Standard Antifungal Therapy Research Articles

Candida albicans growth and germ tube formation can be inhibited by simple diphenyl diselenides [(PhSe)2, (MeOPhSe)2, (p-Cl-PhSe)2, (F3CPhSe)2] and diphenyl ditelluride

Candida species are the fourth most common cause of nosocomial bloodstream infections. An increase in the frequency of infections, which have become refractory to standard antifungal therapy, has been observed. Recent studies have shown that the pro-oxidant properties of diphenyl diselenide (PhSe)(2), a structurally simple organoselenium compound, can be toxic to yeast. The objective of this work was to study, under non-reactive oxygen species (ROS)-generating conditions, the effect of different organochalcogenide compounds [(PhSe)(2), (PhTe)(2), (MeOPhSe)(2), (p-Cl-PhSe)(2) and (F(3)CPhSe)(2)] on growth and germ tube formation by Candida albicans. A decrease in C. albicans growth in the presence of crescent concentrations of (PhSe)(2), (PhTe)(2) and (MeOPhSe)(2) was observed. The organochalcogenide compound concentration needed to inhibit 50% (IC50) of the Candida growth was 0.5-2 and 2-10 μmol l(-1), at a cell density of 10(5) and 10(6) cells ml(-1), respectively. The compounds (p-Cl-PhSe)(2) and (F(3)CPhSe)(2) were able to inhibit the cell growth, although the inhibition was considerably weaker than that by (PhSe)(2), (PhTe)(2) and (MeOPhSe)(2). In Candida suspensions incubated in a medium containing serum as an inducer of germ tube formation, the presence of either (PhSe)(2) or (MeOPhSe)(2) at 10 μmol l(-1) completely inhibited the number of cells which formed germ tubes. These results demonstrate the potential of organochalcogenide compounds to inhibit both C. albicans growth and germ tube formation.

Disseminated Fusarium infection with brain abscesses in a lung transplant recipient

To detail a case of disseminated Fusarium infection in an immunocompromised adult. Fusarium sp. infections are an important cause of fungal keratitis in immunocompetent patients and a recent outbreak related to use of a specific type of contact lens solution made national and international newspaper headlines. While reports of disseminated infection in immunosuppressed patients have appeared over the last 30 years, few have emphasized the neuropathological aspects of this emerging pathogen. Woman with pulmonary sarcoidosis necessitating bilateral lung transplants 4 months prior to her demise who was soon readmitted with viral pneumonia. She developed targetoid skin lesions of her face and thigh; she succumbed before biopsy could be performed. Autopsy revealed systemic organ infection involving lungs, gastrointestinal tract mucosa, bilateral kidneys, and skin. Foci of acute cerebritis showed vessels occluded by hyphal, septate fungi. Fungal culture remains the gold standard for diagnosis, and culture grew Fusarium. Fusarium is resistant to standard antifungal therapies; the increasing use of antifungal medications - as either treatment or prophylaxis - may shift more infections toward unusual species such as Fusarium.

Disseminated cryptococcosis in an HIV-negative pregnancy: a case of cryptococcal septic abortion complicating an immunocompetent pregnancy

Cryptococcus neoformans, a well-known pathogen of the immunocompromised host, is rarely reported as a cause of disseminated infection in the immunocompetent pregnant woman. Reported herein is the case of a young gravid woman, who initially presented with vague systemic symptoms that evolved into a disseminated cryptococcosis, which was resistant to standard parenteral antifungal therapy and resulted in abortion. Experience from this case suggests that cryptococcal infection should be considered in the differential diagnosis of pregnant women presenting with vague systemic symptoms such as fever, abdominal pain, and generalized lymphadenopathy.

Long-Term Efficacy and Safety of TDM-Assisted Combination of Voriconazole plus Efavirenz in an AIDS Patient with Cryptococcosis and Liver Cirrhosis

