Oral than mid stroma with or without

Oral antifungal therapy is recommended in cases ofsevere keratitis. Harrison et al described the grading of a corneal ulcer asmild, moderate and severe on the basis of size and depth of ulcer, infiltratedensity and extent and  scleralinvolvement.28 Severe ulcers are defined as >5mm in size, >50% depthwith dense infiltrates deeper than mid stroma with or without scleralinvolvement.28Other indications of oral therapy include scleral or limbalinvolvement, bilateral ulcers, endophthalmitis, pediatric cases, impendingperforation or perforated corneal ulcer, recalcitrant mycotic keratitis andpost keratoplasty cases.  The Eye Bank Association of America (EBAA) recentlyreleased a report describing a statistically significant increased rate of post-keratoplastyfungal infections of 0.023%.

16 Though the EBAA does not require routine fungal cultures ofdonor corneoscleral rims, 29% of corneal surgeons have made this a routinepractice pattern. In a retrospective study analyzing 3,414 postkeratoplastycases, 5.6% of eyes receiving corneas from culture-positive donor corneoscleralrims developed fungal keratitis and required surgical management to rid theinfection. Though not statistically significant, prophylactic antifungaltherapy resulted in a 7-fold decrease in the rate of postkeratoplasty fungalinfection.

Considering the high predictive value of positive fungal cultures onpostkeratoplasty fungal endophthalmitis and the likelihood of needing surgicalintervention to treat these infections, we agree with the recommendation toroutinely perform fungal cultures on donor corneoscleral rims and initiateprophylactic antifungal treatment for patients having undergone keratoplastycasesof culture-positive donor rims.114Some of the most commonly used systemic antifungalsare ketoconazole, itraconazole, fluconazole and more recently VCZ.18,19,39 Oral VCZ has been used as an adjunct to topical NTM in thetreatment of severe mycotic keratitis and is reported to have a high efficacyin such cases.

19,39The subsequent discussion is about the systemicantifungals. The detailed describtion of the individual clinical studies hasbeen elaborated in table. However, the important outcomes will be covered underthe individual drugs.A.            Ketoconazole An imidazole derivative, which is lipophilic in nature,isgiven in oral formulation (200–400 mg/day).

1051.             Pharmacokinetics andPharmacodynamics Ketoconazole (KCZ)is well absorbed with good tissuedistribution after oral administration with a peak concentration in serum of2–3 ?g/ml 2–3 hr after 200-mg oral dose.105It is a weak dibasic agent and thus requires acidity (pH of3) for dissolution and absorption. Oral bioavailability is maximal when thetablets are taken with a meal while it is reduced in subjects with reduced gastricacidity, such as subjects taking medications known as acid neutralizingmedicines (e.g. aluminum hydroxide) and gastric acid secretion suppressors(e.g.

H2-receptor antagonists, proton pump inhibitors) or subjects withachlorhydria caused by certain diseases.13 In vitro, the plasma protein binding is approximately  99% (mainly albumin). KCZ is widelydistributed into tissues; however, only a negligible proportion reaches thecerebrospinal fluid.

Following absorption from the gastrointestinal tract,it is converted into several inactive metabolites. In vitro studies have shownthat CYP3A4 is the major enzyme involved in the metabolism of KCZ.25 Elimination from plasma is biphasic with a half-life of 2hours during the first 10 hours and 8 hours thereafter. Approximately 13% ofthe dose is excreted in the urine, of which 2 to 4% is unchanged drug. Themajor route of excretion is through the bile into the intestinal tract withabout 57% being excreted in the feces. Coadministration of a number of CYP3A4substrates such as dofetilide, quinidine cisapride and pimozide iscontraindicated. Coadministration with KCZ can cause elevated plasmaconcentrations of these drugs and may increase or prolong both therapeutic andadverse effects to such an extent that a potentially serious adverse reactionmay occur.25Hemady et al found that orally administered KCZ resultedin high corneal concentrations (45.

0±7.6 ?g/g after 1 h) that were stillsubstantial 24 hrs later (55.0±7.

0 ?g/g) in rabbits.362.             Spectrum of action Various in vitro studies demonstrate KCZactivityagainst dermatophytes, yeasts including Candida spp., molds, dimorphic fungi withlimited action against filamentous fungi as well as some bacteria.253.             EfficacyThe use of oral KCZ has been described by variousauthors.

105 Ishibashi et al showed complete healing and regression offungal corneal ulcers in two cases Fusarium positive on culture after startingoral KCZ as an adjunct to topical NTM.37Thomas et alfound that 60% of severe mycotic keratitisresponded to KCZ and advocated that 5% NTM with oral KCZ or itraconazole shouldconstitute primary therapy for severe keratitis.69Revathi et alevaluated the role of topical NTM 5% with andwithout oral KCZ therapy in a randomized control trial and found no significantdifference between the two groups.894.

