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Introduction: The epidemiology of invasive Candida infections is evolving. Infections caused by non- albicans Candida spp. are increasing; however, the antifungal pipeline is more promising than ever and is enriched with repurposed drugs and agents that have new mechanisms of action. Despite progress, unmet needs in the treatment of invasive candidiasis remain, and there are still too few antifungals that can be administered orally or that have CNS penetration., Areas Covered: The authors shed light on those antifungal agents active against Candida that are in early- and late-stage clinical development. Mechanisms of action and key pharmacokinetic and pharmacodynamic properties are discussed. Insights are offered on the potential future roles of the investigational agents MAT-2203, oteseconazole, ATI-2307, VL-2397, NP-339, and the repurposed drug miltefosine., Expert Opinion: Ibrexafungerp and fosmanogepix have novel mechanisms of action and will provide effective options for the treatment of Candida infections (including those caused by multiresistant Candida spp). Rezafungin, an echinocandin with an extended half-life allowing for once weekly administration, will be particularly valuable for outpatient treatment and prophylaxis. Despite this, there is an urgent need to garner clinical data on investigational drugs, especially in the current rise of azole-resistant and multidrug-resistant Candida spp.

Genotypic diversity and fluconazole susceptibility of 82 Cryptococcus neoformans and Cryptococcus gattii isolates from 60 renal transplant recipients in Brazil were characterized. Clinical characteristics of the patients and prognostic factors were analysed. Seventy-two (87.8%) isolates were C. neoformans and 10 (12.2%) were C. gattii. VNI was the most common molecular type (40 cases; 66.7%), followed by VNII (9 cases; 15%), VGII (6 cases; 10%), VNB (4 cases; 6.7%) and VNI/II (1 case; 1.7%). The isolates showed a high genetic diversity in the haplotype network and six new sequence types were described, most of them for VNB. There was a bias towards skin involvement in the non-VNI population (P = .012). VGII isolates exhibited higher fluconazole minimum inhibitory concentrations compared to C. neoformans isolates (P = 0.008). The 30-day mortality rate was 38.3%, and it was significantly associated with fungemia and absence of headache. Patients infected with VGII had a high mortality rate at 90 days (66.7%). A variety of molecular types produce disease in renal transplant recipients in Brazil and highlighted by VGII and VNB. We report the clinical appearance and impact of the molecular type, fluconazole susceptibility of the isolates, and clinical characteristics on patient outcome in this population.

Candida albicans is a leading cause of catheter-associated urinary tract infections and elimination of these biofilm-based infections without antifungal agents would constitute a significant medical advance. A novel urinary catheter prototype that utilizes on-demand surface deformation is effective at eliminating bacterial biofilms and here the broader applicability of this prototype to remove fungal biofilms has been demonstrated. C. albicans biofilms were debonded from prototypes by selectively inflating four additional intralumens surrounding the main lumen of the catheters to provide the necessary surface strain to remove the adhered biofilm. Deformable catheters eliminated significantly more biofilm than the controls (>90% eliminated vs 10% control; p < 0.001). Mechanical testing revealed that fungal biofilms have an elastic modulus of 45 ± 6.7 kPa with a fracture energy of 0.4-2 J m -2 . This study underscores the potential of mechanical disruption as a materials design strategy to combat fungal device-associated infections.

With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.

Introduction: Morbidity and mortality associated with invasive fungal infections (IFIs) remains unacceptably high. Such diseases represent a substantial burden to the healthcare system. New options are needed to address antifungal resistance in existing and emerging pathogens and improve treatment outcomes while minimizing drug-related toxicities and interactions. Awareness of new and potential future options is of great value for those healthcare professionals who care for patients with IFIs. Areas covered: A search of PubMed, infectious diseases conference abstracts and reference lists from relevant publications was conducted and relevant information abstracted. This review describes the limitations of existing systemic antifungal therapies (e.g., resistance, drug-drug interactions, drug-related toxicities) and summarizes data regarding several emerging antifungal compounds including (but not limited to) new triazoles (e.g. isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin Z. Agents in clinical trials such as (but not limited to) new triazoles (e.g., isavuconazole, ravuconazole), echinocandins (e.g., aminocandin) and nikkomycin are included. New formulations of existing drugs including reformulations of miconazole, posaconazole and amphotericin B are also reviewed. Finally, new or novel administration strategies for existing drugs such as combination antifungal therapy, antifungal dose escalation, adjunctive use of iron chelators and preemptive therapy are discussed. Expert opinion: All present antifungal agents have some deficiencies in antifungal spectra, toxicity, pharmacokinetics and/or drug-drug interactions, making them less than ideal for some fungal infections. Therefore, there remains an urgent need to find safe, effective, rapidly fungicidal, broad-spectrum antifungal agents with excellent pharmacodynamics to effectively eliminate the fungus from the body with short antifungal courses.

