Voriconazole: therapeutic review of a new azole antifungalRaoul Herbrecht
The new triazole antifungal, voriconazole (Vfend®, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan®, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).
Département d’Hématologie et d’Oncologie, Hôpital de Hautepierre, 67098 Strasbourg, FranceTel.: +33 388 127 688Fax: +33 388 127 [email protected]
KEYWORDS:aspergillosis, candidiasis, fusariosis
Systemic fungal infections are a serious causeof morbidity and mortality in immunocom-promised patients. The number of patients atrisk of developing a life-threatening fungalinfection has increased dramatically over thepast few decades as more patients undergointensive immunosuppressive regimens formalignancies, bone marrow and solid organtransplantation, and as the AIDS pandemiccontinues to spread. Successful treatment ofthese infections has proved difficult in manypatients and despite the introduction of theazole antifungals fluconazole (Diflucan®,Pfizer Ltd) and itraconazole (Sporanox®, Jans-sen-Cilag Ltd), and lipid formulations ofamphotericin B, mortality from disseminatedfungal infections continues to rise.
Although amphotericin B has broad-spectrumactivity, its use is associated with severe neph-rotoxicity and infusion-related reactions insome patients. Attempts to develop less toxicformulations of the drug have been successfulwith the introduction of liposome-encapsu-lated amphotericin B (AmBisome®, GileadSciences) and amphotericin B lipid complex
(Abelcet®, Elan Pharma Ltd), but the highacquisition costs of these formulations has lim-ited their use clinically. The azole compounds,fluconazole and itraconazole, have also beenused successfully to treat disseminated fungalinfections, but each drug has its drawbacks.Fluconazole has a relatively narrow spectrumof activity and is not effective against patho-genic moulds such as Aspergillus andFusarium spp. In addition, fluconazole resist-ance has been reported, and some species ofcandida, such as Candida glabrata andCandida krusei, are intrinsically less susceptibleto this antifungal agent. Itraconazole has abroader spectrum of activity than fluconazole,but the drug has unpredictable oral bioavaila-bility. Although an intravenous formulation ofitraconazole was released in 2000, this formu-lation is not available in some countries. Forthese reasons, itraconazole has not gainedwidespread use in the treatment of systemicfungal infections.
Voriconazole (Vfend®, Pfizer Ltd) wasdeveloped to fill the gap left by existing anti-fungal drugs and to fulfill the urgent need for
a broad-spectrum antifungal agent that could be administeredboth orally and intravenously. The drug has excellent pharma-cokinetics and is widely distributed in body fluids includingthe cerebral spinal fluid (CSF). It is generally well-tolerated,and the side effects reported seldom lead to drug therapybeing discontinued. Phase II/III clinical trials show that vori-conazole is an effective treatment in immunocompromisedpatients with infections caused by fluconazole-susceptible and-resistant strains of Candida, Aspergillus and Fusarium spp.and Scedosporium apiospermum.
ChemistryVoriconazole ((2R,3S)-2,4-difluorophenyl)-3(5-fluoropyri-midin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol) is a triazoleantifungal agent with a molecular formula of C16H14N5OF3and a molecular weight of 349.3. Voriconazole was devel-oped by the structural modification of fluconazole, whereone triazole moiety was replaced with a fluoropyrimidinegroup and an extra methyl group was added to the propylbackbone (FIGURE 1). This modification has resulted in anantifungal compound with an extended spectrum of activity,particularly against Aspergillus spp. and other pathogenicmoulds, and a low concentration of drug required to inhibit50% of the target enzyme (IC50) of 0.053 µM forAspergillus fumigatus 14-α-sterol demethylase (comparedwith 4.8 µM for fluconazole) [1].
Voriconazole is a white to light-colored powder and has amelting point of 128 to 134°C. The drug is available for oraladministration as tablets and as an intravenous formulationusing sulphobutyl ether β-cyclodextrin (SBECD) as the solubi-lizing agent. For in vitro experiments, solutions of voriconazole(1 mg/ml) can be made up in dimethyl sulfoxide.
PharmacodynamicsAs is the case for fluconazole, voriconazole disrupts fungalergosterol synthesis through the inhibition of the enzyme cyto-chrome (CY)P450-dependent 14α-lanosterol demethylase. Thisprevents the conversion of lanosterol to ergosterol and leads tothe accumulation of toxic sterol precursors including 14α-meth-ylated lanosterol, 4,14-dimethylzymosterol and 24-methylene-dihydrolanosterol. Depletion of ergosterol results in the forma-tion of an abnormal cell membrane, altered membrane fluidityand function, and cessation of fungal growth. The structuralchanges introduced in voriconazole by the introduction of thefluoropyrimidine group are thought to be responsible for thehigher affinity of voriconazole for fungal 14α-demethylase andits cidal activity against pathogenic moulds [2].
Extensive in vitro studies using the National Committee forClinical Laboratory Standards (NCCLS) standardized brothdilution reference techniques (M27-A for yeasts and M38-A formoulds) have shown that voriconazole has broad-spectrumactivity against most pathogenic yeasts, dimorphic fungi andopportunistic moulds [3–6]. A list of voriconazole minimuminhibitory concentration (MIC) values for some of the mostimportant fungal pathogens is given in TABLES 1–3 [7,8].
Voriconazole has fungistatic activity against pathogenicyeasts and is reported to be 10 to 100-times more potentthan fluconazole against Candida spp. [9]. Voriconazolecauses complete inhibition of ergosterol synthesis in bothfluconazole-sensitive and -resistant strains of C. albicans.Furthermore, strains of candida, particularly C. krusei, thathave decreased susceptibility to fluconazole were inhibitedby relatively low concentrations of voriconazole [9]. Thus,voriconazole appears to have activity against Candida iso-lates that are considered to be fluconazole-resistant or sus-ceptible-dose dependent. However, the voriconazole MICvalues were generally slightly higher against these isolatesthan against fluconazole-susceptible strains, suggesting thatsome cross-resistance may occur with voriconazole and otherazole compounds [9].
C. albicans is the species that is most susceptible to theeffects of voriconazole (MIC90: 0.125 µg/ml), whereasC. glabrata and C. krusei are the least susceptible (MIC90:1–2 µg/ml) (TABLE 1). As no breakpoints have yet beenassigned for voriconazole, the relationship between in vitrosusceptibility and clinical outcome remains unclear. Activityof voriconazole against Candida spp. is not concentrationdependent, as demonstrated in in vitro time-kill studiesusing fluconazole-susceptible and -resistant strains. There-fore, increasing the concentration of voriconazole does notincrease its activity.
