Antifungal agents: mechanisms of action

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides--a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.     

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

Novel antifungal agents,targets or therapeutic strategies for the treatment of invasive fungal diseases: a review of the literature (2005-2009)

BackgroundThe incidence and prevalence of serious mycoses continues to be a public health problem. Despite aggressive treatment with new or more established licensed antifungal agents, these infections are an important cause of morbidity and mortality, especially in immunocompromised patients.AimsTo critically review the literature regarding important new developments in the field of antifungal therapy both in the English and Spanish versions.MethodsThe search of the literature focused on different antifungal targets or mechanisms of action as well as new agents or strategies that could improve antifungal therapy.ResultsThe review produced a huge amount of information on the use of virulent factors such as growth, filamentation, pathogen tissue clearance, among others, as putative targets of antifungal activity. More recently, the chemical-genetic relationships for licensed agents as well as for other compounds have been provided by the identification of the genes related to the mechanism of action.ConclusionsAlthough the antifungal activity of numerous compounds has been examined, most of them are at the in vitro or animal models of efficacy stages. Therefore, further investigation should be carried out to realize the true clinical utility of these compounds.     

The Growing Role of Clinical and Genomic Databases in the Development of Antifungal Strategies

Decisions about the prophylactic and empiric use of antifungal agents in immunosuppressed recipients of solid-organ transplants and hematopoietic stem cell transplantation (HSCT) call for up-to-date knowledge regarding which infections are most likely to develop in the populations at risk, but rapidly changing immunosuppressive regimens and the costs of large-scale clinical trials require new ways of gathering these data. Leveraging new clinical data from electronic databases to better understand the changing epidemiology of invasive fungal infection and the patterns of risk factors for adverse effects of antifungal treatment offers a major challenge and opportunity. Evidence-based integration of results generated from traditional prospective clinical trials, clinical and genomic databases, and laboratory-based investigations will enable us to maximize the potential benefits of antifungal agents and reduce their risks.     

Antifungal Dosing in Dialysis and Continuous Renal Replacement Therapy

Appropriate dosing of antifungal drugs is crucial to achieving favorable outcomes in patients with invasive fungal infections. The use of various types of renal replacement therapy (RRT) in patients with severe acute or chronic renal insufficiency adds another level of complexity to the already challenging use of these drugs. The medical literature provides only a limited number of studies specifically addressing the use of antifungal agents in patients receiving RRT, and there are a number of inherent difficulties in interpreting and applying these studies of drug dosing during RRT to individual patients. This article briefly reviews recent studies examining the dosing of antifungal agents during RRT, and also briefly reviews device-related and drug-related factors that determine the removal of drugs during RRT. Finally, this article summarizes current recommendations for dosing of antifungal agents in patients receiving RRT and highlights areas for future study.     

舍曲林抗真菌作用的研究进展

真菌感染的发病率在全球范围内不断上升.随着抗真菌药物的广泛使用,耐药现象日益突出,然而临床上行之有效而且安全的抗真菌药物数量却捉襟见肘.因此寻找新的抗真菌药物是目前的一个热点研究方向.舍曲林是一种选择性5-羟色胺再摄取抑制剂,临床上常用于抑郁症、强迫症及经期综合症等的治疗.10多年前,有学者发现其对念珠菌及曲霉有一定的抑制作用,并对舍曲林的抗真菌机制进行了初步探讨.本文就舍曲林的抗真菌作用进行综述.     

The role of adjuvant agents in treating fungal diseases

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite the recent introduction of new antifungal medications. In this review, the available data on the use of adjuvant agents for the treatment of IFIs are discussed. Cytokines such as interferon-γ, colony-stimulating factors, granulocyte transfusions, and the monoclonal antibody efungumab may have in a role in the management of IFIs through augmentation of the host immune response, whereas pathogen-specific vaccines may help prevent infection. Pentraxin 3, an acute phase protein, may assist in the prevention and treatment of aspergillosis. Deferasirox, an iron chelator, is being investigated as an adjunctive therapy for the treatment of zygomycosis. Lactoferrin, an ironbinding protein, appears to have activity in Candida and Aspergillus infections, and omiganan may help prevent fungal catheter-related infections. Although none of these agents are currently approved for the treatment of IFIs, they may be involved in current and/or future treatment options when used in combination with antifungal drugs.     

