Anidulafungin,a new antifungal drug

ObjectivesThe development of new antifungal drugs has become a challenge for pharmaceutical industry due to the increasing incidence of invasive fungal infections.MethodsExperience of existing antifungal drugs has shown that, like in bacteria against antibiotics, most fungal species, especially in Candida spp, resistance to previously active drugs is developing and constitutes a major problem in treating invasive fungal infections.ResultsAmong series of newer drugs, experimental data and literature search have unravelled a new class of antifungals, Echinocandins which inhibit successfully Candida spp resistant to other drugs such as fluconazole. One drug, anidulafungin has emerged recently in this class as one of the most active in invasive fungal infections.     

Econazole Nitrate-Loaded MCM-41 for an Antifungal Topical Powder Formulation

The aim of this article was to prepare a topical powder for the treatment of fungal infections, such as Candida intertrigo and tinea pedis. Thus, an econazole nitrate (ECO) formulation with improved drug dissolution and proper moisture adsorption was designed. ECO was melt with the mesoporous silicate MCM-41 (drug/MCM-41 1/3) and the resulting inclusion compound was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The drug loading was confirmed by the decrease of specific surface area and pore volume between MCM-41 and the inclusion compound. Formulations containing the inclusion compound were prepared and submitted to in vitro dissolution test and in vitro antifungal activity. A remarkable dissolution rate improvement as well as a higher antifungal activity was observed for the inclusion compound if compared to a commercial product. Moisture sorption properties for MCM-41 and formulations were evaluated as well.     

Gentamicin synergises with azoles against drug-resistant Candida albicans

Candida spp. are the primary opportunistic pathogens of nosocomial fungal infections, causing both superficial and life-threatening systemic infections. Combination therapy for fungal infections has attracted considerable attention, especially for those caused by drug-resistant fungi. Gentamicin (GM), an aminoglycoside antibiotic, has weak antifungal activity against Fusarium spp. The aim of this study was to investigate the interactions of GM with azoles against Candida spp. and the underlying mechanisms. In a chequerboard assay, GM was found not only to work synergistically with azoles against planktonic cells of drug-resistant Candida albicans with a fractional inhibitory concentration index (FICI) of 0.13–0.14, but also synergised with fluconazole (FLC) against C. albicans biofilms pre-formed in <12?h. Synergism of GM with FLC was also confirmed in vivo in a Galleria mellonella infection model. In addition, mechanism studies showed that GM not only suppressed the efflux pump of resistant C. albicans in a dose-dependent manner but also inhibited extracellular phospholipase activity of resistant C. albicans when combined with FLC. These findings suggest that GM enhances the efficacy of azoles against resistant C. albicans via efflux inhibition and decreased activity of extracellular phospholipase.     

Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp.

Candida and Aspergillus infections have emerged as significant pathogens in recent decades. During this same time, broad spectrum triazole and echinocandin antifungal agents have been developed and increasingly used. One consequence of widespread use is leading to the emergence of mutants with acquired resistance mutations. Therefore, accurate susceptibility testing and appropriate clinical breakpoints for the interpretation of susceptibility results have become increasingly important.Here we review the underlying methodology by which breakpoints have been selected by EUCAST (European Committee on Antimicrobial Susceptibility Testing). Five parameters are evaluated: dosing regimens used; EUCAST MIC distributions from multiple laboratories, species and compound specific epidemiological cut off values (upper MIC limits of wild type isolates or ECOFFs), pharmacokinetic/pharmacodynamic relationships and targets associated with outcome and finally clinical data by species and MIC when available. The general principles are reviewed followed by a detailed review of the individual aspects for Candida species and the three echinocandins and for Aspergillus and the three mould-active azoles. This review provides an update of the subcommittee on antifungal susceptibility testing (AFST) of the EUCAST methodology and summarises the current EUCAST breakpoints for Candida and Aspergillus. Recommendations about applicability of antifungal susceptibility testing in the routine setting are also included.     

