The role of murine models in the development of antifungal therapy for systemic mycoses

Animal testing is crucial to the development of new antifungal compounds. This review describes the role that murine and other animal models have played in the development of three classes of antifungal agents: the polyenes, the triazoles and the echinocandins and the ways in which these models have been either the positive link in the path from in vitro studies to the patient, or have foreclosed later clinical evaluation. Efficacy studies in particular mycoses are discussed, as well as studies designed to determine whether combinations of antifungal drugs may have value over single agents.     

New agents to treat life-threatening fungal infections

Fungi can cause life threatening diseases, particularly in patients with weakened immune systems. While treatment options are available for these individuals, dose limiting toxicity and the appearance of drug resistant organisms are growing problems. Therefore, the identification, development, and registration of new, safe, and efficacious agents are needed. Herein, we review recent developments in the field of antifungal drug discovery. We focus on recently launched drugs (triazoles and echinocandins), agents in clinical development, and compounds in discovery.     

Addressing current medical needs in invasive fungal infection prevention and treatment with new antifungal agents,strategies and formulations

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.     

Developments in the treatment of candidiasis: more choices and new challenges

The incidence of oesophageal candidiasis, candidaemia and disseminated candidiasis has increased dramatically. In addition to the amphotericin B formulations and fluconazole, the echinocandins anidulafungin, caspofungin and micafungin and the newer triazoles posaconazole and voriconazole are in the last stages of development and are becoming available for the management of candidiasis. This review presents these new agents and addresses their role in the treatment of candidiasis. All new antifungal agents exhibit potent activity against Candida spp. and echinocandins are fungicidal against most Candida spp. but appear to be less potent against certain species, such as Candida parapsilosis and C. guilliermondii. Systemic antifungal therapy can now be individualised based on the severity of the infection, comorbid conditions and the Candida spp. causing the infection. Studies are needed to investigate the possible development of resistance and the efficacy of these antifungal agents against the more resistant Candida spp.     

Section Review: Anti-infectives: The potential of novel antifungal drugs for the treatment of disease in the immunocompromised host

There is a growing need for new antifungal drugs to complement those already in clinical use. Analogues and new formulations of existing drugs continue to give improvements in chemotherapy, but this account concentrates on possible new areas of development. These have been inspired chiefly by results from screening for new natural products. The most promising are three groups of antibiotics targeting the fungal cell walls. The echinocandins and related lipopeptides and their semisynthetic derivatives, and the papulacandin glycolipids are potent specific inhibitors of β-(1–3)-glucan synthesis. Pradimicins and benanomicins bind to mannan in the cell wall, but then target the cell membrane, disrupting its function. A wide range of other novel antifungal natural products, some with very unusual structures, are currently under critical investigation. The possible selective antifungal activity of members of the families of immunosuppressive drugs, cyclosporins and rapamycins, is worthy of further study. In a different approach, much current research in the metabolism and molecular biology of pathogenic fungi is directed ultimately at rational design of specific antifungal agents, but at present this is a hope for the future.     

Caspofungin

Available systemically effective antifungal agents for the treatment of invasive fungal infections are few. With the increasing recognition of a need for newer antifungal drugs, caspofungin has been introduced as the first member of a new class of compounds called echinocandins. This paper reviews the chemistry and mechanism of action of caspofungin, its activity in vitro and in animal models, and clinical pharmacokinetics,clinical efficacy and safety in patients.     

Antifungal drug discovery, six new molecules patented after 10 years of feast: why do we need new patented drugs apart from new strategies?

After 10 years absence (between 1990-1999) of new antifungal agents and intensive research being introduced into clinical practice, 3 new azoles (Voriconazole - Pfizer, Posaconazole - Schering-Plough, Ravuconazole - Bristol-Myers Squibb) and 3 new echinocandins (Caspofungin - MSD, Anidulafungin - Astellas-Pfizer, Micafungin - Fujisawa) were patented. The question raises if we really need 6 new antifungal agents in such a short time? Perhaps, they are not here because we need them all, but because of at least fifteen years effort of many groups of investigators who successfully discovered, proved and introduced these agents to the drug market. Voriconazole (2000), Posaconazole (2005), Ravuconazole (2007) from the group of azoles; and Caspofungin (2002), Anidulafungin (2004) and Micafungin (2006) from the group of echinocandins, with unique mode(s) of action (cell wall synthesis inhibition) different from polyens, azoles, antimetabolites and new monoclonal antifungal antibody (Mycograb), were approved and introduced to the clinical practice. This paper contains some useful information regarding the recent patents on antifungal drug discovery, their current position in the strategy of treatment of invasive fungal infections is briefly reviewed.     

