenfeld, Cryptococcus keratitis after keratoplasty. Am. J. Ophthal., 1990.

110:p. 320–321.

146Mohan, M., A. Panda and S.K. Gupta, Management of human keratomycosis with miconazole. Aust. N. Z. J. Ophthalmol., 1989. 17: p. 295–297.

147Simonsz, H.J., Keratomycosis caused by Acremonium recifei , treated with keratoplasty, miconazole and ketoconazole. Doc. Ophthal., 1983. 56: p. 131–135.

148DelPrete, A., G. Sepe, M. Ferrante, C. LoVredo, M. Masciello and A. Sebastiani, Fungal keratitis due to Scopularopsis brevicaulis in an eye previously suVering from herpetic keratitis. Ophthalmologica, 1994. 208: p. 333–335.

149Mason, J.O. and J.S. Parker, Subconjunctival miconazole and anterior segment blastomycosis. Am. J. Ophthalmol., 1993. 116: p. 506–507.

150Bloom, P.A., D.A. Laidlaw, D.L. Easty and D.W. Warnock, Treatment failure in a case of fungal keratitis caused by Pseudallescheria boydii . Br. J. Ophthalmol., 1992. 76: p. 367–368.

151Ishibashi, Y. and Y. Matsumoto, Intravenous miconazole in the treatment of keratomycosis. Am.

J.Ophthal., 1984. 97: p. 646–647.

152Ishibashi, Y., Y. Matsumoto and K. Takei, The eVects of intravenous miconazole on fungal keratitis. Am. J. Ophthal., 1984. 98: p. 433–437.

153Anderson, R.L., T.F. Carroll, J.T. Harvey and M.G. Myers, Petriellidium (Allescheria) boydii orbital and brain abscess treated with intravenous miconazole. Am. J. Ophthalmol., 1984. 97: p. 771–775.

154Jones, D.B., Therapy of postsurgical fungal endophthalmitis. Ophthalmology, 1978. 85: p. 357–373.

155Blumenkranz, M.S. and D.A. Stevens, Therapy of endogenous fungal endopthalmitis. Miconazole or amphotericin B for coccidioidal and candidal infection. Arch. Ophthalmol., 1980. 98: p. 1216–1220.

156Sung, J.P. and J.G. Grendahl, Side eVects of miconazole for systemic mycoses. New Engl. J. Med., 1977. 297: p. 786–787.

157Heel, R.C., R.N. Brogden, G.E. Paker, T.M. Speight and G.S. Avery, Miconazole: A preliminary review of its therapeutic eYcacy in systemic fungal infections. Drugs, 1980. 19: p. 7–30.

158Fainstein, V. and G.P. Bodey, Cardiorespiratory toxicity due to miconazole. Ann. Int. Med., 1980.

93:p. 432–433.

159Meunier, F., Zukunftsperspektiven der antimykotischen Therapie. Mycoses, 1994. 37 Suppl.2: p. 77– 82.

160Vantyle, J.H., Ketoconazole-mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy, 1984. 4: p. 343–373.

161Stevens, D.A., The new generation of antifungal drugs. Eur. J. Clin. Microbiol. Infect. Dis., 1988.

7:p. 732–735.

162Ishibashi, Y. and Y. Matsumoto, Oral ketoconazole therapy for experimental Candida albicans keratitis in rabbits. Sabouraudia, 1984. 22: p. 323–330.

163Weiss, J.L. and W.T. Parker, Candida albicans endophthalmitis following penetrating keratoplasty. Arch. Ophthal., 1987. 105: p. 173.

164Komadina, T.G., T.D.I. Wilkes, J.P. Shock, W.C. Ulmer, J. Jackson and R.W Bradsher, Treatment of Aspergillus fumigatus keratitis in rabbits with oral and topical ketoconazole. Am. J. Ophthal., 1985. 99: p. 476–479.

165Goodman, D.F. and W.H. Stern, Oral ketoconazole and intraocular amphotericin B for treatment of postoperative Candida parapsilosis endophthalmitis. Arch. Ophthal., 1987. 105: p. 172–173.

166Sud, I.J. and D.S. Feingold, EVect of ketoconazole on the fungicidal action of amphotericin B in Candida albicans. Antimicrob. Agents Chemother., 1983. 23: p. 185–187.

167Sawy, A.F.E., O.M. Asfour, W.M. Yousef and M. Refai, Schimmelpilze in gesunden und kranken Augen und lokale Behandlung von mykotischer Keratitis mit Ketoconazol-Augentropfen. Hautnah, 1990. 4: p. 48–51.

