Oral than mid stroma with or without

Oral antifungal therapy is recommended in cases of
severe keratitis. Harrison et al described the grading of a corneal ulcer as
mild, moderate and severe on the basis of size and depth of ulcer, infiltrate
density and extent and  scleral
involvement.28 Severe ulcers are defined as >5mm in size, >50% depth
with dense infiltrates deeper than mid stroma with or without scleral
involvement.28Other indications of oral therapy include scleral or limbal
involvement, bilateral ulcers, endophthalmitis, pediatric cases, impending
perforation or perforated corneal ulcer, recalcitrant mycotic keratitis and
post keratoplasty cases.

 

The Eye Bank Association of America (EBAA) recently
released a report describing a statistically significant increased rate of post-keratoplasty
fungal infections of 0.023%. 16 Though the EBAA does not require routine fungal cultures of
donor corneoscleral rims, 29% of corneal surgeons have made this a routine
practice pattern. In a retrospective study analyzing 3,414 postkeratoplasty
cases, 5.6% of eyes receiving corneas from culture-positive donor corneoscleral
rims developed fungal keratitis and required surgical management to rid the
infection. Though not statistically significant, prophylactic antifungal
therapy resulted in a 7-fold decrease in the rate of postkeratoplasty fungal
infection. Considering the high predictive value of positive fungal cultures on
postkeratoplasty fungal endophthalmitis and the likelihood of needing surgical
intervention to treat these infections, we agree with the recommendation to
routinely perform fungal cultures on donor corneoscleral rims and initiate
prophylactic antifungal treatment for patients having undergone keratoplastycases
of culture-positive donor rims.114

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Some of the most commonly used systemic antifungals
are ketoconazole, itraconazole, fluconazole and more recently VCZ.18,19,39 Oral VCZ has been used as an adjunct to topical NTM in the
treatment of severe mycotic keratitis and is reported to have a high efficacy
in such cases.19,39

The subsequent discussion is about the systemic
antifungals. The detailed describtion of the individual clinical studies has
been elaborated in table. However, the important outcomes will be covered under
the individual drugs.

A.            
Ketoconazole

An imidazole derivative, which is lipophilic in nature,is
given in oral formulation (200–400 mg/day).105

1.             
Pharmacokinetics and
Pharmacodynamics

Ketoconazole (KCZ)is well absorbed with good tissue
distribution after oral administration with a peak concentration in serum of
2–3 ?g/ml 2–3 hr after 200-mg oral dose.105It is a weak dibasic agent and thus requires acidity (pH of
3) for dissolution and absorption. Oral bioavailability is maximal when the
tablets are taken with a meal while it is reduced in subjects with reduced gastric
acidity, such as subjects taking medications known as acid neutralizing
medicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors
(e.g. H2-receptor antagonists, proton pump inhibitors) or subjects with
achlorhydria caused by certain diseases.13 In vitro, the plasma protein binding is approximately  99% (mainly albumin). KCZ is widely
distributed into tissues; however, only a negligible proportion reaches the
cerebrospinal fluid.

Following absorption from the gastrointestinal tract,
it is converted into several inactive metabolites. In vitro studies have shown
that CYP3A4 is the major enzyme involved in the metabolism of KCZ.25 Elimination from plasma is biphasic with a half-life of 2
hours during the first 10 hours and 8 hours thereafter. Approximately 13% of
the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The
major route of excretion is through the bile into the intestinal tract with
about 57% being excreted in the feces. Coadministration of a number of CYP3A4
substrates such as dofetilide, quinidine cisapride and pimozide is
contraindicated. Coadministration with KCZ can cause elevated plasma
concentrations of these drugs and may increase or prolong both therapeutic and
adverse effects to such an extent that a potentially serious adverse reaction
may occur.25

Hemady et al found that orally administered KCZ resulted
in high corneal concentrations (45.0±7.6 ?g/g after 1 h) that were still
substantial 24 hrs later (55.0±7.0 ?g/g) in rabbits.36

2.             
Spectrum of action

Various in vitro studies demonstrate KCZactivity
against dermatophytes, yeasts including Candida spp., molds, dimorphic fungi with
limited action against filamentous fungi as well as some bacteria.25