Owing to the morbidity and mortality associated with invasive fungal infections, particularly in the immunocompromised host, development of new agents for both prevention and treatment is essential. Posaconazole is a recently approved extended-spectrum triazole available as an oral suspension. It exhibits fungistatic activity against a variety of fungal pathogens. Pharmacokinetic data in special patient populations (such as neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome, allogeneic hematopoietic stem cell transplant recipients, febrile neutropenic patients and pediatric patients) have been published recently. Controlled clinical trials establish posaconazole's safety and efficacy in infections, such as oropharyngeal candidiasis and prophylaxis against invasive fungal infections. Data are also emerging in the treatment of zygomycosis and selected cases of aspergillosis. Posaconazole is well tolerated during short- and long-term use, with the most commonly reported adverse events being mild-to-moderate gastrointestinal disturbances. Data suggest a relationship between posaconazole plasma concentrations and prophylactic efficacy; however, the role of therapeutic drug monitoring has yet to be completely defined. Since posaconazole is available only as an oral formulation, its use may be limited in critically ill patient populations.

The echinocandins are a new class of antifungals, developed in response to the need for safe and effective antifungals for the treatment of invasive fungal infections. These agents work by inhibiting 1,3-beta-d-glucan synthase, an enzyme essential for production of cell walls in select fungi. Echinocandins appear to demonstrate favourable activity in vitro against a variety of yeasts (including both Candida albicans and non-albicans Candida) as well as select moulds (including Aspergillus spp.) In general, all echninocandins demonstrate a favourable safety profile and require once-daily parenteral administration. Caspofungin is the first of these agents to be available in the US, and is approved for empirical antifungal therapy in febrile neutropenic patients, candidaemia and select forms of invasive candidiasis, and for management of invasive aspergillosis in patients refractory to or intolerant of other therapies. Micafungin was recently approved by the FDA for treatment of oesophageal candidiasis, and for the prophylaxis of fungal infections in haematopoietic stem cell transplant recipients. Emerging data indicate micafungin may have an important role in the treatment of invasive forms of candidiasis. Anidulafungin is an echinocandin approved in the US for treatment of candidaemia and oesophageal candidiasis. Aminocandin (HMR-3702, IP-960) is an investigational agent, with published experience limited to in vitro studies and animal models of infection.

While amphotericin B deoxycholate (Fungizone, Apothecon Pharmaceuticals) has been considered by many to be the gold standard for the treatment for numerous invasive fungal infections for over 45 years, toxicities associated with its use often necessitate treatment modification or discontinuation. Lipid-based formulations, including liposomal amphotericin B (AmBisome, Fujisawa Healthcare, Inc.), were developed to decrease many of these toxicities while retaining broad antifungal spectrum and potency of amphotericin B. In clinical trials, liposomal amphotericin B has demonstrated efficacy comparable to that of amphotericin B deoxycholate while reducing the incidence of treatment-related nephrotoxicity, electrolyte-wasting, and infusion-related reactions. In addition, recent clinical trials have also compared liposomal amphotericin B with other antifungal classes. Acquisition costs of liposomal amphotericin B are substantially higher than those of amphotericin B deoxycholate and other antifungals. While pharmacoeconomic analyses consider outcomes and other treatment-related costs, they have yet to clearly demonstrate the cost-effectiveness of liposomal amphotericin B when compared with amphotericin B deoxycholate or other antifungal agents. This review will focus primarily on recent liposomal amphotericin B experience and attempt to put its use into perspective considering other available antifungal agents.

