Abstract | BACKGROUND: 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:
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Authors | Russell E Lewis, Ronen Ben-Ami, Leyla Best, Nathaniel Albert, Thomas J Walsh, Dimitrios P Kontoyiannis |
Journal | The Journal of infectious diseases
(J Infect Dis)
Vol. 207
Issue 5
Pg. 834-41
(Mar 01 2013)
ISSN: 1537-6613 [Electronic] United States |
PMID | 23242544
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antifungal Agents
- Triazoles
- posaconazole
- Tacrolimus
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Topics |
- Animals
- Antifungal Agents
(administration & dosage, pharmacology)
- Disease Models, Animal
- Drosophila
(microbiology)
- Drug Synergism
- Drug Therapy, Combination
(methods)
- Female
- Mice
- Mice, Inbred BALB C
- Microbial Sensitivity Tests
- Mucormycosis
(drug therapy)
- Rhizopus
(drug effects)
- Tacrolimus
(administration & dosage, pharmacology)
- Treatment Outcome
- Triazoles
(administration & dosage, pharmacology)
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