title: Physiological Differences in Cryptococcus neoformans StrainsIn VitroversusIn Vivoand Their Effects on Antifungal Susceptibility.
abstract: Cryptococcus neoformansis an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub-Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between thein vivoinfection environment and thein vitroAFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid "titan cells," which rarely occur under laboratory conditions. Understanding whether and howC. neoformansdifferentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to thein vivoenvironment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods.
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Nina T
authors.initials: NT
authors.lastname: Grossman
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA acasade1@jhu.edu.
authors.forename: Arturo
authors.identifier: 0000-0002-9402-9167
authors.initials: A
authors.lastname: Casadevall
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D025141:Drug Resistance, Fungal / Q000502:physiology; D015725:Fluconazole / Q000494:pharmacology; D062607:Fungal Capsules / Q000187:drug effects* / Q000502:physiology; D062610:Fungal Polysaccharides / Q000096:biosynthesis; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D015658:HIV Infections / Q000150:complications / Q000382:microbiology / Q000473:pathology / Q000821:virology; D006801:Humans; D008543:Melanins / Q000096:biosynthesis* / Q000235:genetics; D016919:Meningitis, Cryptococcal / Q000150:complications / Q000382:microbiology / Q000473:pathology / Q000821:virology; D008826:Microbial Sensitivity Tests; D010858:Pigmentation / Q000502:physiology; D011123:Polyploidy
chemical_list: D000935:Antifungal Agents; D062610:Fungal Polysaccharides; D005656:Fungal Proteins; D008543:Melanins; D000666:Amphotericin B; D015725:Fluconazole
keywords: Cryptococcus neoformans; amphotericin B; antifungal susceptibility testing; fluconazole