168Torres, M.A., J. Mohamed, H. Cavazos-Adame and L.A. Martinez, Topical ketoconazole for fungal keratitis. Am. J. Ophthal., 1985. 100: p. 293–298.

169Arning, M. and C. Aul, Mykose-Prophylaxe bei neutrozytopischen Patienten. Mycoses, 1994. 37 Suppl. 2: p. 70–76.

170Cauwenbergh, G., Pharmakokinetik von Itraconazol. Mycoses, 1994. 37 Suppl. 2: p. 27–33.

171Petropoulou, T., J. Liese, K. Tintelnot, M. Gahr and B.H. Belohradsky, Langzeitbehandlung mit Itraconazol zur Prophylaxe von Aspergillus-Infektionen bei Patienten mit chronischer Granulomatose (CGD). Mycoses, 1994. 37 Suppl 2: p. 64–69.

172Kreisel, W., Therapie invasiver Aspergillosen mit Itraconazol: Eigene Erfahrungen und Literatur- u¨bersicht. Mycoses, 1994. 37 Suppl. 2: p. 42–51.

173Martino, P., Die Behandlung der invasiven Aspergillose. Mycoses, 1994. 37 Suppl. 2: p. 20–26.

174Massry, G.G., A. Hornblass and W. Harrison, Itraconazole in the treatment of orbital aspergillosis. Ophthalmol., 1996. 103: p. 1467–1470.

175Negroni, R. and A.I. Arechavala, Itraconazole. Pharmacokinetics and Indications. Arch. Med. Res., 1993. 24: p. 387–393.

176Negroni, R., A.M. Robles, A. Arechavala and A. Taborda, Itraconazole in human histoplasmosis. Mykosen, 1989. 32: p. 123–130.

177Just-Nu¨bling, G., Die Therapie der Candidose und Cryptococcose bei AIDS. Mycoses, 1994. 37 Suppl. 2: p. 56–63.

178Jaruratanasirikul, S. and A. Kleepkaew, Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur. J. Clin. Pharmacol., 1997. 52: p. 235–237.

179Thomas, P.A., D.J. Abraham, C.M. Kalavathy and J. Rajasekaran, Oral itraconazole therapy for mycotic keratitis. Mykosen, 1988. 31: p. 271–279.

180Thomas, P.A. and J. Rajasekaran, Treatment of Aspergillus keratitis with imidazoles and related compounds. 1988: Plenum Press.

181Villard, C., C. Lacroix, M.H. Rabot, J.C. Rovira and J.L. Jacquemin, Ke´ratomycose aspergillaire se´ve`re traite´e par itraconazole per os. J. Fr. Ophtalmol., 1989. 12: p. 323–325.

182Ragge, N.K., J.C.D. Hart, D.L. Easty and A.G. Tyers, A case of fungal keratitis caused by Scopulariopsis brevicaulis. Treatment with antifungal agents and penetrating keratoplasty. Br. J. Ophthal., 1990. 74: p. 561–562.

183Carlson, A.N., G.N. Foulks, J.R. Perfect and J.H. Kim, Fungal scleritis after cataract surgery. Cornea, 1992. 11: p. 151–154.

184Guzek, J., J. Roosenberg, D. Gano and I. Wessels, The eVect of vehicle on corneal penetration of triurated ketoconazole and itraconazole. Ophthalmic. Surg. Lasers, 1998. 29: p. 926–929.

185Washton, H., Review of fluconazole. A new triazole antifungal agent. Diagn. Microbiol. Infect. Dis., 1989. 12: p. 229S–233S.

186Brammer, K.W., P.R. Farrow and J.K. Faulkner, Pharmacokinetics and tissue penetration of fluconazole in humans. Rev. Infect. Dis., 1990. 12 Suppl. 1: p. 318–326.

187Grant, S.M. and S.P. Clissold, Fluconazole. Drugs, 1990. 39: p. 877–916.

188O’Day, D.M., G. Foulds, T.E. Williams, R.D. Robinson, R.H. Allen and W.S. Head, Ocular uptake of fluconazole following oral administration. Arch. Ophthal., 1990. 108: p. 1006–1008.

189Savani, D.V., J.R.P.L.M. Cobo and D.T. Durack, Penetration of new azole compounds into the eye and eYcacy in experimental Candida endophthalmitis. Antimicrob. Agents Chemother., 1987. 31:

p.6–10.