Voriconazole demonstrates fungicidal activity againstAspergillus spp., and has similar or more potent activityagainst these moulds than itraconazole or amphotericin B[3]. Voriconazole MIC90 values range from 0.5 to 2 µg/mlfor A. fumigatus, Aspergillus flavus, Aspergillus niger andAspergillus nidulans (TABLE 2) and minimum fungicidal con-centrations for A. fumigatus and A. flavus range from 0.5 to8.0 µg/ml [10]. Furthermore, voriconazole also showedmarked activity against itraconazole- or amphotericin B-resistant isolates of A. fumigatus (voriconazole MIC range:0.25–2.0 µg/ml) [4,11] and amphotericin B-resistantA. terreus (mean MIC for voriconazole: 0.22 µg/ml) [12],with no apparent cross-resistance to these antifungal agents.In a SENTRY surveillance program study of 239 clinical iso-lates of Aspergillus, 98% were susceptible to voriconazoledefined as a MIC of 1 µg/ml or less [13].
N
N
NN NF
OH
F
F
Figure 1. Voriconazole.
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Voriconazole has been shown to have better or comparablein vitro activity than itraconazole and amphotericin B against path-ogenic yeasts, moulds and dimorphic fungi such asCryptococcus neoformans, Malassezia spp., Bipolaris spp.,Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsula-tum, Fusarium spp., Scedosporium apiospermum and dermatophytes(TABLES 2 & 3) [3,7,8].
Resistance of fungal pathogens to fluconazole and itraconazolehas been described in vitro and in vivo. Up to 10% of clinical iso-lates of C. albicans from some patient groups have reduced sus-ceptibility to fluconazole, and a low prevalence of itraconazoleresistance has been reported among Aspergillus spp. [4,11]. Anumber of mechanisms have been implicated in azole resistanceincluding alterations to the 14α-demethylase target enzyme,modifications of sterol synthesis, reduction or overexpression of14α-demethylase and induction of drug-efflux pumps [2].
Fluconazole-resistant C. albicans and C. glabrata isolates havehigher voriconazole MIC90 values than fluconazole-susceptiblestrains, although a recent study suggested that isolates neededto be resistant to both fluconazole and itraconazole to havehigher voriconazole MIC values [14]. The authors suggested thatmore than one mechanism must be induced simultaneously foran isolate to become resistant to voriconazole [14]. This is notthe case with C. krusei, however, where fluconazole- and itraco-nazole-resistant strains appear to have low voriconazole MICvalues [6]. The relationship between the higher MIC90 valuesand clinical efficacy of voriconazole is currently unclear, as nobreakpoints for voriconazole have yet been established.
Voriconazole is 250-times more active against fungal14α-demethylase than against the corresponding mammalianenzyme [2].
Pharmacokinetics & metabolismThe pharmacokinetics of voriconazole have been investigatedin healthy volunteers given single and multiple doses of the
drug orally and intravenously, and in patients treated with thedrug (BOX 1) [1,7,15–19]. Voriconazole is absorbed rapidly follow-ing oral administration, reaching maximum serum concentra-tions within 1 to 2 h. Administering voriconazole with fooddelays the time it takes to reach maximum plasma levels toapproximately 2.5 h, and fat decreases the bioavailability ofvoriconazole, with reductions of 25 and 34% in the area underthe concentration–time curve (AUC) and peak plasma concen-tration (Cmax), respectively. Bioavailability of 90 to 96% hasbeen reported in healthy volunteers [1,19]. Steady-state plasmaconcentrations of 2.2 to 3.4 µg/ml have been reported after oraladministration of voriconazole (200 mg b.i.d.) and 2.7 to6.0 µg/ml after intravenous administration (3–6 mg/kg b.i.d.)[7]. Plasma concentrations in pediatric patients are similar tothose in adults given comparable doses. It should be noted,however, that interpatient variability in Cmax and AUC hasbeen observed after multiple intravenous doses of 3 mg/kg, or200 mg orally twice daily, therefore a wide range of plasmadrug concentrations can be expected in patients treated withthe same dose of voriconazole. Steady-state trough plasma con-centrations are reached after 5 days of oral or intravenousadministration but can be achieved after 3 days if a loadingdose is given. Voriconazole exhibits nonlinear pharmacokinet-ics, due to saturable first-pass metabolism and systemic clear-ance, thus peak plasma concentrations and AUC increase dis-proportionately with increasing dose. Multiple doses ofvoriconazole lead to an eightfold accumulation of the drug dueto reduced systemic clearance; repeated dosing has been shownto result in an AUC which is 2.5-times higher and a Cmax 1.5-times higher than that seen after single dosing. The mean elim-ination half-life of orally administered voriconazole is 6 to12 h, although this is also dose dependent.
Voriconazole binds moderately to plasma proteins(58–65%) [1,15]. The drug penetrates well into body fluidsincluding the CSF, and has a high volume of distribution of
Table 1. Comparative in vitro susceptibilities (MIC90) of pathogenic yeasts to antifungal agents.
C. albicans 0.125 ≤0.015 to >16 8 ≤0.03 to >128 0.25 ≤0.008 to >16 1 ≤0.03 to 2
C. albicans(fluconazole susceptible dose-dependant or resistant)
1 0.015 to 8 ≥128 16 to ≥128 1 0.03 to 1 NA NA
C. tropicalis 0.25 ≤0.0002 to >16 2 ≤0.125 to >128 0.5 ≤0.015 to 16 2 ≤0.03 to 2
C. glabrata 1 ≤0.03 to 8 64 ≤0.125 to >128 4 0.003 to >8 2 ≤0.03 to 2
C. krusei 2 ≤0.03 to 4 >128 0.125 to >128 >64 0.025 to >64 2 0.05 to 2
Cryptococcus neoformans 0.25 0.003 to 4 16 0.05 to >128 0.5 ≤0.008 to 2 1 0.025 to 1
§Data taken from [7,8].MIC: Minimum inhibitory concentration; MIC90: 90% of the MIC; NA: Not applicable.
