title: Tacrolimus enhances the potency of posaconazole against Rhizopus oryzae in vitro and in an experimental model of mucormycosis.
abstract: BACKGROUND
  We hypothesized that tacrolimus, an inhibitor of the calcineurin pathway, would enhance the in vivo activity of posaconazole against Rhizopus oryzae, the Mucorales species most commonly associated with mucormycosis.
  
  
  METHODS
  We examined patterns of growth inhibition and fungicidal activity of posaconazole and tacrolimus, alone and in combination, against R. oryzae in vitro, using multiple methods (ie, hyphal metabolic and fluorescent vital dye reduction assays and measurement of chitin concentrations), and in vivo, using 2 mucormycosis models: an invertebrate model (Drosophila) and a nonlethal murine model of cutaneous mucormycosis.
  
  
  RESULTS
  Combinations of posaconazole and tacrolimus were synergistic in checkerboard assays for 4 clinical isolates of R. oryzae (48-hour fractional inhibitory concentration index, 0.187-0.281). Pharmacodynamic analysis of the combination revealed that the 90% effective concentration threshold of posaconazole activity against R. oryzae could be achieved with 2-fold lower drug concentrations (0.5-1 mg/L) when administered with tacrolimus (0.007-2 mg/L). In vivo, combination therapy was associated with improved survival in the fly model of mucormycosis (65% vs 57% posaconazole alone) and with significant reductions in cutaneous lesions and R. oryzae fungal burden, compared with animals that received posaconazole monotherapy, in the cutaneous model of mucormycosis.
  
  
  CONCLUSIONS
  Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of mucormycosis.
authors.affiliation: Department of Infectious Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Ronen
authors.initials: R
authors.lastname: Ben-Ami
authors.forename: Leyla
authors.initials: L
authors.lastname: Best
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Albert
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004330:Drosophila / Q000382:microbiology; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009091:Mucormycosis / Q000188:drug therapy*; D012233:Rhizopus / Q000187:drug effects*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole; D016559:Tacrolimus