Treatment of candidal infections with fluconazole in neonates and infants.

UNLABELLED: To study the therapy, efficacy and safety of fluconazole in candidal mycoses during neonatal phase and infancy a case review in 53 newborns and infants was performed. The majority of these patients were premature with a median birth weight of 1120 g and born within gestational week 23-38. The median age at the onset of fluconazole treatment was 5 weeks. All patients had underlying diseases and several risk factors, which favored the occurence of a systemic candidal mycosis. Systemic candidiasis was the most frequent diagnosis (75.5%). Fluconazole was administered at a daily dosage of 5-6 mg/kg for a median duration of 21 days. The hepatic, renal and hematologic functions were assessed before, one, two, and three weeks after start of treatment. Yeasts were identified in 37 patients. The most common fungus isolated at baseline was Candida albicans (68%). Clinical cure or improvement was reported in 31 out of 38 patients (81.6%). Mycological cure was achieved in 25 out of 32 newborns and infants. Despite the limited number of patients with outcome data, these preliminary results of a small cohort clearly indicate the effective antifungal therapy with fluconazole in neonates and infants. No serious side effects were observed in fluconazole-treated patients. Two patients with megaureter-megacystis-hydronephrosis syndrome and severe meningoencephalitis showed a mild increase in liver enzymes. - CONCLUSION: Fluconazole seems to be an effective therapy for systemic and other forms of candidiasis in infants including very low birth weight infants (VLBWI; <1500 g). These favorable safety and efficacy data are similar to results obtained with fluconazole in older children and adults. These findings, however, must be supported by larger trials. The recommended daily dose is 5 mg/kg body weight. Only in VLBWI the dosage interval within the first two weeks of life should be prolonged up to 3 days and fluconazole serum levels should be monitored.

Administration of fluconazole in children below 1 year of age.

For this review, 78 studies regarding the use of fluconazole in a total of 726 children below 1 year of age were evaluated. The range of fluconazole dosage was 2-50 mg kg-1 day-1, with 162 days being the maximum duration of treatment. According to current experience, fluconazole seems to be well tolerated and efficacious against systemic candidosis and candidaemia in children below 1 year of age, including neonates and very low-birthweight infants (VLBWIs). The recommended daily dosage is 6 mg kg-1. (In Germany, fluconazole is approved for children between 1 and 16 years in cases in which there is no therapeutic alternative for treatment of systemic infections caused by Candida spp. and Cryptococcus neoformans in a dosage of 3-6 mg kg-1 day-1 and for superficial Candida infections in a dosage of 1-2 mg kg-1 day-1.) In patients with impaired renal function, the daily dose should be reduced in accordance with the guidelines given for adults. In neonates during the first 2 weeks of life, this dosage should be administered only every 72 h. In weeks 2-4 of life, the same dose should be given every 48 h, following which daily dosing is appropriate. This posology is derived from the age-related pharmacokinetics of fluconazole, with a higher volume of distribution and a prolonged plasma elimination half-life, especially during the first month of life. Drug monitoring during treatment should be performed to ensure therapeutic plasma concentrations of fluconazole within a range between 4 and 20 micrograms ml-1. The benefit of fluconazole should be investigated in prospective studies for treatment of systemic candidosis with administration of higher dosages as well as for early empiric therapy in VLBWIs.

Dosage adjustment of fluconazole during continuous renal replacement therapy (CAVH, CVVH, CAVHD, CVVHD).

Continuous arterio-venous haemofiltration (CAVH), continuous veno-venous haemofiltration (CVVH), continuous arterio-venous haemodialysis (CAVHD) and continuous veno-venous haemodialysis (CVVHD) are increasingly used in patients with acute renal failure (ARF). The elimination rate of fluconazole varies considerably depending on the procedure used. (In Germany, fluconazole is approved for the treatment of life-threatening fungal infections caused by Candida spp. and Cryptococcus neoformans at a dosage of up to 800 mg day-1.) The elimination rate of fluconazole by CVVHD depends on the combined dialysate/ultrafiltrate flow rate, but is much higher than achieved with CVVH and intermittent dialysis, with a fluconazole clearance in patients with CVVHD 2 l h-1 exceeding the values of healthy persons. To achieve therapeutic plasma levels during continuous renal replacement therapy, the same loading dose as in patients without renal failure should be administered, followed by a maintenance dose that is adjusted for anuric patients by multiplying by a factor that takes into account the extracorporeal elimination of the absorbed dose (CAVH, CVVH x 2.2, ultrafiltrate flow 0.5 l h-1; CAVHD, CVVHD x 3.8, combined dialysate/ultrafiltrate flow 1.5 l h-1). Despite the broad therapeutic margin of fluconazole, drug monitoring is recommended to achieve therapeutic drug levels in life-threatening indications because there have been only a few investigations of this, all involving relatively low dosages (up to 200 mg day-1).