To report the efficacy, tolerability, and pharmacokinetic effects of combined voriconazole and efavirenz treatment administered at therapeutic drug monitoring (TDM)-based adjusted doses to a patient with AIDS, cryptococcosis, and mild liver cirrhosis. A 40-year-old man with AIDS (hemophiliac, antiretroviral-naïve, plasma HIV-RNA = 290,000 copies/mL, CD4+ lymphocytes = 0), hepatitis C virus-related liver cirrhosis (Child-Pugh class A), and cryptococcal meningitis was failing standard antifungal therapies. He received an antifungal-antiretroviral combination treatment based on the association of voriconazole plus efavirenz. Doses of both drugs were serially adjusted based on their plasma concentrations, which were evaluated at steady-state of each dose combination at least once (week 3.1 or later) as full concentration-time profile (samples collected at 0, 1, 2, 3, 4, 6, 8, 12 h postdose). Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dose adjustment (voriconazole 200 mg twice daily plus efavirenz 300 mg once daily, both administered orally). The patient showed prompt and stable suppression of cryptococcosis and plasma viremia of HIV at long-term follow-up (66 wk), with no significant adverse events. Standard therapies for cryptococcosis in patients with AIDS are often not effective. Voriconazole, despite its promising anticryptococcal efficacy, is currently not approved for cryptococcosis therapy in the US and Europe, nor is it recommended for combination with efavirenz due to the significant pharmacokinetic interactions between the 2 compounds. Thus far, published studies regarding the effects of voriconazole in human cryptococcosis are scarce and none has described the clinical and pharmacokinetic outcomes of a voriconazole/efavirenz combination in patients with AIDS, either with or without liver cirrhosis. The combination of voriconazole and efavirenz at TDM-assisted doses may represent a valuable therapeutic option in AIDS patients with cryptococcosis and mild liver cirrhosis.

Topical and Oral Voriconazole in the Treatment of Fungal Keratitis

We describe two patients with fungal keratitis refractory to standard antifungal therapy whose conditions were managed with voriconazole.The first case is a patient with endophthalmitis and corneal ulcer due to Candida parapsilosis after receiving a corneal transplant. The patient was treated with amphotericin but showed no signs of improvement. Topical voriconazole, oral voriconazole, and intravitreal voriconazole yielded signs of improvement. The second case is a 63-year-old male who underwent a month of empiric treatment with 0.2% topical amphotericin for fungal keratitis but showed no signs of improvement. Treatment was then provided with 1% voriconazole. Both cases showed effective treatment with voriconazole.Voriconazole may be considered as a new method to treat fungal keratitis refractory to standard antifungal therapy.

Posaconazole as Salvage Therapy in Patients With Invasive Fungal Infections After Solid Organ Transplant

The incidence of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients has increased during the past 20 years and is associated with significant morbidity and mortality. In this post hoc analysis of a large, open-label, multicenter study, we evaluated efficacy and safety of posaconazole, a new extended-spectrum triazole, as salvage therapy for IFIs in SOT recipients. Twenty-three SOT recipients with proven or probable IFI and evidence of disease refractory to, or intolerant of, standard antifungal therapies received posaconazole oral suspension (40 mg/mL) 800 mg daily in divided doses. An independent, blinded data-review committee assessed patient diagnosis and outcome. Complete or partial response was documented in 13 of 23 (57%) SOT recipients with proven or probable IFIs, including 1 of 2 (50%) refractory patients, 5 of 8 (63%) intolerant to prior therapy, and 7 of 13 (54%) who were both. Successes by type of IFI included 7 of 12 with invasive aspergillosis, 2 of 2 with invasive fusariosis, 1 of 1 with cryptococcosis, and 1 of 2 with zygomycosis. Treatment-related adverse events (TRAEs) were reported in 12 of 23 patients. Severe TRAEs occurred in 4 of 23 patients including increased levels of cyclosporine or tacrolimus requiring immunosuppressive dose adjustments in three patients and in one, termination of posaconazole. Severe TRAEs associated with renal and liver toxicities were uncommon. Posaconazole was well tolerated and effective against IFIs including invasive aspergillosis, zygomycosis, fusariosis, and cryptococcosis in SOT recipients intolerant of or failing other antifungal therapies. Calcineurin inhibitor levels should be closely monitored in patients treated concomitantly with posaconazole to avoid toxicity from drug interaction.

Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment

The aim of this study is to determine the efficacy and safety of posaconazole in patients with underlying renal impairment. Patients and methods We analysed the efficacy and safety of posaconazole in patients with renal impairment in a post hoc subanalysis of a Phase 3, multicentre, open-label trial in patients with invasive fungal infections (IFIs). In the Phase 3 study, 330 patients intolerant of or with IFIs refractory to standard antifungal therapy received posaconazole 800 mg daily in divided doses. In our subanalysis, 238 patients with proven/probable IFIs, including 65 patients with renal impairment (creatinine clearance < 50 mL/min or serum creatinine (sCR) level >2 mg/dL at baseline) and 173 patients with greater renal function [creatinine clearance >/= 50 mL/min (acceptable renal function)], formed the modified intent-to-treat population. Success was defined as complete or partial response, and non-success was defined as stable disease or treatment failure. Overall response rates were similar in the renal impairment group (49%) and in the acceptable renal function (50%) group. Seventeen of the 41 patients with renal impairment and aspergillosis responded. Adverse events occurred in 32/65 (49%) patients with renal impairment and in 72/173 (42%) patients with acceptable renal function. The most common adverse events in both groups were nausea (14% patients with renal impairment versus 8% with acceptable renal function), altered/elevated levels of other medications (8% versus 2%), increased sCR levels (6% versus 0%), vomiting (6% versus 4%), abdominal pain (5% versus 5%) and dizziness (5% versus 1%). These results suggest that posaconazole is effective and well tolerated in patients with refractory IFIs regardless of renal impairment.

Newer Emerging Pathogens of Ocular Non-Sporulating Molds (NSM) Identified by Polymerase Chain Reaction (PCR)-Based DNA Sequencing Technique Targeting Internal Transcribed Spacer (ITS) Region

Purpose: To apply Polymerase Chain Reaction (PCR)-based DNA sequencing targeting Internal Transcribed Spacer (ITS) region for identification of non-sporulating molds (NSM) to species level which formed 12% of ocular isolates of fungi in a tertiary eye hospital in South India. Materials and Methods:Fifty ocular filamentous fungal NSM isolates recovered from 45 patients were included in the study. PCR-based DNA sequencing technique targeting ITS region was applied to identify NSM. Results: PCR-based DNA sequencing revealed 23 established pathogens involving 8 genera (Aspergillus, Fusarium, Bipolaris, Pythium, Cochilobolus, Exserohilum, Pseudoallescheria, and Scedosporiumspecies) and 27 emerging pathogens involving 7 genera (Botryosphaeria Lasiodiplodia species, Thielavia tortuosa, Glomerulla singulata, Macrophomina phaseolina, Rhizoctonia bataticola, and Podosporaspecies) reported for the first time in literature related to ocular infections. Fifteen (30%) patients with fungal keratitis caused by NSM failed to respond to standard antifungal therapy. Conclusion: PCR-based DNA sequencing technique is a rapid, reliable, and valuable tool to identify 54% of NSM as newer potential pathogens of fungi causing ocular mycoses.

Ability to grow on lipids accounts for the fully virulent phenotype in neutropenic mice of Aspergillus fumigatus null mutants in the key glyoxylate cycle enzymes

Incidence and mortality rates of invasive aspergillosis clearly indicate the need of novel antifungals to treat patients suffering from this disease. Fungal proteins playing a crucial role in pathogenesis and with no orthologue in human cells are considered as primary therapeutic targets for the development of new antifungals with a high therapeutic index, one of the major drawbacks of the standard antifungal therapy, so far. In this work, we have analyzed the role in pathogenesis of the key enzymes of the Aspergillus fumigatus glyxoxylate cycle, isocitrate lyase and malate synthase, two possible candidates to primary therapeutic targets in this fungus. Deletion strains lacking isocitrate lyase (Δ acuD strains) or malate synthase (Δ acuE mutants) were constructed in this work. The Neurospora crassa pyr-4 gene was used as the replacing marker in gene deletion experiments. The pathogenicities of Δ acuD and Δ acuE mutants were tested in neutropenic mice and compared with those of two reference wild-type isolates A. fumigatus 237 and A. fumigatus 293. Interestingly, virulence and cytological studies clearly indicated the dispensability of the A. fumigatus glyoxylate cycle for pathogenicity. In addition, these results suggested the suitability of the pyr-4 gene as a valuable replacing marker for virulence studies in this fungus, a fact that was further confirmed by gene expression analyses. Finally, growth tests were performed to investigate the germination and growth of the Δ acuD and ΔacuE strains in nutrient deprivation environments, resembling the conditions that A. fumigatus conidia face after phagocytosis. Results obtained in this work strongly suggest that the ability to grow on lipids (triglycerides) of A. fumigatus isocitrate lyase and malate synthase deletion strains accounts for their fully virulent phenotype.

