Successful treatment of disseminated cryptococcosis with liposomal amphotericin B and isavuconazole in an adult living with HIV: A case report and literature review.

Treating disseminated cryptococcosis in people with human immunodeficiency virus (HIV) is challenging due to the limited availability of effective antifungals. Although isavuconazole has antifungal activity against Cryptococcus neoformans, clinical evidence is sparse because this new drug has not been approved for the treatment of cryptococcosis in the US or Europe. Here, we report a case of HIV-associated cryptococcal meningitis that relapsed during maintenance therapy with fluconazole. A Japanese man in his 20s was diagnosed with HIV-1 infection and cryptococcal meningitis. The patient was intolerant to flucytosine and was treated with liposomal amphotericin B monotherapy for 2 weeks as induction therapy, followed by fluconazole (400 mg/day) for 3 months as consolidation therapy. Four months after starting maintenance therapy with fluconazole (200 mg/day), the patient presented with fever and cough, leading to readmission to our hospital. Biopsies of a nodule in the left lung and a left cervical lymph node led to the diagnosis of disseminated cryptococcosis (pulmonary cryptococcosis and cryptococcal lymphadenitis). Although a combination of fluconazole and liposomal amphotericin B was ineffective, the patient was successfully treated with an induction therapy combining isavuconazole and liposomal amphotericin B, followed by a maintenance therapy with isavuconazole. The patient received isavuconazole orally except for loading doses, achieving stable blood concentration levels. Moreover, we observed that blood levels of amphotericin B increased gradually with repeated administration. Therefore, isavuconazole may have a potential role in the treatment of cryptococcosis, and clinical trials involving larger numbers of cases are needed to confirm its efficacy and safety.

Using single-dose liposomal amphotericin B for cryptococcal meningitis induction therapy: nurse pearls and practical perspectives.

Background: In Uganda where the burden of HIV-associated cryptococcal meningitis is high, conventional amphotericin B deoxycholate has been standard to manage patients with cryptococcal meningitis in research settings. However, liposomal amphotericin B (AmBisome) is now available via the efforts of UNITAID. We sought to describe our nursing experience using AmBisome within a clinical trial for cryptococcal meningitis. Methods: We describe the experience of using single-dose 10mg/kg liposomal amphotericin B from the perspective of a research nurse in Uganda. Second, we described the process of preparing and administering amphotericin. Third, we assessed the nursing time required for the administration of daily amphotericin B versus single-dose liposomal amphotericin. Fourth, we discuss the major challenges faced while using liposomal amphotericin B. Results: We provide estimates for the nursing time required for reconstituting, filtering, diluting and administering liposomal amphotericin B and a visual aid for nursing tasks. Based on five trained nurses, the process of reconstitution and filtration lasts an average of 52 minutes (Range: 40 to 60 minutes), to reconstitute a mean of 11 (range: 8 to 15) 50mg vials (median weight 55kg). Overall, less nursing time was required for single-dose administration than for daily amphotericin B dosing. From a nursing perspective, liposomal amphotericin B was preferable to amphotericin B deoxycholate due to its reduced infusion reactions and other toxicities. Conclusions: Single-dose liposomal amphotericin B is a better alternative to daily amphotericin B. In addition to less toxicity, nosocomial infections, reduced hospital stay, and the potential for lower hospitalisation costs, the nursing implications should not be discounted. Quality nursing care is a finite resource in low- and middle-income countries, and single-dose amphotericin B reduced the nursing time required for the care of patients with cryptococcal meningitis.

In Uganda where the burden of HIV-associated cryptococcal meningitis is high, conventional amphotericin B deoxycholate has been standard to manage patients with cryptococcal meningitis in research settings. However, liposomal amphotericin B is now available via the efforts of UNITAID. Liposomal amphotericin B is known to be less nephrotoxic than amphotericin B deoxycholate. We demonstrated that liposomal amphotericin B is a better alternative to amphotericin B deoxycholate with less toxicity, nosocomial infections, reduced hospital stay, and the potential for lower costs of hospitalisation for both the patient and the healthcare system given the single, 10 mg/kg regimen. Despite the perceived high cost of liposomal amphotericin B and the tedious reconstitution process requiring training and adequate manpower, we believe that single-dose liposomal amphotericin B has enough advantages over the deoxycholate formulation to compel Ministries of Health to consider procuring liposomal amphotericin B as the drug of choice for the management of HIV-associated cryptococcal meningitis. The rollout will require training to facilitate widespread implementation, and we hope that this paper will serve to facilitate this training for nurses who will be using liposomal amphotericin B.