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4.6 l/kg implying wide tissue distribution. Concentrationsin the CSF are reported to be between 29 and 68% of con-current plasma levels. High concentrations of voriconazolehave been reported in the brain, ocular and hepatic tissue.These observations may be significant in the treatment offungal infections of the central nervous system (CNS) andeye, and in patients with hepatosplenic candidiasis.
Metabolism of voriconazole takes place in the liver via thehepatic CYP450 microsomal enzymes CYP3A4, CYP2C19and CYP2C9. Three major and five minor metabolites havebeen identified, which are eliminated in the urine (~80% ofdose) and feces (~20% of dose). Less than 2% of unchangeddrug is detected in the urine or feces. The major metaboliteis voriconazole N-oxide, which represents approximately72% of metabolites in the plasma. Voriconazole N-oxide hasminimal antifungal activity but can inhibit the metabolismof other 2C9 and 3A4 substrates. The major enzymeinvolved in the metabolism of voriconazole is CYP2C19,which exhibits genetic polymorphism. Between 15 and 20%of Asians are expected to be poor metabolizers of voricona-zole, and have a consequent fourfold higher exposure (AUC)to voriconazole. Conversely, only 3 to 5% of Caucasians andBlacks are expected to show genetic polymorphism and to bepoor metabolizers of voriconazole.
Studies in patients with normal hepatic and renal functionshow similar pharmacokinetics to those observed in healthyvolunteers. However, patients with mild to moderate hepaticimpairment had an AUC which was more than threefoldhigher than that of normal patients [7]. Adjustment of thedosage of voriconazole may therefore be necessary inpatients with abnormal hepatic function. Furthermore,although patients with renal disease had similar voriconazolepharmacokinetics and plasma protein binding to healthyvolunteers, renal impairment was found to decrease theclearance of SBECD, used as the solubilizing agent in theintravenous preparation. Accumulation of SBECD has beenassociated with histological changes in renal tissue in experi-mental animals [20], although studies in human volunteerssuggest that SBECD is well-tolerated, has no toxic effects onthe kidney and is cleared rapidly by renal excretion [21].
Dosage & administrationVoriconazole is available as film-coated tablets (in doses of50 or 200 mg), and as a lyophilized powder consisting of200 mg voriconazole with 3200 mg SBECD that is reconsti-tuted in sterile water for intravenous administration. Vorico-nazole is administered as an initial loading dose followed bymaintenance dosing. In patients with normal hepatic and
Table 2. Comparative in vitro susceptibilities (MIC90) of pathogenic moulds to antifungal agents.
Organism Voriconazole Itraconazole Amphotericin B
MIC90(µg/ml)
MIC range MIC90(µg/ml)
MIC range MIC90(µg/ml)
MIC range
Aspergillus spp.A. fumigatus 1 0.06 to 8 1 0.06 to 32 2 0.125 to 2
A. flavus 2 0.125 to 4 1 0.03 to 16 8 0.125 to 8
A. niger 1 0.125 to 4 1 0.125 to 8 2 0.125 to 4
A. terreus 0.5 0.06 to 0.5 NA NA 8 1 to 16
Fusarium spp. 8 0.25 to 8 >16 0.25 to >64 2 0.5 to 2
Scedosporium apiospermum 2 0.01 to 4 >16 0.03 to >64 16 1 to >16
MIC: Minimum inhibitory concentration; MIC90: 90% of the MIC; NA: Not applicable.
Table 3. Comparative in vitro susceptibilities (MIC90) of dimorphic fungi to antifungal agents.
Organism Voriconazole Itraconazole Amphotericin B
MIC90 (µg/ml) MIC range MIC90 (µg/ml) MIC range MIC90 (µg/ml) MIC range
Histoplasma capsulatum 0.25 ≤0.03 to 2 0.06 ≤0.03 to 8 1 ≤0.03 to 2
Coccidioides immitis 0.25 ≤0.03 to 0.5 1 0.125 to 2 1 1.25 to 2
Blastomyces dermatitidis
0.25 ≤0.03 to >16 0.125 ≤0.03 to >16 0.5 ≤0.03 to 1
MIC: Minimum inhibitory concentration; MIC90: 90% of the MIC.
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renal function, voriconazole should be administered as anintravenous loading dose of 6 mg/kg once every 12 h for thefirst 24 h, followed by maintenance therapy of 4 mg/kgintravenously once every 12 h. In patients weighing 40 kg ormore, the maintenance dose should be 200 mg given orallyonce every 12 h, or 100 mg orally once every 12 h in thoseweighing less than 40 kg. The oral and intravenous mainte-nance doses can both be increased by 50% in patients withrefractory disease.
Oral doses should be taken at least 1 h before or after eating.Patients should be warned about the possible visual disturbancesassociated with voriconazole and should be advised not to driveat night or operate machinery. Patients with mild to moderatehepatic cirrhosis (Child–Pugh class A and B) should receive thenormal loading dose of voriconazole, but the maintenance doseshould be reduced by half. There are no pharmacokinetic dataavailable for patients with severe hepatic cirrhosis (Child–Pughclass C). Patients with renal insufficiency and reduced creatinineclearance (<50 ml/min) should take oral voriconazole butshould not be given the intravenous preparation to preventaccumulation of the solubilizing agent SBECD.
Animal studiesAs the pharmacokinetics of voriconazole in guinea-pigs closelyresemble those in humans, preliminary clinical efficacy studieswith voriconazole were carried out in experimental guinea-pigmodels of fungal infection. A summary of the results from someof these animal studies is shown in TABLE 4.
In neutropenic and non-neutropenic guinea-pigs with systemiccandidiasis, voriconazole achieved similar response rates to flucona-zole and itraconazole, whereas voriconazole was more effectivethan these two antifungals in animals infected with azole-resistantstrains of C. albicans [22], C. glabrata [23] and C. krusei [24].
