The Strength of Synergistic Interaction between Posaconazole and Caspofungin depends on the Underlying Azole-Resistance Mechanism of Aspergillus fumigatus.
Antimicrob Agents Chemother. 2015 Jan 12;
Authors: Mavridou E, Meletiadis J, Rijs A, Mouton JW, Verweij PE
The majority of azole resistance mechanisms in Aspergillus fumigatus account to mutations in cyp51A gene. As azoles are less effective against infections caused by multi-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 method. Pharmacodynamic interactions were assessed with the fractional inhibitory concentration index (FICi) as based on 10% (FICi-0), 25% (FICi-1) or 50% (FICi-2) of growth and FICs were correlated with POSA and CAS concentrations. Synergy and antagonism was concluded when FICi was statistically significant (t test p<0.05) lower than 1 and higher than 1.25, respectively. Significant synergy was found for all isolates with mean FICi-0s ranging from 0.28-0.75 (median 0.46). Stronger synergistic interactions were found with FICi-1 (median 0.18, range 0.07-0.47) and FICi-2 (0.31, 0.07-0.6). The FICi-2 of isolates with tandem repeat containing mutations or M220 were lower than the other isolates (p<0.01). FIC-2 were inversely correlated with POSA MICs (rs=-0.52, p=0.0006) and linearly with the ratio of drug concentrations in combination over 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/CAS against A. fumigatus isolates was 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.
PMID: 25583716 [PubMed - as supplied by publisher]