Effects of Amphotericin B-Conjugated Functionalized Carbon Nanoparticles in the Treatment of Cutaneous Leishmaniasis.

Leishmaniasis is a parasitic disease spread by the bite of an infected sandfly and caused by protozoan parasites of the genus Leishmania. Currently, there is no vaccine available for leishmaniasis in humans, and the existing chemotherapy methods face various clinical challenges. The majority of drugs are limited to a few toxic compounds, with some parasite strains developing resistance. Therefore, the discovery and development of a new anti-leishmanial compound is crucial. One promising strategy involves the use of nanoparticle delivery systems to accelerate the effectiveness of existing treatments. In this study, Amphotericin B (AmB) was incorporated into functionalized carbon nanotube (f-CNT) and evaluated for its efficacy against Leishmania major in vitro and in a BALB/c mice model. The increase in footpad thickness was measured, and real-time PCR was used to quantify the parasite load post-infection. Levels of nitric oxide and cytokines IL-4 and IFN-γ were also determined. We found that f-CNT-AmB significantly reduced the levels of promastigotes and amastigotes of the Leishmania parasite. The nanoparticle showed strong anti-leishmanial activity with an IC50 of 0.00494 ± 0.00095 mg/mL for promastigotes and EC50 of 0.00294 ± 0.00065 mg/mL for amastigotes at 72 h post-infection, without causing harm to mice macrophages. Treatment of infected BALB/c mice with f-CNT-AmB resulted in a significant decrease in cutaneous leishmania (CL) lesion size in the foot pad, as well as reduced Leishmania burden in both lymph nodes and spleen. The levels of nitric oxide and IFN-γ significantly increased in the f-CNT-AmB treated groups. Also, our results showed that the level of IL-4 significantly decreased after f-CNT-AmB treatment in comparison to other groups. In conclusion, our results demonstrate that AmB loaded into f-CNT is significantly more effective than AmB alone in inhibiting parasite propagation and promoting a shift towards a Th1 response.

Formulation Strategies to Overcome Amphotericin B Induced Toxicity.

Fungal infection poses a major global threat to public health because of its wide prevalence, severe mortality rate, challenges involved in diagnosis and treatment, and the emergence of drug-resistant fungal strains. Millions of people are getting affected by fungal infection, and around 3.8 million people face death per year due to fungal infection, as per the latest report. The polyene antibiotic AmB has an extensive record of use as a therapeutic moiety against systemic fungal infection and leishmaniasis since 1960. AmB has broad-spectrum fungistatic and fungicidal activity. AmB exerts its therapeutic activity at the cellular level by binding to fungal sterol and forming hydrophilic pores, releasing essential cellular components and ions into the extracellular fluid, leading to cell death. Despite using AmB as an antifungal and antileishmanial at a broad scale, its clinical use is limited due to drug-induced nephrotoxicity resulting from binding the aggregated form of the drug to mammalian sterol. To mitigate AmB-induced toxicity and to get better anti-fungal therapeutic outcomes, researchers have developed nanoformulations, self-assembled formulations, prodrugs, cholesterol- and albumin-based AmB formulations, AmB-mAb combination therapy, and AmB cochleates. These formulations have helped to reduce toxicity to a certain extent by controlling the aggregation state of AmB, providing sustained drug release, and altering the physicochemical and pharmacokinetic parameters of AmB. Although the preclinical outcome of AmB formulations is quite satisfactory, its parallel result at the clinical level is insignificant. However, the safety and efficacy of AmB therapy can be improved at the clinical stage by continuous investigation and collaboration among researchers, clinicians, and pharmaceutical companies.

A case report: Comorbidity of Rhinocerebral mucormycosis and pulmonary aspergillosis with challenging diagnosis.