Administration of antifungals by routes other than that for which the agent was designed or approved have been utilised in attempts to provide directed therapy, reduce adverse effects and improve drug penetration into selected infection sites, such as the central nervous system, lungs and peritoneum. The most widely investigated agent utilising a novel method of drug delivery is amphotericin B. Dose forms for this agent include topicals (aerosol, nasal spray, irrigations, pastes, absorbable sponges, impregnated bone cement and gelatin), oral dosage forms (solutions, suspensions, tablets and so on) and ophthalmic preparations (drops, ointments and injections). Amphotericin B has been administered by routes such as oral, endobronchial, intrathecal, intracisternal, intra-articular, intraperitoneal, ophthalmic and as an antibiotic 'line lock'. Nystatin has been administered as an aerosol, percutaneous paste and bladder washes. Azoles, such as miconazole, fluconazole, ketoconazole and posaconazole, have been administered by novel methods but to a lesser degree. Most of these reports involve miconazole. The dose forms and routes of administration for azoles have included irrigants (bladder, joint), ophthalmic preparations (eye drops, intraocular injections, ointments), impregnated bone cement, endobronchial and intrathecal administration. Finally, both methylene blue (bladder washes) and flucytosine (peritoneal lavage, ophthalmic eye drops) have also been employed. Adequate evaluations of both the safety and efficacy of these therapies are most often hindered by prior or concomitant antifungal therapies, comorbidities and the lack of controlled clinical trials. In addition, the availability of newer treatment options, which demonstrate significant improvement in drug distribution and treatment-related adverse effects make many such novel modes of administration less practical or necessary. In contrast, the inhalation of antifungal aerosols, such as amphotericin B, is rapidly becoming a viable prophylactic option.

Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.

Scedosporium species are now increasingly isolated from immunocompromised and immunocompetent patients. Unfortunately, Scedosporium species infections are generally resistant to amphotericin B, and S. prolificans strains are particularly resistant to presently-available antifungal agents. Here we review the microbiology, expanding epidemiology, numerous clinical presentations, and diagnostic tools available for Scedosporium species infections. Finally, we detail the available in vitro, animal model, and clinical data on the treatment of Scedosporium species infections with special emphasis on the role of newer antifungal therapies for these recalcitrant infections.

Cryptococcus neoformans is an opportunistic fungal pathogen that infects the human central nervous system. This pathogen elaborates two specialized virulence factors: the antioxidant melanin and an antiphagocytic immunosuppressive polysaccharide capsule. A signaling cascade controlling mating and virulence was identified. The PKA1 gene encoding the major cyclic AMP (cAMP)-dependent protein kinase catalytic subunit was identified and disrupted. pka1 mutant strains were sterile, failed to produce melanin or capsule, and were avirulent. The PKR1 gene encoding the protein kinase A (PKA) regulatory subunit was also identified and disrupted. pkr1 mutant strains overproduced capsule and were hypervirulent in animal models of cryptococcosis. pkr1 pka1 double mutant strains exhibited phenotypes similar to that of pka1 mutants, providing epistasis evidence that the Pka1 catalytic subunit functions downstream of the Pkr1 regulatory subunit. The PKA pathway was also shown to function downstream of the Galpha protein Gpa1 and to regulate cAMP production by feedback inhibition. These findings define a Galpha protein-cAMP-PKA signaling pathway regulating differentiation and virulence of a human fungal pathogen.

Cryptococcus neoformans is an opportunistic fungal pathogen with a defined sexual cycle. The gene encoding a heterotrimeric G-protein beta subunit, GPB1, was cloned and disrupted. gpb1 mutant strains are sterile, indicating a role for this gene in mating. GPB1 plays an active role in mediating responses to pheromones in early mating steps (conjugation tube formation and cell fusion) and signals via a mitogen-activated protein (MAP) kinase cascade in both MATalpha and MATa cells. The functions of GPB1 are distinct from those of the Galpha protein GPA1, which functions in a nutrient-sensing cyclic AMP (cAMP) pathway required for mating, virulence factor induction, and virulence. gpb1 mutant strains are also defective in monokaryotic fruiting in response to nitrogen starvation. We show that MATa cells stimulate monokaryotic fruiting of MATalpha cells, possibly in response to mating pheromone, which may serve to disperse cells and spores to locate mating partners. In summary, the Gbeta subunit GPB1 and the Galpha subunit GPA1 function in distinct signaling pathways: one (GPB1) senses pheromones and regulates mating and haploid fruiting via a MAP kinase cascade, and the other (GPA1) senses nutrients and regulates mating, virulence factors, and pathogenicity via a cAMP cascade.

Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.