The efficacy of voriconazole has also been assessed in guinea-pigswith invasive aspergillosis, pulmonary aspergillosis and aspergil-lus endocarditis. In neutropenic animals with invasive aspergil-losis, voriconazole treatment led to a significant decrease in tis-sue fungal burden compared with untreated control animals[25,26]. Furthermore, the reduction in fungal burden was shownto be dose-dependent and was greater with voriconazole thanwith itraconazole (p < 0.003) [25,26]. A significant improvementin survival and a decrease in fungal burden were also seen inneutropenic guinea-pigs with pulmonary aspergillosis treatedwith voriconazole [26,27], with a trend favoring voriconazoleover amphotericin B [27], and a greater reduction in fungal bur-den with voriconazole compared with itraconazole [26]. Vorico-nazole was also more effective than itraconazole in the prophy-laxis and treatment of A. fumigatus endocarditis in guinea-pigs[28]. Voriconazole (10 mg/kg intraperitoneally b.i.d.), adminis-tered from 2 days before to 3 days after infection, preventedinfection in 92% of animals, whereas itraconazole at the samedose failed to prevent infection in any animal. Cure rates of100, 70 and 0% were reported among animals withA. fumigatus endocarditis treated with voriconazole (10, 7.5and 5 mg/kg, respectively) compared with a cure rate of 0% in
animals treated with 10 mg/kg itraconazole [28]. Voriconazolewas also shown to be effective in the treatment of aspergillosisin neutropenic rabbits and in steroid-treated rats, despite itssuboptimal pharmacokinetics in these animals [29,30].
Voriconazole, fluconazole and itraconazole had similar clinicalefficacy and decreased the fungal burden in the pulmonary andbrain tissue of guinea-pigs with pulmonary and intracranial cryp-tococcosis, whereas amphotericin B was less effective, especiallyin the pulmonary model of infection [31].
Clinical efficacyThe clinical efficacy of voriconazole has been confirmed in anumber of Phase II/III trials, and in a compassionate use pro-gram in both adult and pediatric patients with fungal infectionand in patients with febrile neutropenia. Clinical data collectedto date suggest that voriconazole has an important role in thetreatment of invasive aspergillosis, and oropharyngeal andesophageal candidiasis, and in the more unusual fungal infec-tions such as fusariosis and scedosporiosis where treatmentoptions are limited.
AspergillosisInvasive or disseminated aspergillosis is a serious, life-threateninginfection with associated mortality reported to be over 85% insome patient groups. Autopsy data suggest that the incidence ofthis infection increased 14-fold in the 12 years up to 1992, withan incidence of 5% to over 20% in some at-risk patient popula-tions [32]. Due to the high mortality from this infection(65–90%) [33] and the poor clinical efficacy of existing antifungalagents (amphotericin B preparations and itraconazole), the devel-opment of new antifungal compounds for the treatment of thisinfection has been a priority. Voriconazole, which was developedwith this indication in mind, has potent cidal activity againstAspergillus spp. and has shown promising results in experimentalanimal models of infection.
Box 1. Main pharmacokinetic characteristicsof voriconazole.
• Elimination/metabolism Hepatic(<2% excreted unchanged in urine)
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Voriconazole has been used as primary therapy and as salvagetherapy in a number of controlled and uncontrolled clinical tri-als in immunosuppressed patients with invasive aspergillosis,with encouraging results (TABLE 5). The largest of these studies,conducted by Herbrecht and colleagues for the Invasive FungalInfection Group of the European Organization for Researchand Treatment of Cancer and the Global Aspergillus StudyGroup [34], compared voriconazole with amphotericin B forprimary therapy in 277 patients with invasive aspergillosis.Patients received standard therapy with voriconazole (intrave-nous and oral) or amphotericin B deoxycholate (intravenous),and a complete or partial response was considered to be a suc-cessful outcome. Successful outcomes were recorded in 53% ofpatients given voriconazole (complete: 21%; partial: 32%)compared with 32% of those given amphotericin B (complete:17%; partial: 15%). Survival at week 12 was 71% in the vorico-nazole group compared with 58% in the amphotericin Bgroup. The authors concluded that treatment with voriconazoleresulted in a better clinical response, improved survival andfewer serious adverse reactions than treatment withamphotericin B.
A second, large, open, noncomparative study of voriconazolewas conducted by Denning and colleagues in 116 evaluablepatients with proven or probable invasive aspergillosis [33]. Inthis study, voriconazole was given either as primary therapy oras salvage therapy when treatment with another antifungalagent was considered ineffective or toxic. Good responses(complete or partial) were seen in 58% of hematology patientswho had not undergone allogeneic hematopoietic stem celltransplantation (HSCT), 26% of hematology patients withHSCT, 16% of patients with cerebral aspergillosis, 50% withdisseminated aspergillosis and 60% with pulmonary or trachealaspergillosis. These results compare favorably with thosereported previously with amphotericin B, lipid-associatedamphotericin B and itraconazole.
Similar results have been reported in other studies involvingbone marrow and solid-organ transplant recipients, hematolog-ical malignancies, HIV/AIDS, chronic granulomatous disease,and other immunocompromising conditions (TABLE 5) [35–38],with overall response rates reported to be around 50%.Although voriconazole appears to be most effective when it isgiven as primary therapy, successful outcomes have also beenreported in 40 to 50% of patients with refractory or antifungal-intolerant invasive aspergillosis given voriconazole as salvagetherapy (TABLE 5). Additional reports have also been publisheddocumenting the successful use of voriconazole in the treat-ment of four cases of pulmonary aspergillosis in patients withchronic granulomatous disease [39–42] and patients with cerebralaspergillosis [16,18].
CandidiasisInfections due to Candida spp. are also an important cause ofmorbidity and mortality in immunocompromised patients.Oropharyngeal candidiasis is the most common opportunisticinfection in patients with AIDS, occurring in up to 90% atsome stage during their illness, and is also a frequent problemin patients undergoing chemotherapy for malignancies.Esophageal candidiasis is also associated with severe immuno-suppression and may occur with or without concomitantoropharyngeal involvement. The incidence of esophageal can-didiasis is reported to be as high as 50% in some groups ofpatients with AIDS. Candida spp. are the fourth most commoncause of nosocomial bloodstream infections in the USA.
Most clinical studies have evaluated voriconazole in patientswith esophageal infection and have compared voriconazolewith fluconazole, the current gold standard treatment fororopharyngeal and esophageal candidiasis. A randomized,double-blind, multicenter study of 391 immunocompro-mised patients with mycology and biopsy proven esophagealcandidiasis, including patients with severe AIDS
Table 4. Efficacy of voriconazole in experimental animal models of fungal infection.
Fungal infection Animal Clinical results Ref.
