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.     

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.     

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.     

Antifungal screening and in silico mechanistic studies of an in‐house azole library

Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non‐albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first‐choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in‐house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.     

Using pharmacokinetics and pharmacodynamics to optimise dosing of antifungal agents in critically ill patients: a systematic review

The prevalence of invasive fungal infections (IFIs) caused by Candida spp. is increasing in critically ill patients. Recent development of new antifungal agents has significantly contributed to the successful treatment of IFIs. However, the pharmacokinetics of antifungal agents can be altered in a number of disease states, including critical illness. Therefore, doses established in healthy volunteers and other patient groups may not be appropriate for the critically ill. Moreover, inadequate dosing may contribute to treatment failure and the emergence of resistance. This systematic review provides a critical analysis of the pharmacokinetics of antifungal agents in the critically ill and their relevance to dosing requirements in clinical practice. Based on the limited data available, dosing of some antifungal agents may have to be adjusted in critically ill patients with conserved renal function as well as in those requiring renal replacement therapy. Further research to confirm the appropriateness of current dosing strategies to attain the appropriate pharmacodynamic targets is recommended.     

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.     

Invasive candidiasis and candidemia: from current opinions to future perspectives

Candida spp. are the fourth most common cause of nosocomial bloodstream infections in the United States, as well as the single most important cause of opportunistic fungal infections worldwide. A delayed diagnosis of invasive candidiasis and/or inadequate treatment choice is associated with high mortality rates and prolonged hospital stays. Even though the antifungal armamentarium has been broadened significantly over the last years, the best options for diagnosing and treating invasive candidiasis still remain a matter of discussion. In this article we present and analyze current evidence on the epidemiology, diagnostic methods and treatment options of invasive candidiasis, with a focus on results from randomized clinical trials. Finally, the reader is provided with a brief overview on promising clinical trial designs and antifungals that might shape the treatment of invasive candidiasis in the years to come.     

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.     

Antifungals to treat Candida albicans

Importance of the field: Candida species are the fourth leading cause of nosocomial bloodstream infections in the United States. They are a leading cause of invasive fungal infections and are an emerging problem in hospital medicine.

Areas covered in this review: The antifungal armamentarium for the treatment of systemic fungal infections has increased in recent years and now comprises agents from four main drug classes. This article summarizes the role of antifungal agents in the treatment of infections due to Candida albicans (C. albicans).

What the reader will gain: An extensive summary of currently available antifungal agents active against C. albicans. Clinical trials involving these agents will be discussed. Areas covered include drug pharmacokinetics, mechanisms of action, and toxicities.

Take home message: New antifungal agents have contributed to significant advances in the treatment of C. albicans. A detailed knowledge of differences in spectrum of activity, toxicity profiles, bioavailability, formulations, and drug interactions of these agents is required. Despite these recent advances, the attributable mortality rates of candidemia and invasive candidiasis remain very high, reminding us of the importance of strategies for the prevention of these infections.     

Review of the safety,tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole

SUMMARY

Managing invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits β-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candida infections. The safety and tolerability profile of caspofungin presented with a low incidence of adverse events in clinical trials. Pending further data, coadministration of cyclosporine has been recommended only if the benefit outweighs the risk for patients. Voriconazole has three important side-effects that the clinician must consider: liver abnormalities, skin abnormalities and visual disturbances. Liver abnormalities in particular should be monitored very carefully. The drug interaction profile of voriconazole also warrants a careful evaluation of the concomitant medication, mainly due to cytochrome P450 metabolism. This article reviews the available data concerning the safety and tolerability profiles of each drug, as well as drug interactions and contraindications.     

Pharmacotherapy approaches to antifungal prophylaxis

Introduction: Invasive fungal infection (IFI) is a serious problem due to difficulties in early diagnosis and high mortality. Different approaches are adopted for the treatment and management of IFI, including prophylactic, empiric, preemptive and directed strategies.

Areas covered: This paper reviews the type of pharmacotherapy used for antifungal prophylaxis in infants with extremely low birth weights, pediatric patients with cardiac disease, preterm neonates, pediatric oncology patients, adult cancer patients with neutropenia, adult patients with hematologic malignancy, hematopoietic stem-cell transplantation recipients, organ transplant recipients, HIV-infected patients, immunosuppressed patients treated with moderate or high doses of corticosteroids, and patients with invasive fusariosis, candidemia, invasive candidiasis, systemic mycoses and immunocompromised patients.

