Statins (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during coadministration. Increased statin concentrations in plasma have been associated with rhabdomyolysis (see PRECAUTIONS - DRUG INTERACTIONS).

Benzodiazepines (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration (see PRECAUTIONS - DRUG INTERACTIONS).

Calcium Channel Blockers (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro (human liver microsomes). Therefore, voriconazole may increase the plasma concentrations of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during coadministration. Dose adjustment of the calcium channel blocker may be needed (see PRECAUTIONS - DRUG INTERACTIONS).

Sulfonylureas (CYP2C9 substrates): Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration (see PRECAUTIONS - DRUG INTERACTIONS).

Vinca Alkaloids (CYP3A4 substrates): Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone (CYP3A4 substrate): Voriconazole (200 mg Q12h x 30 days) increased Cmax and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.

Digoxin (P-glycoprotein mediated transport): Voriconazole (200 mg Q12h x 12 days) had no significant effect on steady state Cmax and AUC_τ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole (200 mg Q12h x 5 days) had no significant effect on the Cmax and AUC_τ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

Rifabutin (potent CYP450 inducer): Rifabutin (300 mg once daily) decreased the Cmax and AUC_τ of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state Cmax and AUC_τ of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the Cmax and AUC_τ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone. Coadministration of voriconazole and rifabutin is contraindicated.

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate): Standard doses of voriconazole and standard doses of efavirenz must not be coadministered (see PRECAUTIONS – DRUG INTERACTIONS). Steady state efavirenz (400 mg PO QD) decreased the steady state Cmax and AUC_τ of voriconazole (400 mg PO Q12h for 1 day, then 200 mg PO Q12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO Q12h for 1 day, then 200 mg Q12h for 8 days) increased the steady state Cmax and AUC_τ of efavirenz (400 mg PO QD for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO Q12h on Days 2 to 7) with efavirenz (300 mg PO Q24h on Days 1-7), relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg PO Q12h for 2 days) or efavirenz (600 mg Q24h for 9 days). Coadministration of voriconazole 400 mg Q 12h with efavirenz 300 mg Q24h, decreased voriconazole AUC_τ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUC_τ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.

Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg Q12h and the efavirenz dose is decreased to 300 mg Q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state Cmax and AUC_τ of orally administered voriconazole (200 mg Q12h x 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg Q12h x 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole Cmax and AUC_τ estimates as compared to when voriconazole was given at 200 mg Q12h without phenytoin.

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg) (see DOSAGE AND ADMINISTRATION).

Repeat dose administration of voriconazole (400 mg Q12h x 10 days) increased the steady state Cmax and AUC_τ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when coadministered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with voriconazole (see PRECAUTIONS - DRUG INTERACTIONS).

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Coadministration of omeprazole (40 mg once daily x 10 days) with oral voriconazole (400 mg Q12h x 1 day, then 200 mg Q12h x 9 days) increased the steady state Cmax and AUC_τ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.

Coadministration of voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) with omeprazole (40 mg once daily x 7 days) to healthy subjects significantly increased the steady state Cmax and AUC_τ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half (see PRECAUTIONS - DRUG INTERACTIONS).

The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these drugs.

Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 3 days) and oral contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, Q24h) to healthy female subjects at steady state increased the Cmax and AUC_τ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole Cmax and AUC_τ increased by an average of 14% (90% CI: 3%, 27%)and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for voriconazole, is recommended during coadministration (see PRECAUTIONS - DRUG INTERACTIONS).

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir (CYP3A4 inhibitor and substrate): Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole Cmax and AUC following repeat dose administration (200 mg Q12h for 17 days) in healthy subjects.

Repeat dose administration of voriconazole (200 mg Q12h for 7 days) did not have a significant effect on steady state Cmax and AUC_τ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:

Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors): In vitro studies (human liver microsomes) suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and HIV protease inhibitors (see PRECAUTIONS - DRUG INTERACTIONS).

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers): In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI (see CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS – DRUG INTERACTIONS). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine) (see PRECAUTIONS - DRUG INTERACTIONS). Dose adjustments are required when voriconazole is co-administered with efavirenz (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - DRUG INTERACTIONS).

