J Infect Dis 203: 1324C1332

J Infect Dis 203: 1324C1332. al. 2012). Fungal infections cause life-threatening acute diseases, like cryptococcosis and invasive aspergillosis, severe chronic diseases, such as allergic bronchopulmonary aspergillosis, Rabbit polyclonal to AHR or they may present less-threatening superficial infections, such as vaginitis or oral candidiasis (Warnock 2007). Most invasive fungal infections occur as a consequence of immune suppression that results from conditions, such as AIDS or from treatments, such as chemotherapy for cancer, ABT-492 (Delafloxacin) immunosuppressive therapy for organ transplantation, and corticosteroid therapy for inflammation. More than 90% of reported fungal-associated deaths result from species belonging to three genera: (Brown et al. 2012). Failure to treat effectively, because of inadequate or delayed diagnostics, may result in serious chronic illness or blindness or may be fatal. Recognition of the importance of fungal infections has led to a dramatic rise in the application of antifungal agents for the treatment and prevention of infection. Unfortunately, the treatment options are highly limited, as there are few chemical classes represented by existing antifungal drugs. The antifungal drug classes include: polyenes, azoles, allylamines, flucytosine, and echinocandins (Groll et al. 1998; Kathiravan et al. 2012). The azoles (e.g., fluconazole, voriconazole, and posaconazole) and allylamines (e.g., terbinafine) inhibit ergosterol biosynthesis, whereas polyenes (e.g., amphotericin B) bind to ergosterol in the plasma membrane, where they form large pores that disrupt cell function. Flucytosine (5-fluorocytosine) inhibits pyrimidine metabolism and DNA synthesis. Finally, the echinocandins (caspofungin, anidulafungin, and micafungin) are cell wallCactive agents that inhibit the biosynthesis of -1,3-d-glucan, a major structural component of the fungal cell wall. The widespread use of antifungal agents is presumed to be a factor that promotes drug resistance (Antonovics et al. 2007; Cowen 2008). The emergence of acquired drug resistance among prevalent fungal pathogens restricts treatment options, which alters patient management. A greater understanding of mechanism-specific resistance and the biological factors that contribute to resistance emergence is critical to develop better therapeutics, and to improve diagnostics and intervention strategies that may overcome and prevent resistance. The detailed and complex biological nature of antifungal drug resistance mechanisms will be explored in this review with ABT-492 (Delafloxacin) an emphasis on azoles and echinocandins, the two main classes of drugs used as first-line therapy. ASSESSING RESISTANCE FACTORS Clinical resistance refers to therapeutic failure in which a patient fails to respond to an antifungal drug following administration at a standard dose. The development of antifungal resistance is complex and depends on multiple host and microbial factors (White et al. 1998). Host immune status is a critical factor, as fungistatic drugs must work synergistically to control and clear an infection. Patients with severe immune dysfunction are more likely to fail therapy, as the antifungal drug must combat the infection without the benefit of an immune response (Ben-Ami et al. 2008). The presence of indwelling catheters, artificial heart valves, and other surgical devices may also contribute to refractory infections, as infecting organisms attach to these objects and establish biofilms that resist drug action (dEnfert 2006; Ramage et al. 2009; Bonhomme and dEnfert 2013). Appropriate therapy requires that each drug reach the site of infection at a concentration sufficient for antimicrobial action. The pharmacokinetics of many drugs is known, yet we still do not have a good understanding of drug penetration at all sites of infection. Thus, some microorganisms are exposed to drugs at suboptimal levels. This situation results in cells that persist during therapy and may form subclinical reservoirs seeding new infection. All of these factors contribute to microbial resistance, which refers to the selection of strains that can proliferate despite exposure to therapeutic levels of antifungals. Such strains ABT-492 (Delafloxacin) contribute significantly to drug failures during therapy. Microbial resistance involves both primary resistant strains, which are inherently less susceptible to a given antifungal agent, and secondary resistant strains, which acquire a resistance attribute or trait in an otherwise susceptible ABT-492 (Delafloxacin) strain following drug ABT-492 (Delafloxacin) exposure. The molecular mechanisms involved in acquired resistance are often expressed at various levels in primary resistant strains (Fig. 1), and these will be explored in detail in this review. Open in.