Background: Mucormycosis is a rare opportunistic invasive fungal disease. Rhinocerebral mucormycosis (RCM) is clinically difficult to diagnose, and patients often die due to delayed diagnosis. Case description: A patient with concurrent pulmonary aspergillosis was diagnosed with RCM caused by Rhizopus through metagenomic Next-Generation Sequencing (mNGS). Despite comprehensive treatment including surgery, amphotericin B, and posaconazole, the patient tragically passed away. The treatment was delayed due to repeated cultures of secretions were negative and pathological examination could not clarify which fungus is infected. Conclusion: The clinical manifestations of RCM are not specific in the early stage, but the infection progresses rapidly. Therefore, early and accurate diagnosis is very important. mNGS is helpful for patients suspected of RCM, especially when conventional microbiology tests were negative.

Pre and Post Covid - 19 Experience of the 'Amphotericin Sandwich' Therapy in the Management of Mucormycosis.

Mucormycosis is caused by saprophytic fungi belonging to the species mucorales. The disease commonly affects patients with immunocompromised states such as uncontrolled diabetes, blood disorders and organ transplantation recepients. The usual mode of management is by using antifungals such as amphotericin B and surgery in the form of debridement of the necrotic tissue. A study was conducted on patients of mucormycosis during the pre-Covid-19 and Covid-19 era to evaluate the effectiveness of the Sandwich Therapy of amphotericin B. The mortality rate was found to be 3.57% during the pre- Covid-19 period and 18.8% during the Covid-19 period. This is very low as opposed to 50% quoted by many other studies. The Sandwich Therapy as discussed above for extensive mucormycosis can be useful in curtailing the disease already established to its present location and preventing its further spread either naturally or by the act of debridement per se. It also provides a sustained anti fungal umbrella in the blood to deal with the disease at microscopic level in the blood stream thus reducing mortality.

Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex.

The Candida haemulonii complex includes emerging opportunistic human fungal pathogens with documented multidrug-resistance profiles. It comprises Candida haemulonii sensu stricto, Candida haemulonii var. vulnera, Candida duobushaemulonii, Candida pseudohaemulonii, and Candida vulturna. In recent years, rates of clinical isolation of strains from this complex have increased in multiple countries, including China, Malaysia, and Brazil. Biofilm formation, hydrolytic enzymes, surface interaction properties, phenotype switching and cell aggregation abilities, extracellular vesicles production, stress response, and immune evasion help these fungi to infect the host and exert pathological effects. Multidrug resistance profiles also enhance the threat they pose; they exhibit low susceptibility to echinocandins and azoles and an intrinsic resistance to amphotericin B (AMB), the first fungal-specific antibiotic. AMB is commonly employed in antifungal treatments, and it acts via several known mechanisms. Given the propensity of clinical Candida species to initiate bloodstream infections, clarifying how C. haemulonii resists AMB is of critical clinical importance. This review outlines our present understanding of the C. haemulonii complex's virulence factors, the mechanisms of action of AMB, and the mechanisms underlying AMB resistance.

Invasive Ureteral Aspergillosis Causing an Abscess: A Report of a Rare Case.

Aspergillosis is a vicious fungal infection that can develop in immunosuppressed patients. The presence of aspergillosis in the ureter or elsewhere in the genito-urinary tract is highly uncommon and rarely reported in the literature. Here, we present a 54-year-old gentleman, with uncontrolled diabetes, who presented with urosepsis. Right hydronephrosis and ureteric stricture with urinary extravasation were seen on imaging. Right percutaneous nephrostomy was done, with drainage and analysis of the pus revealing the growth of Aspergillus fumigatus species. On open exploration, a ureteric abscess cavity, which was adherent to the duodenum, was drained and uretero-ureterostomy along with feeding jejunostomy was performed. Histopathological examination and special staining confirmed the growth of aspergillosis. The patient was treated with antifungal agents and responded well with an uneventful post-operative recovery.

Primary treatment of chronic pulmonary aspergillosis with weekly liposomal amphotericin B: A case report from Uganda.

Chronic pulmonary aspergillosis (CPA) treatment in Africa remains unexplored. We present a 23-year-old Ugandan male, previously treated thrice for pulmonary tuberculosis, developing CPA. Imaging showed lung fibrosis, bronchiectasis, and a fungal ball. He received weekly 600mg (10mg/kg) of liposomal amphotericin B for six weeks, leading to marked clinical improvement. Weekly liposomal amphotericin B may be a viable treatment option for CPA in resource-limited settings.

Best Practices in Treatment of Fungal Urinary Tract Infections.

