The future of antifungal agents. Non azole antifungal agents]

We investigated the efficacy of non-azole antifungal agents. Long circulating immunoliposomal amphotericin B was potent in murine invasive pulmonary aspergillosis. The concentration of AMPH-B was still high in the lung after 6 hours of 34A-PEG-liposomal AMPH-B. Lipid nanosphere amphotericin B (NS-718) showed efficacy against pulmonary aspergillosis in rats and pulmonary cryptococcosis in mice. The renal toxicity of NS-718 was estimated to be lower than that of AMPH-B from the results of the toxicity study in the rat infusion model. FK 463, a novel (1,3)-beta-D-glucan synthase inhibitor, showed efficacy against azole-resistant Candida albicans in murine experimental disseminated candidiasis. FK463 could be a promising drug and the therapy of choice for azole resistant C. albicans infection.     

Guidelines for clinical evaluation of topical antifungal agents]

The Japanese Society for Medical Mycology (JSMM) decided in 2002 to establish guidelines for the clinical evaluation of antifungal agents. The JSMM committee presents here guidelines for the clinical evaluation of topical antifungal agents in the dermatology field. Guidelines for the Clinical Evaluation of Antibiotic Agents established by the Japanese Society of Chemotherapy were referred to, and the diseases subjected to clinical evaluation include tinea (tinea pedis and tinea glabrosa), cutaneous candidiasis, and pityriasis versicolor. Among superficial mycoses, tinea pedis is viewed as the pivotal disease because it is intractable and is the most common. Therefore, the clinical efficacy of antifungal agents for external use in this condition should be established, and tinea pedis is subjected to phase III clinical studies. If efficacy of the antifungal agents is confirmed in the treatment of tinea pedis, a comparative study need not necessarily be performed for tinea glabrosa. If the number of patients is adequate for statistical analysis, a comparative study should be considered for both cutaneous candidiasis and pityriasis versicolor. However, if the number of patients is low, the efficacy of the agents should be evaluated based on their antifungal activity on pathogens and the results of open trials, and a comparative study is not necessarily performed for such diseases. The safety should be strictly evaluated.     

Efficacies and clinical roles of new antifungal agents]

Micafungin, a new class of the antifungal agent "echinocandin" released in 2002, and voriconazole, a new triazole antifungal agent released in 2005 in Japan have in vitro activities against Aspergillus spp. Results of large-scale clinical trials in Europe and the United States showed voriconazole to have superior efficacy against invasive pulmonary aspergillosis in comparison with conventional amphotericin B, and caspofungin, a member of the echinocandins, was effective as an empirical antifungal therapy in patients with persistent fever and neutropenia. In this way, choices of therapeutic medicine for aspergillosis are increasing more and more, and it is expected that the method of treatment will change greatly in future. On the other hand, we need to establish a new standard therapy for aspergillosis to avoid the clinical disruption caused by the variety of pharmaceutical choice caused. In this report, we describe the role of new antifungal agents for non-fumigatus Aspergillus infections, and the breakthrough in counteracting fungal infection using these new drugs.     

New antifungal agents

For more than two decades, amphotericin B has been the single broad-spectrum agent for the treatment of systemic mycoses. Amphotericin B is not always effective, must be given parenterally, and is associated with a host of adverse reactions. Despite amphotericin B toxicity, until recently the systemic mycoses did not rate enough attention to prompt a search for new alternatives. However, three recent events have overcome this inertia: the gradually increasing use of potent immunosuppressive agents and broad-spectrum anti-bacterial drugs; the discovery of the relatively nontoxic azole classes of antifungal drugs in the 1980s and the rapid emergence of AIDS, with its severe accompanying opportunistic fungal infections. In just ten years we have seen the emergence of second-generation imidazole and third-generation triazole antifungal drugs and, most recently, entirely new classes of agents. It is remarkable that so many alternatives are becoming available just at the time when new antifungal drugs have become a major need. This discussion will concentrate on the new antifungal drugs of the past ten years, with the exception of developments in the polyenes and flucytosine, which are covered elsewhere.     

Present problems and future trend of antifungals for deep seated mycosis. Azole antifungal agents]

Azole antifungal agents are the most common drugs for the treatment of deep seated mycosis throughout the world, because of their favorable anti-fungal spectrum, pharmacokinetics and safety. However there are some weak points in each drug or class, such as emerging resistance or interactions with other drugs. Many new derivatives are now under pre-clinical and clinical evaluation and among them, voriconazole and SCH56592 are showing satisfactory results in their early clinical studies. At the same time, however the ability of doctors to make an appropriate and logical choice for use of these drugs also essential.     

Update on antifungal agents for paediatric patients

Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas 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 the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.     

Essential genes as potential targets of antifungal agents in pathogenic yeast Candida]

An important point in the development of an antimicrobial agent is whether its target molecules are essential for growth of the microorganism. From this viewpoint, we focused attention on essential genes as potential targets of antifungal agents in the pathogenic yeast Candida. Here we introduce recent attempts for screening, identification, and characterization of essential genes from a haploid yeast Candida glabrata, using temperature-sensitive mutants. Our experimental results suggesting the essentiality of C. albicans PHO85, the homologue of which is known as a negative regulator of the PHO system and as a non-essential gene in Saccharomyces cerevisiae are also described.     