Special pharmacokinetics of fluconazole in septic, obese and burn patients.

Although there are many potential changes of pharmacokinetic parameters in patients with thermal injury, obesity or septicemia, data about the actual effect on pharmacokinetics and clinical efficacy of fluconazole are very limited. As current dosing recommendations are derived from healthy subjects and patients with normal weight, these recommendations may be inaccurate when applied to the patient populations mentioned above. Pharmacokinetic data of 14 patients with thermal injury were reviewed and revealed a shorter half life and more rapid clearance of fluconazole. In a subgroup of five patients, distribution volume was up to 2 times larger as usual with no relationship to creatinine clearance and degree of burns. In one extremely obese patient treated with fluconazole 1200 mg/day, the corresponding mean steady-state plasma concentration and AUC were decreased with an increase of fluconazole clearance possibly due to a larger volume of distribution. In patients with septicemia, fluconazole plasma levels appear to be highly variable. As a considerable number of these patients develops acute renal failure, renal replacement therapy may be indicated which may require substantial dosage modifications of fluconazole.

Role of fluconazole in the long-term suppressive therapy of fungal infections in patients with artificial implants.

With the increased use of artificial implants the management of related infections has become an important challenge. Normally an infected implant would be removed. In many cases this might be contraindicated and drug treatment remains as the only alternative. As microbiological eradication is often impossible, especially in fungal infections at artificial implants (FIAI) long-term suppressive therapy might be required. The objective of this study was to determine the therapeutic value of fluconazole (F) in the management of FIAI. Clinical data of 56 patients (pts) with proven or suspected fungal infections and artificial implants (FIAI) subsequently treated with F were analyzed retrospectively. FIAI caused by species with intrinsic resistance to F have been excluded from the study. The following implants were involved: prosthetic valve endocarditis (PVE) 25 pts (44.6%), intraocular lenses (IL) 9 pts (16.1%), ventriculoperitoneal shunts (VPS) 6 pts (10.7%), knee prostheses (KP) 5 pts (8.9%), biliary stents (BS) 4 pts (7.1%), venous access devices (VAS) 3 pts (5.4%), urinary stents (US) 2 pts (3.6%), breast implant and pacemaker 1 patient (1.8%) each. Underlying diseases were valve insufficiency (in PVE), cataract surgery (in IL), prematurity in newborns (in VPS), arthrosis (in KP), biliary obstruction (in BS), cystic fibrosis (in VAS), and obstructive renal calculi (in US). Candida species (C. spp.) were the most frequently detected causative agents with C. parapsilosis as the leading cause (n = 19; 33.9%). Furthermore C. albicans (n = 15; 26.8%), C. spp. and fungi not further specified (n = 8; 14.3%), C. tropicalis (n = 3; 5.4%), C. glabrata (n = 3; 5.4%), and C. lusitaniae (n = 1; 1.8%) were identified. Acremonium kiliense has been detected in 4 pts (7.1%), Cryptococcus neoformans in 2 pts (3.6%). Histoplasma capsulatum was identified in 1 patient (1.8%). The maximum duration of treatment with F was lifelong with a maximum recorded duration of 4.5 years. The maximum dosage used was 750 mg/d or 50 mg/kg BW in premature infants. No major adverse events were observed. In conclusion, especially the excellent safety profile as well as the documented therapeutic experience justify the use of F as long-term suppressive therapy in FIAI. Higher dosages and even life-long treatment may be needed.

Therapeutic experience with fluconazole in the treatment of fungal infections in diabetic patients.