Fungal pathogens within the urine, specifically Candida species, are a common finding amongst hospitalized patients. Risk factors for the development of candiduria involve patients with indwelling urinary drainage devices, surgical patients, patients undergoing urologic instrumentation, and diabetic patients. Candiduria often presents with an asymptomatic course but can also be a severe life-threatening process. This article will review the epidemiology and risk factors associated with fungal urinary tract infections, and the diagnosis and categorization of these infections along with a review of current medical and surgical treatments for this condition.

Efficacy of Diterpene Polyalthic Acid Combined with Amphotericin B against Leishmania amazonensis In Vitro.

Background/Objectives: Leishmaniasis, a neglected disease caused by Leishmania spp. including L. amazonensis, urgently requires new treatments. Polyalthic acid (PA), a natural diterpene from Copaifera spp., has previously demonstrated significant antiparasitic potential. This study evaluated the leishmanicidal effects of polyalthic acid (PA), alone and with amphotericin B (AmpB), on L. amazonensis promastigote and amastigote forms. Results: PA showed significant activity against promastigotes, with 50% effective concentration (EC50) values of 2.01 µM at 24 h and an EC50 of 3.22 µM against amastigotes after 48 h. The PA and AmpB combination exhibited a synergistic effect on both forms without inducing cytotoxicity or hemolysis. Morphological changes in promastigotes, including vacuole formation and cell rounding, were more pronounced with the combination. Conclusions: These findings suggest that PA and AmpB together could form a promising new treatment strategy against Leishmania infections, offering enhanced efficacy without added toxicity.

Disseminated emergomyces orientalis infection in a patient with systemic lupus erythematosus.

A case of Eimonosis orientalis was reported in a 52-year-old male farmer who presented with cough, phlegm, fever, headache, and nausea for more than 4 days. Haemophilic cells and fungal spores were identified in the bone marrow smear and confirmed as Aemon orientalis by culture. The same bacteria were also isolated from blood cultures.

Specificity of Membrane-Associated J-Domain Protein, Caj1, in Amphotericin B Tolerance in Budding Yeast.

Hsp70:J-domain protein (JDP) machineries play pivotal roles in maintaining cellular proteostasis and governing various aspects of fungal physiology. While Hsp70 is known for its involvement in conferring tolerance to diverse antifungal drugs, the specific contribution of JDPs remains unclear. In this study, we examined the sensitivity of cytosolic JDP deletion strains of budding yeast to amphotericin B (AmB), a polyene antifungal agent widely utilized in fungal disease treatment due to its ability to disrupt the fungal plasma membrane (PM). Deleting Caj1, a PM-associated class II JDP, heightened susceptibility to AmB, and the protection conferred by Caj1 against AmB necessitated both its N-terminal J-domain and C-terminal lipid binding domain. Moreover, Caj1 deficiency compromised PM integrity as evidenced by increased phosphate efflux and exacerbated AmB sensitivity, particularly at elevated temperatures. Notably, phytosphingosine (PHS) addition as well as overexpression of PMP3, a positive PM integrity regulator, significantly rescued AmB sensitivity of caj1Δ cells. Our results align with the notion that Caj1 associates with the PM and cooperates with Hsp70 to regulate PM proteostasis, thereby influencing PM integrity in budding yeast. Loss of Caj1 function at the PM compromises PM protein quality control, thereby rendering yeast cells more susceptible to AmB.

Changes in Electron Paramagnetic Resonance Parameters Caused by Addition of Amphotericin B to Cladosporium cladosporioides Melanin and DOPA-Melanin-Free Radical Studies.

Cladosporium cladosporioides are the pigmented soil fungi containing melanin. The aim of this work was to determine the influence of amphotericin B on free radicals in the natural melanin isolated from pigmented fungi Cladosporium cladosporioides and to compare it with the effect in synthetic DOPA-melanin. Electron paramagnetic resonance (EPR) spectra were measured at X-band (9.3 GHz) with microwave power in the range of 2.2-70 mW. Amplitudes, integral intensities, linewidths of the EPR spectra, and g factors, were analyzed. The concentrations of free radicals in the tested melanin samples were determined. Microwave saturation of EPR lines indicates the presence of pheomelanin in addition to eumelanin in Cladosporium cladosporioides. o-Semiquinone free radicals in concentrations ~1020 [spin/g] exist in the tested melanin samples and in their complexes with amphotericin B. Changes in concentrations of free radicals in the examined synthetic and natural melanin point out their participation in the formation of amphotericin B binding to melanin. A different influence of amphotericin B on free radical concentration in Cladosporium cladosporioides melanin and in DOPA-melanin may be caused by the occurrence of pheomelanin in addition to eumelanin in Cladosporium cladosporioides. The advanced spectral analysis in the wide range of microwave powers made it possible to compare changes in the free radical systems of different melanin polymers. This study is important for knowledge about the role of free radicals in the interactions of melanin with drugs.