             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 2weeks. Other reported side effects include hyperglycemia/hypertension,infertility in young people, QT prolongation, anaphylaxis, adrenalinsufficiency, gynaecomastia, anorexia, hyperlipidemia, increased appetite,insomnia, nervousness, headache, dizziness, paresthesia, somnolence,photophobia, orthostatic hypotension. Others include gastrointestinaldisorders: vomiting, diarrhea, nausea, constipation, abdominal pain, abdominalpain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration,hepatitis, jaundice. Skin and subcutaneous tissues disordersinclude: erythema multiforme, rash, dermatitis, erythema, urticaria, pruritus,alopecia, xeroderma, malaise, edema peripheral, pyrexia, chills and decreasedplatelet count. B.            Amphotericin B (AMB)AMB is a polyene antifungal agent derived from Streptomyces nodosus. It interacts withcell membrane ergosterol, disrupting the membrane function and causes poreformation, leading to cell death. It is poorly soluble in water and highlyphotosensitive so, should be stored in a dark and refrigerated place (2-8°C).

63 Depending on the tissue concentration achieved, it can beeither fungistatic or fungicidal.471.             Spectrum of actionAMB is a broad-spectrum agent and is active againstmost of the fungi.

It is highly active against Cryptococcus and Candida spp.TheMinimum inhibitory concentration (MIC) is reported to be higher for Scedosporiumsppand Fusarium spp.662.             Pharmacokinetics andPharmacodynamics AMB is commonly available in its deoxycholateformulation.

It also has two lipid-based preparations: AMB lipid complex (ABLC)and liposomal AMB (L-AMB). It is available in parenteral formulations only, dueto its insolubility and poor oral bioavailability. The lipid formulationsrequire higher dosage compared to conventional formulation to achieve similarefficacy.

The major advantage of these preparations is reduced renal tubularcell binding, significantly reducing (10-fold to 20-fold) the chances of renaltoxicity.66AMB accumulates mainly in liver and spleen with anelimination t1/2 of > 15 days.  It isnot metabolized and only10% is excreted in urine or faeces.

Since AMB is notmetabolized by hepatic CYP450 enzymes it has a very few drug–drug interactions.4,733.             Side effectsUse of systemic AMB is limited due to its significanttoxicity. Common adverse effects include renal toxicity, electrolyte imbalanceand hepatotoxicity.

66 The risk of renal toxicity is dose-dependent and can bereduced by co-administration of intravenous fluid. Surprisingly, the rate ofnephrotoxicity is significantly lower in children and neonate. The lipid-basedformulations are associated with significantly less nephrotoxicity.

73C.             ItraconazoleIt is a triazole antifungal agent, which acts byinhibition of cytochrome P450 enzymes thereby blocking the synthesis ofergosterol in the cell membrane. Major advantage of triazoles over imidazolesis that they are metabolized slowly with reduced side effects and broaderspectrum of action.

631.             Pharmacokinetics andPharmacodynamics Orally it exhibits lower bioavailability, solubilityand penetration into ocular tissues than other azoles.63 Similar to KCZ, gastric absorption depends upon a lowpH.Itraconazole (ICZ) is available in the form of a capsule as well as oralsolution in combination with hydroxypropyl-b-cyclodextrin. Gastric absorptionof the capsule form is around 55%, which can be increased with gastric acidityand food intake.51,112The oral solution has a greater absorption of around 80% andis not affected by gastric acidity or food intake.

A higher serum concentrationis achieved with solution form than the tablet.80ICZ is highly protein bound (99%) therefore  the ocular concentration has been reported tobe much lower than fluconazole and VCZ.42HenceICZ is usually not recommended for treatment of ocularinfections. ICZ is metabolized mainly by the CYP450 isoenzyme 3A4 and themetabolites 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. 662.             Spectrum of actionICZ has been shown to be active against most Candidaspp, many Aspergillus spp and has minimal activity against Fusarium sppand  Mucorales.143.             EfficacyThomas et al reported that 22/40 cases of mycotickeratitis healed with oral ICZ 200 mg daily for 17 days. In this study betterresponse to ICZ was observed in cases positive for Aspergillus spp.68 In a randomized controlled trial by Agrawal et al the roleof of oral ICZ in addition to topical ICZ was assessed in cases of mycotickeratitis.

Resolution was seen in 42 eyes (77%) while  12 eyes (22.2%) did not respond well. Four ofthese 12 eyes were caused by Fusarium species showing poor efficacy of thisdrug aginst Fusarium spp.

1Bunya et al compared the efficacy of oral VCZ with oralICZ(conventional antifungal treatment) in severe keratomycosis and observedthat VCZ may offer a better efficacy with a faster resolution of infiltratesthan conventional agents.54.             Side Effects The common side effects of ICZ include rash, headache,or gastrointestinal upset.Hepatotoxicity, and liver failure, is the most commonand serious side effect. These azole drugs are contraindicated in pregnancy dueto association with birth defects.66D.            VoriconazoleVCZis an antifungal agent belonging to the azoleschemical family. VCZ (molecular weight 349.

3 g/mol) is a lipophillic derivativeof fluconazole, differing by the addition of a methyl group on the propanololbackbone and by the replacement of a triazole moiety by a fluoropyrimidinering. The mechanism of action has been described in Table 2.1.             Spectrum of activityVCZ has a broad spectrum of action as compared toother azoles. It is active against Candida, Cryptococcus spp and the dimorphicfungal pathogens.

53,76It also exhibits a potent activity against most Aspergillusspp, including AMB–resistant Asp. terreus.22The spectrum of activity of VCZ also includes Fusarium sppand Scedosporiumspp; however, activity against the Mucorales is minimal.It hasexcellent in vitro activity with low MIC values against Candida and Aspergillusspecies known to be resistant to AMB, fluconazole and itraconazole.76Activity against Fusarium species is  variable. 2.             Pharmacokinetics andPharmacodynamics VCZ formulated in capsules is rapidly absorbed with amean time to peak plasma concentration (Tmax) varying between 1.

43 h (200 mg)and 1.81 h (400mg).85The corresponding maximum plasma concentration (Cmax) was1.88?g/mL (200 mg), 4.84 ?g/mL (300 mg) and 5.27?g/mL (400 mg) when determinedafter 7 days of dosing. Oral bioavailability is high(approximately 90%) anddoes 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 bemonitored during therapy. It is recommended to take VCZ 1 hour before or 2 hoursafter a meal due to its decreased absorption in acidic medium. The total dose of VCZ (oral or i.v. administration) isexcreted in 48 hours, predominantly as metabolites (98%).

VCZ (oral or i.v)exhibits non-linear pharmacokinetics (i.e. dose-dependent clearance). Itssystemic bioavailability following oral administration is around 95% and thehighest 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, vitreousand plasma concentration of VCZin 14 patients scheduled for elective pars planavitrectomy following the administration of two 400mg doses of VCZ 12 hoursapart, prior to surgery. The mean plasma,vitreous and aqueous concentrationwere 2.

13?g/ml, 0.81?g/ml and 1.13?g/ml. All these exceeded the MIC90 for awide spectrum of yeasts and moulds.273.

             Efficacy VCZ has been successfully used in various clinicalstudies. Bunya et al evaluated the role of topical and oral VCZ in ninepatients with mycotic keratitis refractory to standard antifungal therapy. Itwas reported that 71.4% of the patients healed.

They concluded that VCZ is anew, promising therapy for refractory mycotic keratitis.5 However, in a recent study by Parchand et al, it wasreported 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 (group3) in mycotic keratitis. But the rate of resolution of hypopyon was fasteringroup 1. 72Recently, MUTT 2 trial, which compared the effect oforal VCZ and oral placebo in severe filamentous mycotic keratitis, concludedthat there was no clinical benefit of adding oral VCZ to topical antifungalagents. But in a subsequent subgroup analysis, favorable response was noted incases of severe Fusarium keratits after addition of oral VCZ to topical NTM.824.

             Side effectsAdverse effects of oral VCZ Includes visualdisturbances such as abnormal vision, color vision changes and photophobia.Approximately 30% patients complain of transient visual changes beginning about30 minutes after administration and subsiding in another 30 minutes. Uncommonlytransient visual hallucinations or confusion may occur. It can also cause skinrashes, ECG changes like QT prolongation and fluoride associated bone toxicity.29Hepatotoxicity leading to elevated liver enzymes can alsooccur.66E.             FluconazoleFluconazole (FCZ)is a first generation triazoleantifungal agent with an improved safety profile as compared to imidazolecompounds. Topical and subconjunctival preparations have been reported to bebeneficial in mycotic keratitis.

69The mechanism of action has been described in table 21.             Spectrum of actionFCZ is active against many Candida spp except Candida krusei.76 It has a narrow spectrum as compared to other triazoles withresistance to filamentous fungi such as Aspergillus spp, Fusarium spp, Scedosporiumspp,or the Mucorales.22,662.             Pharmacokinetics andpharmacodynamicsFCZ has a lower molecular weight and high aqueoussolubility 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.