Expert opinion: Azole drugs are the drugs most often used in cost-effective antifungal prophylaxis of patients with conditions such as immunodeficiency and cancer, which render them highly susceptible to IFI. Fluconazole is the most outstanding example. However, there are many azoles with different pharmacological characteristics that the physician can choose from. Echinocandins have favorable characteristics that make them useful for treating Candida infections. Antibodies, or their engineered derivatives directed against cell-wall polysaccharides and glycopeptides, and some protein epitopes of Candida albicans, appear to be a promising novel approach for prophylaxis against Candida infection and deserve further in-depth investigations.     

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.     

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.     

Emerging echinocandins for treatment of invasive fungal infections

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-β-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.     

Echinocandins: A ray of hope in antifungal drug therapy

Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall.Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis.The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.     

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.     

Evaluation of a novel oxiconazole nitrate formulation: The thermosensitive gel

Superficial fungal infections caused by Candida species are common skin diseases. Therefore, this study aimed to develop a new formulation containing oxiconazole nitrate, which is an azole group derivative for antifungal treatment, as a thermosensitive gel since there has been no literature study until now.MIC value of the novel thermosensitive formulation against three Candida species was calculated and time-dependent antifungal activity analysis was performed. Viscosity, transition temperature T_sol-gel (°C) and gelation time of the thermosensitive gel formulation were also determined in the viscometer. The measurements performed on the tensilometer device were analyzed for adhesion hardness and elongation percentages of the formulation. In the FT-IR spectrometer, the spectrum of solution and gel state was compared between 650 and 4000?cm^?1 and it was found that there is no difference between them.It was found that the temperature is reversible on the formulation and did not cause any disruption of its components. Characterization parameters of the thermosensitive gel formulation containing oxiconazole nitrate and time-dependent activity against Candida species was observed to be the same as those of the solution containing only oxiconazole nitrate. MIC, MFC and time-dependent antifungal analysis did not show any particular difference between formulation and oxiconazole nitrate itself. Thermosensitive gel formulation containing oxiconazole nitrate was found to be effective on superficial fungal infections. We believe it is also appropriate for in vivo usage, but it is necessary to perform animal and human research. It is also needed to evaluate the formulation against other etiologic agents of superficial fungal infections.     

Echinocandins: role in antifungal therapy, 2005

Novel therapies to treat invasive fungal infections have revolutionised the care of patients with candidiasis, aspergillosis and other less common fungal infections. Physicians in the twenty first century have access to safer versions of conventional drugs (i.e., lipid amphotericin B products), extended-spectrum versions of established drugs (i.e., voriconazole), as well as a new class of antifungal agents; the echinocandins. The increased number of options in the antifungal armamentarium is well timed, as the incidence of both invasive candidiasis and invasive aspergillosis, and the financial burden associated with these infections, have increased significantly in the past several decades. The increasing incidence of fungal infections has risen in parallel with the increase in critically ill and immunocompromised patients. Candida is the fourth most common bloodstream isolate, approximately 50% of which are non-albicans species. Estimates suggest there to be 9.8 episodes of invasive candidiasis per 1000 admissions to surgical intensive care units, with attributable mortality at 30% and cost per episode of US44,000 dollars. The burden of candidiasis is even higher in the paediatric population, with Candida being the second most common bloodstream infection. The increase in non-albicans candidiasis mandates the introduction of new antifungal agents capable of treating these often azole-resistant isolates. In addition, there has been a rise in the incidence of invasive aspergillosis, the most common invasive mould infection following haematopoietic stem cell transplantation, with an estimated incidence of 10 - 20%. The mortality associated with invasive aspergillosis has increased by 357% since 1980. Unfortunately, the overall survival rate among patients treated with amphotericin B, and even voriconazole, remains suboptimal, as evidenced by the failure of treatment in 47% of patients in the landmark voriconazole versus amphotericin B trial. Given the increasing incidence and suboptimal outcomes of these serious fungal infections, novel therapies represent an opportunity for significant advancement in clinical care. The current challenge is to discover the optimal place for the echinocandins in the treatment of invasive fungal infections.     

Recent advances in the treatment of life-threatening,invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative.

Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole.

Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.     

Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination

The incidence of invasive fungal infections has been increasing since the 1980s due to a growing population of immunocompromised and critically ill patients with associated risk factors including immunosuppressive chemotherapy, prolonged periods on intensive care units and infection with HIV. Persons who are severely immunocompromised are particularly vulnerable to infection from molds and yeasts that are often found naturally in the environment. In recent years, several new systemic antifungal agents have been released, significantly increasing options for the treatment of the most serious fungal infections. Newly available drugs as those in the echinocandin class include caspofungin, micafungin and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. In this review, the in vitro and in vivo activity of anidulafungin and voriconazole, both new antimycotic substances with a different mode of action, are analyzed.