Safety of different amphotericin B formulations among AIDS patients with invasive fungal disease: a retrospective observational study.

We conducted a retrospective, observational study among acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis or talaromycosis to assess AmB formulations-related adverse events (AEs). Total 205 eligible patients were enrolled. Of them, 139 received AmB therapy, 51 received liposomal AmB (L-AmB) therapy, and 15 received AmB cholesteryl sulfate complex (ABCD) therapy. The incidences of total AEs between the AmB, L-AmB and ABCD group had no significant differences. The ABCD group had significantly higher incidences of hepatotoxicity and hematological toxicity than the AmB and L-AmB groups. The incidence of grade 3-4 hematological toxicity in the ABCD group was significantly higher than that in the AmB and L-AmB groups. Multinomial logistic regression models showed that compared with AmB, ABCD had a higher risk for the occurrence of grade 3-4 hematological toxicity (aOR = 43.924, 95%CI 6.296-306.418; p < 0.001). We demonstrated that ABCD was more prone to hepatotoxicity and hematological toxicity than AmB and L-AmB among AIDS patients, which is worth noting.

Antibiotics stimulates the development of persistent cells in biofilms of Candida albicans bloodstream isolates.

Candida albicans invasive candidiasis is considered a global health problem. In such cases, biofilm formation on implanted devices represents a therapeutic challenge and the presence of metabolically inactive persistent cells (PCs) in these communities increases their tolerance to fungicidal drugs. This study investigated the influence of amoxicillin, AMX; cefepime, CEF; gentamicin, GEN; amikacin, AMK; vancomycin, VAN; and ciprofloxacin, CIP; on the production of PCs in biofilms of C. albicans bloodstream isolates. 48 h-mature biofilms (n = 6) grown in RPMI-1640 supplemented with antibiotics were treated with 100 µg ml-1 amphotericin B and then evaluated for PCs. Biofilms grown in the presence of antibiotics produced more PCs, up to 10×, when exposed to AMX and CIP; 5 × to CEF; and 6 × to GEN and VAN. The results indicate that antibiotics can modulate PC production in C. albicans biofilms. This scenario may have clinical repercussions in immunocompromised patients under broad-spectrum antibiotic therapy.

Biofilms are microbial communities tolerant to antifungals. Our research showed that antibiotics stimulate the formation of persistent cells within Candida albicans biofilms. These are dormant, metabolically silent cells that resist to therapy and can be related to metastatic and recalcitrant infections.

Targeted delivery of amphotericin B-loaded PLGA micelles displaying lipopeptides to drug-resistant Candida-infected skin.

Amphotericin B (AmB) is an antifungal agent administered for the management of serious systemic fungal infections. However, its clinical application is limited because of its water insolubility and side effects. Herein, to apply the minimum dose of AmB that can be used to manage fungal infections, a targeted drug delivery system was designed using lipopeptides and poly(lactide-co-glycolide) (PLGA). Lipopeptides conjugated with PEGylated distearoyl phosphoethanolamine (DSPE) and short peptides via a maleimide-thiol reaction formed nanosized micelles with PLGA and AmB. The antifungal effects of AmB-loaded micelles containing lipopeptides were remarkably enhanced both in vitro and in vivo. Moreover, the intravenous injection of these micelles demonstrated their in vivo targeting capacity of short peptides in a mouse model infected with drug-resistant Candida albicans. Our findings suggest that short antifungal peptides displayed on the surfaces of micelles represent a promising therapeutic candidate for targeting drug-resistant fungal infections.

What makes Candida auris pan-drug resistant? Integrative insights from genomic, transcriptomic, and phenomic analysis of clinical strains resistant to all four major classes of antifungal drugs.