Invasive aspergillosis Guinea-pigs 100% survival versus controls (0%). Significant decrease in fungal burden in liver, lungs, kidney and brain (p < 0.003)
[25]
Guinea-pigs Greater decrease in fungal burden versus itraconazole and amphotericin B (p < 0.05) [26]
Pulmonary aspergillosis Guinea-pigs Dose-dependent decrease in fungal burden. Greater decrease with voriconazole than with itraconazole (p < 0.05)
[26]
Guinea-pigs Increase in survival and decrease in fungal burden versus untreated controls (p = 0.04) [27]
Rats Significantly higher survival than in control group (100 vs. 37%; p < 0.02) [29]
Aspergillus endocarditis Guinea-pigs Infection prevented in 92% of animals; cure in 100% of animals [28]
Disseminated Candida krusei Guinea-pigs Significant decrease in fungal burden (brain, liver and kidneys) versus untreatedcontrols (p < 0.01)
[24]
Disseminated Candida glabrata Guinea-pigs Significant decrease in fungal burden in organ tissues versus untreated controls [23]
Pulmonary and intracranial cryptococcosis
Guinea-pigs Dose-dependent decrease in fungal burden in lungs and brain versus controls (p < 0.05) [31]
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(CD4 < 50 cells/mm3), showed that voriconazole (200 mgorally, b.i.d.) was at least as effective as fluconazole (200 mgorally) with success rates of 98 and 95%, respectively, when theresponse was assessed by esophagoscopy [43]. These results sup-port those of Hegener and colleagues [17] and Ruhnke and col-leagues [44], who reported clinical efficacy of voriconazole of80 to 100% of AIDS patients with esophageal candidiasis,including patients with severe CD4 cell depletion.
The emergence of fluconazole resistance is an importantconsideration when treating AIDS patients with esophagealcandidiasis. Ruhnke and colleagues reported a favorableresponse to voriconazole (200 mg b.i.d.) in six patients withfluconazole-refractory esophageal candidiasis [44], and Hegenerand colleagues reported partial or complete cure in ten out of12 HIV patients, including two with fluconazole-resistantinfection (MIC: ≥64 µg/ml), and one patient infected with adose-susceptible strain (MIC: 16–32 µg/ml) [17]. These prelim-inary results suggest that voriconazole might be suitable for thetreatment of infections caused by fluconazole-resistant isolates,although further studies are clearly warranted.
Few data are currently available on the clinical efficacy ofvoriconazole in patients with systemic candida infection,although a large, multicenter, comparative study of non-neu-tropenic patients with candidemia has recently been completedand the results are expected to be released soon. One publishedstudy reported an overall success rate of 57% when voricona-zole was used on compassionate grounds in patients with candi-diasis (such as esophageal, candidemia and disseminated) whowere at high risk of treatment failure [45]. These authors con-cluded that voriconazole is likely to have a positive impact in atleast 50% of patients with refractory invasive candidiasis. Dueto the good tissue distribution of voriconazole and the highdrug levels achieved in hepatic tissue, this antifungal may playan important role in the treatment of hepatosplenic candidiasisin immunosuppressed patients.
CryptococcosisC. neoformans is a serious cause of meningitis, particularly inpatients with HIV/AIDS. Current treatment of this infectionconsists of combined therapy with amphotericin B plus flucy-tosine (Ancotil®, ICN Pharmaceuticals Ltd) for several weeks,followed by maintenance therapy with fluconazole or itracona-zole for several months or even for life. Data relating to theefficacy of voriconazole in the treatment and maintenance ofC. neoformans infection are limited. However, because of itslow MIC against C. neoformans (MIC90: 0.25 µg/ml) and itsgood penetration into the CSF, voriconazole is likely to play arole in the treatment of infections caused by C. neoformans. Arecent comparative study showed that voriconazole was themost potent azole antifungal agent in vitro against 566 clinicalisolates of C. neoformans from HIV-infected patients [46].Although Perfect and colleagues documented a good clinicalresponse in 39% of patients with refractory cryptococcal men-ingitis [45], most patients had clinically stable disease and over90% were alive at the 90-day follow-up time. Thus, voricona-zole could have a role in the treatment of cryptococcosis, par-ticularly in infections that are refractory to conventional anti-fungal treatment. Further clinical studies in these patients areclearly warranted.
FusariosisLimited clinical data are currently available on the efficacy ofvoriconazole in the treatment of infections caused byFusarium spp., as these infections are generally rare. However,a small number of preliminary studies report exciting resultsin some patients with F. solani infection. In one study, vorico-nazole (6 mg/kg orally, b.i.d., 10 µg/0.1 ml intracamerally,plus 1% voriconazole topical solution applied every hour)resulted in clinical cure in a 16 year old patient with severehypopyon keratitis of the left eye after treatment with fluco-nazole, amphotericin B and itraconazole had failed [47]. In a
Table 5. Response of patients with invasive aspergillosis to voriconazole.
Total numberof patients
Major underlying diseases Nature of voriconazole treatment
§Successful outcome defined as complete plus partial recovery.HSCT: Hematopoietic stem cell transplantation.
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second report, Perfect and colleagues documented a successfuloutcome in five out of 11 (45%) patients with antifungal-refractory Fusarium infection when voriconazole was used as sal-vage therapy [45]. The pooled data on the efficacy of voricona-zole included in the package insert indicate that treatment withthis antifungal resulted in clinical cure in approximately 43% ofpatients (9/21) with fusariosis.
ScedosporiosisInfections caused by Scedosporium spp. are difficult to treat asthey are usually refractory to conventional therapy withamphotericin B. Preliminary studies with voriconazole suggestthat this azole compound may have an important role in thetreatment of scedosporiosis. Complete or partial response rateswere documented in 17 out of 27 (63%) immunosuppressedpatients with S. apiospermum infection, and in two out of seven(29%) patients with S. prolificans infection given voriconazolesalvage therapy (6 mg/kg every 12 h on day 1, followed by4 mg/kg every 12 h) [48]. Walsh and colleagues also documentedcomplete or partial responses in five out of eight (63%) of pedi-atric patients (9 months to 15 years old) with documentedScedosporium infection who were refractory to, or intolerant ofconventional antifungal therapy and were given voriconazole aspart of a compassionate release program [37]. Of these patients,83% with S. apiospermum infection had a successful outcome,whereas two patients with S. prolificans infections failed torespond. In vitro data suggest that most isolates of S. prolificansare resistant to voriconazole, as well as to other systemic antifun-gal agents, thus it is important for the microbiology/mycologylaboratory to speciate any clinically significant isolates ofScedosporium. The efficacy of voriconazole in the treatment ofS. apiospermum infection has been confirmed in a number ofindividual case reports in adult patients, including infections ofthe skin, lungs and CNS [49–53].