Diabetes mellitus is associated with a higher incidence of certain infections, including fungal infections like rhinocerebral zygomycosis (RCZ) and cutaneous candidosis. As the pathophysiology of increased susceptibility to infection of diabetic patients is very complex, a general therapeutic approach is not existing yet. Appropriate diabetes control remains as the best preventive measure. Nevertheless, effective drug therapy is very often required. Fluconazole has proven efficacy in prophylaxis, treatment and suppressive therapy of both systemic and superficial fungal infections, especially in candidosis and cryptococcosis. Therefore it is used routinely against fungal infections in diabetes (FID). Clinical efficacy of fluconazole against cutaneous candidosis, oropharyngeal candidosis (OPC) and vulvovaginal candidosis (VVC) has been confirmed in more than 100 studies, involving more than 10,000 patients (pts). The overall success rate is 90%, with a mean dosage of 100-200 mg/d. In severe cases, e.g. in OPC in late-stage AIDS pts or in recurrent VVC, higher dosages of up to 800 mg/d may be required. In the treatment of RCZ, therapeutic experience with fluconazole is limited. Four diabetic pts have been treated with dosages of 200-300 mg/d and all of them recovered. Nevertheless, treatment of RCZ should include surgical debridement combined with aggressive antifungal therapy. In conclusion, proven efficacy and the excellent safety profile justify the routine use of fluconazole in the treatment of FID.

Therapeutic experience with fluconazole in the treatment of fungal infections in diabetic patients.

Diabetes mellitus is associated with a higher incidence of certain infections, including fungal infections like rhinocerebral zygomycosis (RCZ) and cutaneous candidosis. As the pathophysiology of increased susceptibility to infection of diabetic patients is very complex, a general therapeutic approach is not existing yet. Appropriate diabetes control remains as the best preventive measure. Nevertheless, effective drug therapy is very often required. Fluconazole has proven efficacy in prophylaxis, treatment and suppressive therapy of both systemic and superficial fungal infections, especially in candidosis and cryptococcosis. Therefore it is used routinely against fungal infections in diabetes (FID). Clinical efficacy of fluconazole against cutaeneous candidosis, oropharyngeal candidosis (OPC) and vulvovaginal candidosis (VVC) has been confirmed in more than 100 studies, involving more than 10.000 patients (pts). The overall success rate is 90%, with a mean dosage of 100-200 mg/d. In severe cases, e.g. in OPC in late-stage AIDS pts or in recurrent VVC, higher dosages of up to 800mg/d may be required. In the treatment of RCZ, therapeutic experience with fluconazole is limited1,2 . Four diabetic pts have been treated with dosages of 200-300 mg/d and all of them recovered. Nevertheless, treatment of RCZ should include surgical debridement combined with aggressive antifungal therapy. In conclusion, proven efficacy and the excellent safety profile justify the routine use of fluconazole in the treatment of FID.

Role of fluconazole in the long-term suppressive therapy of fungal infections in patients with artificial implants.

With the increased use of artificial implants the management of related infections has become an important challenge. Normally an infected implant would be removed. In many cases this might be contraindicated and drug treatment remains as the only alternative. As microbiological eradication is often impossible, especially in fungal infections at artificial implants (FIAI) long-term suppressive therapy might be required. The objective of this study was to determine the therapeutic value of fluconazole (F) in the management of FIAI. Clinical data of 56 patients (pts) with proven or suspected fungal infections and artificial implants (FIAI) subsequently treated with F were analyzed retrospectively. FIAI caused by species with intrinsic resistance to F have been excluded from the study. The following implants were involved: prosthetic valve endocarditis (PVE) 25 pts (44.6%), intraocular lenses (IL) 9 pts (16.1%), ventriculoperitoneal shunts (VPS) 6 pts (10.7%), knee prostheses (KP) 5 pts (8.9%), biliary stents (BS) 4 pts (7.1 %), venous access devices (VAS) 3 pts (5.4%), urinary stents (US) 2 pts (3.6%), breast implant and pacemaker 1 patient (1.8%) each. Underlying diseases were valve insufficiency (in PVE), cataract surgery (in IL), prematurity in newborns (in VPS), arthrosis (in KP), biliary obstruction (in BS), cystic fibrosis (in VAS), and obstructive renal calculi (in US). Candida species (C. spp.) were the most frequently detected causative agents with C. parapsilosis as the leading cause (n = 19; 33.9%). Furthermore C. albicans (n = 15; 26.8%), C. spp. and fungi not further specified (n = 8; 14.3%), C. tropicalis (n = 3; 5.4%), C. glabrata (n = 3; 5.4%), and C. lusitaniae (n = 1; 1.8%) were identified. Acremonium kiliense has been detected in 4 pts (7.1%), Cryptococcus neoformans in 2 pts (3.6 %). Histoplasma capsulatum was identified in 1 patient (1.8%). The maximum duration of treatment with F was lifelong with a maximum recorded duration of 4,5 years. The maximum dosage used was 750 mg/d or 50 mg/kg BW in premature infants. No major adverse events were observed. In conclusion, especially the excellent safety profile as well as the documented therapeutic experience justify the use of F as long-term suppressive therapy in FIAI. Higher dosages and even life-long treatment may be needed.

Special pharmacokinetics of fluconazole in septic, obese and burn patients.

Although there are many potential changes of pharmacokinetic parameters in patients with thermal injury, obesity or septicemia, data about the actual effect on pharmacokinetics and clinical efficacy of fluconazole are very limited. As current dosing recommendations are derived from healthy subjects and patients with normal weight, these recommendations may be inaccurate when applied to the patient populations mentioned above. Pharmacokinetic data of 14 patients with thermal injury were reviewed and revealed a shorter half life and more rapid clearance of fluconazole. In a subgroup of five patients, distribution volume was up to 2 times larger as usual with no relationship to creatinine clearance and degree of burns. In one extremely obese patient treated with fluconazole 1200 mg/day*, the corresponding mean steady-state plasma concentration and AUC were decreased with an increase of fluconazole clearance possibly due to a larger volume of distribution. In patients with septicemia, fluconazole plasma levels appear to be highly variable. As a considerable number of these patients develops acute renal failure, renal replacement therapy may be indicated which may require substantial dosage modifications of fluconazole.

[Value of high dosage fluconazole in therapy of candida infections in intensive care medicine]. / Stellenwert von hochdosiertem Fluconazol zur Therapie von Candida-Infektionen in der Intensivmedizin.

The administration of fluconazole in the ICU setting in dosages of > or = 800 mg/day or > or = 10 mg/kg/day has been reported in about 400 patients with candidiasis of different localisation including candidemia, with a rapidly increasing incidence of serious candidal infections. In Germany, fluconazole is approved for therapy of life-threatening infections caused by Candida spp. and Cryptococcus neoformans in a dosage of up to 800 mg/day. Especially in non-neutropenic patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, the results of a limited number of dose-finding trials show dose-dependent response rates. These findings strongly advocate the application of high-dose fluconazole; their evaluation, however, still awaits final clarification. The good safety profile even for maximum dosages of up to 2000 mg/day and the linear, predictable pharmacokinetics up to 1600 mg/day indicate the excellent tolerability of fluconazole in the clinical situation, which justifies prospective, randomized clinical trials with treatment groups as homogeneous as possible for further evaluation of the optimum dosage and duration of treatment in the various types of candidal infection.

[Use of fluconazole in children less than 1 year old: review]. / Anwendung von Fluconazol bei Kindern < 1 Jahr: Ubersicht.

For this review, 78 publications for use of fluconazole in children below 1 year of age were evaluated with a total of 726 patients. The range of fluconazole dosage was 2-50 mg/kg/day with 162 days as maximum duration of treatment. According to the present experience, fluconazole seems to be an efficacious and well tolerated therapy against systemic candidosis and candidemia in children below 1 year of age, including neonates and very low birth-weight infants (VLBWI). The recommended daily dosage is 6 mg/kg. In patients with impaired renal function, the daily dose should be reduced in accordance with the guidelines given for adults. In neonates during the first two weeks of life, this dosage should be administered only every 72 hours. In weeks two to four of life, the same dose should be given every 48 hours. After that daily dosing is appropriate. This posology is derived from the age-related pharmacokinetics of fluconazole with a higher volume of distribution and a prolonged plasma elimination half life especially during the first month of life. Drug monitoring during treatment should be performed to ensure therapeutic plasma concentrations of fluconazole within a range between 4 and 20 micrograms/ml. The benefit of fluconazole should be investigated in prospective studies for treatment of systemic candidosis with administration of higher dosages as well as for early empiric therapy in VLBWI.