Clinical microbiology and infectious diseases. Management of fungal infections

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Despite remarkable progress in mycology, many uncertainties and difficulties remain. Invasive fungal infections are difficult to diagnose. Noninvasive, rapid diagnostic tools, such as the detection of Aspergillus galactomannan antigen in serum or of fungal nucleic acids by molecular methods are promising, but are still under investigation. The other difficulty in diagnosis is the lack of standard, consistent criteria. Very recently, diagnostic criteria based on host factors, as well as clinical features and microbiological results, have been proposed. Treatment of invasive fungal infections is also problematic. The development of novel antifungal compounds constitutes a major advance in antifungal therapy. These include novel azoles such as voriconazole (Pfizer), posaconazole (Schering- Plough), and ravuconazole (Eisai/Bristol-Myers Squibb), and novel echinocandins such as caspofungin (Merck), anidulafungin (Eli Lilly), and micafungin (Fujisawa Pharmaceutical). These agents appear more efficacious and less toxic than currently available antifungal drugs. However, immune status of the host remains one of the major determinants of clinical outcome. This property limits the efficiency of in vitro antifungal susceptibility tests in predicting in vivo outcome. Using immune system modifiers such as cytokines in combination with antifungal agents is beneficial in the improvement of immune status, and thus clinical outcome.     

Echinocandins in the treatment of candidaemia and invasive candidiasis: clinical and economic perspectives

Candidaemia and invasive candidiasis (IC) complicate modern medical therapy, contributing to high morbidity and mortality. Managing candidiasis is costly, with an additional healthcare expenditure of nearly US$300 million annually. Recent consensus guidelines have suggested the use of newer antifungal agents, such as echinocandins, for the treatment of candidaemia and IC owing to promising clinical outcomes compared with older-generation antifungal agents, but at higher drug acquisition and administration costs. Comprehensive cost-effectiveness data for echinocandins in treating candidaemia and IC remain relatively scant, underlining the need for more studies to incorporate robust economic analyses into clinical decisions. Assessment of the cost efficiencies of these expensive antifungal agents is essential for maximising health outcomes within the constraints of healthcare resources. This review will explore the epidemiology of candidaemia and IC in the context of clinical and economic aspects of the antifungal agents used to treat IC, especially the echinocandins. Standardising the outcome measure, methodology and reporting of results used in economic studies is central to ensure validity and comparability of the findings. Future studies comparing the economic advantages of all available antifungal treatment options and in the context of new diagnostic tools for fungal infections are anticipated.     

Update on antifungals targeted to the cell wall: focus on β-1,3-glucan synthase inhibitors

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targeted respectively to chitin synthase (nikkomycins), β-1,3-glucan synthase (echinocandins) and mannoproteins (pradimicins/benanomicins), have entered clinical development. While nikkomycins and pradimicins/benanomicins are no longer in development, echinocandins have emerged as potentially clinically useful and three compounds, caspofungin (MK-991, L-743,872), micafungin (FK-463) and anidulafungin (LY-303366) are in late clinical development (Phase II and III).     

Novel approaches to antifungal prophylaxis

Antifungal prophylaxis represents a significant advance in the management of patients at risk from fungal infections in a variety of settings. Identification of patients at the highest risk and the utilisation of safe and effective drugs maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis has been shown to be useful are bone marrow transplantation, liver and lung transplantation, surgical and neonatal intensive care units, secondary prophylaxis of fungal infections associated with HIV and neutropenia associated haematological malignancies and their treatment. New antifungal agents, such as the echinocandins and the new azoles, are available and have a potential role in antifungal prophylaxis. Future studies should evaluate which strategy is more useful; prophylaxis or pre-emptive therapy.     

Novel approaches to antifungal prophylaxis

Antifungal prophylaxis represents a significant advance in the management of patients at risk from fungal infections in a variety of settings. Identification of patients at the highest risk and the utilisation of safe and effective drugs maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis has been shown to be useful are bone marrow transplantation, liver and lung transplantation, surgical and neonatal intensive care units, secondary prophylaxis of fungal infections associated with HIV and neutropenia associated haematological malignancies and their treatment. New antifungal agents, such as the echinocandins and the new azoles, are available and have a potential role in antifungal prophylaxis. Future studies should evaluate which strategy is more useful; prophylaxis or pre-emptive therapy.     