3.             
Efficacy

The use of oral KCZ has been described by various
authors. 105 Ishibashi et al showed complete healing and regression of
fungal corneal ulcers in two cases Fusarium positive on culture after starting
oral KCZ as an adjunct to topical NTM.37Thomas et alfound that 60% of severe mycotic keratitis
responded to KCZ and advocated that 5% NTM with oral KCZ or itraconazole should
constitute primary therapy for severe keratitis.69Revathi et alevaluated the role of topical NTM 5% with and
without oral KCZ therapy in a randomized control trial and found no significant
difference between the two groups.89

4.             
Adverse reactions

The major adverse effect with oral KCZ is hepatotoxicity,
seen in3.6 – 4.2%cases. Liver and kidney function tests are monitored every 2
weeks. Other reported side effects include hyperglycemia/hypertension,
infertility in young people, QT prolongation, anaphylaxis, adrenal
insufficiency, gynaecomastia, anorexia, hyperlipidemia, increased appetite,
insomnia, nervousness, headache, dizziness, paresthesia, somnolence,
photophobia, orthostatic hypotension. Others include gastrointestinal
disorders: vomiting, diarrhea, nausea, constipation, abdominal pain, abdominal
pain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration,
hepatitis, jaundice. Skin and subcutaneous tissues disorders
include: erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus,
alopecia, xeroderma, malaise, edema peripheral, pyrexia, chills and decreased
platelet count.

B.            
Amphotericin B (AMB)

AMB is a polyene antifungal agent derived from Streptomyces nodosus. It interacts with
cell membrane ergosterol, disrupting the membrane function and causes pore
formation, leading to cell death. It is poorly soluble in water and highly
photosensitive so, should be stored in a dark and refrigerated place (2-8°C).63 Depending on the tissue concentration achieved, it can be
either fungistatic or fungicidal.47

1.             
Spectrum of action

AMB is a broad-spectrum agent and is active against
most of the fungi. It is highly active against Cryptococcus and Candida spp.The
Minimum inhibitory concentration (MIC) is reported to be higher for Scedosporiumspp
and Fusarium spp.66

2.             
Pharmacokinetics and
Pharmacodynamics

AMB is commonly available in its deoxycholate
formulation. It also has two lipid-based preparations: AMB lipid complex (ABLC)
and liposomal AMB (L-AMB). It is available in parenteral formulations only, due
to its insolubility and poor oral bioavailability. The lipid formulations
require higher dosage compared to conventional formulation to achieve similar
efficacy. The major advantage of these preparations is reduced renal tubular
cell binding, significantly reducing (10-fold to 20-fold) the chances of renal
toxicity.66

AMB accumulates mainly in liver and spleen with an
elimination t1/2 of > 15 days.  It is
not metabolized and only10% is excreted in urine or faeces. Since AMB is not
metabolized by hepatic CYP450 enzymes it has a very few drug–drug interactions.4,73

3.             
Side effects

Use of systemic AMB is limited due to its significant
toxicity. Common adverse effects include renal toxicity, electrolyte imbalance
and hepatotoxicity.66 The risk of renal toxicity is dose-dependent and can be
reduced by co-administration of intravenous fluid. Surprisingly, the rate of
nephrotoxicity is significantly lower in children and neonate. The lipid-based
formulations are associated with significantly less nephrotoxicity.73

C.             
Itraconazole

It is a triazole antifungal agent, which acts by
inhibition of cytochrome P450 enzymes thereby blocking the synthesis of
ergosterol in the cell membrane. Major advantage of triazoles over imidazoles
is that they are metabolized slowly with reduced side effects and broader
spectrum of action.63