Voriconazole

Voriconazole (VFEND), a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the cell membrane and halting fungal growth. In the US, intravenous and/or oral voriconazole is recommended in adults for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, disseminated infections caused by Candida spp., oesophageal candidiasis, and in patients with scedosporiosis and fusariosis who are refractory to or intolerant of other antifungal therapy. In Europe, intravenous and/or oral voriconazole is recommended in adults and paediatric patients of at least 2 years of age for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida spp. infections, scedosporiosis and fusariosis. In large randomised trials, voriconazole was an effective and generally well tolerated primary treatment for candidiasis and invasive aspergillosis in adults and adolescents. More limited data also support the use of voriconazole for the treatment of invasive fungal infections in children, in those with rare fungal infections, such as Fusarium spp. or Scedosporium spp., and in those refractory to or intolerant of other standard antifungal therapies. The availability of both parenteral and oral formulations and the almost complete absorption of the drug after oral administration provide for ease of use and potential cost savings, and ensure that therapeutic plasma concentrations are maintained when switching from intravenous to oral therapy. On the other hand, the numerous drug interactions associated with voriconazole may limit its usefulness in some patients. Further clinical experience will help to more fully determine the position of voriconazole in relation to other licensed antifungal agents. In the meantime, voriconazole is a valuable emerging option for the treatment of invasive aspergillosis and rare fungal infections, including Fusarium spp. and Scedosporium spp. infections, and provides an alternative option for the treatment of candidiasis, particularly where the causative organism is inherently resistant to other licensed antifungal agents.

Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis

Caspofungin inhibits synthesis of beta-1,3-glucan, an essential component of the Aspergillus cell wall. This echinocandin has demonstrated efficacy (45% success) as salvage monotherapy of invasive aspergillosis (IA). Interest remains as to whether caspofungin, in combination with other antifungal classes, can improve the efficacy against IA. The study involved 53 adults with documented IA who were refractory to or intolerant of standard antifungal therapy and received caspofungin and 1 other mold-active antifungal agent (at the investigator's discretion). Efficacy was assessed by signs, symptoms, and radiographs at the end of combination therapy and Day 84 after combination therapy initiation. Favorable (complete or partial) responses required significant clinical and radiographic improvement. Diagnoses and outcomes were assessed by an independent expert. Among the 53 patients enrolled the most common underlying diseases were acute leukemia (53%), lymphoma (11%), and chronic leukemia (6%). Pulmonary aspergillosis (81%) was the most common site, and most patients (87%) were refractory to prior therapy. Success at the end of combination therapy and Day 84 was 55% (29/53) and 49% (25/51), respectively. Fifty-seven percent of patients with neutropenia and 54% who received an allogeneic hematopoietic stem cell transplant responded favorably. Survival at Day 84 was 55%. Combination therapy, dosed on average for 31.3 days, was well tolerated. Two (4%) serious drug-related adverse events, both attributed to voriconazole, occurred. None of the patients discontinued caspofungin due to toxicity. Caspofungin in combination with a triazole or polyene was an effective alternative as salvage therapy for patients with recalcitrant Aspergillus infections.

Experiences with Caspofungin Plus Posaconazole in Immunocompromised Adults with Invasive Aspergillosis (IA) Refractory to Prior Standard Therapy.

Background: Aspergillosis is a lethal infection of immunocompromised patients that respond poorly to antifungal therapy. Caspofungin (CAS) or Posaconazole (POS) as salvage monotherapy for IA have response rates of 45% and 42% respectively. Preliminary results of in vitro studies, animal models and clinical studies suggest that combination therapy with azoles and echinocandins may have additive activity against Aspergillus species.Methods: Seven adult patients after unrelated haematopoietic stem cell transplantation, with proven, probable or possible IA (per EORTC/MSG criteria) and refractory to standard antifungal therapy received Caspofungin plus Posaconazole (standard monotherapy dosage). All patients had > 3 days of combination antifungal therapy. Underlying diseases were AML (n=5), Biphenotypic leukaemia (n=1), Mantle cell Lymphoma (n=1). Three patients were neutropenic (ANC<500), all patients received immunosuppressive medication. IA sites were lung (n=6) and liver (n=1). All patients were evaluable for toxicity. Efficacy was assessed by signs, symptoms and CT-scan/ultrasound. Favourable responses (complete or partial) required significant clinical and radiographic/ultrasound improvement.Results: Success at end of combination therapy (EOCT) was seen in six patients (86%). One critically ill patient died (due to bacterial sepsis and severe acute GvHD) four days after first administration of combination therapy. One patient with complete radiographic response died 20 days after EOCT due to bacterial sepsis in relapse of AML. Combination therapy at 4 to 59 (mean 35.7) days was well tolerated. No patient discontinued combination therapy due to toxicity. Follow up from start of combination therapy was 4 to 204 (mean 79.8) days.Conclusion: Randomized trials are warranted to determine whether this combination should be used as primary therapy for aspergillosis.