190Arndt, C.A.S., T.J. Walsh, C.L. McCully, F.M. Balis, P.A. Pizzo and D.G. Poplack, Fluconazol penetration into cerebrospinal fluid. Implications for treating fungal infections of the central nervous system. J. Infect. Dis., 1988. 157: p. 178–180.

191Perfect, J.R., D.V. Savani and D.T. Durack, Comparison of itraconazole and fluconazole in treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob. Agents Chemother., 1986. 29: p. 579–583.

192Aust, R., F.E. Kruse, A. Wildfeuer, G. PfaV, K. Rohrschneider and H.E. Vo¨lcker, Fluconazolspiegel im Kammerwasser nach oraler WirkstoVgabe beim Menschen. Ophthalmologe, 1995. 92: p. 829–832.

193Pfeifer, J.D., G. Grand, M.A. Thomas, A.R. Berger, M.J. Lucarelli and M.E. Smith, Endogenous Pseudallescheria boydii endophthalmitis. Arch. Ophthalmol., 1991. 109: p. 1714–1717.

194Urbak, S.F. and T. Degn, Fluconazole in the treatment of Candida albicans endophthalmitis. Acta Ophthalmol., 1992. 70: p. 528–529.

195Hughes, C.E. and W.H. Beggs, Action of fluconazole (UK 49,858) in relation to other systemic antifungal azoles. J. Antimicrob. Chemother., 1987. 19: p. 171–174.

196Odds, F.C., S.L. Cheesman and A.B. Abbott, Antifungal eVects of fluconazole (UK 49,858), a new triazole antifungal, in vitro. J. Antimicrob. Chemother., 1986. 18: p. 473–478.

197Richardson, K., K.W. Brammer, M.S. Marriott and P.F. Troke, Activity of UK 49,858, a bis-triazole derivate, against experimental infections with Candida albicans and trichophyton mentagrophytes. Antimicrob. Agents Chemother., 1985. 27: p. 832–835.

198Rogers, T.E. and J.N. Galgiani, Activity of fluconazole (UK 49,858) and ketoconazole against Candida albicans in vitro and in vivo. Antimicrob. Agent. Chemother., 1986. 30: p. 418–422.

199Troke, P.F., R.J. Andrews, K.W. Brammer, M.S. Marriott and K. Richardson, EYcacy of UK49,858 (Fluconazole) against Candida albicans experimental infections in mice. Antimicrob. Agents Chemother., 1985. 28: p. 815–818.

200Troke, P.F., R.J. Andrews, M.S. Marriott and K. Richardson, EYcacy of fluconazole (UK-49,858) against experimental aspergillosis and cryptococcosis in mice. J. Antimicrob. Chemother., 1987. 19:

p.663–670.

201Meunier, F., Die Therapie der invasiven Candidosen. Mycoses, 1994. 37 Suppl.2: p. 52–55.

202Phillips, P., S. Shafran, G. Garber, C. Rotstein, F. Smaill, I. Fong, I. Salit, M. Miller, K. Williams, J.M. Conley, J. Singer and S. Ioannou, Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients. Eur. J. Clin. Microbiol. Infect. Dis., 1997. 16: p. 337–345.

203Urbak, S.F. and T. Degn, Fluconazole in the management of fungal ocular infections. Ophthalmologica, 1994. 208: p. 147–156.

204Parkinson, T., D.J. Falconer and C.A. Hitchcock, Fluconazole resistance due to energy-dependent drug eZux in Candida glabrata. Antimicrob. Agents Chemother., 1995. 39: p. 1696–1699.

205Nguyen, M.H., J.E. Peacock, Jr., A.J. Morris, D.C. Tanner, M.L. Nguyen, D.R. Syndman, M.M. Wagener, M.G. Rinaldi, V.L. Yu, The changing face of candidemia. Emergence of non-Candida albicans species and antifungal. Am. J. Med., 1996. 100(6): p. 617–623.

206Van’t Wout, J.W., H. Mattie and R. van Furth, A prospective study of the eYcacy of fluconazole (UK–49,858) against deep-seated fungal infections. J. Antimicrob. Chemother., 1988. 21: p. 665–672.

207Fera, G., A.M. Maci, O. Schiraldi, P. Auteri and S. Santoro, Chorioretinitis caused by Candida albicans with systemic candidiasis in a patient with acquired immunodeficiency syndrome: Results of a treatment with fluconazole. Curr. Ther. Res., 1991. 49: p. 1103–1107.