1.             
Pharmacokinetics and
Pharmacodynamics

Orally it exhibits lower bioavailability, solubility
and penetration into ocular tissues than other azoles.63 Similar to KCZ, gastric absorption depends upon a low
pH.Itraconazole (ICZ) is available in the form of a capsule as well as oral
solution in combination with hydroxypropyl-b-cyclodextrin. Gastric absorption
of the capsule form is around 55%, which can be increased with gastric acidity
and food intake.51,112The oral solution has a greater absorption of around 80% and
is not affected by gastric acidity or food intake. A higher serum concentration
is achieved with solution form than the tablet.80ICZ is highly protein bound (99%) therefore  the ocular concentration has been reported to
be much lower than fluconazole and VCZ.42HenceICZ is usually not recommended for treatment of ocular
infections. ICZ is metabolized mainly by the CYP450 isoenzyme 3A4 and the
metabolites are excreted in both urine and feces.In cases of renal failure,
dose reduction is not required. However, since ICZ is metabolized in liver,
dose reduction is recommended in cases of hepatic impairment. 66

2.             
Spectrum of action

ICZ has been shown to be active against most Candida
spp, many Aspergillus spp and has minimal activity against Fusarium spp
and  Mucorales.14

3.             
Efficacy

Thomas et al reported that 22/40 cases of mycotic
keratitis healed with oral ICZ 200 mg daily for 17 days. In this study better
response to ICZ was observed in cases positive for Aspergillus spp.68 In a randomized controlled trial by Agrawal et al the role
of of oral ICZ in addition to topical ICZ was assessed in cases of mycotic
keratitis. Resolution was seen in 42 eyes (77%) while  12 eyes (22.2%) did not respond well. Four of
these 12 eyes were caused by Fusarium species showing poor efficacy of this
drug aginst Fusarium spp.1Bunya et al compared the efficacy of oral VCZ with oral
ICZ(conventional antifungal treatment) in severe keratomycosis and observed
that VCZ may offer a better efficacy with a faster resolution of infiltrates
than conventional agents.5

4.             
Side Effects

The common side effects of ICZ include rash, headache,
or gastrointestinal upset.Hepatotoxicity, and liver failure, is the most common
and serious side effect. These azole drugs are contraindicated in pregnancy due
to association with birth defects.66

D.            
Voriconazole

VCZis an antifungal agent belonging to the azoles
chemical family. VCZ (molecular weight 349.3 g/mol) is a lipophillic derivative
of fluconazole, differing by the addition of a methyl group on the propanolol
backbone and by the replacement of a triazole moiety by a fluoropyrimidine
ring. The mechanism of action has been described in Table 2.

1.             
Spectrum of activity

VCZ has a broad spectrum of action as compared to
other azoles. It is active against Candida, Cryptococcus spp and the dimorphic
fungal pathogens.53,76It also exhibits a potent activity against most Aspergillus
spp, including AMB–resistant Asp. terreus.22The spectrum of activity of VCZ also includes Fusarium spp
and Scedosporiumspp; however, activity against the Mucorales is minimal.It has
excellent in vitro activity with low MIC values against Candida and Aspergillus
species known to be resistant to AMB, fluconazole and itraconazole.76Activity against Fusarium species is  variable.

2.             
Pharmacokinetics and
Pharmacodynamics

VCZ formulated in capsules is rapidly absorbed with a
mean time to peak plasma concentration (Tmax) varying between 1.43 h (200 mg)
and 1.81 h (400mg).85The corresponding maximum plasma concentration (Cmax) was
1.88?g/mL (200 mg), 4.84 ?g/mL (300 mg) and 5.27?g/mL (400 mg) when determined
after 7 days of dosing. Oral bioavailability is high(approximately 90%) and
does not seem to vary significantly with its dose.85The plasma protein binding of VCZ is moderate (58%).86 It is metabolised in  liver, therefore liver enzymes need to be
monitored during therapy. It is recommended to take VCZ 1 hour before or 2 hours
after a meal due to its decreased absorption in acidic medium.

