title: The strength of synergistic interaction between posaconazole and caspofungin depends on the underlying azole resistance mechanism of Aspergillus fumigatus.
abstract: 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.
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre of Nijmegen, Nijmegen, The Netherlands MavridouRita@gmail.com.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Mavridou
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre of Nijmegen, Nijmegen, The Netherlands.
authors.forename: Antony
authors.initials: A
authors.lastname: Rijs
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre of Nijmegen, Nijmegen, The Netherlands.
authors.forename: Johan W
authors.identifier: http://orcid.org/0000-0001-6736-4149
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Centre of Nijmegen, Nijmegen, The Netherlands.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000378:metabolism; D001393:Azoles / Q000494:pharmacology*; D000077336:Caspofungin; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism; D055666:Lipopeptides; D020080:Tandem Repeat Sequences / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D014230:Triazoles; C101425:posaconazole; D000077336:Caspofungin