The Changing Landscape for Paediatric Regulation of Pharmaceutical Agents with a Focus on Antifungal Agents

The limited paediatric specific data for pharmaceutical agents has been a persistent issue for over a century. Since the late 1990s, two of the world’s largest regulatory agencies, the Food and Drug Administration and the European Medicines Agency, have made concerted efforts backed by federal legislation aimed to improve the availability of paediatric data for many pharmaceutical agents. In the same time frame, there has been considerable research and development of new antifungal agents to help combat life-threatening invasive fungal disease. The evolving landscape of pharmaceutical regulation has helped to establish paediatric appropriate dosing recommendations for a number of these antifungal agents. However, the process by which paediatric data are realized is still too slow often leaving years between the initial adult approved indication and subsequent paediatric indications. This delay in paediatric data continues to perpetuate off-label use of many antifungal therapies in children, which can have negative consequences. As we strive to improve the availability of paediatric data for pharmaceutical agents, there needs to be a focus on timely delivery of these data to eliminate the window between adult and paediatric indications.     

Thiourea, triazole and thiadiazine compounds and their metal complexes as antifungal agents

Many currently available antifungal and antibacterial agents have undesirable toxic effects, and a wide spread use of these drugs has lead to rapid development of drug resistant strains which are the leading cause for treatment failure in both clinical and agricultural applications. The present article provides a synopsis of recent progress in investigations of new classes of antifungal compounds: disubstituted aliphatic and aromatic thioureas, triazole and thiazine compounds which act as ligands for transition metals. Antifungal effects of these compounds and selected metallic complexes versus representative plant pathogenic fungi are reviewed.     

Synthesis and conformational analysis of His-Phe-Arg-Trp-NH2 and analogues with antifungal properties

The synthesis, in vitro evaluation, and conformational study of His-Phe-Arg-Trp-NH2 and related derivatives acting as antifungal agents are reported. Among them, His-Phe-Arg-Trp-NH2 and His-Tyr-Arg-Trp-NH2 exhibited antifungal activity against Cryptococcus neoformans. Antifungal activity of these compounds appears to be closely related to the alpha-MSH effect. A conformational and electronic study allows us to propose a biologically relevant conformation for these tetrapeptides acting as antifungal agents. In addition, these theoretical calculations permit us to determine the minimal structural requirements to produce the antifungal response and may provide a guide for the design of compounds with this biological activity.     

Structure–activity relationship study of nitrosopyrimidines acting as antifungal agents

The design, synthesis, in vitro evaluation, and conformational study of nitrosopyrimidine derivatives acting as antifungal agents are reported. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines have displayed a significant antifungal activity against human pathogenic strains. In this paper, we report a new group of nitrosopyrimidines acting as antifungal agents. Among them, compounds 2a, 2b and 15, the latter obtained from a molecular modeling study, exhibited antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. We have performed a conformational and electronic analysis on these compounds by using quantum mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) obtained from B3LYP/6–31G(d) calculations. Our experimental and theoretical results have led us to identify a topographical template which may provide a guide for the design of new nitrosopyrimidines with antifungal effects.     

Pros and Cons of Extrapolating Animal Data on Antifungal Pharmacodynamics to Humans

Both the incidence of invasive fungal infections and the number of antifungal agents available to clinicians have expanded significantly over the past two decades. Successes with pharmacokinetic and pharmacodynamic evaluations of other antimicrobial agents in animal models and their clinical correlations with patient outcomes have led to an increased number of studies evaluating both old and new antifungal agents. Recently, animal models have successfully defined target pharmacodynamic indices for many antifungal agents and fungal infections, but validation of these targets in human studies is frequently lacking. This article evaluates the potential pros and cons of extrapolating to humans the animal data on antifungal pharmacodynamics.     