Therecommended 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 centralnervous 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% issecreted in urine. Thus, dose reduction is required in cases of renalinsufficiency.

11It is not extensively metabolized in the liver so doseadjustment is not required in hepatic insufficiency. Savani et al reported that FCZ (intravenous) achievedhighest concentration in all ocular tissues as compared to oral KCZ and oralICZ in normal as well as inflamed eyes.92FCZ concentration in aqueous humor was reported to be 64% ofthe plasma concentration. O’Day et al also confirmed good ocular penetration oforal FCZ.67,40Aqueous humor and choroid levels were similar toplasma levels whereas, corneal and vitreous levels were higher than the serumconcentration. Ocular penetration of oral FCZ has also been reported in humanswith endophthalmitis. They showed that it has good ocular penetrationwith aqueousto serum concentration ratio being more than or equal to 80% at 4 to 24 hours.1113.

             Efficacy Oral fluconazole has been used successfully forkeratomycosis. Few case reports showed complete healing of mycotic keratitiswith administration of topical (0.2%) and oral fluconazole.111Thakar et al reported complete healing in a case of mycotickeratitis with deep stromal abscess with oral fluconazole not responding totopical NTM.1044.

             Side effectsCommon systemic side effects include gastririts,headache, skin rashes. In some cases thrombocytopenia, Stevens-Jhonson syndromeand hepatotoxicity have been reported. F.             PosconazolePosconazole (PCZ) is a second-generation triazolesimilar to VCZ.

It is a synthetic structural analog of ICZ and has been usedsuccessfully to treat mycotic keratitis either as a standalone therapy or withother antifungal agents.31.             Spectrum of action PCZ is a broad-spectrum agent similar to VCZ and isfound to be active against most Candida spp.as well as fluconazole-resistantisolates. It is also potent  againstfilamentous fungi like Aspergillus spp,Fusarium spp and Mucorales.

662.             Pharmacokinetics andPharmacodynamicsPCZ is available in the form of oral suspension, adelayed release tabletand an intravenous solution. Absorption depends upon foodintake and is maximum with high-fat meals.

10The newer tablet formulation exhibits a pH-dependent polymermatrix allowing for delayed drug release as well as once daily dosing.Absorption of this tablet form is not influenced by food intake or gastricacidity thereby, allowing for improved bioavailability (54%) and more reliableserum concentrations.24Itis highly protein bound (98%) with poor penetration intothe cerebrospinal fluid and ocular compartments. PCZ is metabolizedmainly inliver and is excreted throughbile and feces.Dose adjustment is not required incases of renal insufficiency but may be required in hepatic insufficiency.

Theelimination half-life is 25 to 35 hours. 663.             EfficacyPCZ has been shown to be effective against mycotickeratitis resistant to common antifungals like KCZ, FCZ and VCZ. Altun et alreported successful healing in two cases of mycotic keratitis with topical(4mg/0.1 ml) and oral PCZ (200mg four times daily), which were not respondingto conventional antifungal therapy (NTM, VCZ, uconazole, and AMB).

3Cuenca-Estrella et al showed PCZ to be effective againstfungal isolates resistant to FCZ and ICZ.12Tu et al reported three cases of recalcitrantFusariumkeratitis treated successfully with PCZ.110Sponsel et al also reported complete healing with oral PCZ200 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.1024.             Side effectsPCZ has been shown to be well tolerated with long-termuse also. The most common side effects were fever, diarrhea, nausea, vomiting,and headache. Others include hypokalemia, rash, thrombocytopenia, and abdominalpain, elevated liver enzyme levels and hepatocellular damage.

Some rare adverseevents include hemolytic uremic syndrome, pulmonary embolus, adrenalinsufficiency, thrombotic thrombocytopenic purpura,and hypersensitivityreactions.23Prolongation of the QT interval may be seen with PCZ as wellas with the other triazole antifungals.G.            EchinocandinsThe echinocandins are a class of semisyntheticlipopeptides which act by disrupting the fungal cell wall by inhibiting thesynthesis 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, andanidulafungin are the main echinocandins, which display a potent activityagainst many Candida spp, as well as Aspergillus spp.

These agents are poorlyabsorbed through the gastrointestinal system and are thus available inparenteral formulations only. They have along half-life of 10–26 hours whichallows for its once daily dosing. They have a limited distribution to thecentral nervous system and ocular tissues leading to a low tissueconcentration. Though, topical caspofungin (0.

5, 1%) has beenreported to be beneficial in refractory mycotic keratitis; intravenous form hasbeen used successfully in cases of endophthalimitis. 74Echinocandins are generally well tolerated with very few sideeffects. The most common side effects include headache, gastrointestinal upset,elevation of liver (aminotransferase) tests, or mild infusion reaction.66