[Status of fluconazole in the therapy of endogenous Candida endophthalmitis]. / Der Stellenwert von Fluconazol in der Therapie der endogenen Candida-Endophthalmitis.

During the clinical course of invasive candidosis, endogenous Candida endophthalmitis (ECE) is associated with a higher mortality. In patients with candidemia, an ECE-incidence of 28 to 37% was reported. In i.v.-drug users, the incidence of Candida infections was 21%. Besides surgical procedures including vitrectomy and enucleation, early initiation of systemic antifungal therapy is decisive for the outcome. The clinical use of fluconazole in ECE is documented in 96 patients and in a minimum of 108 eyes. The mean duration of therapy was 6-8 weeks (maximum duration: lifelong) with an average dosage of 200-400 mg/d (maximum dosage: 800 mg/d and 14 mg/kg BW, resp.). The results reported in the literature show a good clinical efficacy of fluconazole in ECE: 90% response rate (19/21) in patients with/without concomitant vitrectomy and with/without concomitant use of other antifungals, complete disappearance of all eye lesions in 94% (15/16) non-neutropenic patients with candidemia and in 86% (6/7) ECE-patients addicted to heroin. With respect to these favorable results, fluconazole plays an important role in the standard therapy of ECE.

[Fungal arthritis--a rare complication of systemic candidiasis or orthopedic intervention. Review of therapeutic experience with fluconazole]. / Pilzarthritis--eine seltene Komplikation systemischer Candidosen bzw. orthopädischer Eingriffe. Review der Therapieerfahrung mit Fluconazol.

The higher number of implanted artificial joints, the broader use of aggressive treatment regimen, e.g. high-dose chemotherapy and total parenteral nutrition, the increasing use of central venous catheters and a broader use of immunosuppressive drugs are likely to result in a higher incidence of fungal arthritis, especially caused by Candida spp. Therefore, a careful evaluation of the available therapeutic options is necessary. The published clinical data on the therapeutic use of fluconazole in the treatment of fungal arthritis were reviewed. A total of 24 publications report the use of fluconazole in fungal arthritis in 32 patients. The mean duration of therapy was 6 months (maximum duration: 2 years) with an average dosage of 200-400 mg/d (maximum dosage: 800 mg/d). Native arthritis was diagnosed in 27 patients, prosthetic arthritis in 5 patients. In all patients an isolated joint was infected, most frequently the knee joint. Fluconazole was effective and safe in acute therapy alone or in combination with surgery as well as in long term suppression therapy.

[Pharmacokinetics and dosage of fluconazole in continuous hemofiltration (CAVH, CVVH) and hemodialysis (CAVHD, CVVHD)]. / Pharmakokinetik und Dosierung von Fluconazol bei kontinuierlichen Hämofiltrations- (CAVH, CVVH) und Hämodialyseverfahren (CAVHD, CVVHD).

Continuous haemofiltration (CAVH, CVVH) and haemodialysis (CAVHD, CVVHD) are increasingly used in patients with acute renal failure (ARF). The elimination rates of fluconazole vary considerably among the different procedures. In CVVHD, the elimination rate is, depending on the combined dialysate/ultrafiltrate flow rate, the most marked compared to CVVH and intermittent dialysis with a fluconazole clearance exceeding the values of healthy persons in CVVHD 2 L/h. To achieve therapeutic plasma levels during continuous renal replacement therapy, the same loading dose as in patients without renal failure should be applied, followed by the adjusted maintenance dose for anuric patients multiplied by a factor taking the extracorporeal elimination of the absorbed dose into account (CAVH, CVVH: x 2.2, ultrafiltrate flow 0.5 L/h; CAVHD, CVVHD: x 3.8, combined dialysate/ultrafiltrate flow 1.5 L/h). Despite the broad therapeutic margin of fluconazole, drug monitoring is recommended with respect to the very limited number of investigations with relatively low dosages up to 200 mg/day and--which is of paramount importance--to achieve therapeutic drug levels in vital indications.

Plasma and tissue concentrations of fluconazole and their correlation to breakpoints.