Bifonazole. A review of its antimicrobial activity and therapeutic use in superficial mycoses

Bifonazole is a substituted imidazole antifungal agent structurally related to other drugs in this group. It possesses a broad spectrum of activity in vitro against dermatophytes, moulds, yeasts, dimorphic fungi and some Gram-positive bacteria. Both non-comparative and comparative clinical trials have clearly demonstrated the efficacy and safety of various formulations of bifonazole 1% (cream, gel, solution and powder) applied once daily in the treatment of superficial fungal infections of the skin such as dermatophytoses, cutaneous candidiasis and pityriasis versicolor. In comparative studies bifonazole was significantly superior to placebo and at least as effective as alternative imidazole antifungal drugs including clotrimazole, econazole, miconazole, oxiconazole and sulconazole. Preliminary studies in other superficial skin and nail infections/dermatoses suggest that bifonazole may be useful for treating onychomycoses (in a combination cream; bifonazole 1% plus urea 40%), otomycoses, erythrasma, sebopsoriasis, seborrhoeic dermatitis and rosacea. However, controlled trials are needed in each of these clinical settings to assess accurately its relative place in therapy. Thus, bifonazole is an effective and well-tolerated treatment for superficial fungal infections of the skin. Compared with the majority of topical antifungal drugs, which need to be applied at least twice daily, bifonazole offers the convenience of once daily administration, which may improve patient compliance.     

Impaired ergosterol biosynthesis mediated fungicidal activity of oil based tin polymer

Candida represents an important group of opportunistic fungal pathogens which causes infections in immunocompromised patients. The increasing emergence of fungal resistance to currently available antimycotic agents, especially azoles is a major problem. A vegetable-based organotin polymer synthesised by the condensation of fatty amide diol (N, N ¹-bis 2 hydroxy ethyl castor oil fatty amide) and butyl tin chloride dihydroxide has been reported to posses antimicrobial activity. This study is an attempt to investigate the antifungal activity of this compound against several fluconazole-susceptible and resistant clinical Candida isolates and to understand its mode of action. The susceptibility tests for the polymer were carried out in terms of minimum inhibitory concentrations (MICs) and disc diffusion assays against fifty-nine Candida isolates by employing standard protocols. The ergosterol-mediated antifungal activity was analysed by the sterol quantitation method. The organotin polymer was found to be effective, to varying extent, against all the Candida isolates including the resistant ones. It showed a low MIC value, which was fungicidal in contrast to the fungistatic fluconazole and caused considerable impairment of ergosterol biosynthesis in all the strains tested. This compound may be targeting the ergosterol biosynthesis pathway and may be used as an alternative to fluconazole which develops resistance during therapy. The selectively fungicidal characteristics of the organotin polymer indicate that this compound might be a promising antifungal agent.     

In vitro characterization,ADME analysis,and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains

BackgroundCandida species are one of the most common causes of nosocomial bloodstream infections among the opportunistic fungi. Extensive use of antifungal agents, most of which were launched on the market more than 20 years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. We recently described a novel class of antifungal macrocyclic compounds with an amidinourea moiety that is highly active against azole-resistant Candida strains.ObjectiveA compound from this family, BM1, was investigated in terms of in vitro activity against various Candida species, including C. auris isolates, interaction with the ABC transporter, CDR6, and in vivo distribution and safety.MethodsIn vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) were used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis were utilised to evaluate in vivo toxicology, pharmacokinetics, and distribution.ResultsThe current research shows BM1 has a low in vivo toxicity profile, affinity for the renal system in rats, and good absorption, distribution, metabolism, and excretion (ADME). BM1 also has potent activity against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains.ConclusionsThe results confirmed low minimum inhibitory concentrations (MICs) against several Candida species, including preliminary data vs. C. auris. BM1 has good ADME and biochemical characteristics, is suitable and safe for daily administration and is particularly indicated for renal infections. These data indicate BM1 and its derivatives form a novel, promising antifungal class.     

The echinocandins: three useful choices or three too many?

Echinocandins act by inhibiting 1,3-β-d-glucan synthesis in the fungal cell wall. The three licensed agents in this class, namely anidulafungin, caspofungin and micafungin, have a favourable pharmacological profile. These agents are narrow spectrum with clinically relevant activity against Candida and Aspergillus spp. Several trials have established the non-inferiority of these agents over existing agents in the treatment of invasive fungal infections. Caspofungin is also licensed for empirical antifungal therapy of presumed fungal infections in patients with febrile neutropenia. This paper reviews the literature on echinocandins.     