The global epidemic of drug-resistant Candida auris continues unabated. The initial report on pan-drug resistant (PDR) C. auris strains in a hospitalized patient in New York was unprecedented. PDR C. auris showed both known and unique mutations in the prominent gene targets of azoles, amphotericin B, echinocandins, and flucytosine. However, the factors that allow C. auris to acquire pan-drug resistance are not known. Therefore, we conducted a genomic, transcriptomic, and phenomic analysis to better understand PDR C. auris. Among 1,570 genetic variants in drug-resistant C. auris, 299 were unique to PDR strains. The whole-genome sequencing results suggested perturbations in genes associated with nucleotide biosynthesis, mRNA processing, and nuclear export of mRNA. Whole transcriptome sequencing of PDR C. auris revealed two genes to be significantly differentially expressed-a DNA repair protein and DNA replication-dependent chromatin assembly factor 1. Of 59 novel transcripts, 12 transcripts had no known homology. We observed no fitness defects among multi-drug resistant (MDR) and PDR C. auris strains grown in nutrient-deficient or -enriched media at different temperatures. Phenotypic profiling revealed wider adaptability to nitrogenous nutrients and increased utilization of substrates critical in upper glycolysis and tricarboxylic acid cycle. Structural modeling of a 33-amino acid deletion in the gene for uracil phosphoribosyl transferase suggested an alternate route in C. auris to generate uracil monophosphate that does not accommodate 5-fluorouracil as a substrate. Overall, we find evidence of metabolic adaptations in MDR and PDR C. auris in response to antifungal drug lethality without deleterious fitness costs.

Rapid Vision Loss After Root Canal Treatment Due to Invasive Fungal Sinusitis.

We present a novel case of acute invasive fungal rhinosinusitis (AIFRS) following a maxillary molar root canal in a 69-year-old diabetic female, who subsequently developed unilateral vision loss. The patient reported a 1-week history of progressive left facial pain, trismus, and numbness following the procedure. Initial evaluation was unremarkable, but her condition rapidly deteriorated, culminating in complete vision loss in the left eye. Imaging studies revealed opacification of the left-sided sinuses and a rim-enhancing collection in the left pterygopalatine fossa. Surgical debridement confirmed mucormycosis. The therapeutic approach included systemic and retrobulbar amphotericin B administration, along with multiple sinonasal debridements. The patient's poorly controlled diabetes mellitus significantly contributed to the rapid progression of the infection. Retrobulbar amphotericin B injections were effective in managing orbital involvement, thus avoiding the need for exenteration. Early diagnosis and aggressive treatment are paramount in improving outcomes for patients with AIFRS.

[Clinical efficacy and safety of liposomal amphotericin B in the salvage treatment of invasive fungal disease in patients with hematological diseases].

Objective: To investigate the efficacy and safety of liposomal amphotericin B (L-AmB) for the salvage treatment of invasive fungal disease (IFD) in patients with hematological diseases. Methods: Data were retrospectively collected from 80 patients with hematological issues treated with L-AmB between June 2023 and December 2023 after failure of previous antifungal therapy. Baseline patient information, clinical efficacy, and factors affecting the efficacy of L-AmB were analyzed by logistic regression. Moreover, adverse effects associated with L-AmB were evaluated. Results: Among the 80 patients, 9 (11.2%) had proven IFD, 43 (53.8%) had probable IFD, and 28 (35.0%) had possible IFD. The efficacy rate of L-AmB salvage therapy for IFD was 77.5%, with a median daily dose of 3 (range: 1-5) mg·kg(-1)·d(-1) and a median dosing course of 14 (range: 8-25) days. Multivariate logistic regression analysis showed that the disease remission status (OR=4.337, 95% CI 1.167-16.122, P=0.029) and duration of medication (OR=1.127, 95% CI 1.029-1.234, P=0.010) were independent factors affecting the efficacy of L-AmB. The incidence of infusion reactions associated with L-AmB, including fever and chills, was 5.0%. The incidence of hypokalemia was 28.8% (predominantly grades 1-2), and the incidence of nephrotoxicity was 11.3% (predominantly grades 1-2) . Conclusion: L-AmB is safe and effective in the treatment of patients with IFD who are intolerant to or who have experienced no effect of previous antifungal therapy, with a low rate of adverse reactions.