ravuconazole and albaconazole

The frequency and spectrum of fungal infections have been increasing steadily over the last several decades. The reason for this increase may be explained by the increase in the number of immunocompromised patients due to malignancies, AIDS, invasive surgical procedures and transplantation. In parallel with this increase, several therapeutic options have become available but problems such as intrinsic or acquired antifungal resistance have led researchers to develop new antifungal drugs with expanded effectiveness. Reduced toxicity, enhancement of bioavailability and counteraction of resistance are features desired by clinicians. The aim of this article is to summarize the studies involving isavuconazole, ravuconazole, albaconazole, aminocandin and some other investigational antifungal agents. Most data on the clinical use of ravuconazole, isavuconazole and albaconazole are mainly available as meeting abstracts or limited to animal studies or Phase I/II studies in humans. These new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. In addition to activity against Candida and Aspergillus spp., they have a broad spectrum of activity including activity against resistant and emerging pathogens. The real possibilities of these agents will only be fully understood after adequate randomized clinical trials.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis, Invasive; Child; Clinical Trials as Topic; Half-Life; Humans; Lipopeptides; Nitriles; Pyridines; Quinazolines; Thiazoles; Triazoles

Azoles are important compounds for the treatment of fungal infections. This review focuses on three azoles: isavuconazole, ravuconazole and albaconazole (Stiefel). These drugs exhibit a broad spectrum of activity in vitro, including activity against several fungal isolates that are resistant to other azoles. However, poor or limited activity of these compounds has been demonstrated against species of Fusarium and Scedosporium, as well as against Zygomycetes. As isavuconazole and ravuconazole have been developed both as intravenous and oral formulations, these compounds are suitable candidates for the treatment of various invasive fungal diseases. Most clinical trials with albaconazole have targeted mucocutaneous fungal infections. Although all of these agents appear to be well tolerated, cross-resistance is a concern in the azole family of compounds.

Topics: Animals; Antifungal Agents; Clinical Trials as Topic; Drug Resistance, Fungal; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Nitriles; Pyridines; Quinazolines; Thiazoles; Triazoles

In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.

Topics: Antifungal Agents; Fungi; Heterocyclic Compounds; Humans; Lipopeptides; Molecular Structure; Mycoses; Nitriles; Plant Extracts; Plants, Medicinal; Pyridines; Quinazolines; Quinones; Structure-Activity Relationship; Thiazoles; Triazoles

The substantial increase in the rate of azole resistant Candida spp. yeast infections has become a serious treatment problem requiring new and more active antifungal agents. In this study, the in vitro activities of ravuconazole and albaconazole were compared with those of amphotericin B, flucytosine, itraconazole and fluconazole against 162 Brazilian isolates of Candida spp. from which 48 isolates had previously shown lower susceptibility or resistance to fluconazole. Ravuconazole susceptibility ranged from 84.6% (Candida albicans) to 100% for other species and albaconazole MIC(90) was < or =1.0 microg ml(-1) for all the species emphasising the potent activity of these triazoles. To our knowledge this is the first study evaluating the susceptibility of C. dubliniensis to albaconazole.

Topics: Antifungal Agents; Brazil; Candida; Candidiasis; Drug Resistance, Fungal; Fluconazole; Humans; Microbial Sensitivity Tests; Quinazolines; Thiazoles; Triazoles

Eighty-four isolates belonging to eight species that constitute the Pseudallescheria boydii complex were tested against 11 antifungal agents by using the microdilution method. There were significant differences among the species, with Scedosporium aurantiacum being the most resistant. In general, voriconazole was the most active drug, followed by posaconazole.

Topics: Amphotericin B; Antifungal Agents; Candida; Drug Resistance, Fungal; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Ketoconazole; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Naphthalenes; Peptides, Cyclic; Pseudallescheria; Pyrimidines; Quality Control; Quinazolines; Scedosporium; Terbinafine; Thiazoles; Triazoles; Voriconazole

We have studied the in vitro interactions of amphotericin B (AMB) with terbinafine (TBF), itraconazole, voriconazole (VCZ), albaconazole, and ravuconazole (RVZ), as well as TBF combined with the same azoles, against 11 isolates of Fusarium spp. using the fractional inhibitory concentration index. The highest percentage of synergistic interactions was observed for the combinations AMB-RVZ, TBF-VCZ, and TBF-RCZ.

Topics: Amphotericin B; Antifungal Agents; Drug Interactions; Drug Resistance, Fungal; Fusarium; Humans; Itraconazole; Microbial Sensitivity Tests; Naphthalenes; Pyrimidines; Quinazolines; Sensitivity and Specificity; Terbinafine; Thiazoles; Triazoles; Voriconazole

We have determined the in vitro susceptibilities of 57 strains of Cryptococcus gattii to nine antifungal agents and have compared the MICs for these strains with those for C. neoformans. MICs were determined by a microdilution reference method. Albaconazole and ravuconazole (MICs of 0.04 and 0.05 microg/ml, respectively) showed the best activities. Micafungin showed no activity (MIC of >128 microg/ml). In general, C. gattii was less susceptible than C. neoformans to all drugs tested, with the exception of amphotericin B and flucytosine.

Topics: Antifungal Agents; Cryptococcus; Cryptococcus neoformans; Humans; Microbial Sensitivity Tests; Quinazolines; Thiazoles; Triazoles

In order to develop new approaches to the treatment of the severe and usually fatal infections caused by Scedosporium spp., the in vitro antifungal activities of four novel triazoles (posaconazole, ravuconazole, voriconazole, and UR-9825) and some current antifungals (amphotericin B, ketoconazole, itraconazole, and nystatin) were determined. The latter group was clearly ineffective against the two species tested. The four new antifungals showed activity against Scedosporium apiospermum, and UR-9825 and voriconazole were active against S. prolificans.

Topics: Antifungal Agents; Humans; Microbial Sensitivity Tests; Pyrimidines; Quinazolines; Scedosporium; Thiazoles; Triazoles; Voriconazole

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound's half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2, 4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2, 4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candidiasis; Colony Count, Microbial; Fungi; Male; Mice; Molecular Conformation; Quinazolines; Rabbits; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Triazoles