A comprehensive review on potential applications of metallic nanoparticles as antifungal therapies to combat human fungal diseases

Human pathogenic fungi are responsible for causing a range of infection types including mucosal, skin, and invasive infections. Life-threatening and invasive fungal infections (FIs) are responsible for mortality and morbidity, especially for individuals with compromised immune function. The number of currently available therapeutic agents against invasive FIs is limited compared to that against bacterial infections. In addition, the increased mortality and morbidity caused by FIs are linked to the limited number of available antifungal agents, antifungal resistance, and the increased toxicity of these agents. Currently available antifungal agents have several drawbacks in efficiency, efficacy, toxicity, activity spectrum, and selectivity. It has already been demonstrated with numerous metallic nanoparticles (MNPs) that these nanoparticles can serve as an effective and alternative solution as fungicidal agents. MNPs have great potential owing to their intrinsic antifungal properties and potential to deliver antifungal drugs. For instance, gold nanoparticles (AuNPs) have the capacity to disturb mitochondrial calcium homeostasis induced AuNP-mediated cell death in Candida albicans. In addition, both copper nanoparticles and copper oxide nanoparticles exerted significant suppressive properties against pathogenic fungi. Silver nanoparticles showed strong antifungal properties against numerous pathogenic fungi, such as Stachybotrys chartarum, Mortierella alpina, Chaetomium globosum, A. fumigatus, Cladosporium cladosporioides, Penicillium brevicompactum, Trichophyton rubrum, C. tropicalis, and C. albicans. Iron oxide nanoparticles showed potent antifungal activities against A. niger and P. chrysogenum. It has also been reported that zinc oxide nanoparticles can significantly inhibit fungal growth. These NPs have already exerted potent antifungal properties against a number of pathogenic fungal species including Candida, Aspergillus, Fusarium, and many others. Several strategies are currently used for the research and development of antifungal NPs including chemical modification of NPs and combination with the available drugs. This review has comprehensively presented the current and innovative antifungal approach using MNPs. Moreover, different types of MNPs, their physicochemical characteristics, and production techniques have been summarized in this review.     

Synthesis and antifungal evaluation of 6-(N-arylamino)-7-methylthio-5,8-quinolinediones

A series of 6-(N-arylamino)-7-methylthio-5,8-quinolinedione derivatives4a-4l was newly synthesized for the evaluation of antifungal activity. 6-(N-Arylamino)-7-methylthio-5,8-quinolinediones were prepared by regioselective nucleophilic substitution of 6,7-dichloro-5,8-quinolinediones with arylamines in the presence of Ce³⁺, and Na₂S/dimethylsulfate. The MIC values of4a-4l were determined for antifungal susceptibilityin vitro againstCandida species by agar streak method. The derivatives4a-4l had generally potent antifungal activities against all human pathogenic fungi. Especially they had the most potent activity againstC. krusei at 12.5≈0.8 μg/ml. Compounds4d, 4g, 4h, 4j and4k had more potent antifungal activities than fluconazole. Compounds4g and4h completely inhibited the fungal growth at 0.8≈6.3 μg/ml against allCandida species, while fluconazole inhibited the growth at 25 μg/ml. The compounds such as4g and4h containing an N-(4-bromo-2-methylphenyl)- or N-(4-bromo-3-methylphenyl)amino substituent exhibited the most potent antifungal activities.     

Arginolipid: A membrane-active antifungal agent and its synergistic potential to combat drug resistance in clinical Candida isolates

Antifungal drug resistance exhibits a major clinical challenge for treating nosocomial fungal infections. To find a possible solution, we synthesized and studied the antifungal activities of three different arginolipids (N^α-acyl-arginine ethyl ester) against clinical drug-resistant isolates of Candida. The most active arginolipid, oleoyl arginine ethyl ester (OAEE) consisting of a long unsaturated hydrophobic chain, was tested for its mode of action, which revealed that it altered ergosterol biosynthesis and compromised the fungal cell membrane. Also, OAEE was found to exhibit synergistic interactions with fluconazole (FLU) or amphotericin B (AmB) against planktonic Candida cells, wherein it reduced the inhibitory concentrations of these drugs to their in vitro susceptible range. Studies conducted against the C. tropicalis biofilm revealed that the OAEE+AmB combination synergistically reduced the metabolic activity and hyphal density in biofilms, whereas OAEE+FLU was found to be additive against most cases. Finally, the evaluated selective toxicity of OAEE toward fungal cells over mammalian cells could establish it as an alternative treatment for combating drug-resistant Candida infections.     

Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.     

Amphotericin B releasing nanoparticle topical treatment of Candida spp. in the setting of a burn wound

Candida spp. infection in the context of burn wounds leads to invasive disease with a 14–70% mortality rate. Unfortunately, current administrations of AmB, an important therapeutic demonstrating minimal resistance, are only available via potentially cytotoxic IV infusions. In order to circumvent these sequelae, we investigated the efficacy of nanoparticle encapsulated AmB (AmB-np) as a topical therapeutic against Candida spp. (drug release equilibrated solubilized AmB [AmB-sol] included as control). Clinical strains demonstrated equal or enhanced killing efficacy with 72.4–91.1% growth reduction by 4 hours. AmB-nps resulted in statistically significant reduction of fungal biofilm metabolic activity ranging from 80% to 95% viability reduction (P< 0.001). Using a murine full-thickness burn model, AmB-np exhibited a quicker efficiency in fungal clearance versus AmB-sol by day three, although wound healing rates were similar. These data support the concept that AmB-np can function as a topical antifungal in the setting of a burn wound.From the Clinical EditorThe control of fungal infections with Candida species remains a challenge in the context of burn wounds. A nanoencapsulated topical amphotericin-B compound was studied in a murine model of full thickness burn injury, showing remarkable efficacy in controlling Candida infection. This may become a viable alternative to the potentially toxic intravenous formulations.     

Novel 2-Aryloxazoline Compounds Exhibit an Inhibitory Effect on Candida spp., Including Antifungal-Resistant Isolates

Because of the increased resistance to currently available antifungals, fungal infections represent a significant challenge to human health. Herein, we report the synthesis of 2-aryloxazoline derivatives from the reaction between l-threonine and derivatives of salicylic or naphthoic acid. In total, 26 compounds were obtained and tested against species of Candida, Cryptococcus, and Aspergillus. We found that all of the compounds inhibited the growth of Candida species at low concentrations (<0.25 μg/mL) and exhibited reduced hemolytic and cytotoxic activities. Additionally, compounds 4i and 9i were especially effective against antifungal-resistant isolates and the emerging fungus Candida auris. However, the compounds were less active on Cryptococcus and Aspergillus. Because of the improved in vitro antifungal efficacy and attenuated cytotoxicity, these two 2-aryloxazolines obtained from salicylic and naphthoic acid derivatives, respectively, may be considered lead molecules for the development of novel antifungal drugs.     

Diverse role of microbially bioconverted product of cabbage (Brassicaoleracea) by Pseudomonassyringe pv. T1 on inhibiting Candida species

This study was carried out to evaluate the anticandidal effects of bioconverted product, obtained from the microbial conversion of cabbage (Brassicaoleracea) by a bacterial strain Pseudomonassyringe pv. T1 (Ps-T1) against various isolates of Candida species. The diameters of zones of inhibition of bioconverted product of cabbage (10 μl, corresponding to 500 μg/disc) against Candidaalbicans KACC 30003 and 30062, Candidageochares KACC 30061, Candidasaitoana KACC 41238 and Candidaglabrata P00368 were found between 10 ± 1 and 16 ± 0.8 mm. The bioconverted product was tested for the minimum inhibitory and minimum fungicidal concentration values against the tested pathogens which were found in the range of 125-500 and 125-500 μg/ml, respectively. On the viable counts of the tested fungal pathogens, the bioconverted product showed a remarkable anticandidal effect. Also the study of using scanning electron microscopy on the morphology of C.albicans KACC 30062 revealed potential detrimental effect of bioconverted product at MIC concentration. The results of this study suggest that bioconverted product of cabbage by Ps-T1 holds potential therapeutic value and medicinal significance to control Candida species.     

