title: Voriconazole pre-exposure selects for breakthrough mucormycosis in a mixed model of Aspergillus fumigatus-Rhizopus oryzae pulmonary infection.
abstract: Mucormycosis is an uncommon fungal infection that has been increasingly reported in severely immunocompromised patients receiving Aspergillus-active antifungals. Although clinical studies and pre-clinical animal models have suggested a unique predisposition for breakthrough mucormycoses in patients receiving voriconazole, no study has specifically evaluated the selection dynamics of various Aspergillus -active antifungal classes in vivo. We utilized an Aspergillus fumigatus:Rhizopus oryzae (10:1) model of mixed fungal pneumonia in corticosteroid-immunosuppressed mice to compare the selection dynamics of daily liposomal-amphotericin B (L-AMB), micafungin (MCFG) and voriconazole (VRC) therapy. A. fumigatus and R. oryzae lung fungal burden were serially monitored in parallel using non-cross-amplifying quantitative real-time PCR assays for each fungal genus. Additionally, experiments were performed where the R. oryzae component of the mixed inoculum was serially-passed on VRC-containing agar before animal infection. We found prior exposure to voriconazole in vitro, consistently resulted in a 1.5-2 log 10 increase in R. oryzae fungal burden by day +5 in vivo relative to animals infected with the non-VRC preexposed inoculum, irrespective of the antifungal-treatment administered in mice (P ≤ 0.02 all treatment groups). Mice infected with the VRC-preexposed inoculum and subsequently treated with saline or VRC had the highest mortality rates (82-86%), followed by MCFG (55%) then L-AMB (39%, P = 0.04 vs. control). However, in vivo treatment alone with voriconazole alone did not consistently increase the virulence of non- voriconazole preexposed R. oryzae versus controls. We conclude that exposure of R. oryzae sporangiospores to voriconazole in vitro modulates the subsequent growth rate and/or virulence of the fungus in vivo, which reduces effectiveness of Mucorales-active antifungals. The mechanisms underlying this phenotypic change are unknown.
authors.affiliation: Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, TX, USA. rlewis@uh.edu
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Guangling
authors.initials: G
authors.lastname: Liao
authors.forename: Weiqun
authors.initials: W
authors.lastname: Wang
authors.forename: Randall A
authors.initials: RA
authors.lastname: Prince
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009091:Mucormycosis / Q000209:etiology / Q000382:microbiology*; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology; D012233:Rhizopus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D014230:Triazoles / Q000009:adverse effects* / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole