In vitro and in vivo activities of posaconazole against zygomycetes with various degrees of susceptibility.
OBJECTIVE
We analysed the in vitro and in vivo effects of posaconazole and amphotericin B against three clinical isolates of zygomycetes: Lichtheimia corymbifera, F1; and Rhizopus oryzae, F5 and F6.


METHODS
In vitro activities of both drugs were assessed by determining MICs, minimum fungicidal concentrations (MFCs) and fungal damage measured by the XTT assay against either the spores or the hyphal forms. Additionally, the survival curves of neutropenic mice systemically infected with the zygomycete isolates were used as the marker of antifungal response to amphotericin B (1 mg/kg/day) or posaconazole (2.5, 10 and 50 mg/kg/day).


RESULTS
In terms of MICs, posaconazole proved to be active against the three isolates (MICs ranging from 0.125 to 1.0 mg/L). The median posaconazole MFCs were 0.25, 0.5 and >16 mg/L for F1, F5 and F6, respectively. The XTT assay showed that posaconazole was active against spores of all three isolates, but only partially effective against the hyphae. The survival studies showed that amphotericin B at 1 mg/kg/day and posaconazole at 10 mg/kg/day prolonged the survival of the animals infected with L. corymbifera F1. In mice infected with R. oryzae F5, only posaconazole at 50 mg/kg/day significantly prolonged survival, whereas amphotericin B at 1 mg/kg/day was the only regimen active against R. oryzae F6.


CONCLUSIONS
Our findings showed that posaconazole could be useful in the treatment of zygomycosis. Also, we report that an isolate of R. oryzae with low MFC responded to posaconazole, while another isolate with high MFC did not.
Spreghini
Elisabetta
E
Dipartimento di Scienze Biomediche, Clinica Malattie Infettive, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I-Lancisi-Salesi, Via Conca, Torrette, Ancona 60020, Italy.
Orlando
Fiorenza
F
Giannini
Daniele
D
Barchiesi
Francesco
F
D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009090:Mucorales / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D012233:Rhizopus / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D016019:Survival Analysis; D013778:Tetrazolium Salts / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D020096:Zygomycosis / Q000188:drug therapy* / Q000382:microbiology
D000935:Antifungal Agents; D013778:Tetrazolium Salts; D014230:Triazoles; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; C101425:posaconazole; D000666:Amphotericin B