Tacrolimus enhances the potency of posaconazole against Rhizopus oryzae in vitro and in an experimental model of mucormycosis

Russell E. Lewis, Ronen Ben-Ami, Leyla Best, Nathaniel Albert, Thomas J. Walsh, Dimitrios P. Kontoyiannis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)834-841
Number of pages8
JournalJournal of Infectious Diseases
Issue number5
StatePublished - 1 Mar 2013
Externally publishedYes


FundersFunder number
National Institutes of Health
National Cancer InstituteP01CA016672
University of Texas MD Anderson Cancer CenterCA016672


    • Mucormycosis
    • animal models
    • immunocompromised
    • posaconazole
    • subcutaneous
    • tacrolimus


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