Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and, in particular, describes the current understanding of molecular basis of azole resistance in these fungal species.

Candida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and to be commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrated that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris .

Candida auris has rapidly emerged as a health care-associated and multidrug-resistant pathogen of global concern. In this work, we examined the relative expression of the four C. auris genes with the highest degree of homology to Candida albicans CDR1 and MDR1 among three triazole-resistant clinical isolates as compared to the triazole-susceptible genome reference clinical isolate.

Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections annually. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide. In this work, we challenge the current paradigm of clinical triazole resistance in A. fumigatus , by first demonstrating that previously characterized mechanisms of resistance have nominal impact on triazole susceptibility and subsequently identifying a novel mechanism of resistance with a profound impact on clinical triazole susceptibility. We demonstrate that mutations in the HMG-CoA reductase gene, hmg1 , are common among resistant clinical isolates and that hmg1 mutations confer resistance to all clinically available triazole antifungals.

Resistance among Gram-positive organisms has been steadily increasing over the last several years; however, the development of new antibiotics to treat infections caused from these organisms has fallen short of the emergent need. Specifically, resistance among Staphylococcus aureus and Enterococcus spp. to essential antibiotics is considered a major problem. Oritavancin is a semisynthetic lipoglycopeptide antibiotic that was recently approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). While structurally related to vancomycin, oritavancin also possesses unique mechanisms of action that greatly enhance its antimicrobial potency against multi-drug resistant pathogens including both VanA- and VanB-mediated vancomycin-resistant enterococci. Owing to the addition of the highly hydrophobic tail group, oritavancin possesses a prolonged half-life ranging from 200–300 h. Although oritavancin is only currently Food and Drug Administration approved for ABSSSI, this agent may eventually play a role in additional indications where new innovative therapy is needed including bacteremia and deep-seeded, Gram-positive infections such as infective endocarditis or osteomyelitis. This review will focus on oritavancin’s spectrum of activity, mechanisms of action and resistance, pharmacokinetic and pharmacodynamic properties, and the completed and ongoing clinical studies evaluating its use.