New triazoles and echinocandins: mode of action,in vitroactivity and mechanisms of resistance

Abstract

Different types of mycoses, especially invasive mycoses caused by yeasts and molds, are a growing problem in healthcare. The most notable explanation for this increase is a rise in the number of immunocompromised patients owing to advances in transplantation, the emergence of AIDS and a rise in the number of invasive surgical procedures. Despite advances in medical practice, some therapeutic problems remain. In addition, intrinsic or acquired antifungal resistance may pose a serious problem to antifungal therapy. A new generation of triazole agents (voriconazole, posaconazole, isavuconazole, ravuconazole and albaconazole) and the recent class of the echinocandins (caspofungin, micafungin and anidulafungin) have become available, and represent an alternative to conventional antifungals for serious fungal infection management. Currently, only two of the recent triazole generation (voriconazole and posaconazole) and all three echinocandins are available for clinical use. More precisely, voriconazole and posaconazole are indicated for the treatment of invasive fungal infections and the echinocandins for the treatment of specific candidiasis. Voriconazole and posaconazole have a very broad spectrum of antifungal activity that includes Candida species, and filamentous and dimorphic fungi. Their activity extends to both fluconazole- and itraconazole-resistant strains of Candida. A major difference between posaconazole and voriconazole is that posaconazole has activity against Zygomycetes including Mucor spp., Rhizopus spp. and Cunninghamella spp., and voriconazole has no activity against this class of fungi. Ravuconazole, isavuconazole and albaconazole have shown very potent in vitro activity against species of Candida, Cryptococcus and Aspergillus, and they are currently in various stages of development. All three echinocandin agents, caspofungin, micafungin and anidulafungin, are similar in their spectrum of activity. Echinocandins do not possess in vitro activity against important basidiomycetes, including Cryptococcus, Rhodotorula and Trichosporon. This review attempts to deliver the most up-to-date knowledge on the mode of action and mechanisms of resistance to triazoles and echinocandins in fungal pathogens. In addition, the in vitro activity data available on triazoles and echinocandins are reported.

Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model

“…To survey the relationship between C. albicans gene essentiality under standard laboratory conditions (i.e., an in vitro environment) versus survival and pathogenesis in a host (i.e., an in vivo environment), we first examined survival and virulence phenotypes of Tet-regulatable conditional mutants in two essential genes, FKS1 and ERG11. The FKS1 and ERG11 gene products are targeted by echinocandin and azole class therapeutics, respectively (14), and serve as clinically relevant controls whose genetic inactivation should mimic the efficacy of these agents. As expected, under the standard laboratory conditions, both strains failed to grow in media containing tetracycline (Fig.…”

Trichosporon asahii causing nosocomial urinary tract infections in intensive care unit patients: genotypes, virulence factors and antifungal susceptibility testing

“…In this study, we did not choose the newer antifungal agents echinocandins, because Trichosporon is intrinsically resistant to echinocandins. Breakout in patients receiving echinocandin prophylaxis has been reported (Bayramoglu et al, 2008;Fera et al, 2009). On the whole, consistent with a previous report (Wolf et al, 2001), the triazole antifungal agents exhibited greater in vitro activities against planktonic T. asahii.…”

Candidaemia in a tertiary care academic hospital in Italy. The impact of C. parapsilosis complex on the species distribution and antifungal susceptibility

“…Treatment of candidaemia mainly consists of the application of antifungal agents such as fluconazole, amphotericin B and, more recently, echinocandins. However, the widespread use of antifungal agents in the prophylaxis or empirical treatment of invasive mycoses has led to changes in the epidemiology and susceptibility of these yeasts [8,9]. In fact, recent studies highlighted the emergence of strains that are resistant to azoles and echinocandins [10], which might represent a major challenge for prophylactic and therapeutic approaches.…”