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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)834-841
Number of pages8
JournalJournal of Infectious Diseases
Volume207
Issue number5
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

Mucormycosis
Rhizopus
Tacrolimus
Theoretical Models
Skin
Mucorales
Chitin
Invertebrates
Oryza
In Vitro Techniques
posaconazole
Fluorescent Dyes
Diptera
Drosophila
Therapeutics
Growth
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Tacrolimus enhances the potency of posaconazole against Rhizopus oryzae in vitro and in an experimental model of mucormycosis. / Lewis, Russell E.; Ben-Ami, Ronen; Best, Leyla; Albert, Nathaniel; Walsh, Thomas J.; Kontoyiannis, Dimitrios P.

In: Journal of Infectious Diseases, Vol. 207, No. 5, 01.03.2013, p. 834-841.

Research output: Contribution to journalArticle

Lewis, Russell E. ; Ben-Ami, Ronen ; Best, Leyla ; Albert, Nathaniel ; Walsh, Thomas J. ; Kontoyiannis, Dimitrios P. / Tacrolimus enhances the potency of posaconazole against Rhizopus oryzae in vitro and in an experimental model of mucormycosis. In: Journal of Infectious Diseases. 2013 ; Vol. 207, No. 5. pp. 834-841.
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