Posaconazole for treatment of refractory invasive fungal disease

Invasive fungal infections are usually associated with immunocompromised states About 40-60% of these patients are refractory to standard antifungal therapy We describe the effect of posaconazole in the treatment of a 12 years-old girl with uncontrolled diabetes mellitus with life-threatening cerebral mucor mycosis and a 4 year old girl boy with chronic granulomatous disease presenting with invasive Aspergillus nidulans infection.

Topical and Oral Voriconazole in the Treatment of Fungal Keratitis

To describe nine patients with fungal keratitis refractory to standard antifungal therapy whose condition was managed with voriconazole. Retrospective case series. Chart review of patients with fungal keratitis who were treated with topical and oral voriconazole. Nine patients were treated. Two patients were contact lens wearers who used multipurpose cleaning solutions. Corneal isolates found were Fusarium (three patients), Candida albicans (three patients), Alternaria (one patient), Scopulariopsis (one patient), and Scedosporium apiospermum (one patient). Nine patients were treated with topical voriconazole, and eight patients were treated with oral voriconazole. Patients were treated topically for four to 16 weeks (mean, 10 weeks) and orally for five to 17 weeks (mean, 10 weeks). One patient was lost to follow-up. Two patients discontinued the topical voriconazole after one day and four weeks, respectively, because of ocular burning. Of the seven patients who were treated with topical therapy and followed, five conditions healed. Voriconazole is a new, promising therapy for fungal keratitis that is refractory to standard antifungal treatments.

Exploring the Mode-of-Action of Bioactive Compounds by Chemical-Genetic Profiling in Yeast

Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of "chemical-genetic interaction" profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular pathways and proteins affected, we applied both a hierarchical clustering and a factorgram method, which allows a gene or compound to be associated with more than one group. In particular, tamoxifen, a breast cancer therapeutic, was found to disrupt calcium homeostasis and phosphatidylserine (PS) was recognized as a target for papuamide B, a cytotoxic lipopeptide with anti-HIV activity. Further, the profile of crude extracts resembled that of its constituent purified natural product, enabling detailed classification of extract activity prior to purification. This compendium should serve as a valuable key for interpreting cellular effects of novel compounds with similar activities.

Combination Antifungal Therapy in Organ Transplant Recipients

We thank Dr. Bal for his interest in our report and for his comments. Somewhat lower overall mortality rates in lung transplant recipients with invasive aspergillosis in the literature are attributable largely to cases with tracheobronchitis or bronchial anastomotic infections, a locally invasive form of aspergillosis (1). Mortality in the lung transplant recipients with invasive pulmonary aspergillosis is similar to that in other types of organ transplant recipients (1). In our study, 11/13 lung transplant recipients in the combination therapy group had invasive pulmonary aspergillosis, and only two had anastomotic infections (biopsy proven). A beneficial effect of combination therapy in the overall study population could not be attributed to a marginally higher number (P=0.21) of lung transplant recipients in this group (2). Indeed, most of the benefit of combination therapy appeared to be in non-lung transplant recipients. As shown in Table 3 (2), combination therapy was less beneficial in lung transplant recipients and was most beneficial in renal transplant recipients. Lung transplantation when added to the multivariate model in Table 2 (2) showed no correlation with mortality (hazard ratio 1.25; 95% CI: 0.53–2.97, P=0.60). The control group in the study by Herbrecht and colleagues received amphotericin B deoxycholate, and not a lipid formulation of amphotericin B (3). Indeed, there has been much speculation if the results of this study would have been different had a lipid formulation of amphotericin B been used instead of amphotericin B deoxycholate (4). At the time that our study was conceived and planned, lipid formulations of amphotericin B were the standard antifungal therapy for invasive aspergillosis in organ transplant recipients. With regards to mechanical ventilation, combination therapy appeared to be of greater benefit than lipid amphotericin B in ventilated patients. Mortality rate at 90 days was 46% (6/13) in mechanically ventilated patients in the combination therapy group and 74% (17/23) in those in the lipid amphotericin B group (hazard ratio 0.48; 95% CI: 0.20–1.15, P=0.10). Multivariate analysis showed that combination therapy was associated with improved survival in mechanically ventilated patients, but not in nonventilated patients (Table 1). Finally, we concur with the author and have explicitly noted in our paper the need for further studies in this important area.TABLE 1: Effect of combination therapy on 90-day mortality stratified by mechanical ventilationNina Singh Marilyn M. Wagener VA Medical Center and University of Pittsburgh Pittsburgh, PA