Microbiology

Mechanism of Action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Activity In Vitro

Voriconazole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.

Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In clinical studies, the voriconazole MIC₉₀ was 4 µg/mL)*
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum

*In clinical studies, voriconazole MIC₉₀ for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥ 4 µg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC90 was 1 µg/mL (see Table 4).

The following data are available, but their clinical significance is unknown.

Voriconazole exhibits in vitro minimal inhibitory concentrations (MICs) of 1 µg/mL or less against most ( ≥ 90%) isolates of the following microorganisms; however, the safety and effectiveness of voriconazole in treating clinical infections due to these Candida species have not been established in adequate and well-controlled clinical trials:

Candida lusitaniae
Candida guilliermondii

Susceptibility Testing Methods^2,3

Aspergillus species and other filamentous fungi

No interpretive criteria have been established for Aspergillus species and other filamentous fungi.

Candida species

The interpretive standards for voriconazole against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference method M27 for MIC read at 48 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.^2,3

Broth Microdilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 48 hours.² Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of voriconazole powder. The MIC values should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure requires the use of standardized inoculum concentrations.³ This procedure uses paper disks impregnated with 1 µg of voriconazole to test the susceptibility of yeasts to voriconazole at 24 hours. Disk diffusion interpretive criteria are also provided in Table 4.

Table 4: Susceptibility Interpretive Criteria for Voriconazole^2,3

NOTE: Shown are the breakpoints (µg/mL) for voriconazole against Candida species.

The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used for the site of infection. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard voriconazole powder and 1 µg disks should provide the following range of values noted in Table 5.

NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 5: Acceptable Quality Control Ranges for Voriconazole to be used in Validation of Susceptibility Test Results

Activity In Vivo

Voriconazole was active in normal and/or immunocompromised guinea pigs with systemic and/or pulmonary infections due to A. fumigatus (including an isolate with reduced susceptibility to itraconazole) or Candida species [C.albicans (including an isolate with reduced susceptibility to fluconazole), C. krusei and C. glabrata] in which the endpoints were prolonged survival of infected animals and/or reduction of mycological burden from target organs. In one experiment, voriconazole exhibited activity against Scedosporium apiospermum infections in immune competent guinea pigs.

Drug Resistance

Voriconazole drug resistance development has not been adequately studied in vitro against Candida, Aspergillus, Scedosporium and Fusarium species. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.

Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.

Clinical Studies

Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

Invasive Aspergillosis

Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602

The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in Study 307/602. The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg Q12h. Median duration of IV voriconazole therapy was 10 days (range 2-90 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2-232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0-1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1-85 days). Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 6). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 6).

Table 6 also summarizes the response (success) based on mycological confirmation and species.

Table 6: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602

Study 304

The results of this comparative trial (Study 307/602) confirmed the results of an earlier trial in the primary and salvage treatment of patients with acute invasive aspergillosis (Study 304). In this earlier study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 7.

Study 309/604

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 7. Overall mycological eradication for culture- documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 7.

Table 7 Combined Response Data in Salvage Patients with Single Aspergillus Species (Studies 304 and 309/604)

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

Candidemia in nonneutropenic patients and other deep tissue Candida infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 8.

Table 8: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen^a,b

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intraabdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

Esophageal Candidiasis

The efficacy of oral voriconazole 200 mg bid compared to oral fluconazole 200 mg od in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven esophageal candidiasis. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline.Voriconazole and fluconazole (200 mg od) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 9.

Table 9: Success Rates in Patients Treated for Esophageal Candidiasis

Microbiologic success rates by Candida species are presented in Table 10.

Table 10: Clinical and mycological outcome by baseline pathogen in patients with esophageal candidiasis (Study 150-305).

Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection. Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp. - Nine of 21 (43%) patients were successfully treated with voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

REFERENCES

1. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi. Approved Standard M38-P. Clinical Laboratory Standards Institute, Villanova, Pa.

2. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved Standard M27-A. Clinical Laboratory Standards Institute, Villanova, Pa.

3. Clinical Laboratory Standards Institute. Method for antifungal disk diffusion susceptibility testing of yeasts. Approved guideline M44-A. Clinical Laboratory Standards Institute, Villanova, Pa.

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