The prediction of clinical outcome during antifungal therapy is an issue of paramount importance in clinical research, because no consistently reliable parameters are available. Minimum inhibitory concentration (MIC) values and breakpoint interpretation may serve as surrogate criteria until standardized in vitro antifungal susceptibility testing is developed, especially for fluconazole. With reproducible susceptibility testing methods for Candida species now available, tentative fluconazole interpretive breakpoints derived from MIC values determined by the National Committee on Clinical Laboratory Standards (NCCLS) M27-T broth macrodilution method are open for public comment. Besides the in vitro susceptibility of the fungus, clinical response to antifungal therapy with fluconazole depends to a great extent on the daily dose and corresponding plasma and tissue concentrations. Promising results from a few dose-finding studies in non-neutropenic patients show that fluconazole doses of up to 1000 mg day-1 result in higher clinical response rates than lower dosages. Therapeutic success depends substantially on achieving fluconazole plasma and tissue levels that are sufficiently higher than MIC values indicated by in vitro testing. However, this simplified concept must be related to the clinical situation and it is essential to consider the immunological status and underlying disease of the patient. Misinterpretation of MIC values may result in selection of an antifungal agent for life-threatening infections that does not provide optimal efficacy or toleration.

[High-dose therapy with fluconazole > or = 800 mg/day. Review]. / Hochdosis-Therapie mit Fluconazol > oder = 800 mg/die. Literaturübersicht.

The clinical use of fluconazole in dosages > or = 800 mg/day has been reported in about 900 patients against candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients as well as for initial therapy of endemic mycoses. Especially in patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, the results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent response rates. These findings strongly advocate the application of high dose-fluconazole; their evaluation, however, still awaits final clarification. The good safety profile for dosages up to 2000 mg/day and the linear, predictable pharmacokinetics up to 1600 mg/day indicate the excellent tolerability of fluconazole in the clinical situation which justifies prospective, randomized clinical trials with treatment groups as homogeneous as possible for further evaluation of the optimum dosage and duration of treatment.

High-dose therapy with fluconazole > or = 800 mg day-1.

Fluconazole dosages greater than 800 mg day-1 have been reported in about 900 patients treated for candidemia, oropharyngeal candidiasis and cryptococcal meningitis in HIV-infected patients, and for initial therapy of endemic mycoses. In patients with life-threatening infections caused by Candida spp., Cryptococcus neoformans and Coccidioides immitis, results of a limited number of dose-finding trials with non-neutropenic and HIV-infected patients show dose-dependent responses. These study results indicate that higher daily doses of fluconazole than are currently approved for these indications are well tolerated and tend to provide better clinical efficacy in selected patient populations. An excellent safety profile of dosages up to 2000 mg day-1 and linear predictable pharmacokinetics up to 1600 mg day-1 appear to justify further clinical investigations to better determine the optimum dosage and duration of treatment.

[Plasma and tissue concentrations of fluconazole: discussion of the breakpoint problem]. / Plasma- und Gewebekonzentrationen von Fluconazol: Diskussion der Breakpoint-Problematik.

The reliable prediction of the clinical outcome during antifungal therapy is an issue of paramount priority in clinical research, since there are no appropriate parameters available. MIC values and in the future breakpoints may serve as surrogate criteria if further standardization of in vitro antifungal susceptibility testing especially for fluconazole leading to improved interlaboratory reproducibility of the test results can be provided. With reproducible susceptibility testing methods for Candida species now being available, tentative fluconazole interpretative breakpoints derived from MICs determined by the NCCLS M27-T broth macrodilution methodology are now open for public commentary. Besides the proven susceptibility of the fungus, clinical response to antifungal therapy with fluconazole also depends to a great extent on the daily dosage and the corresponding plasma and tissue concentrations as well as the immunological status and the underlying disease of the patient. The promising results of a relatively small number of dose finding studies with fluconazole in non-neutropenic patients indicate that with daily doses up to 1000 mg/die higher clinical response rates compared to those under lower dosages can be achieved. In view of future valid breakpoints, higher corresponding plasma and tissue levels of fluconazole should be achieved on which the therapeutic success depends substantially. However, this simplified concept needs several adjustments. Misinterpretation of MIC values and breakpoints may have as a consequence that patients with often life-threatening fungal infections may not be treated with an efficacious and better tolerated agent.