Voriconazole has comparable or superior clinical activity tothat of amphotericin B and other azoles, including itraconazole,against Scedosporium spp. and Fusarium spp. Voriconazole hasbeen approved by the European Medicines Agency for the treat-ment of infections caused by these pathogens, and by the USFood and Drug Administration in patients with these infectionswhere conventional therapy has failed or has not been tolerated.
Dimorphic fungiA preliminary compassionate study of voriconazole in immuno-compromised patients with documented infection caused byHistoplasma capsulatum and Coccidioides immitis reported suc-cessful clinical, microbiological and radiological cure in 47% ofpatients [54]. These patients had all failed with, or not tolerated,previous antifungal therapy. Further studies in patients withinfections caused by dimorphic fungi are warranted.
Febrile neutropeniaUntil now, steps to prevent invasive fungal infections in patientswith neutropenia and persistent fever have relied on empirictreatment with amphotericin B or liposomal amphotericin B. In
a recent open-label, prospective, multicenter study, voriconazolewas compared with liposomal amphotericin B for the empirictreatment of fungal infection in 837 neutropenic patients withpersistent fever [55]. Overall response rates were 26% in thosereceiving voriconazole and 31% in those given liposomalamphotericin B (95% confidence interval for the difference:10.6 to 1.6 percentage points). This 95% confidence intervalfalls just outside the predefined lower limit of -10 percentagepoints. As a consequence, voriconazole failed to fulfill the protocol-defined criteria for noninferiority to liposomal amphotericin Bwith respect to overall response to empirical therapy. However, astatistically significant difference was reported in favor of vorico-nazole in the number of patients who developed a breakthroughfungal infection; eight were documented in the voriconazolegroup, compared with 21 among patients who received lipo-somal amphotericin B (p = 0.02). Fewer cases of breakthroughinvasive aspergillosis, candidemia and dematiaceous mouldinfections were recorded in the voriconazole group, whereasthere were fewer cases of zygomycosis among patients receivingliposomal amphotericin B. Although the incidence of hepato-toxicity in the two groups was similar, voriconazole was associ-ated with significantly fewer cases of severe infusion-related reac-tions (p < 0.01) and less nephrotoxicity (p < 0.001). Therefore,voriconazole appears to be a suitable alternative toamphotericin B for empiric antifungal therapy in patients at riskfor fungal infection.
Safety & tolerabilityAdverse eventsVoriconazole has a good safety profile and was well-tolerated bypatients taking part in Phase I studies and clinical trials. Themost frequent adverse reactions reported after administration oforal or intravenous voriconazole, are visual disturbances,hepatic abnormalities and skin reactions. Visual disturbances(enhanced light perception, blurred vision, photophobia orchanges in color vision) are usually mild to moderate in sever-ity, occur within 30 min of dosing and usually last for up to30 min [2]. Visual disturbances have been reported in approxi-mately 30% of patients receiving voriconazole in clinical stud-ies and are most common during the first week of therapy.Although the incidence of visual disturbances is quite high,these side effects are usually transient and resolve after thepatient has become tolerant to the drug or the drug has beendiscontinued. Adverse visual events rarely lead to discontinua-tion of therapy and studies in 2000 Phase I and II volunteersdocumented withdrawal of voriconazole treatment in less than1% of cases.
Although visual disturbances are usually mild and transient innature, patients taking the drug should be warned of this possibleside effect, particularly if they are driving or operating machinery.Monitoring of visual acuity, visual field and color perception hasalso been advised if voriconazole is given for more than 28 days.The retina has been shown to be the site of these side effects withdecreased amplitude of electroretinogram waveforms in dogs andhumans. However, no long-term visual sequelae have been
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reported in animal studies. A prospective study looking at thelong-term visual effects of voriconazole after 6 to 12 monthsadministration in humans has recently been completed and theresults are expected to be available later this year.
Mild elevations in hepatic function tests have also beenreported in 4 to 27% of patients receiving voriconazole and aregenerally associated with high plasma levels and/or doses of thedrug [8]. Increased liver enzymes (aspartate transaminase, alaninetransaminase and alkaline phosphatase) and bilirubin levels usu-ally resolve during treatment with or without dose adjustment.Occasional severe hepatic reactions have been reported duringclinical trials, including clinical hepatitis, cholestasis and fulmi-nant hepatic failure with resulting fatalities. These events, how-ever, are more common in patients with other serious underly-ing medical conditions, particularly hematological malignancies.Pooled safety data show that 0.9% of patients receiving vorico-nazole developed hepatic failure leading to death, which is simi-lar to the prevalence reported for comparator drugs. High-riskpatients, particularly those with pre-existing hepatic dysfunc-tion, should be monitored closely before and during voricona-zole therapy, and voriconazole should be discontinued if clinicalsigns and symptoms consistent with liver failure appear thatmight be attributable to the drug.
Mild skin reactions, usually a rash or photosensitivity, havebeen reported in 1 to 19% of patients receiving voriconazole.This is similar to the incidence reported with other antifungaldrugs such as fluconazole and amphotericin B. The type andseverity of the skin reactions with voriconazole can be affectedby coadministration of other medications, such as antihista-mines, steroids or immunosuppressive agents [8]. Discontinua-tion of voriconazole due to adverse skin reactions is a rare event.
Facial erythema, cheilitis and discoid lupus erythematous-like lesions have been described in patients receiving prolongedvoriconazole therapy (200 mg b.i.d. for 12–58 weeks); thesereactions resolved after discontinuation of the drug. Rare casesof Stevens–Johnson syndrome, toxic epidermal necrolysis anderythema multiforme have also been reported. Patients takingvoriconazole should be advised to avoid strong, direct sunlightduring the course of their treatment.
Other adverse reactions reported with voriconazole includehallucinations (4%) and headaches (12–56%).