208Laatikainen, L., M. Tuominen and K. von DickhoV, Treatment of endogenous fungal endophthalmitis with systemic fluconazole with or without vitrectomy. Am. J. Ophthalmol., 1992. 113: p. 205–207.

209Luttrull, J.K., W.L. Wan, B.M. Kubak, M.D. Smith and H.A. Oster, Treatment of ocular fungal infections with oral fluconazole. Am. J. Ophthalmol., 1995. 119: p. 477–481.

210Palacio, A.D., M.S. Cuetara, M. Ferro, E. Perez-Blazquez, J.A. Lopez-Sana, M.P. Roiz, D. Carnevali and A.R. Noriega, Fluconazole in the management of endophthalmitis in disseminated candidosis of heroin addicts. Mycoses, 1993. 36: p. 193–199.

211Zarbin, M.A., E. Becker, J. Witcher, A. Yamani and A.R. Irvine, Treatment of presumed fungal endophthalmitis with oral fluconazole. Ophthalmic Surg. Laser, 1996. 27: p. 628–631.

212Guex-Crosier, Y., J.P. Chave and C.P. Herbort, Postpartum Candida endophthalmitis treated with fluconazole. Ophthalmologica, 1993. 206: p. 214–215.

213Mistlberger, A. and B. Graf, Endogene Candida-Endophthalmitis. Eine neue Therapie. Klin. Mbl. Augenheilk., 1991. 199: p. 446–449.

214Chung, Y.M., J.C. Lin and J.H. Liu, Endogenous Candida endophthalmitis. A case report. Chung Hua I Hsueh Tsa (Taipei), 1994. 53: p. 239–242.

215Henderson, T., Bilateral endogenous Candida endophthalmitis and chorioretinitis following toxic megacolon. Eye, 1996. 10: p. 755–756.

216Borne, M., Ocular fluconazole treatment of Candida parapsilosis endophthalmitis after failed intravitreal amphotericin B. Arch. Ophthalmol., 1993. 111: p. 1326.

217Akler, M.E., H. Vellend, D.M. McNeely, S.L. Walmsley and W.L. Gold, Use of fluconazole in the treament of candidal endophthalmitis. Clin. Infect. Dis., 1995. 20(3): p. 657–664.

218KauVman, C.A., S.F. Bradley and A.K. Vine, Candida endophthalmitis associated with intraocular lens implantation. EYcacy of fluconazole therapy. Mycoses, 1993. 36: p. 13–17.

219Custis, P.H., J.A. Haller and E.D. Juan Jr, An unusual case of cryptococcal endophthalmitis. Retina, 1995. 15: p. 300–304.

220Mahashabde, S., M.C. Nahata and U. Shrivastava, A comparative study of anti-fungal drugs in mycotic corneal ulcer. Indian J. Ophthal., 1987. 35: p. 149–152.

221Kuriakose, T. and P.A. Thomas, Keratomycotic malignant glaucoma. Ind. J. Ophthal., 1991. 39: p. 118–121.

222Espinel-IngroV, A., Evaluation of the in vitro activity of the new triazole voriconazole against opportunistic filamentous and dimorphic fungi. 36. ICAAC (Abstract) (Poster F 84), 1996.

223Hitchcock, C.A., R.J. Andrews, B.G.H. Lewis and P.F. Troke, UK–109,496: A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Antifungal activity in experimental infections with cryptococcus. 35. ICAAC, 1995 Nr. 2740 (Pfizer), 1995.

224Richardson, K., A.S. Bell, R.P. Dickinson, S. Narayanaswami and S.J. Ray, UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections. Synthesis and SAR. Abstract No. ohne (Pfizer GmbH), 1996.

225Hitchcock, C., R.J. Andrews, B.G.H. Lewis and P.F. Troke, UK-109,496: A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Antifungal activity in experimental infections with Aspergillus. Abstract No. 2741 (Poster F74) 35th Interscience Conference on Antimicrobial Agents and Chemotherapy San Francisco, 1996.

226Hitchcock, C.A., G.W. Pye, G.P. Oliver and P.F. Troke, UK-109,496. A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Antifungal activity and selectivity in vitro. Abstract No. 2739(35. ICAAC 1995 F 72), 1996.