The total dose of VCZ (oral or i.v. administration) is
excreted in 48 hours, predominantly as metabolites (98%). VCZ (oral or i.v)
exhibits non-linear pharmacokinetics (i.e. dose-dependent clearance). Its
systemic bioavailability following oral administration is around 95% and the
highest plasma concentration of 6.1±1.4 ?g/mL is attained at 0.6 to 2.3 hours.86,91Hariprasad et al investigated the aqueous, vitreous
and plasma concentration of VCZin 14 patients scheduled for elective pars plana
vitrectomy following the administration of two 400mg doses of VCZ 12 hours
apart, prior to surgery. The mean plasma,vitreous and aqueous concentration
were 2.13?g/ml, 0.81?g/ml and 1.13?g/ml. All these exceeded the MIC90 for a
wide spectrum of yeasts and moulds.27

3.             
Efficacy

VCZ has been successfully used in various clinical
studies. Bunya et al evaluated the role of topical and oral VCZ in nine
patients with mycotic keratitis refractory to standard antifungal therapy. It
was reported that 71.4% of the patients healed. They concluded that VCZ is a
new, promising therapy for refractory mycotic keratitis.5 However, in a recent study by Parchand et al, it was
reported that there was no significant difference in the rate of healing,
duration of healing or visual outcome between oral and topical VCZ (group 1),
oral VCZ and topical NTM (group 2) and oral itraconazole and topical NTM (group
3) in mycotic keratitis. But the rate of resolution of hypopyon was faster
ingroup 1. 72

Recently, MUTT 2 trial, which compared the effect of
oral VCZ and oral placebo in severe filamentous mycotic keratitis, concluded
that there was no clinical benefit of adding oral VCZ to topical antifungal
agents. But in a subsequent subgroup analysis, favorable response was noted in
cases of severe Fusarium keratits after addition of oral VCZ to topical NTM.82

4.             
Side effects

Adverse effects of oral VCZ Includes visual
disturbances such as abnormal vision, color vision changes and photophobia.
Approximately 30% patients complain of transient visual changes beginning about
30 minutes after administration and subsiding in another 30 minutes. Uncommonly
transient visual hallucinations or confusion may occur. It can also cause skin
rashes, ECG changes like QT prolongation and fluoride associated bone toxicity.29Hepatotoxicity leading to elevated liver enzymes can also
occur.66

E.             
Fluconazole

Fluconazole (FCZ)is a first generation triazole
antifungal agent with an improved safety profile as compared to imidazole
compounds. Topical and subconjunctival preparations have been reported to be
beneficial in mycotic keratitis.69The mechanism of action has been described in table 2

1.             
Spectrum of action

FCZ is active against many Candida spp except Candida krusei.76 It has a narrow spectrum as compared to other triazoles with
resistance to filamentous fungi such as Aspergillus spp, Fusarium spp, Scedosporiumspp,
or the Mucorales.22,66

2.             
Pharmacokinetics and
pharmacodynamics

FCZ has a lower molecular weight and high aqueous
solubility as compared to other drugs. It has a high oral bioavailability
(90%), and absorption is not affected by gastric acidity or food.17Oral formulations of this drug include both  tablet and a powder for suspension. The
recommended dosage includes 100-200 mg/day for candidiasis. The long half- life
(approximately 30 hours) and high bioavailability allows for once daily dosage.66FCZ achieves a high concentration in ocular tissues and the central
nervous system. This is due to its low plasma protein binding capacity (10-20%)
and low lipophilicity.111FCZ is primarily cleared in kidney and around 66 to 76% is
secreted in urine. Thus, dose reduction is required in cases of renal
insufficiency.11It is not extensively metabolized in the liver so dose
adjustment is not required in hepatic insufficiency.

Savani et al reported that FCZ (intravenous) achieved
highest concentration in all ocular tissues as compared to oral KCZ and oral
ICZ in normal as well as inflamed eyes.92FCZ concentration in aqueous humor was reported to be 64% of
the plasma concentration. O’Day et al also confirmed good ocular penetration of
oral FCZ.67,40Aqueous humor and choroid levels were similar to
plasma levels whereas, corneal and vitreous levels were higher than the serum
concentration. Ocular penetration of oral FCZ has also been reported in humans
with endophthalmitis. They showed that it has good ocular penetrationwith aqueous
to serum concentration ratio being more than or equal to 80% at 4 to 24 hours.111

3.             
Efficacy

Oral fluconazole has been used successfully for
keratomycosis. Few case reports showed complete healing of mycotic keratitis
with administration of topical (0.2%) and oral fluconazole.111Thakar et al reported complete healing in a case of mycotic
keratitis with deep stromal abscess with oral fluconazole not responding to
topical NTM.104

4.             
Side effects

Common systemic side effects include gastririts,
headache, skin rashes. In some cases thrombocytopenia, Stevens-Jhonson syndrome
and hepatotoxicity have been reported.