Pediatric pharmacology of antifungal agents

Pediatric age groups display important differences in host biology, predisposing conditions, epidemiology, and presentation of fungal infections relative to the adult population. Over the past decade, major advances have been made in the field of medical mycology. Most importantly, an array of new antifungal agents has entered the clinical arena. Although pediatric approval of several of these agents remains to be established, the pediatric development of antifungal agents is moving forward. Invasive fungal infections will remain important causes for morbidity and mortality in immunocompromised pediatric patients. Although the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of individual patients.     

Pharmacology, in vitro activity, and in vivo efficacy of new antifungal agents

Invasive fungal infections remain significant clinical challenges and are associated with high morbidity and mortality in immunocompromised patients. Despite the availability of new antifungal agents, response rates against many of these infections remain suboptimal. In addition, many of the clinically available agents have limited oral bioavailability, are associated with adverse effects due to similarities between fungal and mammalian cells, or have significant drug-drug interactions. For these reasons, there is great interest in developing new antifungal drugs, including those with novel mechanisms of action. This article reviews the pharmacology, in vitro activity, and in vivo effectiveness of new antifungal agents, including members of new classes with novel mechanisms of action and at various stages of preclinical and clinical development. These agents include the triazole isavuconazole, the echinocandin aminocandin, the histone deacetylase inhibitor MGCD290, and the sordarin derivative FR290581.     

Update on Antifungal Resistance and its Clinical Impact

Candida and Aspergillus species are important causes of opportunistic infection in an ever-growing number of vulnerable patients, and these infections are associated with high mortality. This has partly been attributed to the emerging resistance of pathogenic fungi to antifungal therapy, which potentially compromises the management of infected patients. Multi-azole resistance of Aspergillus fumigatus is a current health problem, as well as is the co-resistance of Candida glabrata to both azoles and echinocandins. In most cases, negative clinical consequences of reduced in vitro fungal susceptibility to azoles and/or echinocandins can be traced to acquisition of particular resistance mechanisms. While strategies using antifungal combinations or adjunctive agents that maximize the efficacy of existing antifungals may limit treatment failures, new therapeutic approaches, including antifungal agents with novel mechanisms of action, are urgent. In the meantime, more efforts should be devoted to close monitoring of antifungal resistance and its evolution in the clinical setting.     

An update on the pharmacoeconomics of antifungal pharmacotherapy

The incidence and severity of invasive fungal infections are on the rise and they pose a risk of significant morbidity and mortality. The cost burden of fungal infections in the United States is high. There are many newer, less toxic antifungal agents to manage these challenging infections; however, these agents also carry a high cost of their own. When considering an antifungal agent for a specific patient, it is important to consider safety, efficacy, and cost, thus making it essential to continually evaluate the antifungal pharmacoeconomic literature to assist in the therapeutic decision-making process for patients with invasive fungal infections. Unfortunately, there is a lack of pharmacoeconomic studies addressing the costs associated with the treatment and prevention of fungal infections. Future large-scale clinical studies should include pharmacoeconomic analyses and end points that encompass all costs associated with antifungal drug use, not solely drug acquisition costs.     

Antifungal Therapy in Pediatric Patients

Invasive fungal infections still play a major role in morbidity and mortality in pediatric patients, especially in children undergoing therapy for an underlying malignancy and in preterm infants. Relative to the adult population, pediatric age groups display important differences not only in host biology, predisposing conditions, epidemiology, and presentation of fungal infections, but also in the disposition and clearance of antifungal compounds. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the pediatric development of antifungal agents has moved forward in an exemplary manner, which is essential for the successful management of the individual patient. This article reviews the current data on pharmacokinetics, safety, and dosing of antifungal agents in pediatric patients.     

The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates

The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes) against fluconazole-susceptible (FS) and fluconazole-resistant (FR) C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations.