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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Antimicrob+Agents+Chemother
2015 ; 59
(3
): 1738-44
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The strength of synergistic interaction between posaconazole and caspofungin
depends on the underlying azole resistance mechanism of Aspergillus fumigatus
#MMPMID25583716
Mavridou E
; Meletiadis J
; Rijs A
; Mouton JW
; Verweij PE
Antimicrob Agents Chemother
2015[Mar]; 59
(3
): 1738-44
PMID25583716
show ga
The majority of azole resistance mechanisms in Aspergillus fumigatus correspond
to mutations in the cyp51A gene. As azoles are less effective against infections
caused by multiply azole-resistant A. fumigatus isolates, new therapeutic options
are warranted for treating these infections. We therefore investigated the in
vitro combination of posaconazole (POSA) and caspofungin (CAS) against 20
wild-type and resistant A. fumigatus isolates with 10 different resistance
mechanisms. Fungal growth was assessed with the XTT [2,3-bis
(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt]
method. Pharmacodynamic interactions were assessed with the fractional inhibitory
concentration (FIC) index (FICi) on the basis of 10% (FICi-0), 25% (FICi-1), or
53 0% (FICi-2) growth, and FICs were correlated with POSA and CAS concentrations.
Synergy and antagonism were concluded when the FICi values were statistically
significantly (t test, P < 0.05) lower than 1 and higher than 1.25, respectively.
Significant synergy was found for all isolates with mean FICi-0 values ranging
from 0.28 to 0.75 (median, 0.46). Stronger synergistic interactions were found
with FICi-1 (median, 0.18; range, 0.07 to 0.47) and FICi-2 (0.31; 0.07 to 0.6).
The FICi-2 values of isolates with tandem-repeat-containing mutations or codon
M220 were lower than those seen with the other isolates (P < 0.01). FIC-2 values
were inversely correlated with POSA MICs (rs = -0.52, P = 0.0006) and linearly
with the ratio of drug concentrations in combination over the MIC of POSA (rs =
0.76, P < 0.0001) and CAS (rs = 0.52, P = 0.0004). The synergistic effect of the
combination of POSA and CAS (POSA/CAS) against A. fumigatus isolates depended on
the underlying azole resistance mechanism. Moreover, the drug combination synergy
was found to be increased against isolates with elevated POSA MICs compared to
wild-type isolates.