Treatment of invasive infections due to rare or emerging yeasts and moulds

Emerging fungal infections represent a serious problem in an immunocompromised host. Rapid developments in in vitro antifungal susceptibility testing and the availability of several new antifungal agents have provided excellent opportunities to treat infections that are caused by various Candida spp. and to some extend by Aspergillus spp. However, recently the epidemiology of fungal infections has significantly changed and several new pathogens have emerged. This article attempts to summarise the available data on the management of emerging infections with fungal infections that have recently gained importance. Updated recommendations on antifungal treatment are also discussed.     

Photodynamic inactivation of chlorin e6 with halogen light against dermatophytes

Photodynamic inactivation (PDI) combines a photosensitizer with light in the presence of oxygen, producing reactive oxygen species which will inactivate pathogens. The most common dermatophyte, named T. mentagrophytes, was known to cause various skin infections in human, such as dermatophytosis. In this study, the antifungal activity of chlorin e6-based PDI with halogen light for photodynamic inactivation against T. mentagrophytes was measured. We report for the first time that the chlorin e6-based PDI exhibited a significant antifungal activity against T. mentagrophytes. The use of chlorin e6 as an antifungal photosensitizer for PDI represents a prominent alternative method for treating fungal infections.     

The echinocandin micafungin: a review of the pharmacology,spectrum of activity,clinical efficacy and safety

Micafungin is a relatively broad-spectrum antifungal agent available for clinical use in the US and Japan. By inhibiting the production of β-1,3-glucan, an essential fungal cell wall component, micafungin has reduced toxicity to mammalian cells while maintaining potent antifungal activity against many pathogenic fungi including polyene- and azole-resistant isolates. Indeed, micafungin has been shown to be efficacious in the treatment of infections caused by Candida and Aspergillus species in clinical trials without the associated toxicities of amphotericin B formulations and drug interactions that occur with the azoles. In this review, the pharmacology, spectrum of activity, clinical efficacy and safety profile of micafungin are discussed.     

Role of caspofungin in restoring the impaired phagocyte-dependent innate immunity towards Candida albicans in chronic haemodialysis patients

Phagocyte-dependent cellular immunity in chronic kidney disease patients undergoing haemodialysis treatment is frequently impaired owing to the uraemic state, resulting in an intrinsic susceptibility to developing invasive fungal infections with high mortality rates. Since synergism between phagocytic cells and antifungal drugs may be crucial for successful therapy, the aim of this study was to evaluate the effects exerted by caspofungin (CAS) on the functional activities of polymorphonuclear cells (PMNs) in haemodialysed patients (HDs) towards Candida albicans compared with those of PMNs from healthy subjects (HSs). PMNs were separated from venous blood samples of 66 HDs and 30 HSs (as controls), and measurement of phagocytic and intracellular fungicidal activities of HD-PMNs and HS-PMNs was performed in the presence of CAS at the minimum inhibitory concentration (MIC) and at sub-MICs. CAS-free controls were also included. In the drug-free test condition, no significant difference between the phagocytic activity of HD-PMNs and HS-PMNs was detected. In contrast, a progressive decline in the intracellular killing activity of HD-PMNs against proliferating yeasts was observed. CAS at MIC and sub-MIC levels was able to improve significantly the intracellular fungicidal activity of HD-PMNs against C. albicans, restoring their functionality. These findings provide evidence that CAS exerts a synergistic effect on HD-PMNs against C. albicans, being able to strength the depressed intracellular killing activity. These results corroborate the use of CAS as an effective therapeutic option for the treatment of invasive fungal infections in HDs, in whom even a marginal influence of antifungal drugs on host response may have a relevant effect.     

Antifungal resistance in non- albicans Candida species

Non- Candida albicans species have emerged as important bloodstream pathogens. They tend to have decreased susceptibility to antifungal agents in vitro and cause infections associated with high morbidity and mortality. Fluconazole resistance can emerge in any Candida spp., but is most commonly seen with Candida krusei, for which resistance is universal, and with Candida glabrata. Amphotericin B resistance has also been increasingly reported, most notably in isolates of Candida lusitaniae and Candida guilliermondii. Efforts are underway to correlate in-vitro antifungal susceptibility of individual Candida isolates with response to therapy of patients with candidemia. Future advances in this field might allow physicians to identify Candida isolates resistant to specific antifungal agents and thereby tailor therapy of candidemia.