Journal of Antimicrobial Chemotherapy, Vol 42, 585-590, Copyright © 1998 by The British Society for Antimicrobial Chemotherapy
EK Manavathu, JR Dimmock, SC Vashishtha, J Cutright and PH Chandrasekar
We investigated the in-vitro and in-vivo susceptibility of Aspergillus
fumigatus to the novel conjugated styryl ketone NC1175 and the results were
compared with those obtained for amphotericin B and itraconazole. All 20
clinical isolates of A. fumigatus examined were susceptible to NC1175 (MIC
= 5.54 +/- 2.48 mg/L; range 2.92-11.68 mg/L), and the minimum lethal
concentration (MLC) was only twice the MIC, suggesting that NC1175 is
fungicidal. The mean MIC values of amphotericin B (1.22 +/- 0.58 mg/L;
range 0.5-4 mg/L) and itraconazole (0.37 +/- 0.11 mg/L; range 0.125-0.5
mg/L) were approximately nine- and 22-fold, respectively, lower than that
of NC1175. Both amphotericin B-resistant (n = 18) and
itraconazole-resistant (n = 28) isolates of A. fumigatus were as
susceptible to NC1175 as amphotericin B-, and itraconazole- susceptible
isolates. Kill curve experiments revealed that NC1175 at 23.35 mg/L
(approximately four times the MIC) killed > or = 99% of conidia within
24 h of exposure to the drug. The in-vivo susceptibility of A. fumigatus to
NC1175 was investigated using a murine pulmonary aspergillosis model.
Treatment of infected mice with amphotericin B or NC1175 did not result in
significant improvement of the mean survival (amphotericin B, 7.05 +/- 0.07
days; NC1175, 6.65 +/- 1.25 days) of the animals compared with that of the
placebo group (7.21 +/- 1.20 days). However, semiquantitative organ culture
revealed that clearance of A. fumigatus occurred in 16.6%, 50% and 66.6% of
the mice treated with placebo, NC1175 and amphotericin B, respectively (P
value for the control and the treated groups <0.01). These results
suggest that NC1175 has in-vivo and in-vitro activity against A. fumigatus
and can be used as a prototypic molecule for further development as an
antifungal agent.
ORIGINAL ARTICLES
In-vitro and in-vivo susceptibility of Aspergillus fumigatus to a novel conjugated styryl ketone
Department of Medicine, Wayne State University School of Medicine, Wayne State University, Detroit, MI 48201, USA. aa1388@wayne.edu
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