Update on antifungals targeted to the cell wall: focus on beta-1,3-glucan synthase inhibitors

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targeted respectively to chitin synthase (nikkomycins), beta-1,3-glucan synthase (echinocandins) and mannoproteins (pradimicins/benanomicins), have entered clinical development. While nikkomycins and pradimicins/benanomicins are no longer in development, echinocandins have emerged as potentially clinically useful and three compounds, caspofungin (MK-991, L-743,872), micafungin (FK-463) and anidulafungin (LY-303366) are in late clinical development (Phase II and III).     

Recent advances in antifungal chemotherapy

For over 50 years, amphotericin B deoxycholate (AmBD) has been the 'gold standard' in antifungal chemotherapy, despite its frequent toxicities. However, improved treatment options for invasive fungal infections (IFIs) have been developed during the last 15 years. Newer antifungal agents, including less toxic lipid preparations of AmBD, triazoles and the echinocandins, have been added to our armamentarium against IFIs. Some of these newer drugs can now replace AmBD as primary therapy (e.g. caspofungin for candidiasis, voriconazole for aspergillosis), whilst others offer new therapeutic options for difficult-to-treat IFIs (e.g. posaconazole for zygomycosis, fusariosis and chromoblastomycosis). It is interesting that extended use of newer antifungals such as fluconazole, despite decreasing the mortality attributed to candidiasis, resulted in selection of species resistant to several antifungals (Candida krusei, Candida glabrata); whilst several publications suggest that prolonged use of voriconazole may expose severely immunocompromised patients to the risk of zygomycosis (breakthrough). On the other hand, the differences in the mode of action of newer antifungals such as echinocandins raise the question whether combination antifungal therapy is more effective than monotherapy. Finally, the availability of an oral formulation with excellent biosafety of several newer antifungals (e.g. posaconazole) makes them candidates for prophylactic or prolonged maintenance therapy.     

Safety and interactions of new antifungals in stem cell transplant recipients

Introduction: Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Considerable progress in treating IFDs has been achieved over the last years, through the availability of new, effective drugs. However, many of these newer antifungal agents have some limitations, such as their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article reviews the literature evaluating the safety profile of the lipid formulations of Amphotericin B, echinocandins, and second-generation triazoles. It also discusses the possible drug-drug interactions with some drugs commonly used in allogeneic HSCT. Expert opinion: Nephrotoxicity is the most frequent side effect of lipid formulations of Amphotericin B, which may cause a reduced clearance of the renally eliminated calcineurin inhibitors used for the control of Graft Versus Host Disease. Second-generation triazoles are characterized by a limited toxicity profile, but also by frequent drug-drug interactions with other drugs metabolized by the hepatic enzymes. The echinocandins are characterized by a very low toxicity profile and negligible interactions with other drugs. Such pharmacological knowledge is crucial in the daily care of allogeneic HSCT patients.     

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.     

Echinocandins - an update

Echinocandins and echinocandin-like compounds are non-competitive inhibitors of the synthesis of 1,3-β-D-glucan, a major and essential component in the wall of many important fungal pathogens. Since this polysaccharide is not present in mammalian cells the glucan synthase became an attractive target for the development of new antifungal agents. In the last 25 years, several research institutes claimed new synthetic derivatives of echinocandin B and related natural cyclic hexapeptides with antifungal activity. The main goal is to find glucan synthesis inhibitors with a broad spectrum of fungicidal activity and useful oral bioavailability. In the last 3 years several patents have been filed and papers published, most of them claim novel echinocandin-like compounds, a few present processes for preparing oral echinocandin formulations and others include combinations of echinocandins with other antifungal agents, calcineurin inhibitors or human effector cells.     

我院2017-2019年深部抗真菌药物利用分析

目的:分析评价某三甲专科医院2017-2019深部抗真菌药物的临床使用情况,为深部抗真菌药物的合理规范使用提供参考.方法:利用信息系统,采用金额排序法和用药频度排序法对某三甲专科医院2017-2019年深部抗真菌药物进行统计分析.结果:2017-2019年该院深部抗真菌药物销售金额及所占比例有逐步下降趋势,使用频度排在...     

40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

The 40th ICAAC Meeting provided one of the widest varieties of new antibacterial and antifungal agents in years, with a range of improved ‘classical’ agents (Β-lactams, carbapenems), novel quinolone agents and totally new ideas for novel therapeutic intervention. Among the compounds reported were potent anti-MRSA carbapenems, novel des-fluoroquinolones (BMS 284756/T-3811), non-fluorinated quinolones, quinolone-related antibacterials, novel cephalosporins (cefditoren, RWJ-54428, MC 04546), ketolides (telithromycin, ABT-773), novel streptogramins and novel Β-lactamase inhibitors, bacterial and fungal efflux pump inhibitors and novel antifungals (azasordarins, echinocandins, azoles).