Drug interactionsAs well as being an inhibitor of the hepatic enzymes CYP3A4,CYP2C9 and CYP2C19, voriconazole is also a substrate ofthese enzymes. Thus, other drugs metabolized through thesemetabolic pathways have the potential to interact with vorico-nazole, as shown previously with itraconazole and flucona-zole. The voriconazole drug interactions can be classified intofour types:
• Contraindication
• Dose adjustment of voriconazole or concurrent medication
• Monitor levels or effects of concurrent medication
• No adjustment required
A list of the main drug–drug interactions recognized, themechanisms involved and the clinical recommendations foreach interaction are shown in TABLE 6. In addition, administra-tion of the following drugs is contraindicated with voricona-zole: ritonavir (Norvir®, Abbott Laboratories Ltd) car-bamazepine (Tegretol®, Cephalon UK Ltd), and long-actingbarbiturates, terfenadine, astemizole (Hismanal™, MerckSharpe and Dohme), cisapride (Propulsid®, Janssen–Cilag),pimozide (Orap®, Janssen–Cilag Ltd), quinidine, ergot alka-loids and efavirenz (Sustiva®, Bristol–Myers Squibb) [2]. HIVprotease inhibitors (CYP3A4 inhibitors), such as saquinavir,amprenavir (Agenerase®, GlaxoSmithKline) and nelfinavir(Viracept®, Roche), may affect the metabolism of voriconazoleor their metabolism may be affected by coadministration ofvoriconazole, therefore, patients should be carefully monitoredfor drug toxicity or loss of efficacy during coadministration ofthese drugs.
Conclusion & expert opinionVoriconazole was developed by Pfizer to fill a gap in theantifungal market left by amphotericin B, fluconazole anditraconazole. Although fluconazole has proven clinical effi-cacy in the treatment of infections caused by Candida spp.and C. neoformans, it has poor activity against Aspergillus spp.and other filamentous fungi. Itraconazole, on the other hand,is active against both pathogenic yeasts and moulds but hasnot gained widespread use due to its unpredictable bioavaila-bility and the limited availability of the intravenous formula-tion. The challenge, therefore, was to develop a new antifun-gal agent that had broad-spectrum activity, particularlyagainst Aspergillus spp. and other pathogenic moulds, couldbe administered intravenously and orally, and that had lowdrug-related toxicity. Voriconazole, which was developed bychemical modification of fluconazole, appears to fulfill all ofthe above criteria. Furthermore, this azole antifungal has anexcellent pharmacokinetic profile and is widely distributedthrough all body tissues and fluids, including the CSF, mak-ing it suitable for the treatment of fungal infections involvingmany body sites.
In vitro susceptibility data show that most fungal pathogenshave voriconazole MIC values that are well below the maximumserum levels achieved with the drug after oral and intravenousdosing. Resistance (acquired and intrinsic) to the parent drugfluconazole can be a problem in some Candida spp., and fluco-nazole resistance has also been described in strains ofC. neoformans. Although cross-resistance of yeasts to severalazole compounds, including fluconazole, itraconazole and keto-conazole has been reported, in a study of cross-resistance pat-terns to azole antifungals, Pfaller and colleagues showed that toexpress high voriconazole MIC values, strains of C. albicans andC. glabrata had to be resistant to both fluconazole and itracona-zole, whereas isolates that were resistant to fluconazole alone hadlow voriconazole MIC values [14]. Interestingly, no cross-resist-ance has been reported in C. krusei and this species has low vori-conazole MIC values even when isolates are resistant to both
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fluconazole and itraconazole. Cross-resistance between azoleantifungals is not inevitable and, until voriconazole breakpointshave been established, the impact of these higher MIC values onin vivo susceptibility and clinical efficacy is uncertain. Neverthe-less, the possibility of resistance developing with widespread useof voriconazole, as happened previously with fluconazole,should not be ignored and should be monitored carefully.
Voriconazole has been approved by the FDA for the treatmentof invasive aspergillosis; and serious infections caused byFusarium spp. and S. apiospermum in patients who are intolerantof, or refractory to, other antifungal agents. In Europe, voricona-zole is approved by the EMEA for treatment of invasive aspergil-losis, serious infections caused by Fusarium and S. apiospermum,and fluconazole-resistant serious invasive candida infections(including C. krusei).
Five-year viewClinical trials have shown that voriconazole has proven clinicalefficacy and results in increased survival of patients with inva-sive aspergillosis, compared with amphotericin B. Voriconazoleis likely to gain widespread use in the treatment of this infec-tion, due to its efficacy and its flexibility of administration,compared with amphotericin B preparations.
Increasing numbers of patients undergo immunosuppres-sive therapy for malignancies, bone marrow and organ trans-plantation, and as immunosuppressive regimens becomemore intense, the incidence of serious fungal infections willcontinue to rise. This increase in incidence of fungal infec-tions, such as invasive aspergillosis, will be accompanied bya significant augmentation in hospital costs associated withpatient care. First-line treatment with voriconazole is not
Table 6. Drug–drug interactions observed with voriconazole: clinical recommendations.
Drug Mechanism Results Observations Clinical recommendations
Cyclosporin Voriconazole inhibits CYP3A4 metabolism of cyclosporin
Cyclosporin ↑ ↑ cyclosporin AUC by ~70%↑ cyclosporin trough levels by 2.5.