Caspofungin: an advanced treatment approach for suspected or confirmed invasive aspergillosis

Invasive aspergillosis occurs in a wide range of immunocompromised patients and is typically associated with an extremely poor prognosis. Caspofungin represents an additional therapeutic alternative to standard antifungal therapies in patients with suspected or confirmed invasive aspergillosis, as evidenced by a growing body of experience confirming its utility in treating this patient population. Caspofungin has demonstrated clinical efficacy when administered as salvage therapy in patients refractory to or intolerant of standard antifungal therapies, as first-line empirical therapy in patients with persistent febrile neutropenia and as combination therapy in difficult-to-treat patients refractory to or intolerant of standard therapies. Further studies are warranted to establish the effectiveness of caspofungin either alone or in combination as primary therapy for invasive aspergillosis.

Posaconazole as Salvage Treatment for Invasive Fusariosis in Patients with Underlying Hematologic Malignancy and Other Conditions

Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a > or = 70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. These results suggest that posaconazole is useful for the treatment of invasive fusariosis.

Cerebral blastomycosis: a case series incorporating voriconazole in the treatment regimen

Cerebral blastomycosis is a rarely reported disease. We report three cases of cerebral blastomycosis previously treated with standard antifungal therapy, which were subsequently successfully treated with voriconazole. The first is a 29-year-old man who initially presented with concomitant cutaneous and osseous blastomycosis; the second is a 50-year-old man who initially presented with prostatic, pulmonary and cutaneous lesions. The third patient was a 63-year-old man who presented with hemiplegia and multiple intra-cerebral blastomycomas. This report represents the first two documented relapses, in Canada, of CNS blastomycosis following treatment with itraconazole and, to our knowledge, among the first three worldwide human cases of cerebral blastomycosis treated successfully with voriconazole.

Intravenous Itraconazole vs. Amphotericin B Deoxycholate for Empirical Antifungal Therapy in Patients with Persistent Neutropenic Fever

BackgroundAmphotericin B dexoycholate is currently the standard empirical antifungal therapy for neutropenic patients with hematologic malignancies and who also have persistent fever that does not respond to antibacterial therapy. The antifungal triazoles offer a potentially safer and effective treatment alternative to Amphotericin B dexoycholate.MethodsWe assessed the efficacy and safety of intravenous itraconazole, as compared with the efficacy and safety of amphotericin B deoxycholate, as an empirical antifungal therapeutic agent in a matched case-control clinical trial from June 2004 to August 2005.ResultsEfficacy was evaluated in 96 patients (48 received itraconazole and 48 received amphotericin B deoxycholate) and all the patients who received the study drugs were evaluated for safety. The baseline demographic characteristics were well matched. The overall success rates were 47.9% for itraconazole and 43.8% for amphotericin B deoxycholate (% difference: 4.1% [95% confidence interval for the difference: -15.8 to 24]), which fulfilled the statistical criteria for the non-inferiority of itraconazole. The proportions of patients who survived for at least seven days after discontinuation of therapy or who were prematurely discontinued from the study were not significantly different between the two groups. The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in both groups. More patients who received amphotericin B deoxycholate developed nephrotoxicity, hypokalemia or infusion-related events than did those patients who received itraconazole (nephrotoxicity: 16.7% vs. 1.8%, hypokalemia: 66.7% vs. 24.6%, and infusion-related events: 41.7% vs. 3.5%, respectively).ConclusionsIntravenous itraconazole is as effective as amphotericin B deoxycholate and it is generally better tolerated than amphotericin B deoxycholate when it is given as empirical antifungal therapy for Korean patients with persistent neutropenic fever.