F.             
Posconazole

Posconazole (PCZ) is a second-generation triazole
similar to VCZ. It is a synthetic structural analog of ICZ and has been used
successfully to treat mycotic keratitis either as a standalone therapy or with
other antifungal agents.3

1.             
Spectrum of action

PCZ is a broad-spectrum agent similar to VCZ and is
found to be active against most Candida spp.as well as fluconazole-resistant
isolates. It is also potent  against
filamentous fungi like Aspergillus spp,Fusarium spp and Mucorales.66

2.             
Pharmacokinetics and
Pharmacodynamics

PCZ is available in the form of oral suspension, a
delayed release tabletand an intravenous solution. Absorption depends upon food
intake and is maximum with high-fat meals.10The newer tablet formulation exhibits a pH-dependent polymer
matrix allowing for delayed drug release as well as once daily dosing.
Absorption of this tablet form is not influenced by food intake or gastric
acidity thereby, allowing for improved bioavailability (54%) and more reliable
serum concentrations.24Itis highly protein bound (98%) with poor penetration into
the cerebrospinal fluid and ocular compartments. PCZ is metabolizedmainly in
liver and is excreted throughbile and feces.Dose adjustment is not required in
cases of renal insufficiency but may be required in hepatic insufficiency. The
elimination half-life is 25 to 35 hours. 66

3.             
Efficacy

PCZ has been shown to be effective against mycotic
keratitis resistant to common antifungals like KCZ, FCZ and VCZ. Altun et al
reported successful healing in two cases of mycotic keratitis with topical
(4mg/0.1 ml) and oral PCZ (200mg four times daily), which were not responding
to conventional antifungal therapy (NTM, VCZ, uconazole, and AMB).3Cuenca-Estrella et al showed PCZ to be effective against
fungal isolates resistant to FCZ and ICZ.12Tu et al reported three cases of recalcitrant
Fusariumkeratitis treated successfully with PCZ.110Sponsel et al also reported complete healing with oral PCZ
200 mg 4 times daily and topical PCZ (100 mg/ml prepared from an oral solution)
in a case of Fusarium keratitis resistant to AMB and NTM.102

4.             
Side effects

PCZ has been shown to be well tolerated with long-term
use also. The most common side effects were fever, diarrhea, nausea, vomiting,
and headache. Others include hypokalemia, rash, thrombocytopenia, and abdominal
pain, elevated liver enzyme levels and hepatocellular damage.Some rare adverse
events include hemolytic uremic syndrome, pulmonary embolus, adrenal
insufficiency, thrombotic thrombocytopenic purpura,and hypersensitivity
reactions.23Prolongation of the QT interval may be seen with PCZ as well
as with the other triazole antifungals.

G.            
Echinocandins

The echinocandins are a class of semisynthetic
lipopeptides which act by disrupting the fungal cell wall by inhibiting the
synthesis of b-1,3 glucan, a fungal cell wall polysaccharide.66 This results in its fungicidal activity for Candida spp,
whereas a fungistatic effect for Aspergillus spp.Caspofungin, micafungin, and
anidulafungin are the main echinocandins, which display a potent activity
against many Candida spp, as well as Aspergillus spp.These agents are poorly
absorbed through the gastrointestinal system and are thus available in
parenteral formulations only. They have along half-life of 10–26 hours which
allows for its once daily dosing. They have a limited distribution to the
central nervous system and ocular tissues leading to a low tissue
concentration.

Though, topical caspofungin (0.5, 1%) has been
reported to be beneficial in refractory mycotic keratitis; intravenous form has
been used successfully in cases of endophthalimitis. 74Echinocandins are generally well tolerated with very few side
effects. The most common side effects include headache, gastrointestinal upset,
elevation of liver (aminotransferase) tests, or mild infusion reaction.66