↓ cyclosporin dose by half when starting voriconazole.Monitor cyclosporin levels carefully
Indinavir Indinavir inhibits CYP450 metabolism of voriconazole
Omeprazole Competitive inhibition of omeprazole and voriconazole metabolism by CYP2C19 and CYP3A4
Voriconazole and omeprazole ↑
↑ voriconazole Cmax and AUC↑ omeprazole Cmax and AUC↑ exposure to voriconazole and omeprazole
↓ dose of omeprazole by half when starting voriconazole. No change in voriconazole dose
Phenytoin Voriconazole inhibits CYP2C9 metabolism of phenytoin
Phenytoin induces CYP3A4 metabolism of voriconazole
Phenytoin ↑
Voriconazole ↓
Phenytoin AUCs ↑ by ~80%↓ in voriconazole Cmax and AUC
Monitor phenytoin levels and phenytoin-related adverse eventsAdjust voriconazole dose to 5 mg/kg intravenously or to 400 mg, orally, twice daily
Prednisolone Competitive inhibition of CYP3A4 Prednisolone ↑ Small ↑ in prednisolone levels Slight accumulation of voriconazole
No dose adjustment required
Rifabutin Rifabutin induces CYP450 metabolism of voriconazole
Voriconazole inhibits CYP3A4 metabolism of rifabutin
Voriconazole ↓
Rifabutin ↑
↓ in voriconazole Cmax (66%) and AUC (79%)
If benefits of coadministration outweigh risks, ↑ voriconazole dose to 5 mg/kg intravenously, twice daily, or 400 mg orally, twice daily. Monitor total blood count and adverse events (e.g., uveitis)
Rifampin Rifampin induces CYP450 metabolism of voriconazole
Voriconazole ↓ ↓ voriconazole Cmax (92%) and AUC (96%)
Rifampin contraindicated with voriconazole
Sirolimus Voriconazole inhibits CYP3A4 metabolism of sirolimus
Sirolimus ↑ Sirolimus contraindicated with voriconazole
Tacrolimus Voriconazole inhibits CYP3A4 metabolism of tacrolimus (dose-dependent)
Tacrolimus ↑ ↑ tacrolimus Cmax (2.2-fold) and AUC (3.2-fold)
↓ tacrolimus dose by a third when starting voriconazole.Monitor plasma levels frequently
Warfarin Voriconazole inhibits CYP29C metabolism of warfarin
Warfarin effect ↑ ↑ Voriconazole prothrombin time Monitor prothrombin time.Adjust warfarin dose if necessary
AUC: Area under the curve; Cmax: Maximum concentration; CY: Cytochrome.
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only supported by its increased efficacy overamphotericin B, but also because it has been estimated toreduce hospital stay and the associated costs of hospitaliza-tion [55]. The efficacy of voriconazole at preventing break-through fungal infections, its lower acquisition costs com-pared with lipid formulations of amphotericin B, and thedecreased incidence and severity of adverse reactions com-pared with amphotericin B may result in reduced hospitalcosts. Thus, use of voriconazole is supported not only by itsclinical efficacy but also by economic criteria.
It is often possible to increase the efficacy of an antimicrobialagent by using it as combination therapy. Combination ther-apy with voriconazole and other antifungal drugs has alreadybeen evaluated in vitro against a number of fungal pathogens.Synergy has been reported between voriconazole and terbin-afine (Lamisil®, Novartis Pharmaceuticals UK Ltd) againstcandida isolates, particularly those with higher voriconazoleMIC values, A. fumigatus, A. niger and zygomycetes, and noantagonism was reported between the two drugs [56]. The syn-ergy and combined use of these two antifungal agents, which
is thought to be due to their combined effects on differentstages of the ergosterol biosynthetic pathway, warrants furtherinvestigation, as MIC values for Aspergillus spp. are at leasttwo dilutions lower than with either drug alone. In contrast toterbinafine, in vitro antagonism has been reported betweenamphotericin B and azole drugs, including voriconazole. Fur-ther studies are required to establish the role of combinationtherapy with voriconazole and other antifungal drugs such ascaspofungin in the treatment of fungal infections.
To date, the FDA has not approved voriconazole for thetreatment of candida infections, although the EMEA hasapproved voriconazole for the treatment of patients with flu-conazole-resistant candida infection. Data from a large-scaleclinical trial of voriconazole for candidemia in non-neutro-penic patients are anticipated in the near future, and thesemay affect future prescribing practices for candida infections.For now, the primary indication of voriconazole will be thetreatment of invasive aspergillosis, and fusariosis and sce-dosporiosis in patients who are refractory to, or intolerant of,conventional antifungal agents.
Key issues
• Voriconazole is formulated as tablets (50 and 200 mg) and as an intravenous preparation with the solubilizing agent sulphobutyl ether β-cyclodextrin. It has excellent pharmacokinetics with a bioavailability of 90 to 96% and a maximum concentration of 2.7 to 6 µg/ml after intravenous administration (3–6 mg/kg twice daily), and 2.0 to 3.4 µg/ml after oral dosing (200 mg twice daily). Voriconazole has a volume of distribution of 4.6 l/kg and is rapidly distributed throughout body tissues and fluids, including the cerebrospinal fluid, eye and hepatic tissue. Voriconazole is generally well-tolerated with few mild to moderate, transient adverse events reported.
• Voriconazole has a broad spectrum of activity, with low maximum inhibitory concentration values for pathogenic yeasts (Candida spp. and Cryptococcus neoformans), dimorphic fungi and pathogenic moulds. Unlike its parent compound, fluconazole, voriconazole has potent cidal activity against Aspergillus spp., and is active against Fusarium spp. and Scedosporium apiospermum. Voriconazole is inactive against zygomycetes.
• In controlled, multicenter clinical trials in immunosuppressed patients with a range of fungal infections, voriconazole proved to have similar or more potent clinical efficacy than fluconazole, itraconazole and amphotericin B in the treatment of oropharyngeal/esophageal candidiasis (including infections caused by fluconazole-resistant strains), disseminated aspergillosis, fusariosis and scedosporiosis caused by S. apiospermum.
• Resistance to voriconazole does not appear to have been documented to date, although the relationship between in vitro susceptibility and clinical efficacy has not yet been established. Data from studies with Candida spp. suggest that isolates need to be resistant to both fluconazole and itraconazole to have higher voriconazole minimum inhibitory concentration values. Susceptibility of fungal pathogens to voriconazole should be monitored carefully to ensure that resistant isolates do not emerge as significant fungal pathogens.
• Voriconazole has been approved by the US Food and Drug Administration for the treatment of invasive aspergillosis; and serious infections caused by Fusarium spp. and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. The European Medicines Agency has approved voriconazole for treatment of invasive aspergillosis, serious infections caused by Fusarium spp. and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei ).
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• Rabbit model demonstrating the efficacy of voriconazole in pulmonary aspergillosis.
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•• Randomized, comparative study demonstrating superiority of voriconazole over amphotericin B in invasive aspergillosis.
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•• Shows that voriconazole is as effective as fluconazole in esophageal candidiasis.
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•• Details the activity of voriconazole in various severe invasive fungal infections.
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•• Large randomized study comparing voriconazole and liposomal amphotericin B for the empiric therapy of persistent febrile neutropenia.
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Affiliation• Raoul Herbrecht, MD
Département d’Hématologie et d’Oncologie, Hôpital de Hautepierre, 67098Strasbourg, FranceTel.: +33 388 127 688Fax: +33 388 127 [email protected]