Comparative study of two systems for the determination of the sensitivity of yeasts to antifungal agents]

One hundred yeast strains (including 60 Candida albicans) were tested in two laboratories using two different antifungal susceptibility test kits, ATB Fungus and Mycostandard. Tests were carried out under everyday work conditions. Four antifungal agents were compared: amphotericin B, flucytosine, miconazole, and ketoconazole. Results were discrepant in 19.2% (77/400) of cases. Following retesting of discordant cases with both kits, the agreement rate for strain characterization was 95.5%. Few discrepancies were seen with flucytosine. Conflicting results obtained with amphotericin B were due to poor reproducibility of Mycostandard results, especially for species other than C. albicans. In contrast, reproducibility of the ATB Fungus kit was inadequate for miconazole. The rate of discrepant results was greatest for ketoconazole. Intermediate susceptibility was seen more often with ATB Fungus for C. albicans and with Mycostandard for C. glabrata and C. krusei. The lack of reproducibility under routine working conditions should lead gallery manufacturers to strive to achieve clearer readings.     

Status and issues of preclinical evaluation of the therapeutic effects of newly developed antifungal agents]

Preclinical evaluation of the efficacy of an antifungal agent is basically conducted by measuring both the in vitro and the in vivo antifungal activity of the drug using appropriate infection models. Although the first requisite for a method measuring in vitro activity is to obtain results with good reproducibility, an additional requirement is that there be good correlation with the in vivo activity, as described later. For the first condition, in recent years the National Committee for Clinical Laboratory Standards in the United States and the Standardization Committee of the Japanese Society for Medical Mycology have proposed reference techniques with the objective of standardizing drug susceptibility testing; these have been used extensively in measuring antifungal activities of novel agents. However, there are several issues involved when these methods are applied to newly developed drugs. First, standard methods are for particular currently available antifungal agents, but MIC determining standards have not been established for other agents. Reproducibility is therefore not guaranteed. Second, there is a question of whether reliable results can be obtained to test an antifungal spectrum with a limited number of fungal species. On the other hand, in vivo evaluation of novel antifungal agents is extremely important to predict the clinical outcome at the preclinical stage. The important requirements for this in vivo experimental system are: use of an animal model of mycosis that resembles the pathophysiology in humans; use of an administration schedule corresponding to that used in clinical studies, and evaluation of the therapeutic effect considering the dose and administration period. This review presents the present status of preclinical evaluation test methods and discusses the issues.     

Role of Candida allergen in atopic dermatitis and efficacy of oral therapy with various antifungal agents]

We studied whether fungal allergens play a role in exacerbating the clinical symptoms of atopic dermatitis (AD). We found that the percentage of the patients who showed CAP-RAST positive (2 < or = score) to Candida albicans (Ca) was significantly higher in the patients with severe symptoms and high serum IgE level than those with mild symptoms and lower IgE. This was also true for the patients with CAP-RAST positive to Pityrosporum ovale (Po). AD patients with their symptoms localized to head and neck showed significantly higher tendency to have positive CAP-RAST (2 < or = score) to Ca and Po when compared to those with their eruption distributing to the extremities. We then evaluated the efficacy of oral therapy with antifungal agents in 140 cases of refractory AD with positive CAP-RAST to Ca. Good or excellent response was obtained in 60% with fluconazole, 35% with itraconazole, 31% with amphotericin B, 28% with nystatin. The present finding that amphotericin B and nystatin, both of which are not absorbed through intestine, were effective for approximately a third of the patients indicates that Ca in the intestine plays an important role in triggering AD symptoms. Fluconazole was more effective than amphotericin B and nystatin, suggesting that fungal colonizing in other parts of the body but the digestive tract also play a role in the exacerbation of AD symptoms.     

Torulopsis glabrata. Morphologic characteristics, biotyping and sensitivity to isolates of antifungal agents in vitro]

The authors described morphological and biochemical properties of twenty strains of Torulopsis glabrata and two strains of T. candida and T. sphaerica, mostly of human origin. By means of eight biotyping tests based on the evaluation of so-called resistograms the isolates of T. glabrata were divided into eight biotypes. The authors discussed the problem of possible use of biotyping of T. glabrata in investigations of the epidemiology and pathogenesis of mycoses caused by this microorganism. In investigations of the sensitivity of strains of Torulopsis spp. to nine antimycotic agents in vitro it was revealed that the isolates were sensitive to all polyene antibiotics (amphotericin B, nystatin and pimaricin) and to 5-fluorocytosine. The sensitivity to azole chemotherapeutic agents (clotrimazole, econazole, miconazole, ketoconazole and itraconazole) was more varied: some strains were resistant to clotrimazole and econazole.     

In vitro and in vivo evaluation of antifungal agents

The evaluation of any antifungal agent involves the determination of its in vitro and in vivo activity against pathogenic and/or opportunistic fungi. The in vitro evaluation is followed by an in vivo evaluation in animal models, and clinical trials in humans. From the first report of the efficacy of the iodides for the treatment of sporotrichosis (1903) until the introduction of the imidazoles (azoles, 1960s), the number of antifungal agents available was very limited, including griseofulvin (1939), nystatin (1950), amphotericin B (1956), and flucytosine (1964). This paper briefly reviews the status of the antifungal agents currently used, and gives a more in depth evaluation of progress during recent years in the search for new antifungal drugs. Efforts to improve the efficacy of the current antifungal agents are also reviewed.