227Andrews, R.J., C.A. Hitchcock and B.G. Lewis, A novel, wide-spectrum triazole derivate for the treatment of fungal infections. Antifungal activity in experimental infections with Aspergillus. 35. ICAAC 1995 Abstract No.F74 (Pfizer), 1995.

228Andrews, R.J., C.A. Hitchcock, B.G.H. Lewis and P.F. Troke, UK-109,496. A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Antifungal activity in experimental infections with Cryptococcus. Abstract No. 2740 (Poster F 75) 35th Interscience Conference on Antimicrobial Agents and Chemotherapy San Francisco 1995, 1996.

229Troke, P.f., K.W. Brammer, C.A. Hitchcock, N. Sarantis and S. Yonren, UK-109,496. A novel, widespectrum triazole derivate for the treatment of fungal infections. Activity in systemic candidiasis models and early clinical eYcacy in oropharyngeal candidiasis. Abstract No. 2737 35. ICAAC 1995, F 73 (Pfizer GmbH), 1996.

230Dupont, B., D. Denning, H. Lode, N. Sarantis, P.F. Troke and S. Yonren, UK-109,496. A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Clinical eYcacy on chronic invasive aspergillosis. Interim analysis results. Abstract No.2735 35. ICAAC 1995, F81 (Pfizer GmbH), 1996.

231Denning, D.W., A. del Favero, E. Gluckman, D. Norfolk, M. Ruhnke, N. Sarantis and P.F.T.S. Yonren, UK-109,496. A novel, wide-spectrum triazole derivative for the treatment of fungal infections. Clinical eYcacy in acute invasive aspergillosis. Interim analysis results. Abstract No. 2734 (Pfizer GmbH)35.ICAAC 1995, F 80, 1996.

232Denning, D.W., L.H. Hanson and D.A. Stevens, In vitro activity of saperconazole (R66 905) compared with amphotericin B and itraconazole against Aspergillus species. Eur. J. Clin. Microbiol. Infect. Dis., 1990. 9: p. 693–697.

233O’Day, W. Head, R. Robinson, T. Williams and R. WolV, Ocular pharmacokinetics of saperconazole in rabbits. Arch. Ophthalmol., 1992. 110: p. 550–554.

234Robinson, H.J., O.E. Graessle, E.G. Lehman, K.L. Kelley, R.F. GeoVroy and C. Rosenblum, Ocular absorption of thiabendazole-14C by the rabbit. Am. J. Ophthal., 1966. 62: p. 710–715.

235Upadhyay, M.P., E.P. West and A.P. Sharma, Keratitis due to Aspergillus flavus successfully treated with thiabendazole. Br. J. Ophthal., 1980. 64: p. 30–32.

236Gale, G.R., Experimental chemotherapy of fungus infections. Lab. Invest., 1962. 11: p. 1209–1216.

237Mohan, M., S.K. Gupta, V.K. Kalra, R.B. Vajpayee and M.S. Sachdev, Topical silver sulphadiazine. A new drug for ocular keratomycosis. Br. J. Ophthal., 1988. 72: p. 192–195.

238Sykes, E.M., Fungus infections of the cornea. Texas State J. Med., 1946. 42: p. 330–332.

239Bell, R.W. and A.C. Ellison, Potassium iodide dosage levels. Am. J. Ophthal., 1970. 70: p. 151–152.

240Ellison, A.C. and E. Newmark, Potassium iodide in mycotic keratitis. Am. J. Ophthal., 1970. 69:

p.126–129, Erga¨nzung 70 (1970) 152.

241Lynn, J.R., Fusarium keratitis treated with cycloheximide. Am. J. Ophthal., 1964. 58: p. 637–641.

242Duhamel, C., S. Lemarinier, D. Barbiers, D. Perrine and P. Lecoq, Modifications induites in vitro par le nitrate de phenylmercure sur des champignons responsables de keratites. J. Fr. Ophtalmol., 1995. 18: p. 819–821.

243Dermoumi, H., In vitro susceptibility of fungal isolates of clinically important specimens to itraconazole, fluconazole and amphotericin B. Microbiology, 1994. 40: p. 92–98.

244Gunshefski, L., M.J. Mannis, J.S. Cullor, I.R. Schwab, J. Jaynes, L. Smith, E. Mabry and C.J. Murphy, In vitro antimicrobial activity of Shiva-11 against ocular pathogens. Cornea, 1994. 13:

p.237–242.

245Rahman, M., D. Minassian, M. Martin and G. Johnson, Trial of chlorhexidine gluconate for fungal corneal ulcers. Ophthalmic Epidemiol., 1997. 4: p. 141–149.

246Schiraldi, G., M. Colombo, S. Harari, S. Cicero, G. Ziglio, M. Ferrarese, D. Rossato and E. Soresi, Terbinafine in the treatment of non-immunocompromised compassionate cases of bronchopulmonary aspergillosis. Mycoses, 1996. 39: p. 5–12.

247Gupta, A., J. Gonder, N. Shear and G. Dilworth, The development of green vision in association with terbinafine therapy. Arch. Ophthalmol., 1996. 132: p. 845–846.

248Hoogenboom, E., J. Ransdell, W. Ellis, R. Kavlock and F. Zeman, EVects on the fetal rat eye of maternal benomyl exposure and protein malnutrition. Curr. Eye Res., 1991. 10: p. 601–612.

249Walsh, T.J. and N. Giri, Pradimicins. A novel class of broad-spectrum antifungal compounds. Eur. J. Clin. Microbiol. Infect. Dis., 1997. 16: p. 93–97.

250Koc, A.N., K. Erkilic, N. Evrensel and A. Coskun, A case of Alternaria keratitis treated with fluconazole. Eur. J. Clin. Microbiol. Infect. Dis., 1997. 16: p. 322–323.

251Valluri, S., R.S. Moorthy, P.E. Liggett and N.A. Rao, Endogenous Aspergillus endophthalmitis in an immunocompetent individual. Int. Opththalmol., 1993. 17: p. 131–135.

252Levin, L., R. Avery, J. Shore, J. Woog and A. Baker, The spectrum of orbital aspergillosis. A clinicopathologial review. Surv. Ophthalmol., 1996. 41: p. 142–154.

253Heier, J., T. Gardner, K. McGuire and J. Stock, Proptosis as the initial presentation of fungal sinusitis in immunocompetent patients. Ophthalmology, 1995. 102: p. 713–717.

254Gottlieb, J., I. McAllister, Fraco, F. Guttman and A. Vine, Choroidal blastomycosis. A report. Retina, 1995. 15: p. 248–252.

255Pye, G., G. Oliver and P. Troke, UK 109,496, a novel, widespectrum triazole derivative for the treatment of fungal infections. Antifungal activity and selectivity in vitro. (Pfizer GmbH) 35. Intersci. Antimicrob. Agents. Chemother., San Francisco 1995 Abstract Nr. /72, 1996.

256Hester, D.E., J.A. Kylstra and D.E. Eifrig, Isolated ocular cryptococcosis in an immunocompetent patient. Ophthalmic Surg., 1992. 23: p. 129–131.

257Dorey, S., D. Barrie and P.F.A.A.W. Barrie Fa¨lschlich, Fungal keratitis caused by curvularia lunata, with successful medical treatment. Eye, 1997. 11: p. 754–755.

258Barton, K., D. Miller and S.C. Pflugfelder, Corneal chromoblastomycosis. Cornea, 1997. 16: p. 235– 239.

259Dijstra, J.W.E., Histoplasmosis. Dermatol. Clin., 1989. 7: p. 251–258.

260Lehrer, R.I., D.H. Howard, P.S. Sypherd, J.E. Edwards, G.P. Segal and D.J. Winston, Mucormycosis. Ann. Int. Med., 1980. 93: p. 93–108.

261Ferry, A.P. and S. Abedi, Diagnosis and management of rhino-orbitocerebral mucormycosis (phycomycosis). Ophthalmol., 1983. 90: p. 1096–1104.

262Lee, B., H.E. Grossniklaus and A. Capone, Ovadendron sulphureo-ochraceum endophthalmitis after cataract surgery. Am. J. Ophthalmol., 1995. 119(3): p. 307–312.

263Kanungo, R. and R. Srinivasan, Corneal phaeophyphomycosis due to Exserohilum rostratum. Acta Ophthalmol. Scand., 1996. 74: p. 197–199.

264Ruben, S., Pseudallescheria boydii keratitis. Acta Ophthalmol, 1991. 69: p. 684–686.

265Nunery, W.R., M.G. Welsh and R.L. Saylor, Pseudallescheria boydii (Petriellidium boydii ) infection of the orbit. Ophthalmic Surg., 1985. 16: p. 296–300.

266Thomas, P.A., C.M. Kalavathy, D.J. Abraham, J. Rajasekaran, Oral ketoconazole in keratomycosis, Ind. J. Ophthal., 1987;35:197–203.